The High Risk Newborn 1

The High Risk
Newborn
Senior Editors
Amitava Sen, Kolkata Nitin K Shah, Mumbai

Anand Pandit, Pune Padma K, Thiruvananthapuram
Anil Narang, Chandigarh Praveen Kumar, Chandigarh
Armida Fernandez, Mumbai Raj Kumar Kayal, Guwahati
Arvind Saili, New Delhi Ramji S, New Delhi
Ashok K Deodari, New Delhi Sabarinathan K, Thiruvananthapuram
Bhatia BD, Varanasi Santosh K Bhargava, New Delhi
Dadhich JP, New Delhi
Satish Saluja, New Delhi
Dutta AK, New Delhi
Shanmugha Sundaram, Chennai
Girish Gupta, Pune
Shantharam Baliga B, Mangalore
Guha DK, New Delhi
Shashi N Vani, Ahmedabad
Harish Chellani, New Delhi
Shikhar Jain, Indore
Jana AK, Vellore
Snehapalan V, Thiruvananthapuram
Jayam S, Chennai
Sourabh Dutta, Chandigarh
Kumutha J, Chennai
Sushma Nangia, New Delhi
Madhuri V Kulkarni, Mumbai
Maiya PP, Bangalore Swarna Rekha Bhat, Bangalore
Malik GK, Lucknow Tanmaya R Amladi, Mumbai
Mathur NB, New Delhi Uma S Nayak, Vadodara

Nair PMC, Thiruvananthapuram Vinod K Paul, New Delhi
Neelam Kler, New Delhi Zulfikar Ahamed, Thiruvananthapuram
The High Risk
Newborn
Editor in Chief
MKC Nair
Professor of Pediatrics and Clinical Epidemiology
Director, Child Development Centre, Medical College Campus
Thiruvananthapuram, Kerala, India
Academic Editors
Naveen Jain
Senior Consultant, Neonatology
Kerala Institute of Medical Sciences, Anayara
Srinivas Murki
Consultant Neonatologist
Fernandez Hospital, Hyderabad
Andhra Pradesh, India
Executive Editor
A Parthasarathy
Formerly Professor of Pediatrics
Madras Medical College and
Deputy Superintendent,
Institute of Child Health and Hospital for Children
Chennai, Tamil Nadu, India
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The High Risk Newborn
© 2008, Jaypee Brothers Medical Publishers
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Contributors
Abbas Hyderi MD Dinesh Kumar Chirla

Fellow in Neonatal Perinatal Medicine Director, Department of Neonatology
University of Calgary, Alberta Canada Rainbow Children’s Hospital
[email protected] Hyderabad, India
[email protected]
Amuchou Singh Soraisham DM (Neo)
Assistant Professor Elsie Philip
Division of Neonatology Formerly Professor and Head
Alberta Children’s Hospital, Calgary, Canada Department of Pediatrics
[email protected] Medical College
Thiruvananthapuram, Kerala
Archana P Bilagi India
Consultant Neonatologist
St. Philomena’s Hospital, Bangalore, India Gurdev Chowdhary DM (Neo)
[email protected] Consulant Neonatology
Kindney and Lifeline Medical Institution
Arvind Shenoi DM (Neo) Jalandhar, Punjab, India
Head of Neonatology and Paediatrics [email protected]
Manipal Hospital, 98, Airport Road
Bangalore, India Jaikrishan Mittal DM (Neo)
[email protected] Chief Neonatologist
Chaitanya Hospital
Ashish Mehta Chandigarh, India
Arpan Newborn Care Centre [email protected]
Ahmedabad, India
[email protected] John BM
Classified Specialist
Babu George MPhil (Beh Ped) Command Hospital
Medical Superintendent Bangalore, India
Child Development Centre [email protected]
Medical College Campus
Thiruvananthapuram, India Jyothi R
[email protected] Consultant Occupational Therapy
Child Development Centre
Daljit Singh DM (Neo) Medical College Campus
Special Advisor Pediatrics Thiruvananthapuram
Command Hospital, Bangalore, India Kerala, India
[email protected]
Karthik Nagesh N
Deepa Jayaprasad Head, Division of Neonatology and
Consultant Adolescent Pediatrics Formerly Head of Pediatrics
Child Development Centre Director, Pediatric Research Division
Medical College Campus Manipal Hospital, Airport Road
Thiruvananthapuram Bangalore, India
Kerala, India [email protected]
vi THE HIGH RISK NEWBORN
Lakshmi MA Naveen Jain DM (Neo)

Pre-school Teacher Senior Consultant, Neonatology
Child Development Centre Kerala Institute of Medical Sciences
Medical College Campus Thiruvananthapuram, Kerala, India
Thiruvananthapuram
[email protected]
Kerala, India
Latha S Neetu Gupta MD (Ped)
Pre-school Teacher Junior Consultant
Child Development Centre Pediatrics and Neonatology
Medical College Campus Kerala Institute of Medical Sciences
Thiruvananthapuram
Kerala, India
[email protected]
Manoj Modi
DNB Fellow, Department of Neonatology Pankaj Garg
Centre for Child Health Consultant, Department of Neonatology
Sir Ganga Ram Hospital, New Dehi, India
Centre for Child Health
[email protected]
Sir Ganga Ram Hospital
Meharban Singh New Delhi, India
Former Professor and Head [email protected]
Department of Pediatrics
All India Institute of Medical Sciences
Prasanna GL
New Delhi, India
Developmental Therapist
[email protected]
Mini AO Medical College Campus
Developmental Therapist Thiruvananthapuram
Child Development Centre Kerala, India
Thiruvananthapuram
Rajeev K
Kerala, India
MKC Nair PhD (Devepl Neuro) Child Development Centre
Professor of Pediatrics and Medical College Campus
Clinical Epidemiology
Thiruvananthapuram
Director, Child Development Centre
Kerala, India
[email protected] Ramesh Agarwal DM (Neo)
Assistant Professor
Mohan BK Department of Pediatrics
Registrar
All India Institute of Medical Sciences
Manipal Hospital
New Delhi, India
98, Airport Road, Bangalore, India
[email protected] [email protected]
Narayanan Potti Ranjan Kumar Pejaver

Consultant Family Physician Consultant Neonatologist
KR Hospital, Bangalore
Thiruvananthapuram Hon Professor KIMS, Bangalore, India
Kerala, India [email protected]
CONTRIBUTORS vii
Ravishankar K DM (Neo) Sathy M Pillai
Sowmya Neonatal – Perinatal Center Chief Infertility Specialist
Hyderabad, India Samad Hospital, VV Road
[email protected] Patoor, Thiruvananthapuram
Kerala, India
Rekha S [email protected]
Consultant Ophthalmology
Child Development Centre Srinivas Murki DM (Neo)
Medical College Campus Consultant Neonatologist
Thiruvananthapuram Fernandez Hospital
Kerala, India Bogul Kunda, Abids
Hyderabad, India
Resmi VR [email protected]
Child Development Centre Suman Rao PN DM (Neo)
Medical College Campus Associate Professor
Thiruvananthapuram Department of Pediatrics
Kerala, India St. John’s Medical College Hospital
Bangalore, India
Rhishikesh Thakre DM (Neo) [email protected]
Neo Clinic, 27, Samarth Nagar
Aurangabad, India Sunitha RM
[email protected] Developmental Therapist
Sanjay Wazir DM (Neo) Medical College Campus
Consultant Neonatologist Thiruvananthapuram
The Cradle, Apollo Hospital Initiative Kerala, India
Gurgoan, India [email protected]
[email protected]
Suvasini Sharma
Sankar VH DM (Genetics) Senior Resident
Consultant Geneticist Department of Pediatrics
Department of Pediatrics All India Institute of Medical Sciences
Medical College, Thiruvananthapuram, India New Delhi, India
[email protected] [email protected]
Foreword
The accreditation process of Level-II care introduced by National Neonatology

Forum (NNF) standardized and accelerated the growth of special care units
for high risk neonates in our country. With the introduction of DM
(Neonatology) training programme there has been a phenomenal growth
of Neonatal Intensive Care Units (NICU) in India.
The ultimate determinant of the quality of care delivered by such units
is the intact survival rates of the neonates treated by them. Survival rates
alone cannot be the end point to assess NICU treatment protocols. Experi-
ences of the western world have clearly shown the importance of simulta-
neously organizing early intervention programmes for high risk babies in
order to reduce the potential burden of neurodevelopment disabilities. From
survival to intact survival is a real challenge of modern neonatal intensive
care. This book will go a long way in meeting that challenge. There has been
a genuine need for an Indian book specifically focusing on the outcome of
graduates of NICUs.
The major highlight of this book is the attempt to review the relationship
of risk factors, the brain damage caused, and neurodevelopmental out-
come and link the same to NICU management principles. This book focuses
on the follow-up in the first two years of post-natal period. Details of specific
neurodevelopment disabilities, available elsewhere, have been rightly omit-
ted.
I am glad to see so many of my colleagues and former neonatology
students contributing to this book. My special congratulations to Dr Naveen
and Dr Srinivas for a job well done. Dr MKC Nair and Dr A Parthasarathy
team has once again shown the same magic touch, as in the IAP Textbook
of Pediatrics.
Dr ON Bhakoo MD FIAP, FAMS, FNNF
National President NNF (1985-89)
Formerly Professor and Head, Pediatrics and Neonatology
Postgraduate Institute of Medical Education and Research
Chandigarh, India
Preface
In India, neonatal mortality has remained static over the last several years.
Majority of mortality could be explained by infection (52%), asphyxia
(20%) and low birth weight (17%), all of which are preventable. At the
community level, we have made a conscious shift from “diagnosis based”
approach to “illness based protocols” in the integrated management of
neonatal and childhood illness (IMNCI), a concept endorsed by both
National Neonatology Forum and the Indian Academy of Pediatrics. At
the tertiary level health care, Neonatal Intensive Care Units (NICUs) across
the country have definitely improved the survival chances of many high
risk babies, who otherwise would have succumbed easily.
Now, the question asked more often is, whether we are increasing
the incidence of developmental delay and disability by saving more and
lower birth weight and other at-risk babies. Unfortunately we do not
have hard data on this. Our understanding of risk factors for neuro-
developmental disabilities has made definite progress, yet we still cannot
predict outcome in every individual case. But, we surely know that the
answer probably lies in promoting “developmental friendly well baby clinic”
concept and mother oriented early stimulation at home for all babies
especially for preterm/ IUGR babies. Infact, it may be now considered
unethical to have a level-II and level-III NICU, without having a neonatal
follow-up and developmental stimulation program. The lack of a “standard-
protocol” for neurodevelopmental follow-up and availability of trained
personnel has been the major limiting factors. The one year Postgraduate
Diploma in Developmental Neurology course for doctors and two years
Master of Health Science (MHSc) in Clinical Child Development course
for nurses, therapists and doctors, being conducted by Child Development
Centre, in association with Institute of Distance Education, University of
Kerala is a step in the right direction.
This book attempts to organize currently available knowledge

on risk factors affecting neurodevelopment, best practices in modifying
these risks and explains simple neurodevelopmental assessment techniques.
It also discusses, in detail the early stimulation program that can be initiated
in the neonatal period and management of developmental delay in the
xii THE HIGH RISK NEWBORN
first two years, with the ultimate objective of minimizing child hood
disability. The emphasis in this book has been in organizing current
evidence into simple protocols that can be practiced at all levels
of care. We do hope that you would find this book useful and pardon
us for inadequacies inevitable in the first edition of any book.
Editors
Acknowledgements
Altaf Jameel Khan, Resident, KIMS, Thiruvananthapuram

Amarjeet S Wagh, Resident, KIMS, Thiruvananthapuram
Antony VJ, Registrar, KIMS, Thiruvananthapuram
Anzad MA, Resident, KIMS, Thiruvananthapuram
Arun SR, Registrar, KIMS, Thiruvananthapuram
Asokan N, PA to Director, CDC, Thiruvananthapuram
George Jose, Registrar, KIMS, Thiruvananthapuram
Kavitha S, Resident, KIMS, Thiruvananthapuram
Prameela Joji, Registrar, KIMS, Thiruvananthapuram
Radhika S, Senior Registrar, KIMS, Thiruvananthapuram
Smitha K, Developmental Therapist, KIMS, Thiruvananthapuram
Sreeshanth MK, Developmental Therapist, KIMS, Thiruvananthapuram
Suja Haneef, Resident, KIMS, Thiruvananthapuram
Syed Tajammul, Resident, KIMS, Thiruvananthapuram
Contents
SECTION 1: INTRODUCTION
1. Introduction to the High Risk Newborn ......................... 3
MKC Nair, Babu George, Elsie Philip
SECTION 2: PREMATURITY AND LOW BIRTH WEIGHT

2. Preterm Brain Injury.....................................................13
Naveen Jain, Neetu Gupta
3. Preterm/Low Birth Weight ...........................................29
Rhishikesh Thakre
SECTION 3: NEONATAL ENCEPHALOPATHY

4. Perinatal Asphyxia .........................................................41
Karthik Nagesh N
5. Neonatal Seizures ..........................................................62
Srinivas Murki
SECTION 4: METABOLIC PROBLEMS

6. Hypoglycemia .................................................................73
Suman Rao PN
7. Neonatal Jaundice .........................................................82
Srinivas Murki
8. Inborn Errors of Metabolism (IEM)..............................88
Suvasini Sharma, Ramesh Agarwal
SECTION 5: RESPIRATORY PROBLEMS

9. Apnea .......................................................................... 101
Sanjay Wazir
10. Meconium Aspiration Syndrome (MAS) ..................... 117
Amuchou Singh Soraisham
11. Persistent Pulmonary Hypertension of
Newborn (PPHN) ........................................................ 126
Amuchou Singh Soraisham, Abbas Hyderi
xvi THE HIGH RISK NEWBORN
SECTION 6: PERFUSION PROBLEMS

12. Neonatal Shock ........................................................... 143
Gurdev Chowdhary
13. Neonatal Sepsis .......................................................... 157
John BM, Daljit Singh
SECTION 7: INTERVENTIONS
14. Pain and Analgesia ...................................................... 175
Jaikrishan Mittal
15. Neonatal Transport ....................................................... 186
Dinesh Kumar Chirla
16. Perinatal Steroids ........................................................ 194
Ravishankar K
17. Mechanical Ventilation ................................................. 198
Ashish Mehta
SECTION 8: NEURODEVELOPMENTAL ASSESSMENT

18. Risk Stratification for Neurodevelopmental Disability 207
Naveen Jain, MKC Nair
19. Clinical Examination Protocol ...................................... 209
20. Screening Protocol ....................................................... 216
SECTION 9: NEURODEVELOPMENTAL FOLLOW-UP

21. Discharge Protocol...................................................... 225
22. Follow-up Protocol ...................................................... 230
23. Organization of Neurodevelopmental Follow-up ........ 236
SECTION 10: DEVELOPMENTAL EVALUATION

24. Developmental Evaluation ..................................................... 243
Babu George, Narayanan Potti, MKC Nair
SECTION 11: EARLY DEVELOPMENTAL STIMULATION

25. Early Stimulation in NICU ........................................... 259
Prasanna GL, Rajeev K, MKC Nair
CONTENTS xvii
26. Early Stimulation after Discharge ............................... 264
Sunitha RM, Lakshmi MA, Babu George
27. Early Stimulation Protocol ........................................... 270
Resmi VR, Latha S, MKC Nair
SECTION 12: DEVELOPMENTAL THERAPY

28. Motor Stimulation in Early Infancy ............................. 279
Jyothi R, Deepa Jayaprasad, MKC Nair
29. Vision and Hearing Stimulation in Early Infancy ........ 287
Mini AO, Rekha S, MKC Nair
SECTION 13: PRENATAL STRATEGIES

30. Prenatal Risk Factors ................................................... 295
Archana P Bilagi, Ranjan Kumar Pejaver
31. Multiple Fetal Pregnancies .......................................... 312
Arvind Shenoi, Mohan BK
32. Assisted Reproductive Technique—Is It Safe? ............ 319
Sathy M Pillai
SECTION 14: UNEXPLORED TERRITORIES

33. Nutrition, Fluid and Electrolytes.................................. 329
Pankaj Garg, Manoj Modi
34. Follow-up Research—Some Methodological Issues...... 338
Rhishikesh Thakre, MKC Nair
SECTION 15: COUNSELING

35. Genetic Counseling—High Risk Pregnancy .................. 347
Sankar VH
36. Parent Counseling ........................................................ 356
Meharban Singh
Index...........................................................................................................................363
Abbreviations
NICU Neonatal Intensive Care Unit

CNS Central Nervous System
NDD Neurodevelopmental Disability
HIE Hypoxic Ischemic Encephalopathy
IVH Intraventricular Hemorrhage
PVL Periventricular Leukomalacia
WMD White Matter Disease
CP Cerebral Palsy
MR Mental Retardation
MSAF Meconium Stained Amniotic Fluid
PPHN Persistent Pulmonary Hypertension of Newborn
MAP Mean Arterial Pressure
ELBW Extremely Low Birth Weight
VLBW Very Low Birth Weight
LBW Low Birth Weight
SVC flow Superior Vena Caval Flow
EEG Electroencephalogram
CSF Cerebrospinal Fluid
LP Lumbar Puncture
CLD Chronic Lung Disease
BPD Bronchopulmonary Dysplasia
ROP Retinopathy of Prematurity
NEC Necrotizing Enterocolitis
PDA Patent Ductus Arteriosus
ANS Antenatal Steroids
nCPAP Nasal Continuous Positive Airway Pressure
DDST Denver Development Screening Test
BSID Bayley Scale of Infant Development
Section 1
Introduction
1. Introduction to the High Risk Newborn
MKC Nair, Babu George, Elsie Philip
1
Introduction to the
High Risk Newborn
Sustained global initiatives and efforts of local governments have improved

child survival in most parts of the world and hence, now the focus should
shift to quality of survival. Although the infant mortality in India has fallen
significantly, the neonatal mortality is remaining by and large static and
we do know that low birth weight is the major contributor. 1 In the India
CLEN multicentric neonatal health research initiative (NHRI) study, the
causes of neonatal deaths as per verbal autopsy were respiratory distress
syndrome (57%), low birth weight (51%), birth injury/asphyxia (42%),
neonatal sepsis complex (36%), pre-maturity (29%), congenital
malformations (13%), hypothermia (12%), jaundice (4%) neonatal tetanus
(3%) and causes not known (3%).2 Poverty, illiteracy and poor
environmental hygiene are factors detrimental to child survival and
development, especially so for the marginalized and vulnerable groups.3
Parenting practices do play an important role in child survival and
development. In a recent study on parenting practices, early child-care
practices were reaching high standards, even in tribal and economically
backward areas, probably explaining the better indicators observed in
Kerala.4
AT-RISK CONCEPT ..............................................................................

Child development is a dynamic process of optimally utilizing the genetic
potential of the baby, within the context of the environment made available,
so as to enable him/her to achieve the full potential. Although a continuous
process, the first one-year of life and pre-school years are the most critical
period in the child’s development. The difficult part is identifying babies
at-risk for poor development. A risk factor is something that increases
the likelihood of getting a disease or condition. The division of risk as
mild, moderate and high is often arbitrary. Hence the concept of “at-
4 THE HIGH RISK NEWBORN
risk” newborns may be replaced by the concept of “optimality”. Newborns

with a low “optimality score” are considered highly likely to develop
neurodevelopmental disabilities later in life. Which ‘high risk’ newborns
require periodic screening, ideally needs to be determined locally, keeping
in mind the feasibility and cost-effectiveness of any neonatal follow-up
program. It must, however, be remembered that many babies not
considered “at-risk” may also manifest developmental problems as they
grow. These babies would obviously not be seen during “at-risk” focused
follow-up screening.5
Risk factors for developmental deficits may be grouped under four
categories; biological risk, genetic and metabolic disorders, environmental
risk, and no apparent risk.6 Low birth weight babies form the single largest
group of easily identifiable babies at-risk for poor development. Around
two out of three babies weighing less than a kilogram at birth will suffer
some degree of disability, usually as a result of lack of oxygen or brain
hemorrhage.7 Half of surviving very preterm babies, grow up to be mentally
or physically disabled.8 Although developmental delay is more likely to
be found among babies with risk factors (at-risk concept), the large majority
born with a risk factor are likely to develop normally. On the other hand
cerebral palsy and mental retardation are also observed among the large
group of babies born normally without any apparent risk. The concept
of “double vulnerability” means that a baby with a biological risk factor
like low birth weight is more likely to fare poorly if born into a family
with poor child rearing capabilities as compared to one with a positive
environment. This is very relevant in the Indian context.
FOLLOW-UP AND EARLY INTERVENTION .....................................

In a follow-up study of graduates of level-II neonatal nursery, multiple
regression analysis for Bayley scores at 1 and 2 years showed that after
adjusting for the significant risk factors for development–birth weight,
neonatal seizure, congenital anomaly, intrauterine infection, mother’s
education, type of baby, occupation of father and residence–the babies
who had intervention had significantly higher Bayley scores compared
to control babies. Also, the observation that for increase of every 500
grams, there was a significant and consistent increase in mean values
of neurodevelopmental outcome indicators at 1 and 2 years and that
in every birth weight group, the mean values were higher for the
intervention group, suggest that early intervention is effective across the
birth weight groups .9 Developmental follow-up of at-risk babies supported
by early intervention therapy is the answer, as shown in the experience
of the developed countries.10 Meta-analysis of early intervention efficacy
INTRODUCTION TO THE HIGH RISK NEWBORN 5
studies done at Utah State University has shown that early intervention
is effective in improving the developmental status, although there is still
no uniform agreement as to whether the effects last long.11
LOW BIRTH WEIGHT ..........................................................................

A recent meta-analysis to review the effectiveness of early developmental
intervention post-discharge from hospital for pre-term (less than 37 weeks)
infants on motor or cognitive development concluded that intervention
improved cognitive outcomes at infant age (0 to 2 years). However, there
was significant heterogeneity between studies for cognitive outcomes at
infant age.12 It has been shown that 40% reduction in poor performance
could be achieved among low birth weight babies, by CDC model early
stimulation.13,14 By early “Infant Stimulation” we mean early interventional
therapy for babies at-risk for developmental delay and periodic
developmental assessment. A team of professionals consisting of
developmental pediatrician, developmental tester, developmental therapist
and developmental teacher chalk out programmes of various activities
including play, passive exercises and also teach the same to the mother,
to help her to do the therapy at home. Improvement in one functional
area helps the child to improve functions in other areas.
In the Indian context, it appears that reduction of low birth weight
should be the centre point of our thoughts and actions, whether it is
for reduction of mortality, morbidity, childhood disability and poor scholastic
performance. In order to reduce the burden of low birth weight with
the resultant consequences, it is important to understand the community
attributable risk factors for low birth weight. In a large community study
in India, reporting a 29% LBW incidence had described the following
population attributable risks for LBW: Socioeconomic status (41.4%), severe
anemia in pregnancy (34.5%), maternal height (29.5%) and maternal
pre-pregnant weight (22.9%), highlighting the importance of improving
pre-adolescent and adolescent girls’ nutrition.15 However, it is to be
appreciated that low birth weight has an intergenerational effect and
interventions in one generation alone cannot address the issue fully.
NEWBORN ENCEPHALOPATHY .........................................................

Newborn encephalopathy represents the neurological manifestations of
central nervous system injury due to any cause obvious or not so obvious,
that occurs in the first few hours or days of life. The importance of intra-
uterine asphyxia in the genesis of hypoxic-ischemic brain injury is well
known. In a retrospective survey of 100 infants with hypoxic-ischemic
encephalopathy there was evidence of intra-uterine hypoxia in 90% and

only in 10% was the insult postnatal.16 Similarly, Brown et al in a series
of 91 infants with hypoxic-ischemic encephalopathy reported intrauterine
insult in 91% and postpartum insult in 9%. 17 Two well conducted studies,
a large prospective US national collaborative perinatal project (NCPP)
and case control study in western Australia stand testimony to this.18,19
Newborn encephalopathy as described by Sarnat and later by Fenichel,
particularly with seizures and recurrent apnoea has been demonstrated
to be an important predictor of subsequent motor and cognitive handi-
caps.20,21 Clinical presentation of birth asphyxia with severe newborn
depression has demonstrated that most children who survived with sequelae
had clinical signs of encephalopathy during the neonatal period.22 Hence
prevention of perinatal asphyxia with better obstetric care, resuscitation
using positive pressure ventilation, with or without oxygen and optimal
brain protective immediate postnatal care would be the ideal solution.
But in a vast country like India with extremes of perinatal care, abolishing
post asphyxial encephalopathy would be a distant dream. Also it has
been demonstrated that pyritinol, a widely used so-called neurotonic has
no positive effect in improving the neurodevelopmental status of post
asphyxial encephalopathy babies at one year of age and hence its use
should be dissuaded.23
INTRAUTERINE INFECTIONS ..............................................................

Severe forms of disability are not common and are often due to congenital,
genetic, metabolic causes or intrauterine infections and need specific
preventive strategies.24 Recurrent pregnancy wastage due to maternal
infections transmissible in utero at various stage of gestation can be caused
by a wide array of organisms which include the TORCH complex
(toxoplasma gondii, rubella virus, cytomegalovirus, herpes simplex virus)
and other agents like Chlamydia trachomatis, Treponema pallidum, Niesseria
gonorrhoeae, HIV etc. Toxoplasmosis acquired during pregnancy may
cause damage to the fetus.25 Seroepidemiological studies have shown that
10-20 percent of women in childbearing age in India are susceptible to
Rubella infection.26 Infection with Rubella during pregnancy may lead
to congenital malformation in 10-54 percent of cases.27 The infection
caused by CMV in adult is usually asymptomatic but its significance is
many times increased when it occurs during pregnancy. However, the
rate of primary CMV infection is significantly higher for pregnant women
from low socioeconomic group.28 The mother is the usual source of
transmission of HSV to the fetus or newborn. Primary HSV infection
during first half of pregnancy is associated with increased frequency of
spontaneous abortion, still birth, and congenital malformation.29
ENVIRONMENTAL FACTORS .............................................................
Poverty, environmental deprivation and inadequacy of early stimulation
are much more common and therefore need an integrated program of
nutrition and developmental stimulation. Developmental research has clearly
shown that both socioeconomic status (SES) and aspects of the home
environment account for a significant proportion of the variance in cognitive
functioning of both healthy and pre-term children. In addition, researchers
have also established that the home environment may serve as a protective
factor for children.30 It is suggested that early social environment plays
a role in mediating establishment of neural networks that regulate a child’s
response to stress and capacity for self-control.31 Secure and stable
relationships with caring adults assure that young children are adequately
nourished and protected from dangerous illnesses, exposure to toxins,
and hazards that can lead to preventable injuries. It also provides preventive
health check-ups, protect from excessive stress and afford predictable daily
routines that convey a sense of security. These influences contribute
significantly to healthy brain development that depends upon the care
and support provided by individuals in the community as well as in the
family.32
POLICY IMPLICATION .........................................................................

In those parts of the country, where maternal education is poor, one
of the strategies would be providing family counseling by regularly visiting
families having specially identified persons such as pregnant mothers, post
natal mothers, 0-2 months old (neonatal) babies, and 2-24 months old
babies, observing and monitoring their parenting behavior, until such
desirable changes are evident.33 Not withstanding the isolated centers of
excellence, the overall quality of institutional neonatal care and postnatal
follow-up care at home, remains unsatisfactory in India. It is in this context
that the Indian Academy of Pediatrics and the National Neonatology Forum
had resolved as early as 2004, to consolidate their ongoing partnership
by looking at newer objectives and methods to improve the existing status
of neonatal and child health in India.34 It is the same realization that
necessitated provision of a group of community volunteers (ASHA) under
national rural health mission (NRHM) and addition of the neonatal
component in the integrated management of childhood illness (IMCI) in
India.
REFERENCES ........................................................................................
1. Nair MKC, Jana AK, Niswade AK. Editorial. Neonatal Survival and Beyond. Indian
Pediatr 2005;42:985-8.
2. Niswade AK, Zodpey SP, Ughade SN, et al. Neonatal Health Research Initiative
- Phase-I Report, Clinical Epidemiology Unit, Government Medical College, Nagpur,
2004.
3. Nair MKC, Rekha Radhakrishnan S. Early Childhood Development in Deprived
Urban Settlements. Indian Pediatr 2004;41:227-237.
4. Nair MKC, Sumaraj L , Padmamohan J, Radhakrishnan R, Rajasenan Nair V,
George B, Suresh Kumar G. Parenting practices in Kerala : A cross-sectional study.
Vulnerable children and Youth Studies 2007;2(1):71-7.
5. Prahbhjot Malhi, ‘Screening Young Children for Delayed Development, Indian
Pediatr 1999;36:569-577.
6. Nair MKC. Editorial. Simplified developmental assessment. Indian Pediatr 1991;
28:837-40.
7. http://news.bbc.co.uk/1/hi/health/694966.stm.
8. Disability risk for early babies. http://news.bbc.co.uk/1/hi/health/873976.stm.
9. Nair MKC, Elsie Philip, Jeyaseelan L, Babu George, Suja Mathews, Padma K.
Effect of CDC Model Early Stimulation among At-risk Babies – A Randomized
Controlled. Trial Ph.D Thesis, submitted to University of Kerala 1997.
10. Nair MKC. Editorial. Symposium: Early Interventional Therapy. Indian J Pediatr
1992;59:657-9.
11. White K, Casto G. An integrative review of early intervention efficacy studies with
at risk children: Implications for the handicapped. Analysis and Intervention in
Developmental Disabilities 1985;5:7–31.
12. Spittle AJ, Orton J, Doyle LW, Boyd R. Early developmental intervention programs
post hospital discharge to prevent motor and cognitive impairments in preterm
infants. Cochrane Database Syst Rev. 2007; 2: CD005495.
13. Nair MKC. Early Child Development – Kerala Model. Global Forum for Health
Research, Forum-3, Geneva, Switzerland, 1999.
14. Nair MKC, Early stimulation CDC Trivandrum Model. Indian J Pediatr. 1992;59:
663-7.
15. Hive SS, Genetra. Determinants of Low Birth Weight: A Community based
prospective Cohort study. Indian Pediatr 1994;31:1221-5.
16. Volpe JJ. Observing the infant in the early hours after asphyxia. In: Gluk L (Ed.)
Intrauterine asphyxia and the developing fetal brain. Chicago: Year Book Publishing
Company 1977:263-83.
17. Brown JK, Purvis RJ, Farfar JO, et al. Neurological aspects of perinatal asphyxia.
Dev Med Child Neurol 1974;16:567-80.
18. Nelson KB, Ellenberg H. Antecedents of cerebral palsy: multivariate analysis of
risk. N Engl J Med 1986;315:81-6.
19. Blair E, Stanley FJ. Intrapartum asphyxia: A rare cause of cerebral palsy. J Pediatr
1988;112:519.
20. Nelson KB. Ellenberg JH. Neonatal signs as predictors of cerebral palsy. Pediatrics
1979;64:225-32.
21. Low JA, Galbraith RS, Muir DW, et al. The predictive significance of biological
riskfactors for deficits in children of higher risk population. Am J Obstet Gynecol
1983;145:1059.
22. Scott. Out come of severe birth asphyxia. Arch Dis Child 1976;51:712-16.
23. Nair MKC, Babu George, Jeyaseelan L. Pyritinol in Term Post Asphyxial
Encephalopathy Babies - A Randomized Controlled Double Blind Trial. M.Med.Sc.
Thesis Submitted to University of Newcastle, Australia, 1994.
24. Nair MKC, Geroge B. Early Detection and Early Intervention Therapy for
Developmental Delay. In: IAP Textbook of Pediactrics, Jaypee Brothers Medical
Publishers, New Delhi, Third edition 2006; 834-835.
25. Sharma P, Gupta T, Ganguly NK, Mahajan RC, Malla N. Increasing Toxoplasma
seropositivity in women with bad obstetric history and in new borns. Natl Med
J 1997;10:65-66.
26. Seth P, Manjunath N, Balaya S. Rubella infection: the Indian scene. Rev Infect
Dis 1985;7 (Suppl. 1):S64.
27. Peekham C. Congenital infections in the United Kingdom before 1970; the
prevaccine era. Rev Infect Dis 1985; (7 Suppl. 1):S1.
28. Stagno S, Pass RF, Cloud G, et al. Primary cytomegalovirus in pregnancy. Incidence
transmission to fetus and clinical outcome. JAMA 1986;256:1904-86.
29. Sergio S, Whitley RJ. Herpes infections of pregnancy. N Eng J Med 1985;313:1327-
30.
30. Juliet M. Coscia, Bruce K. etal. Effects of Home Environment, Socioeconomic
Status, and Health Status on Cognitive Functioning in Children with HIV-1 Infection.
Journal of Pediatric Psychology 2001;26(6):321-9.
31. Janet A. DiPietro - Department of Population and Family Baby and the Brain:
Advances in Child Development Annual Review of Public Health Vol. 21:455-
71.
32. National Scientific Council on the Developing Child, Young Children Develop
in an Environment of Relationships, 2006. www.developingchild.net.
33. Nair MKC. Neonatal Survival - Role of Family Counsellor. Indian Pediatr 2004;
41:1201-2.
34. Nair MKC, Armida Fernandez. Indian Academy of Pediatrics and National
Neonatology Forum–Areas of Partnership. Indian Pediatr 2004;41:987-8.
Section 2
Prematurity and
Low Birth Weight
2. Preterm Brain Injury
3. Preterm/Low Birth Weight
Naveen Jain, Neetu Gupta
2
Preterm Brain Injury
Very preterm babies (gestation < 32 weeks) are at increased risk of

neurodevelopmental disability. Most neurodevelopmental impairments are
likely to be the consequence of brain damage of perinatal origin. Majority
of these lesions can be identified in the neonatal period with the use
of cranial ultrasound. IVH–PVH and (While matter damage) WMD
(parenchymal echo-densities, cystic PVL, Ventriculomegaly) are
the best recognized preterm brain injuries associated with adverse
neurodevelopmental outcomes.
Adverse neurodevelopmental outcome in very preterm babies depends

primarily on the severity of the intracranial lesion, rather than on gestational
age.
CURRENT UNDERSTANDING OF PATHOPHYSIOLOGY1,2 .................

The site of origin of PVH-IVH is the sub-ependymal germinal matrix.
During fetal development, the sub-ependymal germinal matrix is a site
of neuronal proliferation and glial cell proliferation until approximately
32 weeks’ gestation. The proliferating cells of the germinal matrix are
rich in mitochondria and, therefore, are quite sensitive to ischemia.
Supplying this area of metabolically active differentiating cells is a primitive
and fragile rete like capillary network. This fragile capillary network
is the site at which PVH-IVH hemorrhage occurs.
Two major factors that contribute to the development of PVH-IVH
are:
a. Loss of cerebral auto regulation and
b. Abrupt alterations in cerebral blood flow and pressure.
In the absence of autoregulation, the systemic blood pressure becomes
the primary determinant of cerebral blood flow and pressure, a pressure-
passive situation. When a pressure-passive circulatory pattern is challenged

with fluctuations of cerebral blood flow and pressure, hemorrhage can
occur. The capillaries of the immature germinal matrix possess neither
tight junctions between endothelial cells nor a strong basement membrane.
Therefore, increased flow and pressure may rupture the delicate capillaries,
leading to bleeding. IVH is considered to be a consequence of ischemia–
reperfusion of the preterm/immature germinal matrix of the brain.
The significance of alterations in cerebral blood flow is perhaps
not only in the generation of hemorrhage but in more diffuse brain
injury as well. Two disorders that may coexist with IVH are global hypoxic-
ischemic injury (loss of cerebral volume–ventriculomegaly) and
periventricular leukomalacia (PVL). Both significantly affect the
neurologic outcome in infants.
It is alteration in cerebral blood flow that’s the cause of concern in
prophylactic use (rapid infusions) of indomethacin. Although, indomethacin
might improve the risk of PVH-IVH, it may be increasing the risk of
periventricular leukomalacia.
The pathogenesis of grade IVS hemorrhages/intra parenchymal
hemorrhages (IPH) differs. IPH appears to result from hemorrhagic venous
infarctions surrounding the terminal vein and its feeders. A peculiar
anatomic arrangement is considered as reason for proneness to IPH.
Following parenchymal hemorrhages, necrotic areas form cysts that may
become contiguous with the ventricles (porencephalic cysts).
The other mechanism by which long-term neurological outcome can
be altered is through the development of post hemorrhagic hydrocep-
halus. The mechanisms by which hydrocephalus develop include:
a. Decreased absorption of cerebrospinal fluid (CSF) secondary to
obstruction of arachnoid villi by blood and debris or the development
of obliterative arachnoiditis (i.e. communicating hydrocephalus) and
b. Obstruction to CSF circulation (i.e. obstructive hydrocephalus).
The major sequel of PVH-IVH relate to the destruction of cerebral

parenchyma-white matter damage (Ventriculomegaly, periventricular
cystic leukomalacia) and the development of post hemorrhagic hydro-
cephalus.
The white matter is arranged such that tracts innervating the lower
extremities are nearest to the ventricles, followed by those innervating
the trunk, the arm, and, finally, the face. This anatomical arrangement
accounts for the greater degree of motor dysfunction of the extremities
PRETERM BRAIN INJURY 15
as compared to the face (spastic hemiplegia in unilateral lesions and spastic
diplegia or quadriplegia in bilateral lesions).
Evidence of antenatal insult: Chorioamnionitis has been considered
as a serious risk factor for WMD. Histopathological evidence of acute
inflammatory placental lesions is the best predictor of occurrence of neonatal
IVH.
CLINICAL PRESENTATION OF PVH-IVH .........................................

Postnatally, most hemorrhages occur when the neonate is younger than
72 hours, with 50% of hemorrhages occurring on the first day of
life. Hence, most preventive strategies are directed at perinatal
care and cerebral perfusion on 1st day of life. PVH-IVH can occur
when the individual is older than 3 days, especially if a significant life-
threatening illness arises.
Most infants are asymptomatic or demonstrate subtle signs that are
easily overlooked. PVH-IVH subsequently is found on surveillance
sonography. A catastrophic presentation is sudden and significant
deterioration associated with anemia, metabolic acidosis, glucose instability,
respiratory acidosis, apnea, hypotonia, and stupor. This is associated with
high risk of death. Between the two extremes of presentation, infants
might demonstrate varying degrees of neurological and systemic signs.
Currently it is recognized that neurologic sequelae are better
associated with WMD (parenchymal echodensities, cystic PVL,
ventriculomegaly). Hence, a new practical approach to describing
ultrasound findings is:
Classification of hemorrhagic and/or ischemic abnormalities

detected by cranial ultrasound examinations
• Isolated GM and/or IVH

• Parenchymal echodensities and/or lucencies with or without GM and/or IVH
• Ventricular enlargement with or without GM and/or IVH
GM/IVH—Germinal matrix / intraventricular hemorrhage
Many of these ultrasound findings are noted late, around term gestational
age or even later. 30% of children who developed (Cerebral palsy) CP
after major ultrasound abnormalities would have not been diagnosed
if ultrasound scans had been restricted to the first 4 weeks after
birth.
IMPACT ON NEURODEVELOPMENT3-5 ................................................................

CP is the primary neurological disorder observed after PVH–IVH and
WMD, though mental retardation, language disorders, seizures and
others can ensue as well.
CEREBRAL PALSY
IVH-PVH and WMD are major determinants of neurodevelopmental
outcomes in preterm born infants. In a review of 15 studies, Holling and
Leviton showed that 59% of neonates with periventricular echolucen-
cies developed CP. In EPIPAGE, a population based of nearly 3000
preterms from 9 centers in France, among 76 children with cystic PVL,
44 (58%) developed CP. As expected, the risk of CP is higher when
cystic PVL is bilateral and when the injury is in the parietal and
occipital lobes.
Incidence of CP increases with decreasing gestation–20% at
< 27 weeks, 12% at 27 to 28 weeks, 8% at 29 to 31 weeks, and 4%
at 32 weeks. Increased risk of CP with decreasing gestational age is partly
or may be wholly attributable to cerebral abnormalities. 17% of
children with isolated grade III IVH and 25% of children with white matter
damage had CP, compared with only 4% of children with normal ultrasound
scans.
Studies have shown that only preterm infants with IVH differ from
term infants in neurological examination findings. The rates of CP,
which were 20%–32% in group with IVH compared with only 5%–6%
for the group without IVH. This finding represents a 4-to 5-fold increase
among children with IVH.
PVL is the most powerful independent predictor of CP in
extremely preterm infants (27 weeks’ gestation or less).
BEST PRACTICES - INTERVENTIONS TO PREVENT

PRETERM BRAIN INJURY6 ............................................................................................
A. Prenatal
1. Prevention of prematurity
a. Timing of delivery
b. Tocolysis
2. Antenatal Steroids (ANS)
3. Antibiotics in prelabour rupture of membranes (pROM)
4. In utero transport
5. Mode of delivery of preterm
B. Optimize Peripartum Management
1. Resuscitation
a. Trained personnel for preterm delivery
b. Avoid unsafe practices
2. Delay cord clamping
3. Establish cardiorespiratory stability before surfactant administration
C. Management of Preterm Baby
1. Cerebral Perfusion
a. Optimize therapy for systemic hypoperfusion
b. Use postnatal indomethacin judiciously
c. Implement Measures to Minimize Pain and Stress Responses
(fluctuations in cerebral perfusion)
2. Optimize Respiratory Management
a. Synchronized ventilation
b. Avoid hypocapnea
c. Avoid routine chest physiotherapy
d. Avoid routine suctioning
e. Neuromuscular paralysis
f. Sedation
g. Use Postnatal Dexamethasone Judiciously
h. Limit Sodium Bicarbonate Use
3. Correct coagulopathy
4. Administrator Strategies in NIW
5. Unproven therapies
a. Magnesium sulfate (antenatal)
b. Ethamsylate, vitamin E
D. Screening and Diagnosis of Preterm Brain Injury
1. Clinical examination
a. Head circumference
b. Popliteal angle
2. Neurosonographic Screening for IVH–PVH and WMD.
PRENATAL
Prevention of Prematurity
There is an inverse relation between neurodevelopmental disability and
gestation. The auto regulatory abilities of cerebral blood flow in neonates
vary inversely to gestational age at birth. Prevention of preterm birth
should decrease the risk of brain injury. (Some of the large population
studies have observed that gestation ceases to be an independent risk
factor if IVH-PVH and WMD are not present).
• Timing of delivery: Risk of continuing pregnancy with an

unfavorable in utero environment must be weighed against early
delivery and increased risk of IVH at borderline gestations. This is
particularly important at gestations below 29 weeks where continuation
of pregnancy must be preferred, if maternal safety permits.
• Tocolysis:7 Short delays in preterm birth can enable women to reach
specialist care and receive antenatal steroids. When tocolysis is indicated
for women in preterm labor, calcium channel blockers (usually
nifedipine) are preferable to other tocolytic agents compared, mainly
betamimetics. Twelve randomized controlled trials involving 1029 women
were included. When compared with any other tocolytic agent (mainly
betamimetics), calcium channel blockers reduced the number of women
giving birth within seven days of receiving treatment (relative risk (RR)
0.76; 95% confidence interval (CI) 0.60 to 0.97) and prior to 34
weeks’ gestation (RR 0.83; 95% CI 0.69 to 0.99). Calcium channel
blockers also reduced the requirement for women to have treatment
ceased for adverse drug reaction (RR 0.14; 95% CI 0.05 to 0.36),
the frequency of neonatal respiratory distress syndrome (RR 0.63; 95%
CI 0.46 to 0.88), necrotising enterocolitis (RR 0.21; 95% CI 0.05
to 0.96), Intraventricular hemorrhage (RR 0.59, 95% CI 0.36
to 0.98) and neonatal jaundice (RR 0.73; 95% CI 0.57 to 0.93).
There is insufficient information on which to base decisions about the
role of COX inhibition (Indomethacin) for women in preterm labor.
Betamimetics help to delay delivery for women transferred to tertiary
care or completed a course of antenatal corticosteroids. However,
multiple adverse effects must be considered. The data are too few
to support the use of any particular betamimetics.
Antenatal Steroids (ANS)8-12

The antenatal use of betamethasone improves intact survival and decreases
the incidence of IVH and severe grades of IVH. (Level-1 evidence)
In babies born at or before 31 weeks gestation when mothers were
administered antenatal steroids. (RR 0.54, 95% CI 0.43 to 0.69, 13 studies,
2872 infants). Antenatal steroids (ANS) must be given to a mother
in preterm labor, as it reduces brain injury of the preterm baby.
• Preferred dosing: Betamethasone 12 mg 24 hours apart intra
muscular. Try to deliver 24 hours after the course is completed.
• Incomplete course of ANS
Even an incomplete course of antenatal corticosteroids is associated
with reduction in the rate of Intraventricular hemorrhage.
• Alternate regimen
Dosing betamethasone in 12-hour intervals may result in similar
neonatal outcomes compared to the standard 24-hour regimen
when delivery is likely to occur within 48 hours of therapy initiation.
• Chorioamnionitis and ANS
A complete course of antenatal steroids appeared to extinguish
any association between in utero inflammation (chorio-
amnionitis) and adverse neurological outcome.
• Repeat doses of prenatal corticosteroids for women at risk
of preterm birth. If ANS was grows for pretend preterm delivery
and the baby is not delivered in a week the effect of ANS dicreases
and it is a practice in many units to repeat ANS for the anticipated
loss of effect. Repeat dose(s) of prenatal corticosteroids reduce the
occurrence and severity of neonatal lung disease and the risk of
serious health problems in the first few weeks of life. These short-
term benefits for babies support the use of repeat dose(s)
of prenatal corticosteroids for women at risk of preterm
birth. However, these benefits are associated with a reduction in
some measures of weight, and head circumference at birth, and
there is still insufficient evidence on the longer-term benefits and
risks. No statistically significant differences were seen for periventricular
hemorrhage and periventricular leukomalacia. (2000 women
between 23 and 33 weeks’ gestation).
• Betamethasone vs dexamethasone
Most studies favor use of Betamethasone. Some have noted better
neonatal outcomes with dexamethasone.
Antibiotics in Prelabour Rupture of Membranes (pROM)13

The use of antibiotics for mother following pROM is associated with a
statistically significant reduction in chorioamnionitis, preterm delivery and
abnormal cerebral ultrasound scan prior to discharge from hospital (RR
0.82, 95% CI 0.68 to 0.98). The choice of antibiotic may have to be
based on local culture reports. Appropriate antibiotic therapy must
be started for the mother having preterm rupture of membranes
as it reduces preterm brain injury.
In-utero Transport
Encourage delivery in a tertiary center with a NICU. If preterm labor
is inevitable, babies must be transported to referral center in-utero (before
delivery) rather than after birth. Outborn or transported infants
consistently have higher rates of IVH and cystic PVL.
Mode of Delivery of Preterm15

Infants with early IVH (noted on first scan at less than 6 hours age)
were significantly more likely to be born by vaginal delivery in
nearly 250 very preterm babies born in two cohorts (1995–1996 adjusted
odds ratios [OR]: 13.29; 1998–1999 adjusted OR: 18.15). But prospective
studies have not been able to demonstrate benefit of caesarean (decreased
risk for mortality or IVH).
There is an increased incidence of mortality and morbidity for the
VLBW breech infant delivered vaginally.16 Cesarean delivery may
improve outcome for these infants. (Higher incidence of grade III or grade
IV IVH (18.8% vs. 3.5%, P < 0.001 in VLBW babies delivered by vaginal
route).
OPTIMIZE PERI-PARTUM MANAGEMENT

Resuscitation
a. Resuscitation of preterm baby by trained personnel: Maternal
fetal medicine specialists and neonatologists should manage pre-term
labor and delivery. No literature is available, but it was a prominent
feature at the best-performing hospitals.
b. Avoid harmful practices: Gentle handling—avoid painful stimula-
tion to initiate breathing, the baby should not be held in a head
down (hanging) position. Care should be taken to prevent over
zealous ventilation and hypocarbia. Administer bolus medications
slowly (like volume expanders) and sodabicarbonate is best
avoided.
Need for CPR in extreme preterm was associated with a clear
increase in neurological morbidity, with a three-time greater risk of
brain damage.17
Delay Cord Clamping18

Delaying cord clamping by 30 to 120 seconds, rather than early clamping,
seems to be associated with less need for transfusion and less intraventricular
hemorrhage. Seven studies (297 infants) were eligible for inclusion. Delayed
cord clamping was associated with fewer transfusions for anemia (three
trials, 111 infants; relative risk (RR) 2.01, 95% CI 1.24 to 3.27) or fewer
“low blood pressures” (two trials, 58 infants; RR 2.58, 95% CI 1.17
to 5.67) and less intraventricular hemorrhage (five trials, 225 infants;
RR 1.74, 95% CI 1.08 to 2.81) than early clamping.
Establish Cardiorespiratory Stability before Surfactant Administration
Most of the benchmark sites did not use prophylactic surfactant, but ample
evidence supports this therapy. The benchmark sites were very good at
stabilizing the infants before surfactant. One study indicates that giving
surfactant 10 minutes after birth is better than immediate instillation.
MANAGEMENT OF PRETERM BABY

Cerebral Perfusion19
Superior vena caval flow is currently considered as best indicator of systemic
and cerebral blood flow. Infants with low superior vena caval (SVC) flow
after birth, in first few hours of life, have higher incidence of IVH when
SVC flow normalizes (ischemia reperfusion) and CP in future. Low SVC
flow is associated with lower gestation, no antenatal steroids,
severe RD (higher mean airway pressure), large PDA (>1.6 mm)
• Optimize therapy for systemic hypoperfusion: Treat only overt
hypovolemia such as obvious blood loss from placenta previa,
cord rupture, and so forth with fluid boluses. Without overt
hypovolemia, use maximum of 2 volume boluses. Give bolus infusions
over >30 minutes.
Volume bolus – seems to be inferior to dopamine in increasing
blood pressure in hypotensive preterms. No documented difference
in cerebral flow, but increase in severe IVH (borderline significance).
Dopamine/dobutamine—In preterm infants with low systemic blood
flow, there is some evidence that dobutamine is better than dopamine
at increasing and maintaining systemic blood flow although dopamine
is better in increasing blood pressure.
• Use postnatal indomethacin judiciously: Decreases the incidence
of IVH in VLBW and increases the risk of intestinal perforation and
renal insufficiency. Recently, the trial of indomethacin prophylaxis in
preterms study indicated that although infants who are given
indomethacin do have less severe hemorrhages, they do not
have a better cognitive outcome at 18 months. The expert suggested
that perhaps indomethacin be reserved for certain at-risk infants,
such as those for whom the mother had not received antenatal
betamethasone or had chorioamnionitis, rather than giving it to
all infants.
• implement measures to minimize pain and stress responses (fluctuations
in cerebral perfusion)
• Avoid early lumbar puncture, prevent pneumothorax, and control
seizures.
• Provide developmental care, decrease noise, and minimize handling

and lighting.
• Use narcotic sedation judiciously.
• Instillation of mydriatics, rapid colloid infusion (eg, exchange transfusion),
changes in pH, PaCO2, and PaO2, apnoea and anemia are factors
that can alter cerebral blood flow and are associated with IVH.
• Position of UAC 20-high UAC positioning is suggested as a possible cause
for IVH. Surfactant causes sudden change in mean airway pressure
and cerebral perfusion, although, there is no evidence that it increases
risk of IVH.
Optimize Respiratory Management

a. Synchronized ventilation—Use either SIMV or HF(O)V with
optimal volume strategy
b. Avoid hypocapnia—The consensus is to keep PCO2 > 40 mm Hg.
c. Avoid routine chest physiotherapy—The procedure can be
devastating, especially in the first 72 hours.
d. Avoid routine suctioning—It is well documented that changes occur
in blood pressure, cerebral blood flow, and intracranial pressure during
suctioning.
e. Neuromuscular paralysis—For ventilated preterm infants with
evidence of asynchronous respiratory efforts, neuromuscular
paralysis with pancuronium seems to have a favorable effect on
intraventricular hemorrhage and possibly on air leak. Uncertainty
remains, however, regarding the long-term pulmonary and neurologic
effects, and regarding the safety of prolonged use of pancuronium
in ventilated newborn infants. The routine use of pancuronium or
any other neuromuscular blocking agent in ventilated newborn infants
cannot be recommended based on current evidence.
f. Sedation: Morphine, Fentanyl, Midazolam21—Morphine infusions,
although they cause hypotension, can be used safely for most preterm
neonates but should be used cautiously for 23- to 26-week neonates
and those with preexisting hypotension.
g. Use Postnatal Dexamethasone Judiciously
h. Avoid early use of postnatal dexamethasone. Early (before day 14
of life) postnatal dexamethasone is associated with a higher incidence
of CP or significant neurodevelopmental handicap. Another study has
shown increased risk of ICH. Avoid prolonged courses of postnatal
dexamethasone.
i. Limit Sodium Bicarbonate Use: The American Heart Association
recognizes only 3 situations in which NaHCO3 is useful:
hyperkalemia, urinary bicarbonate loss, and prolonged cardiac
arrest. There is substantial evidence that diluting the bicarbonate and
infusing it slowly is preferable to rapid concentrated infusions. If
sodabicarbonate is actually indicated give over 30 minutes.
Correct Coagulopathy22,23
The role of bleeding in producing neurological deficit is now being
considered lesser in importance in IVH-PVH and WMD than to the
global ischemia that follows. Studies have demonstrated coagulation
defects (platelet count, function, PT, APTT) in babies who eventually had
IVH. Also, in thrombocytopenic VLBW babies incidence of IVH, severe
IVH and neurological deficits was higher. But, platelet transfusions did
not seem to reduce IVH rates in very preterm babies. The development
of IVH in a study was strongly associated with lower gestational age but
not with the severity or age of onset of thrombocytopenia.
Currently, there is not enough evidence to suggest that platelet
transfusion or coagulopathy correction by blood products would reduce
incidence or severity of IVH. Data based on clinical practices suggest that
in preterm sick babies, it may be appropriate to administer blood products
as per current transfusion practice guidelines.
Administrative Strategies in NICU24

NICUs with high patient volume and high Neonatologist/staff ratio
had lower rates of severe IVH. Quality improvement collaborative (breath
savers) demonstrated improvement in both clinical care processes
and clinical outcomes (including decrease in severe IVH) during the
Neonatal Intensive Care Quality Collaborative.
Unproven Therapies
a. Magnesium sulfate14—The role for antenatal magnesium sulphate
therapy as a neuroprotective agent for the preterm fetus is not
yet established.
In a study, antenatal magnesium sulphate was given to women
threatening or likely to give birth at less than 37 weeks’ gestational
age – there was no significant effect of antenatal magnesium therapy
on neurologic outcomes. There was a significant reduction in the
rate of substantial gross motor dysfunction (RR 0.56; 95% CI
0.33 to 0.97; two trials; 2848 infants).
b. Ethamsylate, vitamin E—There is limited evidence that postnatal
vitamin E and ethamsylate reduce IVH.25
SCREENING AND DIAGNOSIS OF PRETERM BRAIN INJURY

Clinical Examination
a. Head circumference—head circumference increasing by more than
1 cm per week can be a pointer to IVH. This may be used for screening
when facilities to do frequent neurosonogram are not available.
b. Popliteal angle—tightness and other general tone abnormalities point
to IVH.
Neurosonographic Screening for IVH – PVH and WMD

As PVH-IVH can occur without clinical signs, serial neurosonogram
examinations are necessary for the diagnosis
• Routine screening cranial ultrasound examinations are recommended
for all infants born at 32 weeks’ gestation or earlier. Close to
25% of infants with gestation <30 weeks have significant cranial
Ultrasound (US) abnormalities that trigger important changes in acute
and long-term care.
• Routine cranial ultrasound examinations are recommended at about
the second week (7-14 days) and the sixth weeks of life (36-
40 weeks age) (at discharge) to predict long-term outcomes. Early
USG may help in guiding parents but does not accurately predict
outcomes. This recommen-dation is designed to detect both clinically
unsuspected IVH and evidence for PVL and/or ventriculomegaly.
• Grades 3 and 4 IVH, cystic PVL, and moderate to severe
ventriculomegaly determined by US have all been shown to be
significantly associated with CP at 2 to 9 years of age in VLBW PT
infants. Grade 4 IVH, and ventriculomegaly have been significantly
associated with mental retardation and neuropsychiatric disorders. The
is a 10-fold elevation in the risk of adverse outcome for VLBW PT
infants with US evidence of grades 3 and 4 IVH, cystic PVL, and
moderate to severe ventriculomegaly.
• Infants who have hemorrhagic lesions or any white matter or cystic
lesions evident on cranial ultrasound examinations require close,
systematic follow-up after their discharge from NICU to facilitate
the timely initiation of interventions.
• Severe cranial ultrasound abnormalities predict motor disability strongly,
but one third of infants with CP had no ultrasound abnormalities.
Caregivers should be aware that there would be differences in the
diagnosis and interpretation of cranial ultrasound examinations according
to the available ultrasound technology and expertise. The studies should
be performed by a consistent, small number of well-trained radiologists
or radiology technicians. The most accurate interpretation is based on
real-time or video evaluation. A standardized set of image cuts based
on an agreed on “gold standard” is also important. An agreed-on system
of interpretation, consisting of both text and an image set, should be
used. Serial studies should be performed to optimize correct diagnosis
of choroid plexus and germinal matrix lesions.
• MRI—role not clearly defined diffusion weighted MRI can
diagnose brain injury very early (days).
May be used in ELBW at 36 – 40 weeks if clinical suspicion on USG
Superior to USG and CT in prognosis (diagnosis and classification)
Logistics—availability, repeat testing, sedation, cost limit universal
application.
TREATMENT OF IVH ...........................................................................

A. Treatment of acute IVH - Supportive measures – Maintain normal
blood pressure and perfusion, control seizures, ventilation as needed,
correct low platelet and coagulation deficiencies, PRBC in case of resultant
anemia. Avoid drugs like aminophylline for apnoea, sodabi-
carbonate for acidosis.
B. Treatment of posthemorrhagic hydrocephalus
• Repeated lumbar punctures, diuretics to reduce CSF production
(Acetazolamide/CA inhibitors and furosemide) not only fail to prevent
shunt dependence, death or disability, but have significant adverse
effects. (Cochrane review) Intraventricular fibrinolytic therapy
(Streptokinase - instillation into the Intraventricular space) is also
not useful.
• Surgical interventions26,27 such as subcutaneous reservoir and
external drain have not been subjected to controlled trial. External
ventricular drainage (EVD) was found to be an effective and safe
therapy for rapidly progressive PHH and increased intracranial pressure.
Ventriculoperitoneal and ventriculosubgaleal (VSG) shunting
remain the definitive treatments for posthemorrhagic hydrocephalus
requiring surgical intervention.
Ventriculoperitoneal shunt is not feasible in the early phase after IVH
but, despite the problems with blockages and infections, it remains the
only option for infants with excessive head expansion over periods of
weeks. New treatment approaches aimed at preventing hydrocephalus
are needed.
VSG shunts offer a simple, effective, and relatively safe means of
temporizing hydrocephalus, and they avoid the need for external drainage
or frequent CSF aspiration in these medically unstable infants until the
CSF characteristics and abdomen are acceptable for ventriculoperitoneal
shunting.
KEY POINTS – reducing NDD due to preterm brain injury (WMD)

1. Adverse neurodevelopmental outcome in very preterm babies depends
primarily on the severity of the intracranial lesion (WMD) rather than on
gestational age.
2. In preterm babies with WMD, CP is the commonest NDD. CP is present
in about 60% VLBW babies with WMD.
3. But, one third of preterm infants with CP had no ultrasound abnormalities.
4. Conservative management of preterm labor may be preferred and attempts
made to prolong pregnancy at gestations lower than 29 weeks. If a tocolytic
must be used, calcium channel blockers are preferred.
5. ANS are probably the most important determinants of all complications of
prematurity and antecedent brain injury. ANS must be administered
whenever preterm delivery is suspected at gestation less than 34 weeks.
Betamethasone is the currently recommended steroid (2 doses at 24 hrs
interval) although dexamethasone is also tried, and faster regimens,
incomplete courses are also considered useful. Repeating courses of ANS
in case of prolongation of pregnancy is debated, but evidence currently
seems to favor repeating.
6. Antibiotics administered to mother in preterm rupture of membranes reduces
preterm brain injury.
7. Outborn, transported babies are at increased risk of IVH and in-utero
transport must be encouraged.
8. Vaginal delivery is a risk factor for IVH in VLBW, especially in breech
presentation.
9. Optimum resuscitation, delay in cord clamping and stabilization before
surfactant administration reduces the risk of IVH.
10. Loss of auto-regulation of cerebral circulation and fluctuations in cerebral
blood flow form the central basis of IVH. Prevent perfusion problems
especially on 1st day. Dopamine seems to be better than normal saline
boluses. Without overt hypovolemia, use maximum of 2 volume boluses.
Give bolus infusions over >30 minutes.
11. Indomethacin – decreases incidence of IVH, but not risk of NDD at 18
months. Currently Indomethacin is not routinely indicated; it may be useful
in very preterm babies when mother has chorioamnionitis or no ANS given.
12. Low SVC flow is a reliable indicator of cerebral perfusion and is associated
with lower gestation, no antenatal steroids, severe RD (higher mean airway
pressure), large PDA (>1.6 mm).
13. Optimal respiratory care – prevent hypocarbia, use opioid analgesia only
selectively (avoid in extreme preterm and hypotensive babies). Avoid routine
suctioning, chest physiotherapy, noxious/painful procedures. Avoid post natal
steroids, sodabicarbonate.
14. Correct coagulopathy, although the same need not reduce risk of IVH.
15. IVH could be asymptomatic; routine neurosonogram screening is indicated
in all babies less than 32 weeks. A late scan at 36 - 40 weeks corrected
age correlates best with long term outcomes.
16. The ultrasound should be performed by a consistent, small number of well-
trained radiologists or radiology technicians or trained neonatologist.
17. Repeated lumbar punctures, diuretics to reduce CSF production are
unproven therapies and not adequately fested.
18. Surgical treatments for posthemorrhagic hydrocephalus are also not tested
in systematic/planned trials.
Withdrawal of Care Decision in Severe IVH28
1. The health care team and the parents of a high-risk infant working
together should make decisions about withdrawal of intensive care.
2. Compassionate basic care to ensure comfort must be provided
to all infants, including those for whom intensive care is not being
provided.
3. The decision to continue intensive care should be based only on the
judgment that the infant will benefit from the intensive care. It
is inappropriate for life-prolonging treatment to be continued when
the condition is incompatible with life or when the treatment is judged
to be harmful, of no benefit, or futile.
REFERENCES ........................................................................................
1. Vergani P, Patanè L, Doria P, et al. Risk factors for neonatal intraventricular
haemorrhage in spontaneous prematurity at 32 weeks gestation or less. Placenta.
2000; 21(4):402-7.
2. Salafia CM, Minior VK, Rosenkrantz TS, Pezzullo JC, Popek EJ, Cusick W, Vintzileos
AM. Maternal, placental, and neonatal associations with early germinal matrix/
intraventricular hemorrhage in infants born before 32 weeks’ gestation. Am J
Perinatol. 1995; 12(6):429-36.
3. Ancel PY, Livinec F, Larroque B, et al. CP Among Very Preterm Children in
Relation to Gestational Age and Neonatal Ultrasound Abnormalities: The EPIPAGE
Cohort Study. Pediatrics 2006; 117 (3): 828-835.
4. Vollmer B, Roth S, Baudin J et al. Predictors of Long-Term Outcome in Very
Preterm Infants: Gestational Age Versus Neonatal Cranial Ultrasound. Pediatrics
2003; 112 (5): 1108-1114.
5. Vohr BR, Wright LL, Dusick AM, et al. Neurodevelopmental and Functional
Outcomes of Extremely Low Birth Weight Infants in the National Institute of Child
Health and Human Development Neonatal Research Network, 1993-1994.
Pediatrics 2000; 105 (6): 1216-1226.
6. Carteaux P, Cohen H, Check J et al. Evaluation and Development of Potentially
Better Practices for the Prevention of Brain Hemorrhage and Ischemic Brain Injury
in Very Low Birth Weight Infants. Pediatrics 2003; 111 (4): pp. e489-e496.
7. Israel Neonatal Network. Weintraub Z, Solovechick M, Reichman B, et al. Effect
of maternal tocolysis on the incidence of severe periventricular/intraventricular
haemorrhage in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed.
2001; 85(1):F13.
8. Haas DM, McCullough W, McNamara MF, Olsen C. The first 48 hours: Comparing
12-hour and 24-hour betamethasone dosing when preterm deliveries occur
rapidly. J Matern Fetal Neonatal Med. 2006; 19(6):365-9.
9. Elimian A, Figueroa R, Spitzer AR, Ogburn PL, Wiencek V, Quirk JG. Antenatal
corticosteroids: are incomplete courses beneficial? Obstet Gynecol. 2003;
102(2):352-5.
10. Kent A, Lomas F, Hurrion E, Dahlstrom JE. Antenatal steroids may reduce adverse
neurological outcome following chorioamnionitis: neurodevelopmental outcome
and chorioamnionitis in premature infants. J Paediatr Child Health 2005; 41:186-
90.
11. Crowther CA, Harding JE. Repeat doses of prenatal corticosteroids for women
at risk of preterm birth for preventing neonatal respiratory disease. Cochrane
Database of Systematic Reviews 2000, Issue 2. Art. No.: CD003935.
12. Ogunyemi D. A comparison of the effectiveness of single-dose vs multi-dose
antenatal corticosteroids in pre-term neonates. J Obstet Gynaecol. 2005;
25(8):756-60.
13. Kenyon S, Boulvain M, Neilson J. Antibiotics for preterm rupture of membranes.
Cochrane Database of Systematic Reviews 2003, Issue 2. Art. No.: CD001058.
DOI: 10.1002/14651858.CD001058.
14. Mittendorf R, Dammann O, Lee KS. Brain lesions in newborns exposed to high-
dose magnesium sulfate during preterm labor. J Perinatol. 2006;26 (1):57-63.
15. Paul DA, Sciscione A, Leef KH, Stefano JL. Caesarean delivery and outcome
in very low birthweight infants. Aust N Z J Obstet Gynaecol 2002; 42(1):41-
5.
16. Görbe E, Chasen S, Harmath A, Patkós P, Papp Z. Very-low-birthweight breech
infants: short-term outcome by method of delivery. J Matern Fetal Med. 1997;
6(3):155-8.
17. Sánchez-Torres AM, García-Alix A, Cabañas F, Elorza MD, Madero R, Pérez J,
Quero J. Impact of cardiopulmonary resuscitation on extremely low birth weight
infants. An Pediatr (Barc). 2007; 66(1):38-44.
18. Mercer JS, Vohr BR, McGrath MM, Padbury JF, Wallach M, William Oh. Delayed
Cord Clamping in Very Preterm Infants Reduces the Incidence of Intraventricular
Hemorrhage and Late-Onset Sepsis: A Randomized, Controlled Trial. Pediatrics
2006. 117 (4): 1235-1242.
19. Osborn DA, Evans N, and Kluckow M. Hemodynamic and Antecedent Risk Factors
of Early and Late Periventricular/Intraventricular Hemorrhage in Premature Infants
Pediatrics 2003. 112 (1): 33-39.
20. Schick JB, Beck AL, DeSilva HN. Umbilical artery catheter position and
intraventricular hemorrhage. J Perinatol. 1989; 9(4):382-5.
21. Hall RW, Kronsberg SS, Barton BA, PhD, Kaiser JR, Anand KJS, for the NEOPAIN
Trial Investigators Group. Morphine, Hypotension, and Adverse Outcomes Among
Preterm Neonates: Who’s to Blame? Secondary Results From the NEOPAIN Trial.
Pediatrics 2005; 115 (5): 1351-1359.
22. Bonifacio L, Petrova A, Nanjundaswamy S, Mehta R. Thrombocytopenia related
neonatal outcome in preterms. Indian J Pediatr. 2007; 74(3):269-74.
23. Andrew M, Castle V, Saigal S, Carter C, Kelton JG. Clinical impact of neonatal
thrombocytopenia. J Pediatr. 1987; 110 (3):457-64.
24. McLendon D, Check J, Carteaux P, et al: Implementation of potentially better
practices for the prevention of brain hemorrhage and ischemic brain injury in
very low birth weight infants. Pediatrics 2003; 111(4): e497-503.
25. Brion LP, Bell EF, Raghuveer TS. Vitamin E supplementation for prevention of
morbidity and mortality in preterm infants. Cochrane Database of Systematic
Reviews 2003, Issue 4. Art. No.: CD003665. DOI: 10.1002/14651858.
CD003665.
26. Rahman N, Murshid WR, Jamjoom ZA, Jamjoom A. Neurosurgical management
of intraventricular haemorrhage in preterm infants. J Pak Med Assoc. 1993; 43
(10):195-200.
27. Fulmer BB, Grabb PA, Oakes WJ, Mapstone TB. Neonatal ventriculosubgaleal
shunts Neurosurgery. 2000; 47(1):80-3.
28. Committee on Fetus and Newborn. Non-initiation or Withdrawal of Intensive
Care for High-Risk Newborns. Pediatrics 2007; 119 (2) ,401-403.
Rhishikesh Thakre
3
Preterm/Low Birth Weight
As increasing numbers of smaller babies, preterm and IUGR, graduate

from intensive care nurseries, there is concern regarding the future health
and long-term “neurodevelopmental outcomes” of these survivors. 1 Because
these children are not a homogeneous group, they have a broad spectrum
of growth, health, and developmental outcomes including childhood
disability, further classified as mild, moderate, and severe.2 Definitions of
specific learning problems vary across studies and regions.
FACTORS AFFECTING LONG-TERM NEURO-

DEVELOPMENTAL OUTCOME ...........................................................
Social and environmental disadvantages clearly affect the long-term
developmental outcomes of low birth weight children, whether measured
in terms of maternal education, race, or social class. For most low birth
weight children, social risk factors have a far greater effect on
long-term cognitive outcomes than do biological risk factors. However,
biological factors have more important influences on outcome for
children with severe neurological insult and in ELBW babies3,4
There is also evidence that the cognitive deficits specifically associated with
social or environmental risk become more pronounced over time.5,6 Most
studies have failed to find evidence supporting long-term effects of social
factors on very low birth weight infants when compared with normal
birth weight children.2,4,7 There is little doubt, however, that the combined
effects of severe neonatal illness and a deprived environment can be
devastating.7-9
Low birth weight is considered as a composite index of biological risk.
(Table 3.1). The biological risk factors include male sex, asphyxia, apnea,
periventricular hemorrhage, meningitis, seizures, hypoglycemia, poly-
cythemia, severe hyperbilirubinemia, chronic lung disease. These compli-
cations of prematurity occur more commonly in infants with birth weights

of less than 1500 grams and 1000 grams (which explains why this
birth weight group is at greatest biological risk). Intrauterine growth failure
in preterm very low birth weight children does not seem to contribute
to poor developmental outcome over and above that resulting from
prematurity and its complications. However, those with severe growth
failure may have a poorer outcome. Pathological preterm brain injury
includes periventricular leukomalacia and cerebral atrophy, which can result
in CP, nonspecific hypotonia, and cognitive and neuropsychological sub-
normality. Lesser degrees of brain damage are thought to be responsible
for fine motor impairments, visuo-perceptual problems, difficulties with
mathematics, and hyperactivity.
Table 3.1: Univariate associations between antecedents and

cerebral palsy in VLBW infants11,12
Exposure Summary Odds Ratio

Associated with increased risk
Intrauterine infection 2.2 (1.6–3.1)

Death of a co-twin 10.5 (5.3–20.9)
Placental abruption 1.4 (1–2.2)
Intrapartum acidosis 2.5 (1.3–4.6)
Neonatal acidosis —
Hypothyroxinemia 4.4 (1–18.6)
Neonatal sepsis 2.7 (1.9–3.9)
Neonatal hypotension 2.6 (1.7–4.2)
Respiratory distress syndrome 1.8 (1.1–2.9)
Assisted ventilation 5.3 (2.8–10.3)
Hypocarbia 2.7 (1.1–6.4)
Pneumothorax 3.3 (2.1–5.4)
Neonatal chronic lung disease 3 (2–4.6)
Antenatal corticosteroids 0.7 (0.5–1)
Magnesium sulfate 0.5 (0.3–0.7)
Pre-eclampsia 0.4 (0.3–0.6)
Fetal growth restriction 0.5 (0.3–0.8)
NEURODEVELOPMENTAL OUTCOMES OF PRETERM/LBW ........

A significant proportion of brain growth, development, and networking
occurs during the last weeks of gestation and after birth. Developing
brain tissues are vulnerable to injury during this critical period. Insult may
result in direct injury to developing tissues or disruption of critical pathways
needed for neuronal and glial development.13 For most preterm infants
PRETERM/LOW BIRTH WEIGHT 31
of > 32 weeks’ gestation, survival and longer term neurodevelopment
are similar to those of infants born at term. The period between
20 and 32 weeks after conception is one of rapid brain growth and
development. Greatest impairment occurs in the 0.2% of infants
born before 28 weeks’ gestation, or with birth weights of < 1000
g (extremely low birth weight).14-16 Illness, under nutrition, and infection
during this time may seriously compromise neurodevelopment. Infants
who are born after exposure to infection and asphyxia have worse
outcomes than those who are born after only one or neither of the
two processes.
CEREBRAL PALSY (CP)

Incidence of CP increases with decreasing maturity or decreasing birth
weight. The slight increase in CP prevalence that is seen reflects the increase
in CP in VLBW infants, which is entirely a consequence of their increasing
survival. Incidence of CP at all birth weights has been static over the
years.17-19 The recent decline in CP in VLBW may reflect improvements
in perinatal care. The most common forms of CP in children who
have been born preterm are spastic hemiplegia (unilateral) or quadriplegia
(bilateral). The functional consequences can vary from abnormalities of
muscle tone or power that do not cause serious problems, to severe
impairments that result in considerable lifelong disability and handicap,
such as being unable to walk or to feed independently. Brain damage
‘–’ periventricular hemorrhage, particularly periventricular cystic leukomalacia
and post-hemorrhagic hydrocephalus are strong predictors of future
neurodevelopmental problems, especially CP.
VISUAL IMPAIRMENT 20, 21
• ROP: Most visual impairment in very preterm infants is secondary to

retinopathy of prematurity (ROP), and in developed countries is the
commonest cause of childhood blindness, visual field defects, and
refractive errors.
• Strabismus and refractive errors are also very common.
• Cortical visual impairment
• Contrast sensitivity, field of vision and color vision.
Single early visual acuity measures may be misleading, multiple measures
are required to aid prognosis.
HEARING IMPAIRMENT 22
The etiology of sensori-neural hearing loss is probably multifactorial, with
a variety of interacting factors that are related to illness severity. Hearing
impairment is associated with delayed language development. Even very

preterm infants with normal hearing may also develop speech and language
problems. Deafness, affects 2 to 3% of low birth weight children. There
seems to no added risk in the smallest of babies.
INTELLIGENCE QUOTIENT (IQ)

There is a gestational age-related drop in IQ of infants born before 33
weeks. In the Bavarian Longitudinal Study (BLS) there was no relationship
between IQ and GA from 33 to 42 weeks but below 33 weeks, IQ
scores decreased linearly by an average of 2.5 points with each
weekly decrease in GA (from 32 to 27 weeks). VLBW babies have
problems in nonverbal reasoning and simultaneous information processing.
IQ is also strongly related to socio economic status for both term and
extreme preterm populations. Case-control studies have shown that very
preterm children have intelligence quotient (IQ) scores significantly lower
than term peers, even in those who are free of severe disability.
A study comparing VLBW survivors born in the early 1980s to those
born in the mid-1990s suggests that despite improved neonatal care and
survival intelligence scores have not changed. 23 A recent systematic review
found that the IQ of extremely low birth weight children is on average
10 points lower than in children who were born at term.
LEARNING DIFFICULTIES
Non-verbal reasoning, visuo-spatial skills and the ability to perceive, integrate
and process stimuli simultaneously are particularly compromised by very
preterm birth. Such impaired processing capacity may underlie the
behavioral, social and academic difficulties frequently observed in this
population. Learning difficulties are often associated with problems such
as visual or hearing impairment, but children can have isolated cognitive
problems. Learning problems among low birth weight children have been
documented by teacher or parent ratings of school performance and
direct assessments of academic skills in clinical settings. At school age,
up to 50% of infants born before 28 weeks’ gestation need some
form of additional educational support. Other reported problems at
school age include poorer vocabulary skills and significant delays in reading,
spelling and mathematics. In studies involving very low birth weight children,
rates of special education placements are reported to be closer to 50%
or higher.24,25 There is also a tendency for increasing rates of special
education with decreasing birth weight.
A study at 8 years of age documents lower rates of disability for ELBW
children born in the 1990s compared to the early 1980s.26 Meta-analysis
of the cognitive and behavioral outcomes of preterm school-age children
versus term born controls showed significantly poorer cognitive scores
(weighted mean difference 10.9; 95% CI (9.2-12.5) with scores being
directly proportional to the degree of immaturity. Longitudinal studies
have typically failed to find evidence of ‘catch-up’ growth over time,
with some identifying a trend towards deteriorating performance in
comparison to term peers.
ATTENTION DEFICIT HYPERACTIVE DISORDER16

Increased prevalence of ADHD has been found in 12-year old VLBW
children (23%) compared to matched term controls (6%, p < 0.0001)
and in 10-year-old extreme preterm children (20%) versus controls (8%,
p < 0.05). In heavier children (LBW, <2000 g) the prevalence of ADHD
has been found to be 10% (versus controls 1%, p = 0.0001). Neonatal
white matter injuries, particularly parenchymal lesions and ventricular
enlargements, have been found to be strongly predictive of ADHD in
LBW/ELBW children, suggesting a more biologically determined form
of ADHD.
SOCIAL DEVELOPMENT, BEHAVIOR AND PSYCHOLOGICAL PROBLEMS

There is a higher incidence of behavioral problems in extremely low birth
weight children of school age, with attention deficit, social, and thought
processing problems being the most commonly detected. Behavioral
problems have mainly been described in children with cognitive deficits
and neuro-motor dysfunction, suggesting brain injury as a cause of these
problems. The types of behavioral problems reported in low birth weight
children include conduct disorder, hyperactivity, and attention weaknesses.
Early social development—for example, responsive smiling and recognizing
family members—may be delayed in preterm infants. Interactive and
imaginative play may also be delayed. As behavioral problems can adversely
affect school performance and development of social relations, these are
important long-term effects of preterm birth.
GROWTH27,28
Growth attainment of low birth weight children is less than that of their
normal birth weight peers. Birth-weight-related differences in mean weight,
height, and head circumference increase with decreasing birth weight.
Poor growth attainment is seen in both preterm and term children who
are born small for age following intrauterine growth failure, and also in
preterm children who have normal intrauterine growth but fail to grow
after birth because of severe neonatal complications of prematurity such
as chronic lung disease. Although very little catch-up of head size

occurs after one year of age, catch-up of weight and height can
occur later. The major determinants of catch-up growth include the
duration and severity of the initial growth failure, as well as the genetic
growth potential of the child as measured by parental height.
HEALTH OUTCOMES
The most common medical conditions found in low birth weight children
are asthma, upper and lower respiratory infections, and ear
infections. Low birth weight children are re-hospitalized for the above
medical conditions as well as for surgeries, mainly of the eyes (strabismus),
ears, nose, and throat (ear tubes, adenoids, tonsils, tracheal complications);
orthopedic surgery is also performed for CP.29,30 Although respiratory
infections decrease after two years of age, health problems persist and
contribute to excessive bed days, restricted activity, school absence, and
poor school performance.
QUALITY OF LIFE
It is estimated that the academic achievement of approximately 30% to
50% of VLBW born children is in the subnormal range, fewer graduate
from high school, 20% to 30% exhibit the attention deficit hyperactivity
disorder, and approximately 25% to 30% are affected by psychiatric
disorders at adolescence.31, 32 Extremely preterm children have higher
rates of re-hospitalization, special health care needs and functional
limitations at school age. Reported rates of re-hospitalization for ELBW
survivors range from 31-82% over the first 2 years of life.33 Although
the rates of re-hospitalization decline after the first 2 years of life, the
higher rate of readmission for extremely preterm children continues into
later childhood. The most recent long-term study of extremely premature
infants’ now entering adulthood reports no significant differences
between the ELBW adults and term-born controls with regard to rates
of high school graduation, college enrollment, permanent employ-
ment and independent living status.34,35 A recent study of the children
has reported no difference in the self-reported health-related quality
of life between impaired and non-impaired ELBW children at young
adulthood.36
PRACTICE POINTERS ..........................................................................

• Advances in neonatal care have improved perinatal outcome
considerably, but the falling threshold of viability has created a new
set of dilemmas for parents and caregivers. The overall prognosis remains
poor in neonates who are born before 26 weeks’ gestation.
• Although preterm survivors continue to constitute a high-risk population
for various kinds of disability, particularly CP, the advances in neonatal
intensive care have allowed far more infants to survive without CP
than with it. Neonatal intensive care has been successful in improving
long-term outcomes for premature infants.
• Most children with CP are not born preterm. However, preterm infants,
particularly those born after very short gestations, are at increased
risk of CP.
• Outcomes improve with increasing gestational age, although for any
given length of gestation survival varies with birth weight.
• Preterm/LBW are at risk of spectrum of neurological disorders ranging
from CP to lesser and more subtle degrees of neuro-motor abnormality.
• Continued research and attempts to decrease the rate of low birth
weight and associated perinatal medical sequelae are of primary
importance.
• Ongoing documentation of the long-term outcome of low birth weight
children needs to be mandated, as does the implementation of
environmental enrichment programs to help ameliorate the long-term
consequences for infants who are born low birth weight.
• It is important to recognize that there is no moral difference between
disabled and able-bodied children and adults born preterm or LBW
and we should try not to impose our own values or prejudices.
REFERENCES ........................................................................................
1. Neil Marlow.The need to understand perinatal outcomes. Seminars in Fetal and
Neonatal Medicine 2007;12:329-331.
2. Teplin, S.W., Burchinal, M., Johnson-Martin, N., et al. Neurodevelopmental, health,
and growth status at age 6 years of children with birth weights less than 1001
grams. Journal of Pediatrics 1991:118:768-77.
3. Cohen, S., Parmelee, A., Sigman, M., and Beckwith, L. Antecedents of school
problems in children born premature. Journal of Pediatric Psychology (1988)
13:493-508.
4. Hack, M., Breslau, N., Weissman, B., et al. Effect of very low birthweight and
subnormal head size on cognitive abilities at school age. New England Journal
of Medicine 1991;325:231-37.
5. Resnick, M.B., Stralka, K., Carter, R.L., et al. Effects of birth weight and
sociodemographic variables on mental development of neonatal intensive care
unit survivors. American Journal of Obstetrics and Gynecology 1990;162:374-
78.
6. Collin, J.F., Halsey, C.L., and Anderson, C.L. Emerging developmental sequelae
in the “normal” extremely low birth weight infant. Pediatrics 1991;88:115-20.
Saigal, S., Szatmari, P., Rosenbaum, P., et al. Cognitive abilities and school
performance of extremely low birthweight children and matched term controls
at age 8 years: A regional study. Journal of Pediatrics 1991;118:751-60.
7. Hunt, J.V., Bruce, A.B., Cooper, B.A.B., and Tooley, W.H. Very low birthweight
infants at 8 and 11 years of age: Role of neonatal illness and family status.
Pediatrics 1988;82:596-603.
8. Cohen, S., Parmelee, A., Sigman, M., and Beckwith, L. Antecedents of school
problems in children born premature. Journal of Pediatric Psychology 1988;
13:493-508.
9. Leonard, C.H., Clyman, R.I., Piecuch, R.E., et al. Effect of medical and social
risk factors on outcome of prematurity and very low birth weight. Journal of
Pediatrics 1990;116:620-26.
10. Perlman JM, Tack EC. Renal injury in the asphyxiated newborn infant: relationship
to neurological outcome. J Pediatr 1998;113:875–9.
11. T. Michael O’shea, Olaf Dammann. Antecedents of CP in very low birth weight
infants. Clinics in Perinatology-Volume 27, issue 2 (june 2000).
12. MC Hermensen. Perinatal causes of CP. Clin Perinatol 33 (2006) xv– xvi
13. Ira Adams-Chapman. Neurodevelopmental Outcome of the Late Preterm Infant.
Clin Perinatol 2006;33:947–64.
14. Barry M. Lester Cynthia L. Miller-Loncar. Biology versus environment in the
extremely low–birth weight infant. Clinics in Perinatology - Volume 27, Issue
2 (June 2000).
15. Michael Colvin, William McGuire, Peter W Fowlie. Neurodevelopmental outcomes
after preterm birth. BMJ (329), 2004.
16. Joe Fawke. Neurological outcomes following preterm birth. Seminars in Fetal
and Neonatal Medicine 2007 12, 374-382.
17. Nigel Paneth, MD, MPHa,b,T, Ting Hong, MD, MSca, Steven Korzeniewski, The
Descriptive Epidemiology of CPClin Perinatol 2006;33:251– 267.
18. Cooke RWI. Preterm mortality and morbidity over 25 years.Arch Dis Child Fetal
Neonatal Ed 2006;91:293e4.
19. Platt MJ, Cans C, Johnson A, Surman G, Topp M, Torrioli MG, et al. Trends
in CP among infants of very low birthweight (<1500 g) or born prematurely
(<32 weeks) in 16 European centres: a database study. Lancet 2007;369:43-
50.
20. Anna R. O’Connor, Alistair R. Fielder. Visual outcomes and perinatal adversity.
Seminars in Fetal and Neonatal Medicine 2007;12:408414.
21. Atkinson J, Braddick O. Visual and visuocognitive development in children born
very prematurely. Prog Brain Res. 2007;164:123-49.
22. Marlow ES, Hunt LP, Marlow N. Sensorineural hearing loss and prematurity.
Arch Dis Child Fetal Neonatal Ed 2000;82(2):F1414.
23. Hansen BM, Greisen G. Is improved survival of very-low-birthweight infants in
the 1980’s and 1990’s associated with increasing intellectual deficit in surviving
children? Dev Med Child Neurol 2004;46:812e5).
24. Ross, G., Lipper, E.G., and Auld, P.A.M. Educational status and school-related
abilities of very low birth weight premature children. Pediatrics 1991;88:1125-
34.
25. Vohr, BR. and Garcia-Coll, C.T. Neurodevelopmental and school performance
of very low birthweight infants: A seven-year longitudinal study. Pediatrics 1985;
76:345-50.
26. Doyle LW, Anderson PJ. Improved neurosensory outcome at 8 years of age
of extremely low birth weight children born in Victoria over 3 different eras.
Arch Dis Child Fetal Neonatal Ed 2005;17:1-11.
27. Ross, G., Lipper, E.G., and Auld, P.A.M. Growth achievement of very low
birthweight premature children at school age. Journal of Pediatrics 1990;117:307-
12.
28. Casey, P.H., Kraemer, H.C., Bernbaum, J., et al. Growth status and growth rates
of a varied sample of low birth weight, preterm infants: A longitudinal cohort
from birth to three years of age. Journal of Pediatrics 1991;119:599-605.
29. Hack M, Taylor G, Klein N, et al. School age outcome in children with birth
weight under 750g. N Engl J Med 1994;331:753– 9.
30. Whitfield MF, Eckstein RV, Holsti L. Extremely premature (< 800g) school children:
multiple areas of hidden disability. Arch Dis Child 1997;77:F85– 90.
31. Stjernqvist K, Svenningsen NW. Ten year follow-up of children born before 29
gestational weeks: health, cognitive development, behavior and school
achievement. Acta Pediatr 1999; 88:557–62.
32. Hack M, Flannery DJ, Schluchter M, et al. Outcomes in young adulthood for
very low birthweight infants. N Engl J Med 2002;346:149–57.
33. Mutch L, Newdick M, Lodwick A, Chalmers I. Secular changes in rehospitalization
of very low birth weight infants. Pediatrics 1986;78:164e71.
34. Yuksel B, Greenough A. Birth weight and hospital readmission of infants born
prematurely. Arch Pediatr Adolesc Med 1994;148:384-8.
35. Saigal S, Stoskop B, Streiner D, Boyle M, Pinelli J, Paneth N, et al. Transition
of extremely low-birth-weight infants from adolescence to young adulthood:
comparison with normal birthweight controls. JAMA 2006;295 (6):667e75.
36. Saigal S, Stoskopf B, Pinelli J, Streiner D, Hoult L, Paneth N, et al. Self-perceived
health-related quality of life of former extremely low birth weight infants at young
adulthood. Pediatrics 2006;118(3):1140e8.
Section 3
Neonatal
Encephalopathy
4. Perinatal Asphyxia
5. Neonatal Seizures
Karthik Nagesh N
4
Perinatal Asphyxia
It is all too familiar a scenario for neonatologists to see the sequence

of events associated with an acute fetal circulatory collapse followed by
the birth of a sick and acidotic baby, requiring aggressive resuscitation
and then developing an encephalopathy culminating in a neurologically
impaired neonate. However, it is difficult to clearly prognosticate very early
as to what is the likely outcome of this sick baby, who has suffered from
hypoxic-ischemic insult in the intra-partum period, both in terms of immediate
survival and long-term neurodevelopmental outcome. Approximately 23%
of the 4 million annual global neonatal deaths are attributable to asphyxia.
10-20% of asphyxiated infants die, and 20-45% of survivors have neuro-
developmental disability (NDD).
DEFINITION OF PERINATAL ASPHYXIA ..........................................

There is a general lack of an accepted definition for hypoxic ischemic
injury. Asphyxia is defined as impairment of placental or pulmonary
gas exchange resulting in hypoxemia, hypercapnia and a mixed respiratory
and metabolic acidosis. Since there is simultaneous occurrence of hypoxia
and ischemia, the term hypoxic-ischemic insult is now preferred.1 The clinical
diagnosis of perinatal asphyxia is based on several criteria, the two main
ones being evidence of cardio-respiratory and neurological depression,
defined as an APGAR score remaining less than 7 at 5 minutes after birth,
and evidence of acute hypoxic compromise with acidemia, defined as an
arterial blood pH of less than 7 or base excess greater than 12 mmol/
L. In many settings however, it may be impossible to assess fetal or neonatal
acidemia.2,3
INCIDENCE/PREVALENCE ...................................................................
Approximately 23% of the 4 million annual global neonatal deaths are
attributable to asphyxia. Post-asphyxial hypoxic-ischemic encephalopathy
(HIE) occurs in approximately 1 to 2 infants per 1000 live term births.

Significant proportions of these infants die or survive with severe long-
term morbidity. Among term infants, 6% to 23% of cases of Cerebral Palsy
(CP) are attributable to intra-partum asphyxia.4-7
Estimates of the incidence of perinatal asphyxia vary depending on
the definitions used. In developed countries, the incidence of severe perinatal
asphyxia (causing death or severe neurological impairment) is about
1/1000 live births and overall rate varies from 1.8 to 6.7 per 1000 live
births.4, 5 In developing countries, perinatal asphyxia is probably much
more common. In developing countries, the incidence is much higher varying
from 9.4 per 1000 live births to 229 per 1000 live births. As per NNPD
report of 2000, perinatal asphyxia was present in 1.4% of all intramural
births and it was the primary cause in 20% of all deaths.8 However, even
this probably represents an underestimate of the true community incidence
of perinatal asphyxia in resource poor countries. Of the estimated 1.2 million
neonatal deaths in India every year, 300000 –350000 deaths occur due
to perinatal asphyxia. Despite advances in neonatal care, deaths due to
asphyxia have remained relatively unchanged.
IMPACT OF PERINATAL ASPHYXIA ON

NEURODEVELOPMENTAL OUTCOME ...............................................
Perinatal asphyxia affects dominantly the motor system, but can affect
cognitive function without very significant involvement of the motor pathways.
The expected long-term neurological abnormalities after perinatal asphyxia
include CP (athetoid and spastic tetraplegic in term neonates), learning
deficits, seizures /epilepsy; lower IQs, visual and hearing impairments.
CEREBRAL PALSY
Athetoid (dyskinetic) CP
This type of CP is by far the most likely subtype to be caused by acute
perinatal hypoxic-ischemia at term and the evidence for a causal link is
strong.13 There is an acute fetal bradycardia (which may or may not be
associated with a ‘sentinel event’ such as uterine rupture, or cord prolapse),
followed by the birth of a baby with low APGAR scores needing resuscitation
and who then develops an encephalopathy and on neuro-imaging shows
abnormalities in the deep grey matter of the brain. Approximately 80%
of all cases of dyskinetic CP are caused by intra-partum hypoxic-
ischemia at term. Specifically, damage which occurs as a result of a
short period of profound hypoxic ischemia causes injury to parts of the
brain with a high metabolic rate, correspondingly high blood supply, high
PERINATAL ASPHYXIA 43
glucose metabolism and a large number of excitatory glutaminergic inputs.
The brainstem is commonly affected in a very severe abrupt insult. Babies
with the basal ganglia/thalamus predominant pattern have the most intensive
need for resuscitation and most severe clinical encephalopathy and seizures.
Data suggests that cooling is most likely to be effective in this group
especially if started soon after the hypoxic-ischemic insult before the secondary
wave of neuronal death. One MRI study demonstrated a decrease in basal
ganglia and thalamic lesions in those who had a moderately abnormal
recording on the amplitude integrated EEG prior to the onset of cooling.15,16
Spastic Tetraplegic CP17

This is the second subtype of CP that can be caused by intrapartum
hypoxic ischemia at term. Spastic tetraplegic CP is almost always associated
with a very severe disability in the long-term; hardly any of these children
can walk and the vast majority has learning disability, with about half
also requiring treatment for epilepsy. MR imaging of the brain of these
children usually reveals either parasagittal cerebral injury or damage to
the deep grey matter with involvement of the white matter and cerebral
atrophy. A prolonged period of mild to moderate hypotension can cause
damage to the brain in the parasagittal zones (‘watershed areas’) that lie
between the territories of the circulation of the anterior, middle and posterior
cerebral arteries.
Parasagittal cerebral injury usually causes tetraplegic CP, often with learning
difficulties. Postnatal head growth is usually poor and the end-stage MR
imaging shows atrophy, with ventricular dilatation and widening of the
inter-hemispheric fissure and extra-cerebral space.
Hemiplegic CP
In general, hemiplegic CP is not due to perinatal hypoxic-ischemia
and one important cause is focal cerebral infarction, e.g. a ‘stroke’
(either arterial or venous).18 Common risk factors for an arterial stroke
in the newborn period, include a ‘complicated’ delivery with a long, slow
primigravid labour in the occipito posterior position, and several inherited
thrombophilic tendencies.
Ataxic CP
This disability is very unlikely to be due to perinatal hypoxic-ischemic damage
at term.
EPILEPSY
Epilepsy is the most common additional disability (apart from learning
difficulty) affecting children with CP who had a potentially damaging
encephalopathic illness at term, affecting up to 50% of children with spastic
quadriplegia.13 It would be very unusual to see epilepsy without an
associated motor disability as the sole disabling condition as a result
of perinatal hypoxic-ischemic damage.
VISUAL IMPAIRMENT
Isolated visual impairment is not likely to be due to perinatal
hypoxic-ischemia: Many children with hypoxic-ischemic brain damage
have visual impairment as part of their overall disability. Isolated visual
impairment or delayed cortical development, without accompanying damage
to the motor system, is not seen. Children with moderate basal ganglia
lesions have abnormal visual function with poor acuity and weak stereopsis
but did develop useful vision.13
HEARING IMPAIRMENT
Some view that hypoxia damages the hair cells of the cochlea and hearing
impairment is often due to hypoxic-ischemia.21
In general, the prevalence of hearing impairment in cohorts of children
who had an early neonatal encephalopathy at term is not significantly
increased compared to those without an encephalopathy.13
LEARNING DISABILITY
In addition to functional motor impairment, cognitive impairment is a
significant problem in children who have experienced intrapartum hypoxia-
ischemia at term.19 In general, learning difficulties that are caused by hypoxic-
ischemia at term occur in conjunction with CP that causes a severe
motor disability. The presence of abnormal cognitive outcomes, at later
time points to postnatal environment, socioeconomic conditions and access
to rehabilitation services.
Memory Problems and Problems with Executive Functioning

There are case reports of striking and specific memory problems in individuals
with bilateral hippocampal atrophy, some of whom were born at term
with birth depression and developed an encephalopathy.20
ATTENTION DEFICIT HYPERACTIVITY DISORDER AND
BEHAVIORAL PROBLEMS
Many children with CP have fidgety behaviour, poor concentration and
distractibility, which affect their education and lives, although of course
these problems are not confined to such children.
AUTISM AND PERVASIVE DEVELOPMENT DISORDERS

There is currently no evidence that autism is caused by intrapartum
hypoxic ischemia.
HOW ASPHYXIA CAUSES NEUROLOGICAL BRAIN DEFICITS12 .

In the healthy fetus, there are many adaptive responses to hypoxia-ischemia
like redistribution of cardiac output to the vital organs, preferential oxygenation
to vital centers to the brain, increased myocardial contractility, accelerated
anaerobic glycolysis, etc. Cerebral auto-regulation of cerebral blood
flow (CBF) initially maintains brain perfusion in spite of an initial drop
in the mean BP. The range of blood pressure within which CBF is maintained
in newborns is 60–100 mm Hg. With prolonged asphyxia, the early
compensatory adjustments fail and CBF may become dependant on systemic
blood pressure (pressure-passive). Brain hypoxia occurs when blood pressure
falls, leading to intracellular energy failure. During the early phases

of brain injury, brain temperature drops and local release of the
neurotransmitter GABA increases; these changes reduce cerebral
oxygen demand, transiently minimizing the impact of asphyxia.
However, prolonged hypoxic-ischemic damage can cause neuronal death.
The majority of injury leading to neuronal death occurs after
recovery from the initial insult and the concept of two stages
of neuronal injury are now formulated.
PRIMARY NEURONAL INJURY

Neuronal cell membranes get affected functionally due to hypoxic-ischemic
injury causing intracellular energy depletion. Hence there is failure
of ionic pump mechanism at the cell membrane level which leads to excess
sodium, calcium and water entering the cell causing cytotoxic neuronal
injury and death. In addition to this mechanism of neuronal death it is
now clear that a majority of cell death occur later even some hours or
days after reviving from the insult.
SECONDARY NEURONAL INJURY

Reperfusion of the affected neuronal tissues after a hypoxic-ischemic insult
initiates a host of biochemical reactions at the cellular level. The immediate
reperfusion which follows resuscitation is possibly due to accumulation of
lactic acid causing cerebral vasodilatation.
Free Radical Injury

Reactive oxygen metabolites including oxygen and hydroxyl free radicals
further damage the arteriolar endothelium which stimulates xanthine oxidase
production leading to further generation of oxygen free radicals which
overwhelm endogenous scavenger mechanisms, damage cellular lipids,
proteins and nucleic acids and thereby the blood brain barrier.
Excitotoxic Amino Acid Injury

Hypoxic-ischemic insult causes release of excessive amounts of the excitatory
neurotransmitter glutamate which acts on the NMDA receptors (N methyl
D aspartate receptors) which are post synaptic ion channels allowing thereby
sodium and calcium to enter the neuronal cells causing immediate
neuronal death from the osmolar load. Certain regions of the brain appear
to be particularly sensitive to NMDA-related injury, especially the basal
ganglia and perirolandic cortex, which are particularly vulnerable in neonates
following severe hypoxic-ischemic insult. Elevated intra-mitochondrial calcium
interferes with function and may stimulate further reactive oxygen metabolites
to be produced. Further, these excitotoxins, because of provoking excessive
calcium influx causes delayed neuronal death by activation of undesirable
enzyme and secondary messenger systems (e.g. Ca2+ dependant lipases
and proteases).
Nitric Oxide
Nitric oxide is generated in the cell as the result of stimulation of nitric
oxide synthase [NOS]. This generates another reactive metabolite,
peroxynitrite, causing lipid peroxidation of intracellular membranes with
consequent loss of cell function.
Apoptosis
It is now recognized that neuronal death may occur as a result of necrosis,
probably initiated through excessive calcium entry, or apoptosis in which
the cell appears to initiate its own demise. Necrosis is initiated by external
factors, mitochondrial injury and disruption of the cell. Apoptosis is regulated
by genetic factors with little loss of cellular membrane integrity,
leading to contraction of the cells, which are subsequently consumed
by macrophages. Other triggers of apoptosis include cytokines (tumour
necrosis factor alpha), reactive oxygen metabolites and NO.
NEUROPATHOLOGY .............................................................................
There is no single distinct or uniform pathological appearance of the brain
following hypoxia-ischemia. The pattern of injury depends upon the severity
of asphyxial insult (total versus partial), its timing and duration (acute versus
chronic), the developmental maturity of the brain and regional variations
in vulnerability (due to local vascular factors, distribution of NMDA receptor
etc.).
a. Cerebral edema: Within 24-48 hours gross swelling of the cerebral
tissue may occur, with marked flattening and widening of the gyri plus
obliteration of the sulci, seen on imaging or at post mortem. It arises
through two mechanisms: ‘cytotoxic’, when membrane pump failure
leads to intracellular fluid accumulation, and ‘vasogenic’, when the
impaired blood-brain barrier permits capillary leak and interstitial fluid
accumulation.
b. Selective neuronal necrosis: This is the most commonly observed
pathology following hypoxia-ischemia in term infants, affecting neurons
in a scattered fashion and often widely distributed throughout the grey
matter. The cerebral cortex layers III and IV and the hippocampus appear
particularly vulnerable. This injury occurs at specific sites to specific

cell types (neurons>glia) e.g. CA1 region of the hippocampus, Purkinje
cells of the cerebellum (term neonates), intergranule cells of the cerebellum
(premature neonates) and brain stem nuclei.This may be due to differing
metabolic rates of the various neural structures.
c. Basal ganglia and brainstem: In animal models this pattern of injury
is seen following ‘acute total asphyxia’ rather than ‘chronic partial
asphyxia’. Basal ganglion injury is thought to be responsible for the
dyskinetic type of CP seen in survivors of hypoxia-ischemia, and abnormal
signal intensity in the basal ganglia is a common finding on magnetic
resonance imaging (MRI). If the infant survives for several months, an
abnormal myelination pattern is detected on MRI. This is responsible
for the marble-like appearance of the basal ganglia seen at post mortem,
known as ‘status marmoratus’.
d. Parasagittal injury: This is an ischemic injury affecting the cerebral
cortex and sub-cortical white matter in vascular watersheds between
the anterior, middle and posterior arteries, giving rise to a para-sagittal
distribution, and is often symmetrical.
e. White matter injury: Ischemic insults in preterm infants produce
‘periventricular leukomalacia’ (PVL) as the periventricular glia is vulnerable
to ischemia in preterm infants. When ischemic white matter injury occurs
at term, it usually results in sub-cortical leukomalacia. The survivors
of the most severe insults usually show a mixed pattern of injury, referred
to as multi-cystic leukoencephalopathy.
f. Focal cerebral infarction: Infarction of a major cerebral artery, most
commonly the left middle cerebral artery, has in the past been reported
in association with asphyxia, but it is now realized that this lesion occurs
much more commonly in infants with no evidence of intrapartum
asphyxia.
ETIOLOGY AND RISK FACTORS FOR PERINATAL ASPHYXIA ..

Perinatal asphyxia may occur in utero, during labor and delivery, or in
the immediate postnatal period. There are numerous causes, including
placental abruption, cord compression, trans-placental anesthetic or narcotic
administration, intrauterine pneumonia, severe meconium aspiration,
congenital cardiac or pulmonary anomalies, and birth trauma. Postnatal
asphyxia can be caused by an obstructed airway, maternal opiates, which
can cause respiratory depression, or congenital sepsis. There is considerable
debate as to the extent of hypoxia-ischemia at birth contributing to the
totality of brain injury and the literature has always suggested that the
brain may have been significantly impaired by events during pregnancy
and that birth asphyxia is just the final insult making a relatively small
contribution to the burden of damage.
Recent MRI and autopsy studies however, have shown contrarily, that
80% of babies with neonatal encephalopathy showed only evidence
of an acute insult without any evident earlier pathology.9 Hence,
evidence for intra-partum asphyxia should always be sought. In
preterm babies in addition to intra-partum hypoxic-ischemic insult many
antenatal and postnatal problems like infections, respiratory distress, IVH
and leukomalacia can affect neurological morbidity; unlike in term babies
where only the hypoxic-ischemic insult plays a role.
MONITORING TOOLS FOR PERINATAL ASPHYXIA AND

THEIR CLINICAL VALUE .....................................................................
INTRA-PARTUM FETAL MONITORING

• Electronic fetal monitoring (EFM) and fetal scalp pH monitoring:
When considering the need to deliver the baby on the basis of an
abnormal ECG trace alone, it is recommended that additional fetal
blood sampling (FBS) also should be undertaken where possible. A
pH of less than 7.20 indicates that delivery should be carried out as
rapidly as possible. However, meta-analyses of randomized controlled
trials comparing. EFM + FBS versus intermittent auscultation do not
really show any reduction in intra-partum deaths or CP, despite
an increase in cesarean section rates.14 The prevalence of CP in two
randomized controlled trials with follow-up data was not significantly
altered by EFM + FBS. The only benefit however, in neonatal outcome
seen after electronic fetal monitoring was a reduction in the incidence
of early neonatal seizures.1
• Fetal ECG analysis: It appears that a normal heart rate pattern
may be reassuring (negative predictive value of adverse outcome
>96% in most studies) but an abnormal fetal heart rate pattern is
poorly predictive of fetal compromise.1 A recent study showed that
close CTG monitoring with additional ECG ST-waveform analysis resulted
in better intra-partum intervention with a significantly lower rate of acidotic
umbilical artery pH values compared with standard CTG monitoring
alone.25
• Others
• Fetal pulse oximetry: Signal quality derived is limited and the
technique has not been tested in large-scale clinical practice,
substantiate its usefulness.
• Near-infrared Spectroscopy: During labor, an optical probe is

inserted through the dilated cervix and on to the fetal head to assess
the anterior cerebral artery flows and oxygen saturation. A study
of 41 fetuses during labor demonstrated good correlation between
the mean cerebral oxygen saturation shortly before delivery and
the umbilical arterial acid-base status immediately after birth suggesting
it to be a useful clinical tool to screen babies for perinatal hypoxia.26
CLINICAL ASSESSMENT AFTER BIRTH

• Severity of encephalopathy: Sarnat and Sarnat introduced a good
grading system22 to describe the neurological abnormality, which they
referred to as hypoxic-ischemic encephalopathy (HIE) and which has
been modified by Levene et al23 which is an excellent and simple
clinical tool to assess and screen these babies.
• Multi-organ Dysfunction: During hypoxia-ischemia, blood flow is
redistributed in order to preserve circulation to the most vital organs-
the brain, heart and adrenals. This is at the expense of the kidneys,
liver and gastro intestinal tract, which are therefore vulnerable to hypoxic
ischemic damage. Such damage to these and other organs serve as
a further marker of hypoxia-ischemia.
POSTNATAL INVESTIGATIONS
Accurate early detection is required in assessing the efficacy of potential
neuro-protective therapies. However, some of the newer imaging techniques
have not been still fully evaluated because accurate neuro-developmental
follow-up data is still awaited.
Cranial Ultrasound
Ultrasound has proved most useful in the detection of IVH and ischemic
lesions in preterm infants, and it can also be of use in asphyxiated term
infants.1,10,13 Initially, cerebral edema can be recognized by a generalized
increase in echo-density, a loss of anatomical landmarks, indistinct sulci
and compression of the ventricles. ‘Slit –like’ ventricles are seen normally
in the first 24 hours in term infants, and are only abnormal if persisting
for more than 36 hours. The presence of edema is not a useful
prognostic sign, but later ultrasound scan findings associated with a poor
neurodevelopmental outcome include bilateral, uniformly echogenic injury,
diffuse parenchymal echodensities (thought to represent neuronal necrosis);
multi-focal cystic changes; periventricular echodensities; and ventriculomegaly
with cortical atrophy.
CT Scan
CT scan is most useful as a prognostic help when done about
4-6 weeks13 after asphyxia. During acute stages, CT shows reversal
sign-diffuse cerebral hypodensity with loss of gray white differentiation but
with relatively increased density of deep nuclear structures. In chronic
cases CT shows changes in basal ganglia and thalamus (although the MRI
is more sensitive). These areas express a featureless appearance, with
loss of distinction of deep nuclear structures and usually clearly
decreased attenuation of these structures, which gradually deteriorates over
several months. Rarely the injury can develop calcification. Because
of the relatively superficial nature of the parasagittal cerebral injury
it is more difficult to appreciate it on CT scan unless it is very
severe. Periventricular leukomalacia in preterm infants can be seen in
CT scans as periventricular hypo density with a propensity for involvement
of anterior and posterior periventricular areas.
Magnetic Resonance Imaging (MRI)

MRI, particularly when accompanied by diffusion-weighted images
(DWI) becomes the diagnostic modality of choice, as it is very
sensitive for the demonstration of all neonatal hypoxic-ischemic lesions
subsequent to the neonatal period.10, 13 DWI often can show abnormalities
within the first few hours after the insult and is pragmatically useful.
DWI reveals restricted water diffusion not apparent on conventional MRI
by detecting differences in rates of diffusion of water protons. Atrophy
of thalamus, basal ganglia usually accompanied by increased signal
on T2W images is prominent especially in children with extra-pyramidal
affection. The sequelae of PVL are distinctive and consist of decreased
periventricular white matter, especially in the peri-trigonal area, compen-
satory ventricular dilation and increased signal in periventricular white matter
on T2W images.
Cerebral Blood Flow Velocities
Using pulsed wave duplex Doppler with real-time analysis of the Doppler
signal from a major cerebral artery (often the anterior), the cerebral
blood flow can be determined. The end tidal CO2 should be kept in the
normal range because hypercapnia causes cerebral acidosis and may cause
cerebral vasodilation which may cause more flow to uninjured areas with
relative ischemia to damaged areas and extension of infarct size. Excessive
hypocapania may decrease CBF. Hyperventilation is not recommended.
The decreasing diastolic blood flow velocity in relation to the
peak systolic blood flow velocity (Pourcelot’s resistivity index
<0.55) is associated with a poor outcome in asphyxiated infants.

The cerebral blood flow velocities can take 24 hours to become abnormal
following hypoxia-ischemia, and have been found to be of little prognostic
value if performed at 6 hours.27
Magnetic Resonance Spectroscopy

Intra-cerebral energy states can be measured in vivo by magnetic resonance
spectroscopy (MRS) technique. Phosphocreatinine (PCr) and inorganic
phosphate (Pi) can be measured from the phosphorus-31 spectra. The
PCr/Pi ratio represents the phosphorylated energy status within the brain,
and a low PCr/Pi ratio in asphyxiated neonates is associated with
later neurodevelopmental impairment. Prolonged high levels of lactate
peaks predict a bad outcome.28
EEG and Amplitude Integrated EEG (aEEG)—

Cerebral Function Monitoring
The severity of EEG abnormalities and the duration are of prognostic
importance. Recovery of normal EEG background by day 7 is
associated with a normal outcome. In contrast a burst suppression
pattern or isoelectric pattern on any day is invariably associated
with a poor outcome.10 Amplitude-integrated EEG recordings (Cerebral
function monitor) obtained continuously from bipolar electrodes have recently
been advocated as an objective tool for early prediction of poor outcome.
It was able to predict the neurological outcome as early as within 12
hours of life in a recent study.40 Their use may lie in the use of newer
therapies, which have to be administered within a short window period
after birth. The aEEG can be used to predict infants at high risk for HIE
.aEEG was predictive of an abnormal outcome with a sensitivity of 78%
and specificity of 94%, positive predictive value of 85% and a negative
predictive value of 92%. This was much better than either test alone.
BRAIN-ORIENTED MANAGEMENT OF PERINATAL ASPHYXIA ....

In the immediate postpartum period when resuscitation is being undertaken,
it may not be possible to determine whether the neurological and cardio-
respiratory depression is secondary to hypoxia–ischemia, or to another
condition such as feto-maternal infection or metabolic disease. Consequently,
resuscitation and early management will often be of suspected rather than
confirmed perinatal asphyxia.
• Resuscitation – as per NRP guidelines
• Correct hypoxia and under-ventilation
• Correct perfusion
• Inotrope support31
• Seizure control
• Blood glucose levels between 75 and 100 mg/dl
• Fluid restriction: Systematic review identified no RCTs on the effects
of fluid restriction in infants with perinatal asphyxia.
• Osmotic agents: Mannitol has been used in a number of uncontrolled
case series. In a heterogeneous group of 225 asphyxiated infants
1g/kg of mannitol was given either early (before 2 hours) or later following
hypoxic-ischemia in a non-randomised fashion; the early-treatment group
had a better outcome.1,10
RESUSCITATION IN ROOM AIR VERSUS 100% OXYGEN

One systematic review found lower mortality in infants resuscitated
in room air when compared with 100% oxygen.32 The review
(5 RCTs, 1737 term and preterm infants with low APGAR scores at birth)
found that resuscitation in room air was associated with a significantly
lower mortality compared with resuscitation using 100% oxygen (AR 69/
881 [7.8%] with air vs 111/856 [13.0%] with 100% oxygen; OR 0.59,
95% CI 0.48 to 0.74)]. There is some evidence that using lower concentrations
of oxygen limits oxidative stress and secondary neuronal death.33
SELECTIVE HEAD COOLING

In a study by Gunn et al36 selective head cooling was accomplished by
circulating water at 10°C through a coil of tubing wrapped around the
head (CoolCap). A servo controlled overhead heater was used to maintain
rectal temperature at 34°C to 35°C. Placing a cap forms the other method
of inducing hypothermia, from cooled packs around the head at a temperature
of 10°C and adjusting this temperature in order to maintain nasopharyngeal
temperature at a range between 34°C and 35°C.
SYSTEMIC HYPOTHERMIA
One systematic review and three subsequent RCTs37 found no significant
effect of hypothermia on mortality or neurodevelopmental disability in infants
with perinatal asphyxia. However, one RCT reported a significantly reduced
incidence of the composite outcome “death or moderate/severe disability”
in infants treated with systemic hypothermia compared with normothermia.
A large randomized study of whole body hypothermia by Shankaran
et al38 (demonstrated protection among all infants (irrespective of severity
of HIE) studied at 18 to 22 months. Death or moderate or severe disability
occurred in 45/102 (44%) in the hypothermia group versus 64/103 (62%)
in the control group (risk ratio 0.72, 95% CI 0.54–0.95, p=0.01) and
the number needed to treat (NNT) was 6 infants. The rate of CP
was lower in the hypothermia group, 19% vs 30% (risk ratio 0.68, 95%
CI 0.38–1.22, p=0.20). Combining the results of the above trials suggests
that mild hypothermia is associated with a significant reduction
in death and disability in neonates with HIE.
At this point in time, one may opine that the results of the brain cooling
studies in newborn infants with HIE appear favourable, but they do not
provide the necessary evidence of efficacy. The feasibility studies as well
as the randomized trials support the safety of mild to moderate hypothermia
with minimal adverse events in the infants studied.
MAGNESIUM SULPHATE
The limited evidence from one small RCT found that, when assessing
reductions in the composite adverse outcome of survival, abnormal cranial
CT and EEG results, and failure to establish oral feeding by 14 days of
age, magnesium sulphate /dopamine combination was more effective than
no drug treatment.
ANTIOXIDANTS (ALLOPURINOL)
One systematic review provided insufficient evidence from two small RCTs
about the effects of antioxidants in infants with perinatal asphyxia. One
subsequent small RCT found no significant difference in mortality between
infants treated with allopurinol and placebo. 35 No significant difference
was found between treatments in the composite outcome of rates
of death or developmental delay (method of assessment not reported).
CALCIUM CHANNEL BLOCKERS

The use of calcium channel blockers has been associated with clinically
important hypotension in severely asphyxiated newborn infants. We found
no systematic review or RCTs on the effects of calcium channel blockers
in infants with perinatal asphyxia.
HYPERBARIC OXYGEN TREATMENT

In a study done in China, lower rates of mortality and adverse neurological
outcomes were reported in infants treated with hyperbaric oxygen.
7 RCTs, 675 infants. (OR 0.26, 95% CI 0.14 to 0.46). However, the RCTs
included in the review used poor methods, and potential publication bias
was reported. Therefore, the results should be approached with caution.39
THERAPIES WHERE RISKS EXCEED LIKELY BENEFIT
• Corticosteroids: Although corticosteroids may reduce cerebral edema,
data from studies in older children or adults with cerebral hypoxia,
and from animal studies, suggest that steroids do not improve neurological
outcomes. In a small case series of newborn infants with birth asphyxia
treated with dexamethasone, there was no evidence of an effect on
cerebral perfusion pressure.29 We found no systematic review or
RCTs on the effects of corticosteroids in infants with perinatal
asphyxia.
• Hyperventilation: No systematic systematic review or RCTs were
found though,on the effects of hyperventilation in infants with
perinatal asphyxia.30 Hyperventilation is not recommended.
• Anticonvulsants (Prophylactic): One systematic review of three small
RCTs, which used flawed methods, found no significant difference in
mortality or neurodevelopmental outcomes between barbiturates and
no drug treatment in term infants with perinatal asphyxia. One subsequent
RCT found no significant difference in mortality prior to hospital discharge
in asphyxiated term or near term infants with hypoxic–ischemic
encephalopathy treated with phenobarbital versus standard care. 34 The
systematic review, 3 RCTs, 110 term infants, compared barbiturate versus
no drug treatment and found no significant difference in mortality
or in rates of severe neurodevelopmental disability in the
77 survivors.34
PREDICTORS OF OUTCOME1,6,7,10,11,13 (TABLE 4.1) ....................

Data from the national collaborative perinatal project and the British national
child development study suggest that perinatal factors (labor and
delivery) contribute little to the incidence of mental retardation
and seizure. Only 3 to 13% of infants with CP had evidence of actual
intra-partum asphyxia. Many classically suspected obstetric events do not
correlate with CP. Most of the factors, however, reflect preexistent
unpreventable sources of neurologic dysfunction that occur independent
of asphyxia but that might also predispose to concomitant asphyxia at
birth.
• Fetal distress: No constant relationship between measures of fetal
distress and subsequent long-term neurologic outcome has been
demonstrated. Most infants with only one of the fetal distress
predictors do not develop CP.24 Meconium staining (98% do not
develop), pH < 7.1 (no correlation to CP), more than 5 minutes to
the first cry (98 % do not develop CP) and 10 minute APGAR score
< 3 (83% do not develop CP). These indices actually reflect clinical
status during the perinatal period than they do the ultimate long-term
outcome. However, clustering perinatal events does improve
prediction of CP. For example, seizures, occurring alone, are associated
with CP in only 0.13%, but low APGAR score, signs of HIE, and seizures
occurring together were identified a small subgroup in whom the risk
for CP was 55%.
• Acidosis: It is associated with a poor outcome only when it occurs
in combination with abnormal fetal heart rate patterns, depressed
APGAR scores and significant neonatal encephalopathy.
• Intra-uterine passage of meconium: This actually occurs in 10-
20% of all term deliveries and it is often taken is a marker of fetal
distress. However, only 0.4% of term infants with meconium stained
liquor develop CP. Richey et al found no correlation between the
passage of meconium and markers of acute asphyxia (umbilical
arterial pH, lactate and hypoxanthine).
Table 4.1: Predictors of long-term neurodevelopmental
outcome in perinatal asphyxia
Parameter Abnormalities and long-term outcome

Fetal acid base Umbilical artery pH < 7.1, Base deficit > 11:
measurements major neurological deficits in 14%
Extended APGAR score At 20 minutes < 3: CP in 57% survivors
Severity of the encephalopathy Mild-no neurological sequelae
Moderate- 25% have neurological sequelae
Severe-100% have neurological sequelae
Seizures Early onset and refractory seizures
Elevated CPK BB > 5 IU
Oliguria Persistently <1 ml/kg/hr for the first 36 hours
of life
Background EEG Burst suppression pattern on any day.
Isoelectric tracing on any day
Brainstem auditory, Visual Abnormal latencies and amplitude ratios
and Somatosensory evoked
potentials
Neurologic examination at If abnormal, predicts long-term abnormality
end of 1st week of life
head growth If slow in the first month, is a poor prognosis
Source: Reddy AR, Kumar Praveen. Journal of Neonatology, Year : 2004, Volume:
18, Issue: 2.
• APGAR score: A hypoxic-ischemic insult need not always result in
a low APGAR score, unless the insult occurs immediately prior to birth.
Neonates with neonatal encephalopathy following a low APGAR
score (<4) followed to 8 to 13 years showed a 3.3 times risk of
problems with mathematics, a 4.6 times risk of problems with reading,
a 7 times risk of epilepsy, 13 times risk of minor motor problems,
and 14 times risk of attention deficit- hyperactivity disorder compared
to controls with normal APGAR scores and no neonatal encephalopathy.
• Prolonged depression (lower extended APGAR score): Increases
the risk of death or major neurological disability. Term infants with
APGAR scores 0 to 3 at 10, 15, 20 minutes have mortality rates of
18, 48 and 59% respectively. In survivors, the CP rates are 5, 9, 57%
respectively.
• Outcome in relation to severity of HIE: (Table 4.2).
Table 4.2: HIE grade vs Risk of severe handicap in survivors

HIE Percentage Likelihood ratio (95% CI)
Mild (I) 1.6 0.05 0.02-0.15
Moderate (II) 24 0.94 0.71-1.23
Severe (III) 78 10.71 6.71-71.1
• Neonatal seizures: Seizures of early onset (<12 hours) that are difficult
to control when accompanied by signs of asphyxia in multiple systems.
The neonate with seizures was 50 to 70 times more likely to have
CP than those without seizures. One half of babies who required
resuscitation for 5 minutes after birth and subsequently developed seizures
die.
• Cerebral edema and increased ICP (>10 mm Hg): Uncommon,
when present, denotes extensive cerebral necrosis rather than swelling
of intact cells, and has a uniformly bad prognosis. ICP is regarded
as an effect rather than a cause of brain damage.
• MRI findings: MRI showing abnormality in DWI correlate with poor
outcomes in both premature and term neonates.
LATE NEUROLOGICAL DISABILITY ASSOCIATED WITH

HYPOXIA-ISCHEMIA ..............................................................................
Early assessment of asphyxiated babies allows better correlation between
perinatal event and later outcome. Later follow-up, although necessary
for assessment of higher-order cognitive functioning, is likely to be confounded
by environmental influences. There is little data on long-term outcome
of asphyxiated infants. A follow-up of asphyxiated babies to 8 years age
showed that there is a graded effect of severity of the asphyxial insult
on the IQ. At 3.5 years, the children with moderate HIE had a median
(Stanford Binet) IQ of 92.3 compared with 101.5 in babies with mild
HIE. At 8 years there was a difference of 11 points. The difference was

that of 17 points when those with moderate HIE were compared to the
unasphyxiated group.
KEY POINTS
1. 6% to 23% cases of CP in babies born at term gestation are attributable
to intra-partum asphyxia.
2. Although asphyxia is defined differently, the essence is evidence of prenatal
events/fetal distress, need for extensive resuscitation at birth, neonatal
encephalopathy, metabolic acidosis and multi-organ injury.
3. Athetoid CP (as a result of a short period of profound fetal hypoxic ischemia)
and spastic tetraplegic CP (after a prolonged period of mild to moderate
fetal hypotension) are the common motor disorders associated with perinatal
asphyxia. Ataxic and hemiplegic CP are seldom related to perinatal asphyxia.
4. Epilepsy is the most major co-morbidity of CP in babies with perinatal asphyxia.
But, asphyxia is seldom the cause of epilepsy in isolation.
5. Although vision and hearing abnormalities are present in children with CP,
perinatal asphyxia per se does not increase risk of these sensory problems.
Behavioral problems and autism are again not primary outcomes of perinatal
asphyxia. Learning disabilities are seen in some children with serious motor
involvement, and may be compounded by postnatal care and environmental
factors.
6. During the early phases of brain injury, brain temperature drops and local
release of the neurotransmitter GABA increases; these changes reduce
cerebral oxygen demand, transiently, minimizing the impact of asphyxia.
7. Prolonged hypoxic-ischemic damage can cause neuronal death; majority
of this occurs after recovery from the initial insult and is the result of two
stages of neuronal injury.
a. Primary neuronal injury is the result of intracellular energy depletion
and sodium, calcium and water entering the cell as a result of ionic
pump failure.
b. Secondary neuronal death
i. Reperfusion results in biochemical reactions – release of oxygen free
radicals, nitric oxide which cause oxidative injury to cell components
and excitotoxic amino acids that cause entry of sodium and calcium
and cell death by osmolar load.
ii. Besides necrosis of cells by external mediators, apoptosis, i.e.
genetically mediated cell death with no loss of cell integrity, is
accelerated.
8. MRI and autopsy studies show that 80% of babies with neonatal
encephalopathy showed evidence of only an acute insult without any evident
earlier pathology, hence, evidence for intra-partum asphyxia should always
be sought.
9. Electronic fetal heart monitoring and fetal blood sampling for acidosis have
resulted in increased emergency caesarian rates, but, no definite decrease
in intra-partum mortality or CP. However, there is a decrease in incidence
of early neonatal seizures.
10. Normal heart rate patterns are reassuring, but, abnormal pattern is a poor
predictor of fetal distress.
11. Levene’s modification of Sarnat staging is excellent simple tool to assess
severity of neonatal encephalopathy following perinatal asphyxia.
12. Cerebral edema demonstrated on ultrasound is not a useful prognosticating
tool. Only diffuse injury detected later in clinical course correlates with risk
of CP.
13. CT scan is most useful prognostic tool when used at 4-6 weeks of life.
It shows loss of distinction of deep nuclear structures and a featureless
appearance. Para-saggital injury is difficult to appreciate on CT, unless it
is severe.
14. MRI with DWI is the investigation of choice in perinatal asphyxia. It can
pick up changes hours after injury.
15. Cerebral blood flow abnormalities are detected by Doppler after 24 hours
of asphyxial event. Decreased diastolic flow in relation to systolic flow in
major cerebral vessels correlates with poor outcomes.
16. Recovery of normal EEG background by day 7 is associated with a normal
outcome. In contrast, a burst suppression pattern or iso-electric pattern on
any day is invariably associated with a poor outcome.
17. aEEG predicts poor outcomes more accurately than any other test done
singly. This can predict outcomes as early as at 12 hours of birth. It is
easily done bed side test.
18. Corner stones of therapy are to prevent post natal injury to brain
a. timely and appropriate resuscitation
b. optimize respiration
c. optimize circulation
d. optimize metabolic status–glucose and electrolytes
19. Avoid hyperthermia
20. Control seizures, use anticonvulsants if all metabolic causes excluded. Stop
anticonvulsants once seizures controlled and neurological examination is
normal. (preferably stop anticonvulsants before discharge from NICU).
21. Fluid restriction and anti-edema (osmotic agents) although common practice,
are not supported by evidence.
22. Corticosteroids, hyperventilation, prophylactic anticonvulsants, alkali therapy
are therapies associated with more risks than benefit.
23. Resuscitation in room air and selective head cooling are newer therapies
that seem to be promising and are areas of current research.
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Srinivas Murki
5
Neonatal Seizures
NEONATAL SEIZURE—A SERIOUS RISK FACTOR FOR NDD .....

Seizure is the manifestation of a serious neurological dysfunction in
a neonate. The mortality of infants developing seizures during the neonatal
period has shown a decreasing trend over time (dropped from 40% to
20%), but, long-term neurodevelopmental sequelae in survivors has remained
unchanged. The risk of NDD in a neonate with seizure is very high
- around 30%; nearly 20% have recurring seizures in childhood.
Survivors are at risk of abnormal head growth, abnormal motor examinations,
cognitive, visual problems (squint, refractory errors) and recurrent seizures
during or beyond infancy.
HOW SEIZURES CAUSE THE BRAIN DAMAGE?

Seizures in neonates are most often secondary to a recognizable neuronal
insult – hypoxia-ischemia, infection, vascular, metabolic. Primary seizure
disorders are rare. The extent of brain damage will depend on the nature
and severity of the underlying insult.
A seizure by itself can disrupt the development of maturing
nervous system. A cascade of biochemical/molecular pathways is normally
responsible for brain plasticity or activity-dependent development of the
maturing nervous system. Depending on the degree of brain immaturity,
seizures may disrupt the processes of cell division, migration, myelination,
sequential expression, receptor formation, and stabilization of synapses,
each of which contributes to degrees of neurological sequelae.
WHO IS AT RISK OF SEIZURES AND UNDER WHAT

CLINICAL CIRCUMSTANCES?
The list of conditions leading to neonatal seizures is very vast. Common
causes are – perinatal asphyxia and birth trauma, prematurity (IVH), serious
NEONATAL SEIZURES 63
neonatal illness with encephalopathy (hypoglycemia, hyponatremia,
meningitis), cerebral malformations (abnormal head size and shape), neural
tube defects, in born error of metabolism. In term babies in utero strokes
may cause seizures and encephalopathy in otherwise normal appearing
neonate.
Any neonate with encephalopathy – poor feeding, decreased activity
must be closely observed for subtle/obvious seizures. Monitoring with
EEG may be advisable (when feasible) in babies with seriously abnormal
sensorium.
OUTCOME PREDICTORS IN NEONATAL SEIZURES .....................

ETIOLOGY
The extent of brain damage and eventual outcomes will depend on the
nature and severity of the underlying insult. In asphyxia, seizures
occur as an epiphenomenon and hence the severity of asphyxial insult
would determine the long-term morbidity and not the seizure frequency
or type. Seizures after IVH are likely in babies with severe brain injury
- parenchymal hemorrhagic infarction or ventricular dilatation, these are
the real determinants of outcome. In focal seizures due to thrombo-occlusive
diseases, infarction with edema on the diffusion weighted MRI would pin
point the timing of brain injury and this would have implications on the
long-term outcomes.
In arterial strokes, abnormal inter-ictal EEG background, MRI showing
involvement of entire vascular territory or involvement of multiple arteries
is associated with unfavorable outcomes.
Encephalitis and meningitis are examples of postnatal disease processes
that can cause brain injury, with coincidental occurrence of neonatal seizures.
Brain damage in these infants occurs either directly from central nervous
system infection or from inflammatory response to eliminate the source
of infection.
Seizures in children with inborn errors of metabolism are associated
with brain malformation or damage. Abnormalities in cortical or white
matter development at variable prenatal time periods may contribute to
the later expression of neonatal seizures, as well as other neurological
morbidities.
TYPE OF SEIZURE
Seizures should be classified into one of the four categories
a. Subtle (ocular phenomenon, oral-buccal-lingual movements, apnea, limb
movements, and autonomic phenomenon)
Etiology of seizures Abnormal outcomes (%)

IEM and cerebral dysgenesis 100% (almost)
Hypoxic ischemic encephalopathy (grade-II/III) 50%
Bacterial meningitis 50%
Hypoglycemia 50%
Cerebral venous thrombosis 25 %
SAH 0% (almost)
Late hypocalcemia 0 %
b. Clonic (focal or multifocal)

c. Tonic (focal or generalized) and
d. Myoclonic (focal, multifocal, generalized)
Neonates with subtle or generalized seizures are more likely to
have CP, epilepsy and mental retardation. Those with > 2 seizures types
are likely to have abnormal outcomes.
DURATION OF SEIZURE
Increasing seizure duration implies a higher risk for seizure-induced
brain damage. Uncoupling of clinical from electrographic seizures
could occur in 25% of neonates with seizures after the use of an antiepileptic
medication and in paralyzed neonates. Clinical seizures are often masked.
Use of continuous bed-side electroencephalogram is critical in evaluating
neonatal seizures. Scher et al identified that nearly one third of term neonates
having seizures exhibited electrographic status epilepticus, defined as either
30 minutes of continuous electroencephalographic seizures or 50% of the
electroencephalographic recording time, with or without the expression of
coincident clinical signs.
ORIGIN OF SEIZURE
Seizures originating within deep gray matter structures (i.e., hippocampus
or basal ganglia) and neocortical regions (arcuate fibers within the depths
of cortical sulci, with gyral deformation i.e., ulegyria) are common after
an asphyxial insult. Injury to these regions is increasingly associated with
neurological morbidities including epilepsy. The model of “dual-pathology”
which has been applied to pediatric epilepsy patients may also apply to
neonatal seizure patients. Mesial temporal sclerosis and cortical dysplasias
seen on MRI are also associated with neonatal seizures and with subsequent
epilepsy or other neurologic sequelae. Deep white matter necrosis contributes
to the formation of acquired focal cortical dysplasia during fetal or preterm
life. This results in aberrant gray neuronal aggregate formation in response
to gliotic or cystic white matter regions. This type of injury may then leave
the fetus or infant vulnerable to further brain damage because of intra-
partum or neonatal diseases.
TIMING OF INSULT
Ante-partum, intra-partum, and neonatal time periods each encompass
pathogenic mechanisms which separately or cumulatively can be responsible
for brain damage. Chronic placental lesions which occurred during the
ante-partum time period may result in a neonate with seizures, either as
a result of an ante-partum disease process or from an intra-partum asphyxial
event precipitated by uteroplacental insufficiency under conditions of fetal
stress. In a study of preterm and term neonates from 23 to 42 weeks
corrected age with electrically confirmed seizures, a significant association
(odds ratio of 12) was observed between infants with seizures after
intrapartum asphyxia and chronic placental lesions compared with
those having intrapartum asphyxia and only acute placental lesions.
GESTATIONAL AGE
Lower the gestational age worse is the outcome.
NEUROIMAGING
Infants with abnormal neuroradiologic studies (CT/MRI) are more likely
to have a poor outcome than those with normal studies. Furthermore,
infants with parenchymal brain injury are more likely to have poor
outcome than those with normal studies or those with extra-parenchymal
injury. Multifocal/diffuse cortical lesions or primarily deep gray
matter involvement on MRI are strongly associated with poor outcome.
Outcome is favorable in infants with MRI studies that either are normal
or show extra-parenchymal or focal cortical lesions.
EEG
EEG is a must in all neonates with seizures and encephalopathy.
Background EEG abnormalities would have bearing on long-term
outcomes. Background EEG patterns suggesting poor outcome (80% or
more abnormal) are isoelectric, burst suppression, undifferentiated low voltage,
diffuse slow activity and gross asynchrony. Serial EEGs are more
predictive than a one time record.
Seizure management in neonates may be improved with routine
monitoring of amplitude integrated EEG/ video EEG. Electroclinical
uncoupling could occur in nearly 30% of neonates with seizures. Monitoring
with aEEG improves detection of electrical seizures and control of
electrographic seizures with antiepileptic medications, would improve
the long-term outcomes. In an observation by Toet et al, a strikingly lower

incidence of post neonatal epilepsy (9.4%) was observed in term infants
who received treatment for both clinical and sub-clinical (aEEG seizures)
seizures, compared with 20-50% reported in other studies treating only
clinical seizures.
The video EEG is of particular diagnostic value in infants whose seizures
are subtle, or easily confused with non-epileptic motor behavior. Video-
EEG monitoring studies have shown that these types of movements (eg,
generalized tonic posturing, motor automatisms, jitteriness, and some
myoclonic jerks) are not associated with ictal EEG patterns. These behaviors
may represent “brainstem release” or other non-epileptic phenomena.
Anticonvulsant medications are not indicated for such non-epileptic
events and even may exacerbate some movements.
NEUROLOGICAL EXAMINATION
A normal neurological examination during the neonatal period and
early infancy predicts a uniformly favorable outcome at 12 and 18 months;
an abnormal examination at these times is an unreliable predictor.
BEST PRACTICES FOR THE MANAGEMENT OF

NEONATAL SEIZURES ........................................................................
PREVENTION
Prevention/management of primary diseases that can cause CNS insults
(discussed under various heads in the chapters that follow)
SCREENING AND DIAGNOSIS

Bed side EEG, aEEG, video EEG
MANAGEMENT OF SEIZURE
Treatment of Neonatal Seizures—Acute Event
Immediate management of seizures includes stabilization, identification
of the cause and specific treatment, and if needed, administration
of an antiepileptic drug (AED) to prevent seizure recurrence. Before AED
are administered, seizures caused by metabolic disorders, hypo-
glycemia, hyponatremia, hypocalcemia, hypomagnesemia, or hypophos-
phatemia require correction of the metabolic abnormality. It is a misconception
that metabolic abnormalities do not respond to AED.
AED: Phenobarbitone (Pb) and phenytoin (PHT) are effective as first line
AED for control of neonatal seizures. It is preferable to use monotherapy
for seizure control. Gal and colleagues studied Pb monotherapy and reported
ultimate seizure control in 85%, with effective concentrations between 10.1
and 46.4 mg/L. A total of 60% responded at levels of 20 mg/L or less,
28% responded at levels between 20 and 30 mg/L, and 12% were controlled
at a level greater than 30 mg/L. PHT when given as a 15 to 20 mg/
kg loading dose results a therapeutic level of 14.5±3 mcg/mL.
PHT should be infused no faster than 1 mg/kg per minute to avoid
cardiac arrhythmias or hypotension, and the cardiac rate and blood pressure
should be monitored. Fosphenytoin, the prodrug of phenytoin, does not
cause the same degree of hypotension or cardiac abnormalities, has high
water solubility (therefore can be given IM), and is less likely to lead to
soft-tissue injury compared with phenytoin. It is dosed in PHT equivalents
at 1.5 mg/kg (1.5 mg/kg of fosphenytoin is equivalent to 1 mg/kg of PHT).
If seizures do not respond to initial treatment with Pb, traditionally PHT
is administered, followed by Lorazepam (LZP) or midazolam. With ongoing
seizures, look for a specific cause requiring specific treatment,
such as basic metabolic disorders, the inborn errors of metabolism (IEM),
and certain dependency and deficiency states. Of special concern are
pyridoxine (B6) and folinic acid-dependent conditions.
If seizures continue despite Pb, PHT, and a benzodiazepine, other AEDs
are required (Intravenous: clonazepam, paraldehyde, midazolam, valproic
acid, thiopental, lidocaine, and pyridoxine. Oral: clonazepam, vigabatrin,
lamotrigine, topiramate, valproic acid and folinic acid).
Investigating a Neonate with Seizures

Electrolytes, CSF analysis (Table 5.1), EEG, and a neuroimaging
study should be obtained in nearly all infants who have neonatal seizures.
Blood and CSF cultures should be obtained, and the child should
receive appropriate antibiotics until bacterial infections are excluded .If there
is a clinical indication of viral encephalitis, specifically HSV, a PCR and
culture for HSV may be obtained while the child is treated empirically
with antiviral agents such as acyclovir.
The choice of neuroimaging is frequently debated. If the infant is
critically ill, bedside cranial ultrasonography may be the study of choice
until the child is sufficiently stable for CT or MRI. CT is helpful for identifying
acute intracranial hemorrhages or calcifications. MRI is the study of choice
for patterns of hypoxic-ischemic brain injury and to identify cerebral
dysgenesis.
Table 5.1: Baseline Investigations in neonate with seizures apart from

EEG and neuroimaging
Blood tests Random sugar, ionized calcium, sodium, magnesium,
Arterial blood gas, lactate and ammonia.
Thrombophilic work up if cerebral arterial or venous
infarct is suspected.
CSF Cell count, glucose, protein, bacterial culture
Herpes simplex virus (HSV) polymerase chain reaction
and culture if HSV encephalitis is suspected
Lactate and amino acids if IEM suspected
Urine Urine culture for CMV if IU infection suspected.

Toxicology screen and S-sulphocysteine for sulfite
oxidase deficiency.
If seizures continue despite phenobarbitone, phenytoin and or a

benzodiazepine, the cause must be specifically investigated and treated.
Search for metabolic abnormalities and IEMs. Of special concern are
pyridoxine (B6), folinic acid-dependent conditions and glucose transporter
defects. These disorders are considered when there is no perinatal or
intrapartum insult. IEMs have been associated with neonatal seizures, and
the evaluation of these conditions should include investigations that are
specific to the case.
Discontinuation of Anticonvulsants after Control of Seizure

When seizures are controlled, Volpe recommends a stepwise approach to
discontinuation.
Neurologically normal at discharge: Discontinue AED if the neurological
examination is normal at discharge from NICU.
Neurologically abnormal at discharge: Consider the cause of seizure,
example – cerebral dysgenesis would not recover and AED must continue.
Continuation of medication would depend on the AED used for treatment.
If the patient is receiving PHT, it is best discontinued or another AED
considered, depending on the cause of the seizures.
If neurological examination results remain abnormal, the clinician
should repeat an EEG and continue Pb until the EEG results are available
and normal. If the neurological status is normal at a 1-month re-evaluation,
Pb can be discontinued over 2 weeks; Even if the neurological status is
not normal but the EEG shows no epileptiform abnormalities, Pb can
be tapered. If epileptiform features remain, AEDs should be continued,
with the sequence repeated at 3 months.
Brod and colleagues demonstrated that a normal EEG reading is a
reliable predictor of success in tapering AEDs: 18 of 22 term infants and
9 of 10 preterm infants remained seizure-free after a normal EEG reading.
Because AEDs may have detrimental effects on the developing
brain, they should be discontinued as soon as possible. Pb has
retarded brain growth in rats. Multiple AEDs have caused toxic effects
in cell cultures and have been implicated in apoptosis. AEDs also may
interfere with cognitive functioning.
KEY POINTS: reducing NDD due to neonatal seizures

• Neonatal seizure is a manifestation of serious neurological dysfunction
• The risk of NDD in a neonate with seizure is very high - around 30%; nearly
20% have recurring seizures.
• Extent of brain damage will depend on the nature and severity of the
underlying insult
• Seizure by itself can disrupt the development of maturing nervous system,
depending on the degree of brain immaturity (gestation).
• Any baby with significant encephalopathy is at risk of seizures, it would be
ideal to monitor them with an EEG.
• Outcome predictors and modification.
Risk factor Low risk for NDD High risk of Poor outcome predictor
NDD
Seizure Late hypocalcemia HIE Cerebral dysgenesis/IEM

Subarachnoid hemorrhage Meningitis Prolonged seizure
Hypoglycemia Abnormal neuro-examination
Abnormal imaging
Abnormal EEG
• Best practice guidelines

• Screening and diagnosis – Monitoring any neonate with encephalopathy
with bed side EEG (or aEEG, video EEG) is recommended.
• Management of the risk event
• Stabilize
• Correct metabolic causes
• AED may have detrimental effects on the developing brain; they should
be discontinued as soon as possible.
• AED if necessary – prefer to use mono therapy
• Continue AED if neurological exam abnormal at discharge
• Reassess at 1month – neurological exam and EEG normal–stop
anticonvulsants
• Normal EEG reading is a reliable predictor of success in tapering AED
• If not reassess at 3 months
• Implementation
• Responsibility – pediatrician, pediatric neurologist, neuro-radiologist
• Resource requirements
• EEG – neurologist familiar with EEG of newborn including pre-terms
• Neuro-imaging – USG portable – pediatrician/radiologist
• CT/MRI – neurologist familiar with CT/MRI newborn including pre-terms
• Metabolic studies – labs for screening and diagnosis
• Drug level monitoring – mandatory for appropriate management of recurring
seizures.
BIBLIOGRAPHY .....................................................................................
1. Clancy RR. Summary proceedings from the neurology group on neonatal seizures.
Pediatrics 2006;117:s23-27.
2. Scher MS. Neonatal Seizures and Brain damage. Pediatr Neurol 2003; 29:381-
390.
3. Tekgul H, Gauvreau K, Soul J, Murphy L, Robertson R, Stewart J, Volpe J,
Bourgeois B and Plessis A. The current etiologic profile and neurodevelopmental
outcome of seizures in term newborn infants. Pediatrics 2006; 117;1270-80
4. Westas LH, Rose I. Continuous brain function monitoring: state of the art in
clinical practice. Seminars in Fetal and Neonatal Medicine 2006; 11: 503e511.
Section 4
Metabolic
Problems
6. Hypoglycemia
7. Neonatal Jaundice
8. Inborn Errors of Metabolism (IEM)
Suman Rao PN
6
Hypoglycemia
Hypoglycemia is probably the most common cause of easily

preventable NDD in neonates.
PATHOPHYSIOLOGY OF HYPOGLYCEMIA .....................................

The basis of neonatal hypoglycemic encephalopathy is that glucose is
the primary metabolic fuel for brain. The brain utilizes about 20
times more glucose than muscle and fat tissues. Infants have a large brain
to body weight ratio (12% in infants versus 2% in an adult), resulting
in a higher glucose turnover rate of 6 mg/kg/min in infants compared
with 2 mg/kg/min in adults. Further, 90% of total body glucose utilization
in infants is by the brain. Hypoglycemic injury has a predilection for the
posterior cerebrum—the occipital cortex and the lesions involve the
upper cortical neuronal layers. The caudatoputamen is involved more
heavily near the white matter and near the angle of the lateral ventricle;
and the hippocampus shows dense neuronal necrosis at the crest of the
dentate gyrus. With MRI, a pattern of predominantly parieto-occipital
white matter abnormalities, often in association with abnormal signal
in the deep grey matter structures of the thalamus or basal ganglia,
has been identified on follow-up of neonates who had experienced
symptomatic hypoglycemia, findings-distinct to hypoglycemia.
Immediately after birth, the glucose levels decrease, reach a nadir in
the first two hours of life and then gradually increase to normoglycemic
levels due to glycogenolysis and later by gluconeogenesis from glycerol
and alanine. Lipids are important not only as a source of glycerol for
gluconeogenesis but also as a source of free fatty acids, which produce
ketone bodies. Ketone bodies, can cross the blood-brain barrier. The
neuronal fuel economy depends not only on the circulating blood glucose
concentration, but also upon the availability of alternative fuels such
as ketone bodies, lactate and possibly amino acids. The local adaptation
of the microcirculation, the interaction with other brain cells, and the
concurrent neonatal conditions such as hypoxia and sepsis also
determine the neuronal response to hypoglycemia.
The newborn brain is relatively resistant to the deleterious effects of
hypoglycemia compared to the adult brain. The major reasons for this
relative resistance are:
• Diminished cerebral energy utilization
• Increased cerebral blood flow with even moderate hypoglycemia
• Increased cerebral uptake and utilization of lactate
• Resistance of the heart to hypoglycemia.
Hypoglycemia however potentates the deleterious effects of hypoxemia,
asphyxia, ischemia and seizures. These suggest that degrees of hypoxemia
or asphyxia or moderate hypotension which alone would not cause brain
injury might do so when hypoglycemia is present concurrently. These
observations emphasize the importance of controlling ventilation, circulatory
function and seizures in hypoglycemic infants.
IMPACT ON NEURODEVELOPMENT .................................................

Neurodevelopment sequelae include disturbances of neurological and
intellectual function-motor deficits, especially spasticity and ataxia, seizure
disorders, autistic features, learning and behavioral problems and a smaller
head circumference.
Neurological outcome depends on the rapidity of appropriate therapy
and control of the associated disorders.1,2,3
• Hypoglycemia, if severe or prolonged, results in injury primarily to
neurons but to glia as well.
• Severity of hypoglycemia < 25 mg/dl.4,5
• Recurrence of hypoglycemia (6,7) – When hypoglycemia was present
on 5 or more days, the incidence of cerebral palsy or developmental
delay is increased by a factor of 3.5.
• Duration of hypoglycemia.4,8
• When associated with other insults to brain, e.g. hypoxia-ischemia,
hypoglycemia of a degree not sufficient to cause brain injury alone
can cause neuronal injury.
In a study of 90 infants with hyperinsulinemic hypoglycemia, Menni
et al documented psychomotor retardation in 26% of the patients, 8%
with major retardation and 18% with an intermediate disability. 9 Transient
mild hypoglycemia in healthy, term LGA newborns does not appear to
be harmful to psychomotor development at the age of 4 years.10
HYPOGLYCEMIA 75
EPIDEMIOLOGY .....................................................................................
As per the National Neonatal Perinatal database 2002-2003, the incidence
of hypoglycemia in all neonates is 0.9%.11 Hypoglycemia is commoner
in sick neonates unable to feed normally and dominantly on
intravenous fluids. Preterm babies, growth restricted neonates, and infant’s
delivered to mothers with diabetes are at increased risk of hypoglycemia.
The incidence depends upon the population screened, the time of screening,
the time and type of feeding and above all, the definition of hypoglycemia.
DEFINITION OF HYPOGLYCEMIA .....................................................

Unfortunately, the actual level or duration of hypoglycemia that is harmful
to an infant’s developing brain is not known. Although symptomatic babies
are act grater risk there is not good correlation between plasma glucose
values, clinical symptoms and long-term sequelae.12 Attempts have
been made to identify a threshold blood glucose concentration below
which there is a substantial likelihood of functional impairment, particularly
of the brain.
The clinical, epidemiological and metabolic approaches have little
relevance to outcomes.
Neurophysiological approach: Koh et al in a study of 17 neonates
demonstrated alteration of brain stem auditory and somatosensory evoked
potentials at blood glucose concentrations < 47 mg %.13 Cerebral blood
flow changes have been described at blood glucose concentrations of
30 mg%.
Neurodevelopmental approach: A deleterious effect on subsequent
cognitive development has been described in infants whose plasma glucose
was less than approximately 47 mg% at least on one occasion on three
or more separate days. In another study of 661 infants weighing less
than 1750 g at birth, a strong association was described between
hypoglycemia < 47 mg% on > 5 days and lower Bayley developmental
scores at 18 months of age.6
Concept of ‘Operational threshold’: The concept of a rigid threshold
blood glucose concentration as a definition of hypoglycemia applicable
to all neonates at all times has been challenged. Instead, practical ‘operational
thresholds’ are proposed — blood glucose concentrations at which
clinical interventions, e.g. increased feed should be initiated. Such
thresholds do not define “normal or abnormal” blood glucose concentrations
but provide a margin of safety and thus enable the clinician to target
the nutritional management of a baby towards ‘normoglycemia’.14
CORNBLATH’S ‘OPERATIONAL THRESHOLD’

• Baby with abnormal clinical signs—operational threshold is 45 mg%.
• At risk infants with no clinical signs—operational threshold is 36 mg%.
• Infants with hyperinsulinism—operational threshold is 63 mg%.
BEST PRACTICES ................................................................................

Who should be screened?
Unwell infants and ‘at risk’ infants should be screened for hypoglycemia
• Unwell infants: As the symptoms of hypoglycemia are non-specific,
all unwell infants should be routinely screened for hypoglycemia at
regular intervals.14
• ‘At-risk’ infants who require monitoring of blood glucose concentrations
are:
A. Maternal conditions
– Diabetes (pregestational and gestational)15
– Drug treatment (b-blockers, oral hypoglycemic agents)
– Intrapartum glucose administration.
B. Neonatal problems
– Preterm
– Intrauterine growth restriction16
– Perinatal hypoxia-ischemia
– Hypothermia
– Infection
– Polycythemia
– Infants on parenteral nutrition
– Following exchange transfusion
– Obvious syndromes (e.g. midline defects, Beckwith-Wiedemann
syndrome).
WHO SHOULD NOT BE SCREENED?

Normal healthy term AGA infants on breastfeeding should not be screened
as a routine.3 This may have an adverse effect on breastfeeding.15,16
Moreover, asymptomatic neonates should not be screened in the first
3 hours of life as this would detect only the physiological nadir and the
blood glucose rises significantly by 3 hours of age.17
WHO SHOULD DO THE SCREENING?

The nursing personnel should monitor the ‘at risk’ newborn for
hypoglycemia. At various teaching institutions, with poor nurse: infant
ratio, the monitoring for hypoglycemia may be assigned to junior doctors/
resident doctors.
HYPOGLYCEMIA 77
WHAT ARE THE BEST SCREENING TOOLS?
The ideal method of blood sugar estimation should be rapid, accurate,
inexpensive, require a small sample volume, preferably based on whole
blood and available for point-of-care testing.
Reagent strips and glucose reflectance meters are used extensively for
screening for hypoglycemia owing mainly to their convenience, cost and
rapidity, these devices lack reproducibility and quality-control assurance,
are subject to error from skin-cleansing agents and hematocrit variation,
and are thus notoriously inaccurate and unreliable for estimation of blood
glucose in babies. Any abnormal value should be confirmed by a
laboratory test. However, considering the risk of brain injury, the
intervention for hypoglycemia should be instituted. Care should
be taken to ensure the heel prick is at the recommended lateral aspect
of the heel, the cleansing agent is dry before the prick and an adequate
sized drop of blood is obtained without squeezing the heel.
The laboratory sample should be processed immediately as the glucose
value falls by 18 mg % per hour. This can be avoided by collecting
the sample in fluoridated tube. Plasma or serum is the preferred sample
for measurement of glucose by the analytical procedures in the laboratory,
whilst whole blood samples are often used for point-of-care testing due
to their ease. Whole-blood-based methods are affected by varying
hematocrit in the neonates. Plasma blood glucose values tend to be about
10-18% higher. Recently, an accurate and precise isotope dilution mass
spectroscopy (ID GC-MS) method has been proposed as a reference
method for determining glucose in whole blood.
RECENT ADVANCES IN MEASURING BLOOD GLUCOSE ...........

The glucose measuring devices are based on glucose oxidase, glucose
dehydrogenase, or hexokinase/glucose-6-phosphate dehydrogenase reac-
tions. In recent years, the incorporation of direct measuring electrochemical
glucose biosensors into the blood gas and electrolyte analysers has added
a further dimension to the measurement and reporting of blood glucose
concentrations. Typically, the biosensors report blood glucose ‘concentrations’
6-10% higher than those reported by the traditional methods involving
sample dilution.17
CLINICAL DIAGNOSIS
Hypoglycemia is asymptomatic on more than half the occasions. The signs
and symptoms of hypoglycemia, when present, are often non-specific.
Irritability, jitteriness, feeding difficulties, lethargy, cyanosis, tachypnea, and
hypothermia can all be manifestations of hypoglycemia, but these are
also early signs of a number of other disorders, including septicemia,

congenital heart disease, ventricular hemorrhage and respiratory distress
syndrome. It is important to have a high index of suspicion for
hypoglycemia when evaluating an infant with any of the above symptoms,
since prolonged hypoglycemia causes severe neuroglycopenia with resultant
seizures, coma, neurological damage and even death.
PREVENTION OF HYPOGLYCEMIA ...................................................

Prevention of neonatal hypoglycemia begins in pregnancy, labor, delivery
and continues into early neonatal period. The control of maternal diabetes,
toxemia, nutrition and factors that cause prematurity must be optimal.
Postnatally, the emphasis is on:
• Identification of the high risk neonate
• Minimization of energy expenditure by maintenance of temperature
• Implementation of early oral feedings
• Blood glucose level determinations in the high risk newborn
• Delay discharge of preterm babies till firm establishment of oral feedings
to prevent post-discharge hypoglycemia
• Careful monitoring for clinical symptoms.
BEST MANAGEMENT PRACTICES ....................................................

When to treat?
Based on the neurophysiological, epidemiological and clinical observations,
blood glucose values < 45 to 50 mg% requires intervention. This
value is higher than the previously recommended 40 mg% considering
the lack of precise information regarding the level of blood glucose below
which neuronal injury is likely to occur and also considering the ample
evidence that blood glucose levels are not accurate predictors of brain
glucose. In case of hyperinsulinism the target blood glucose levels should
be 63 mg%.
Therapy for hypoglycemia includes:

• Encourage and assist oral feeding and frequent monitoring for
hypoglycemia in the asymptomatic low risk neonates.
• If hypoglycemia is severe (<25), recurrent, symptomatic or noted in
high risk neonates give minibolus of 2 ml/kg 10% dextrose. Lilien
et al demonstrated the effectiveness and apparent safety of the
‘minibolus’ instead of bolus of 0.5 to 1.0 g/kg (2-4 ml/kg of 25%
glucose).18 The minibolus avoids hyperglycemia, osmotic diuresis,
dehydration, and rebound hypoglycemia.
HYPOGLYCEMIA 79
• Minibolus should be followed by on uninterrupted.
• IV infusion of glucose to provide a GIR of 6-8 mg/kg/min.
• If the blood sugar levels are not “normal” in spite of above said infusion
rate, higher concentrations of glucose infusion must be used to achieve
greater infusion rates, conventionally targeting an increase of 2 mg/
kg/min.
WHEN SHOULD FURTHER INVESTIGATIONS BE DONE?

An underlying metabolic-hormonal etiology should be suspected when
the hypoglycemia is of unusual severity or occurs in an otherwise low-
risk infant such as:
• Symptomatic hypoglycemia in a healthy, well grown term infant
• Hypoglycemia with seizures or abnormalities of consciousness
• Persistent or recurrent hypoglycemia
KEY POINTS: Reducing NDD due to hypoglycemia

• Hypoglycemia is probably the most common cause of easily preventable
NDD in neonates.
• The basis of neonatal hypoglycemic encephalopathy is that glucose is the
primary metabolic fuel for brain and the basal requirements are higher in
neonates. The injury has a predilection for the parietooccipital whitematter
(MRI)
• Outcome predictors—alternative fuels such as ketone bodies, lactate and
possibly amino acids. The local adaptation of the microcirculation, concurrent
neonatal conditions.
Risk factor Low risk for NDD High risk of NDD Poor outcome predictors
Hypoglycemia Transient mild Delay in correction Symptomatic (neuro)

hypoglycemia of hypoglycemia hypoglycemia-seizures, coma
in infants not recurrent Associated CNS insults
at risk severe < 25
• Hypoglycemia is commoner in sick neonates unable to feed normally and

dominantly on intravenous fluids.
• Preterm babies, growth restricted neonates, and infant’s delivered to mothers
with diabetes are at increased risk of hypoglycemia.
• Prevention
– Identification of the high risk neonate
– Minimization of energy expenditure by maintenance of temperature
– Implementation of early oral (breast) feedings
– Blood glucose level determinations in the high risk newborn
– Delay discharge of at risk babies till firm establishment of oral feedings to
prevent post-discharge hypoglycemia
– Blood glucose values < 45 to 50 mg% require intervention. In case of
hyperinsulinism the target blood glucose levels should be 63 mg%.
• Treatment may be initiated based on reagent strip value, but diagnosis must
be confirmed by lab sugars.
• Hypoglycemia requiring >10 mg/kg per min of glucose

• Hypoglycemia in association with other abnormalities (midline defects,
micropenis, exomphalos, erratic temperature control)
• Family history of sudden infant deaths, Reye’s syndrome, or
developmental delay.
FURTHER READING
1. Hypoglycemic injury to the immature brain. Yager JY. Clin Perinatol 2002; 29:651–
674.
UNANSWERED QUERIES/FURTHER RESEARCH17,19

Future research should concentrate on:
• Development of a bedside glucose analyser comparable to the laboratory-standard.
• Mechanisms of hypoglycemic neural injury and refinement of thresholds of safe
blood glucose concentrations based on their relationship with both acute and
long-term neurological outcomes.
REFERENCES
1. Volpe JJ. Hypoglycemia and Brain Injury. Neurology of the Newborn, ed 4,
Philadelphia, 2001, WB Saunders 497-520.
2. Yalnizoglu D, Haliloglu G, Turanli G, Cila A, Topcu M. Neurologic outcome
in patients with MRI pattern of damage typical for neonatal hypoglycemia. Brain
Dev. 2007;29:285-92.
3. Yager JY. Hypoglycemic injury to the immature brain. Clin Perinatol 2002;29:651–
674.
4. Koivisto M, Blanco-Sequeiros M, Krause U. Neonatal symptomatic and
asymptomatic hypoglycaemia: a follow-up study in 151 children. Dev Med Child
Neurol 1972;14:603–14.
5. Stenninger E, Flink R, Eriksson B, Sahlen C. Long-term neurological dysfunction
and neonatal hypoglycaemia after diabetic pregnanacy. Arch Dis Child 1998;
79:F174–179.
6. Lucas A, Morley R, Cole TJ. Adverse neurodevelopmental outcome of moderate
neonatal hypoglycemia. BMJ 1988;297:1304–8.
7. Duvanel CB, Fawer C-L, Cotting J, et al. Long-term effects of neonatal hypoglycemia
on brain growth and psychomotor development in small-for-gestational age
preterm infants. J Pediatr 1999;134:492–8.
8. Singh M, Singhal PK, Paul VK, et al. Neurodevelopmental outcome of
asymptomatic and symptomatic babies with neonatal hypoglycemia. Indian J
Med Res 1991;94:6–10.
9. Menni F, Lonlay P, Sevin C, Touati G, Peigne G, et al. Neurologic outcomes
of 90 neonates and infants with persistent hyperinsulinemic hypoglycemia.
Pediatrics 2001;107:476–9.
10. Brand PLP, Molenaar NLD, Kaaijk C, Wierenga WS. Neurodevelopmental outcome
of hypoglycaemia in healthy, large for gestational age, term newborns. Arch Dis
Child 2005;90:78–81.
HYPOGLYCEMIA 81
11. Report of the National Neonatal Perinatal Database. National Neonatology Forum,
India, 2002-2003.
12. Sunehag AL, Haymond MW. Glucose extremes in newborn infants. Clin Perinatol
2002;29:245-60.
13. Koh THHG, Aynsley-Green A, Tarbit M, Eyre JA. Neural dysfunction during
hypoglycaemia. Arch Dis Child 1988;63:1353-8.
14. Cornblath M, Hawdon JM, Williams AF, Aynsley-Green A, Ward-Platt MP, Schwartz
R, et al. Controversies regarding definition of neonatal hypoglycaemia: suggested
operational thresholds. Pediatrics 2000;105:1141-5.
15. Hoseth E, Joergensen A, Ebbesen F, Moeller M. Blood glucose levels in a
population of healthy, breast fed, term infants of appropriate size for gestational
age.Arch Dis Child Fetal Neonatal Ed 2000;83:F117–F119.
16. Haninger NC, Farley CL. Screening for hypoglycemia in healthy term neonates:
effects on breastfeeding. Midwifery Womens Health 2001;46:292–301.
17. Deshpande S, Platt MW. The investigation and management of neonatal
hypoglycaemia. Seminars in Fetal and Neonatal Medicine 2005;10:351-61.
18. Lilien LD, Pildes RS, Srinivasan G. Treatment of neonatal hypoglycemia with
minibolus and intravenous glucose infusion. J Pediatr 1980;97:295–8.
19. Boluyt N, Kempen A, Offringa M. Neurodevelopment After Neonatal
Hypoglycemia: A Systematic Review and Design of an Optimal Future Study
Pediatrics 2006;117:2231-43.
Srinivas Murki
7
Neonatal Jaundice
Jaundice is a common physiological event. It can lead to bilirubin

encephalopathy and chronic sequalae in a minority. In neonates with bilirubin
encephalopathy, 80% either die in the neonatal period or end up having
sequalae such as athetoid CP, tone abnormalities, lower IQs and
or sensorineural hearing deficit. Term and near term healthy neonates
with serum bilirubin > 20 mg/dl, even in the absence of any clinical signs
of encephalopathy could have acute effect on the auditory brainstem, minor
motor disturbances, dysconjugate gaze and suspicious neurological
examinations. But no chronic sequalae such as CP or sensorineural hearing
deafness are reported (Table 7.1). However in the presence of co-morbid
factors, low birth weight or hemolysis, rarely, permanent ill effects could
be seen on the auditory and cognitive functions.
HOW BILIRUBIN CAUSES BRAIN DAMAGE?

Bilirubin is the metabolic product of Hemoglobin (commonly, ineffective
erythropoiesis). In blood it is bound to albumin and is excreted from the
liver after conjugation. However, is when the capacity of albumin to bind
bilirubin is exceeded, free bilirubin exists in the blood. It is the free bilirubin
which crosses the blood brain barrier (BBB) and causes neurotoxicity. The
factors which increase the level of free bilirubin or those which
damage the BBB increase the risk of bilirubin induced brain damage
(BIND).
• Endogenous substances such as free fatty acids, organic anions
• exogenous substances such as sulphonamides, salicylates, ceftriaxone,
moxalactum and benzoates displace bilirubin from albumin and increase
the free bilirubin
• Acidosis, hyperosomolar solutions, asphyxia, intracranial hemorrhage,
abrupt increase in blood pressure, abrupt increase in venous back pressure
and meningitis damage the BBB and precipitate BIND.
NEONATAL JAUNDICE 83
In the brain bilirubin affects every aspect of cellular function. It damages
the neurons by membrane injury and excito-toxic mechanisms similar
to hypoxic ischemia and hypoglycemia. The typical areas affected
in BIND are globus pallidus, subthalamic nuclei, hypothalamic sectors CA
2, 3 (only in term), hippocampus, substantia nigra, cochlear nuclei,
occulomotor nuclei, reticular formation, dentate nuclei, Purkinje cells and
anterior horn cells. This pattern of distribution is ascribed to - differential
blood flow patterns, local susceptibility of blood brain barrier and differential
abundance of gangliosides. Concomitant intrauterine growth restriction
(IUGR), prematurity, asphyxia, hypoglycemia, intracranial
hemorrhage, infections, trauma, TNF and endotoxins increase
neuronal susceptibility to BIND.
EXPECTED LONG-TERM SEQUELAE OF SEVERE JAUNDICE ...

Chronic kernicteric sequelae include sensori-neural hearing deafness, tone
abnormalities (hypotonia or dystonia), minor neurological abnormalities,
abnormal DDST and lower intelligence quotients. The earliest changes
of bilirubin encephalopathy (non clinical) are seen on the MRI, auditory
brainstem evoked responses, somato-sensory evoked responses and
cry analysis.
MRI
In severe jaundice bilateral symmetrical hyperintense signals are seen in
the globus pallidus on both T1 and T2 weighted images (Fig. 7.1). High
signal intensity also has been seen in hippocampus and the thalamus.
These MRI changes could disappear with treatment of jaundice
but persistent abnormal signals on the MRI could predict long-
term neurological deficits.
BERA
Waves I, III, and IV/V complex are normally present in full-term neonates.
Wave I represents the auditory nerve, wave III the superior olive, and
wave IV-V complex the lateral meniscus and inferior colliculi, respectively.
The latter three sites are classically involved in kernicterus. Severe jaundice
leads to loss of waves IV and V, and prolonged latency of the brainstem
response (wave I-III, I-V, and Wave III-V: Fig. 7.2). These changes represent
aberrant brainstem function, at both upper and lower brainstem levels.
The auditory brainstem response reflects auditory neural function; aberrant
auditory brainstem response recordings may represent only a part of a
more widespread neural malfunction. Persistent abnormalities on the
Figure 7.1: Classical MRI changes: Hyperintense

signals in the globus pallidus
Hyperbilirubinemia–Neonate
Figure 7.2: BERA in hyperbilirubinemia showing relation of bilirubin (BR) to

BERA changes. Increasing levels of jaundice decreases amplitude of Wave IV/
V and increased brainstem latencies. However, these changes are transient
and disappear by 3 to 4 months in most neonates
BERA at 3 and 9 months of age could predict long-term hearing

deficits and sometimes neurological handicaps.
The classic Perlstein’s tetrad of kernicterus includes extrapyramidal
abnormalities, sensori-neural hearing loss, gaze abnormality, and dental
dysplasia. In the first year, infants typically feed poorly, develop high-
pitched cry; examination may show persistent and often-
obligatory atonic neck reflex and righting reflexes. Babies are
hypotonic but have exaggerated deep tendon reflexes.
Athetosis (involuntary, sinuous, writhing movements) may develop as
early as 18 months but may be delayed as late as 8 to 9 years. Chorea
and dystonia are the other abnormal movements, which can occur in these
children. Affected children may also have dysarthria, facial grimacing, drooling
and difficulty in chewing or swallowing.
Hearing loss is generally most severe in high frequencies and is usually
bilateral. The hearing deficit even when severe, very often escapes
clinical detection for months or even longer and this may be reflected
in delayed acquisition of language. The pathological substrate for hearing
deficit resides in the neurons in the brainstem particularly the cochlear
nuclei and in the auditory nerve. Thus hearing disturbance is both peripheral
and central. Auditory system is the most sensitive neural system in bilirubin
injury and hence hearing impairment is always present in any form of
bilirubin encephalopathy. Extrapyramidal symptoms in children without
hearing impairment rules out bilirubin brain injury.
Gaze abnormality, in particular, limitation of upward gaze is typical
of bilirubin brain injury. Occasionally both horizontal and vertical movements
are affected. In most cases vertical eye movements can be elicited by
Doll’s eye maneuver, thus indicating the lesion is above the level of occulo-
motor nuclei.
About 75% of children with kernicterus have some degree of dental
enamel hypoplasia. A smaller percentage has green discoloration of teeth.
Marked intellectual deficits occur only in a minority of patients with
kernicterus. Most of these patients are mistaken to be mentally retarded
because of their contorted countenance and writhing limbs, as well as
undetected hearing deficits.
BEST PRACTICES: REDUCING NDD DUE TO NEONATAL JAUNDICE

1. Follow the AAP guidelines for the screening and management of severe
hyperbilirubinemia. It allows a lower threshold for near term babies,
infants of diabetic mothers, those with hemolysis, and G6PD deficient
neonates.
2. Early and aggressive therapy (one line below the indicated line on
AAP chart) is indicated in babies with IUGR, asphyxia, sepsis, acidosis,
symptomatic hypoglycemia and certain East Asian races.
3. MRI, BERA and periodic neurological assessment should/may be done
in all babies with acute bilirubin encephalopathy and in all those with
TSB>20 mg/dl. An initial normal BERA and or MRI is reassuring.
If the initial BERA is abnormal repeat may be requested at ages of
Table 7.1: Outcomes of babies with severe jaundice but no clinical

encephalopathy
Study No. of Bilirubin Outcomes Remarks
neonates levels (TSB)
Vohr et al 50 10- 20m g/dl On day 1 to 2: BNBAS. Jaundiced Most babies included
(1990) (14.3mg/dl) infants had significantly lower BNBAS had ABO
scores in every behavioral item incompatibility
except autonomic stability. Significant
correlations were found in increased
levels of TSB with decreased scores
on the individual BNBAS items.
Wolf et al 45 28.5 + 6.3 4 months of age: infant motor screening Included premature
(1997) (IMS). Linear correlation showed an infants
association between maximum TSB and
test rating at 4 months (r = .32, P <.05)
and test scores at 4 months (r = .44,
P < .03).
Agarwal et 55 22.4 + 2.7 At 1 year of age: DDST. Neurological
al (1998) mg/dl development was normal in all infants
with TSB levels of 15–20 mg/dL, in
89% of infants with TSB levels of
21–25 mg/dL, and in 67% infants
with TSB >25 mg/dL.
Wolf et al 35 25-35 mg/dl At 1 year of age: Bayley (BSID-PDI). Eight
(1999) (23%) term infants, with a mean TSB level
of 33.4 mg/dL, had abnormal and suspect
BSID.Twenty-seven (77%) term infants,
with a mean TSB level of 26.5 mg/dL,
scored normal on the BSID.
Chen et al 72 10- >20 mg/dl DDST at 1 year. None of infants with
(1995) TSB<20 mg/dl had abnormal findings.
22% with TSB > 20 mg/dl had
abnormal findings in gross and fine
motor sectors.
Yilmetz 87 10-30 mg/dl At 10 – 72 months: TSB < 20 mg/dL
(2001) did not show any neurological
abnormalities, whereas 9.3% of the
subjects with TSB 20–23.9 mg/dL had
only disconjugate gaze and 17.6% of
the subjects with TSB > 24 mg/dL had
neurological manifestations.
Valaes 45 16-20 mg/dl At 61 – 81 months of age: visual-motor Included premature
(1980) integration test. Degree of jaundice was infants
found not to be associated with neuro-
logical scores.
Newman 659 25-29 and At 2 years: severe jaundice did not Term and near term
(2006) > 30 mg/dl affect the cognition or behavior or infants included
neurological examinations. However,
those with positive DCT had lower
cognitive scores but had no effect on
the behavior or neurological
examination
3 and 9 months and if the initial MRI is abnormal, a repeat scan may
be done at an age of 9 months.
4. In high risk neonates with severe hyperbilirubinemia, periodic neurological
assessment of tone and neurodevelopment should be done at 3 monthly
intervals in the first one year of life and at 6 monthly intervals till
5 years of life.
5. Appropriate physiotherapy, medications for choreoathetosis, early hearing
aids for sensorineural deafness improve the long-term outcomes of
neonates with BIND.
Suvasini Sharma, Ramesh Agarwal
8
Inborn Errors of Metabolism (IEM)
Inborn errors of metabolism (IEM) are rare disorders characterized by a

block at some point in the normal metabolic pathway caused by a genetic
defect of a specific enzyme. The number of diseases in humans attributable
to inherited point defects in metabolism now exceeds 500.1 While the
individual diseases are rare, they collectively account for a significant
proportion of neonatal and childhood morbidity and mortality. Metabolic
diseases have a varied clinical presentation involving virtually all the organ-
systems. Some of them are amenable to treatment and in many others
it is possible to make an antenatal diagnosis thereby preventing recurrence.
Therefore, an accurate diagnosis is important.
The estimated burden of IEM is 3-4/1000 live births. As high as 20%
of acute illnesses in newborns in developed countries are due to IEM.
There is a paucity of data on the epidemiology of IEM in Indian population.
In a hospital-based study in India, biochemical screening of 4,400
cases of mental retardation revealed that 5.8% were due to a
metabolic disorder.2 In a study at AIIMS, out of over 2000 cases referred
with diagnosis of suspected IEM, 1.9% were found to have amino acid
disorders.3 The common disorders reported were homocystinuria, alka-
ptonuria, maple syrup urine disease, and non-ketotic hyperglycinemia.
CURRENT UNDERSTANDING OF PATHOPHYSIOLOGY .................

The clinical features of IEM are a result of metabolic disturbances caused
by deficiency of some catalytic or transport protein. This could have any
of the following consequences.4
ACCUMULATION OF A SUBSTRATE
Substrate accumulation is the major pathogenetic factor in many IEM,
e.g. Tay-Sachs disease (accumulation of GM2 ganglioside leading to cerebral
INBORN ERRORS OF METABOLISM (IEM) 89
neurodegeneration), urea cycle disorders (accumulation of ammonia resulting
in encephalopathy), phenylketonuria (accumulation of phenylalanine leading
to mental retardation).
ACCUMULATION OF A NORMALLY MINOR METABOLITE

In some IEM, the primary cause of disease is accumulation of a normally
minor metabolite produced in excess, because of block in the major
degradative pathway, e.g. in untreated galactosemia, cataracts result because
of accumulation of galactitol, a normally minor metabolite of galactose.
DEFICIENCY OF A PRODUCT
This is another important primary consequence of many inherited metabolic
diseases. The extent to which it contributes to disease depends on the
importance of the product, e.g. Hartnup disease (deficiency of product
niacinamide leading to pellagra), lysinuric protein intolerance (deficiency
of product ornithine leading to hyperammonemia).
SECONDARY METABOLIC PHENOMENA

Because of the close relationship between the various processes comprising
intermediary metabolism, enzyme deficiencies invariably have secondary
metabolic effects, e.g. glycogen storage disorder type 1 (secondary metabolic
effects include lactic acidosis, hyperuricemia, and hypertriglyceridemia), and
methylmalonic acidemia (secondary metabolic effects include hyper-
ammonemia and hyperglycinemia).

As mentioned above, IEM are responsible for about five percent cases
of mental retardation and global developmental delay. They rare cause
isolated developmental delay, mostly present with other clinical
clues.5 However, they remain an important cause to be looked for as
specific therapy may be available, acute metabolic decompensation may
be avoided, and accurate prognosis and genetic counseling can be offered
to the families.
COMMON NEUROLOGICAL PRESENTATIONS ASSOCIATED

WITH IEM INCLUDE4 ............................................................................................................
Many of the disorders may not have neonatal signs or symptoms but their
screening is possible in perinatal period and therapy may start in the
asymptomatic newborn (e.g. PKU).
CHRONIC ENCEPHALOPATHY WITHOUT

NON-NEURONAL INVOLVEMENT
Patients often have predominant features of grey or white matter involvement.
Disorders with predominant grey matter involvement present with
developmental delay or regression of attained milestones, cognitive earlier
than motor, seizures, vision problems, e.g neuronal ceroid lipofuscinosis.
Disorders with predominant white matter involvement present with motor
regression, spasticity and ataxia, e.g. metachromatic leukodystrophy.
CHRONIC ENCEPHALOPATHY WITH NON-NEURAL INVOLVEMENT

Include disorders like mucopolysaccharidoses (hepatosplenomegaly,
dysostosis multiplex, coarse facies in addition to psychomotor retardation),
Menke’s disease (kinky hair, seizures, and severe regression).
ACUTE ENCEPHALOPATHY
Urea cycle defects, organic acidemias, fatty acid oxidation defects (More
likely to present in neonatal period).
SEIZURES
Seizures without other manifestations may be seen in some IEM e.g.
pyridoxine dependency, folinic acid responsive seizures, glucose transporter
defect.
STROKE
IEM are important causes of stroke and stroke like episodes in children.
Examples of such IEM include homocystinuria, Fabry disease, organic
acidemias and mitochondrial disorders.
MOVEMENT DISORDERS
Extrapyramidal features like dystonias and choreoathetoid movements are
predominant features in some IEM, e.g. glutaric aciduria type 1, Lesch-
Nyhan disease.
ATAXIA
Intermittent ataxias are seen in urea cycle defects, organic acidemias, pyruvate
dehydrogenase deficiency. Progressive ataxias are seen in abetalipo-
proteinemia, mitochondrial defects etc.
MYOPATHY
Glycogen storage diseases, fatty acid oxidation defects, mitochondrial
disorders.
MANAGEMENT AND PREVENTION ...................................................
IEM clinically manifesting in the neonatal period are usually severe and
are often lethal if proper therapy is not promptly initiated. Clinical findings
are usually non-specific such as poor feeding, lethargy, drowsiness
and failure to thrive; and may mimic sepsis. A high index of suspicion
needs to be maintained in all acutely sick newborns, especially if the
illness occurred after a period of apparent normalcy. The following
circumstances increase the likelihood of the presence of an underlying IEM:
• Parental consanguinity
• Previous history of neonatal death
• Rapidly progressive encephalopathy of unknown etiology
• Severe metabolic acidosis
• Hyperammonemia
• Peculiar odor.
INVESTIGATIONS ..................................................................................
Metabolic investigations should be initiated as soon as the possibility is
considered. The outcome of treatment of many IEM, especially those
associated with hyperammonemia, is directly related to the rapidity
with which appropriate management is instituted.
First line investigations include:
• Blood counts (neutropenia and thrombocytopenia seen in organic
acidemias)
• Blood urea and electrolytes (low blood urea in urea cycle defects)
• Blood gases and lactate
• Blood ammonia
• Liver function tests (hepatic derangements in fatty acid oxidation defects)
• Urine reducing substances and ketones.
Second line investigations:
• Urine amino acids and organic acids
• Plasma amino acids
• Lactate/pyruvate ratio
• Urinary orotic acid
• Biotinidase levels.
Neuroimaging:
Neuroimaging especially MRI may provide helpful pointers towards
etiology while results of definitive investigations are pending. Some IEM
may be associated with structural malformations, e.g. Zellweger syndrome
has diffuse cortical migration and sulcation abnormalities. Agenesis of corpus

callosum has been reported in Menke’s disease, pyruvate decarboxylase
deficiency and nonketotic hyperglycinemia.6 Examples of other neuroimaging
findings in IEM include:
• Maple syrup urine disease: brainstem and cerebellar edema
• Propionic and methylmalonic acidemia: Basal ganglia signal change
• Glutaric aciduria: frontotemporal atrophy, subdural hematomas.
TREATMENT ...........................................................................................
In most cases, treatment needs to be instituted empirically before definitive
diagnosis. The aims of treatment are to:7
• Reduce the formation of toxic metabolites by decreasing substrate
availability (by stopping feeds and preventing endogenous catabolism)
• Provide adequate calories
• Enhance the excretion of toxic metabolites.
• Institute co-factor therapy for specific disease and also empirically until
diagnosis is established.
IMMEDIATE THERAPY
• Stop oral feeds, process/ store blood and urine samples before stopping
feeds
• Start parenteral fluids
• Correct dehydration, acidosis and dyselectrolytemias
• Start specific therapy if any: e.g. sodium benzoate for hyperammonemia
• Monitor and maintain vitals, blood sugar, electrolytes, and blood gases
• Severe hyperammonemia: peritoneal or hemodialysis may be needed.
LONG-TERM TREATMENT
The following modalities are available:
Dietary Treatment
This is the mainstay of treatment in phenylketonuria, maple syrup urine
disease, homocystinuria, galactosemia, and glycogen storage disease type
I and III. Some disorders like urea cycle disorders and organic acidurias
require dietary modification (protein restriction) in addition to other modalities.
Acceleration of Removal of Substrate

Toxic metabolites which are produced due to the block, are removed by
various mechanisms. Examples include peritoneal dialysis, hemodialysis,
continuous venous-venous hemofiltration for treatment of urea cycle disorders
with sodium benzoate and sodium phenylbutyrate.
Reaction Product Replacement
Examples include creatine monohydrate in guanidinoacetate methyltrans-
ferase deficiency, arginine in argininosuccinicaciduria, L-Serine in 3-phos-
phoglycerate dehydrogenase deficiency.
Enzyme Replacement Therapy (ERT)

The principle behind ERT is that the missing enzyme is supplied exogenously,
through repeated intravenous infusion. ERT is now commercially available
for three lysosomal storage disorders: Gaucher disease (recombinant human
macrophage-targeted glucocerebrosidase), Fabry disease (human alpha-
galactosidase) and Hurler disease (human alpha L-iduronidase). Phase I
and II trials in Pompe’s disease have also shown promise. Clinical trials
are also underway for MPS II (Hunter disease) and MPS VI (Maroteaux-
Lamy disease). Responses to ERT in these disorders have generally been
encouraging although the degree and extent of benefit vary considerably.8
Cofactor Replacement Therapy

The catalytic properties of many enzymes depend on the participation
of non-protein prosthetic groups, such as vitamins and minerals, as obligatory
co-factors. The following co-factors may be beneficial in certain IEM:9
• Thiamine: Mitochondrial disorders, thiamine responsive variants of MSUD,
PDH deficiency and complex I deficiency)
• Riboflavin: Glutaric aciduria Type I, Type II, mild variants of ETF, ETF-
DH, complex I deficiency
• Pyridoxine: 50% of cases of homocystinuria due to cystathionine -
synthetase deficiency, pyridoxine dependency with seizures, xanthurenic
aciduria, primary hyperoxaluria type I, hyperornithemia with gyrate
atrophy
• Cobalamin: Methylmalonic acidemia (cblA, cblB), homocystinuria and
methylmalonic acidemia (cblC, cblD, cblF)
• Folinic acid: Hereditary orotic aciduria, Methionine synthase deficiency,
Cerebral folate transporter deficiency, hereditary folate malabsorption,
Kearns-Sayre syndrome
• Biotin: Biotinidase deficiency, holocarboxylase synthetase deficiency.
PREVENTION .........................................................................................
GENETIC COUNSELLING AND PRENATAL DIAGNOSIS
Most of the IEM are single gene defects, inherited in an autosomal recessive
manner, with a 25% recurrence risk. Therefore, when the diagnosis is known
and confirmed in the index case, prenatal diagnosis can be offered, wherever
available for the subsequent pregnancies. The samples required are chorionic
villus tissue or amniotic fluid. Modalities available are10:
• Substrate or metabolite detection: useful in phenylketonuria,
peroxisomal defects.
• Enzyme assay: useful in lysosomal storage disorders like Niemann-
Pick disease, Gaucher disease.
• DNA based (molecular) diagnosis: Detection of mutation in proband/
carrier parents is a prerequisite.
NEONATAL SCREENING ......................................................................

Newborn screening is a public health initiative to ensure a healthy start
for the newborn. Although it is well established in developed countries,
India does not as yet have a provram at a national level. Goals of screening
include: medical intervention in pre-symptomatic stage (e.g. phenylketonuria
and congenital hypothyroidism), screening for reproductive planning (e.g.
in carriers for Tay-Sach disease) and to determine the epidemiology of
various IEM. There is a limited experience from India on neonatal screening.
A pilot program carried out in Hyderabad on 20,000 babies revealed a
high prevalence of congenital hypothyroidism (1: 1985), followed by
congenital adrenal hyperplasia (1: 2600) and aminoacidopathies (1: 3771).11
Techniques of screening include bacterial inhibition assay or “Guthrie’s’
test for phenylketonuria (now seldom used), tandem mass spectrometry
(used for organic acidemias and aminoacidopathies), radioimmunoassay
(for hormonal analysis), enzyme assay (galactosemia, biotinidase deficiency),
and specific mutation testing (useful when small number of mutations are
responsible and disorder is relatively common).
Disorders which can be detected by tandem mass spectrometry (TMS)
include aminoacidopathies (phenylketonuria, MSUD, homocystinuria,
citrullinemia, argininosuccinic aciduria, hepatorenal tyrosinemia), fatty acid
oxidation defects, organic acidemias (glutaric aciduria, propionic acidemia,
methylmalonic acidemia, isovaleric acidemia). The cost of this procedure is high,
a limiting factor in resource poor countries. The predictive value of a positive
screening test is less than 10%; i.e. 90% of positive results are not indicative of
an IEM.12 Being a costly investigation, adequate discretion should be exercised
in ordering a TMS test. Based on estimates of the incidence of various IEM, it
has been predicted that one out of 4000 newborns would be identified
presymptomatically with a treatable IEM.4
Problems associated with TMS include confusing reports which can result
in a dilemma both in the healthy newborn and newborn with suspected
IEM. For example, TMS has resulted in the identification of apparently
healthy individuals with acylcarnitine abnormalities. Another frequently
encountered abnormality is elevated C5OH (3-hydroxyisovalerylcarnitine).
The significance of these abnormalities is unclear; some causes maybe-
maternal enzyme deficiency, enzyme polymorphisms or lab error. Close
follow-up with clinical and biochemical monitoring are needed to determine
the significance of the abnormality in any individual infant.
FREQUENTLY ASKED QUESTIONS ...................................................

WHAT SAMPLES SHOULD BE OBTAINED IN AN INFANT WITH
SUSPECTED IEM WHEN DIAGNOSIS IS UNCERTAIN AND DEATH SEEMS
INEVITABLE?
Some patients with IEM will not survive, despite intensive treatment. In
such cases, establishing a diagnosis is very important for genetic counselling
and later prenatal diagnosis. Parents should be explained the prognosis
and permission for samples/ biopsies obtained. The following samples should
be taken as part of a ‘metabolic autopsy’:
• Blood: 5-10 mL; frozen at -20°C; both heparinized and EDTA samples
to be taken.
• Urine: freeze at -20°C
• CSF
• Skin biopsy: including dermis in culture medium or saline with glucose
• Liver, muscle, kidney and heart biopsy (in cases of cardiac involvement)
• Clinical photograph (in cases with dysmorphism)
• Infantogram (in cases with skeletal abnormalities).
HOW SHOULD A NEWBORN WITH A HISTORY OF SIBLING DEATH

WITH SUSPECTED IEM BE MANAGED?
In such cases feeds should be started under monitoring. A suggested protocol
is to start with oral dextrose feeds and after 24 hours add medium chain
triglycerides. Monitor sugar, blood gases, ketones, ammonia. If all tests
are within normal limits, add low protein milk. Repeat tests after 48 hours;
if negative; start breast feeds. After 48 hours, tandem MS and urine organic
acid tests should be obtained.
SHOULD ALL CHILDREN WITH GLOBAL DEVELOPMENTAL DELAY OR

MENTAL RETARDATION BE TESTED FOR IEM?
IEM’s are responsible for only 5% of cases of global developmental delay.
However, diagnosis is i e likelihood for an underlying IEM and testing
in such cases can be considered:
• Parental consanguinity
• Unexplained neonatal or infantile deaths

• Encephalopathy
• Protein aversion
• Self-injurious behavior
• Seizures
• Regression of attained milestones
• Hypotonia
• Extrapyramidal features
• Hepatosplenomegaly
• Cardiomyopathy
• Failure to thrive
• Recurrent vomitings.
WHAT IS TANDEM MASS SPECTROMETRY (TMS)?

TMS is a technically advanced method in which compounds are separated
by molecular weight by means of a mass spectrometer. The analysis of
acylcarnitines, amino acids, and other metabolic intermediates is performed
on dried blood spots. TMS has revolutionized newborn screening for IEM
in developed countries. As mentioned earlier problems with TMS include
prohibitively high cost and low positive predictive value. Cost effectiveness
studies available from a few developed countries suggest screening for
a few presymptomatically treatable IEM’s e.g. Phenylketonuria and
Medium-chain acyl CoA dehydrogenase deficiency.
UNANSWERED QUERIES/ FURTHER RESEARCH

There is a paucity of data regarding the epidemiology of IEM in India.
Large-scale studies are needed to understand the prevalence and clinical
profile of various IEM so that newborn screening programs can be planned.
The treatment of IEM in developing countries remains a frustrating
experience despite timely diagnosis. Special diets and enzyme replacement
therapy are prohibitively expensive, most patients can not afford even co-
factor therapy. Research is needed on indigenous diets in IEM.
Newer treatments for IEM include: solid organ transplant, bone marrow
transplant, and single gene transfer therapy. The goal of therapy is to
achieve the incorporation and expression of sufficient amounts of normal
genetic material in appropriate tissues to achieve long-term correction of
genetic defect. Liver transplant is beneficial in tyrosinemia, glycogen storage
disorders, urea cycle disorders.
The rationale behind bone marrow transplantation (BMT) is that a
reconstituted hematopoetic system from a healthy matched donor will contain
stem cells that can produce the missing enzyme. BMT has been atleast
partially successful in severe MPS I, MPS II, MPS VI, mannosidosis, Wolman’s
disease, metachromatic leukodystrophy, and Krabbe’s disease.13
Single gene transfer therapy is still in the experimental stage. For lysosomal
storage disorders, two different approaches to gene therapy are being pursued.
The first involves the direct delivery of genes to specific organs, such as
the central nervous system, using viral vectors. A second approach involves
genetically altering hematopoetic stem cells from patients to produce the
missing enzyme and returning the altered cells to the patient through BMT.
Both approaches have shown promise in animal models.14
KEY POINTS – reducing NDD due to IEM

1. IEM are responsible for about five percent cases of mental retardation and
global developmental delay. They rarely cause isolated developmental delay;
mostly they present with other clinical clues.
2. Presentations include acute/chronic encephalopathy with/without non-neuronal
involvement, seizures, movement disorders, muscle weakness etc.
3. The basis of disease is accumulation of a normal/abnormal metabolite/or
deficiency resulting from enzyme defect. Some of these are treatable and
some form basis of prenatal testing and counseling
4. In many IEM, e.g. hyperammonemia, outcomes depend directly on early
diagnosis and treatment.
5. Most IEM are single gene defects with AR inheritance and allow opportunity
for prenatal diagnosis.
6. Neonatal screening for IEM although expensive, offers an opportunity for pre-
symptomatic diagnosis. The current concerns are the large number of false positives
and difficult availability of definitive therapies (drugs and special diets).
SUGGESTED READING .......................................................................

• Scriver CR, Beaudet AL, Sly WS and Valle D (Eds). (2001). The metabolic
and molecular basis of inherited disease, 8th Ed, New York: McGraw-Hill.
• Kumta NB. Inborn errors of metabolism (IEM)- an Indian perspective. Indian
J Pediatr 2005;72:325-32.
• Verma IC. Burden of genetic disease in India. Indian J Pediatr 2000; 67: 893-8.
• ICMR Collaborating centres and central co-ordinating unit. Multicentric study on genetic
causes of mental retardation in India. Indian J Med Res 1991;94:161-9.
• Carballo EC. Detection of inherited neurometabolic disorders- A practical clinical
approach. Pediatr Clin N Am 1992;39:801-20.
• Saudubray JM, Ogier H, Bonnefont JP. Clinical approach to inherited metabolic
diseases in the neonatal period: A 20-year survey. J Inherit Metab Dis 1989;
12(Suppl 1):25-41.
INTERNET RESOURCES ......................................................................

1. www. ncbi.nlm.nih.gov/entrez/query/fcgi: Excellent search engine for articles and
abstracts in vast array of journals dating over 50 years.
2. www.genetests.org: resource for information on clinics and laboratories providing

genetic diagnostic services.
3. www.slh.wisc.edu/newborn/guide: guide to newborn screening.
4. archive.uwcm.ac.uk/uwcm/mg/docs/oth_mut.html: Index of locus specific mutation
databases with many links.
5. www.rarediseases.org: information and links related to several inherited diseases.
REFERENCES ........................................................................................
1. Childs B, Valle D, Jimenez-Sanchez. The Inborn error and biochemical variability.
In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds). The metabolic and
molecular basis of inherited disease, 8th ed, New York: McGraw-Hill, 2001:
155-6.
2. ICMR Collaborating centres and central co-ordinating unit. Multicentric study on genetic
causes of mental retardation in India. Indian J Med Res 1991; 94:161-9.
3. Kaur M, Das GP, Verma IC. Inborn errors of amino acid metabolism in North
India. J Inherit Metab Dis 1994;17:1-4.
4. Cleary MA, Green A. Developmental delay: when to suspect and how to investigate
for an inborn error of metabolism. Arch Dis Child 2005;90:1128-32.
5. A Clinical guide to inherited metabolic diseases. JTR Clarke. 3rd Ed (2006),
Cambridge University Press, Cambridge.
6. Blaser S, Feigenbaum A. A Neuroimaging approach to inborn errors of metabolism.
Neuroimag Clin N Am 2004; 14:307-329.
7. Kabra M. Dietary management of Inborn errors of metabolism. Indian J Pediatr
2002; 69: 421-26.
8. Brady RO, Schiffmann R. Enzyme-replacement therapy for metabolic storage
disorders. Lancet Neurol 2004;3:752-56.
9. Saudubray JM, Sedel F, Walter JH. Clinical approach to treatable inborn metabolic
diseases: an introduction. J Inherit Metab Dis 2006; 29: 261-74.
10. Elias S, Simpson JL, Shulman LP. Techniques for prenatal diagnosis. In: Rimoin
DL, Connor JH, Pyeritz RE, Korf BR (Eds). Emery and Rimoin’s Principles and
practice of medical genetics. Churchill-Livingstone, London 2002: 802-25.
11. Radharamadevi and Naushad SM. Newborn screening in India. Indian J Pediatr
2004;71:157-60.
12. Nicholson JF, Pesce MA. Laboratory testing in infants and children. In: Behrman
RE, Kleigman RM, Jenson HB (Eds). Nelson textbook of pediatrics 17th edn,
Philadelphia: Saunder, 2004: 2393-96.
13. Malatack JJ, Consolini DM, Bayever E. The status of hematopoetic stem cell
transplantation in lysosomal storage disease. Pediatr Neurol 2003; 29: 391-403.
14. Sands MS, Davidson BL. Gene therapy for lysosomal storage diseases. Mol
ther 2006; 13: 839-49.
Section 5
Respiratory
Problems
9. Apnea
10. Meconium Aspiration Syndrome (MAS)
11. Persistent Pulmonary Hypertension
of Newborn (PPHN)
Sanjay Wazir
9
Apnea
Apnea or cessation of breathing is common in preterm babies born before

34 weeks gestation and almost universal in babies born before 26 weeks.
Despite being such a common problem, we are neither sure of the
impact, apnea has on the neurodevelopmental outcome of neonates
nor are we sure that treatment of apnea by different modalities
improves neurodevelopment.
DEFINITION ............................................................................................
Most of the available literature defines apnea in infants as breathing pauses,
which last more than 20 seconds, or a shorter duration if associated with
bradycardia or oxygen desaturation.1 However, there is no consensus
about the duration of apnea, the degree of change in oxygen desaturation,
or severity of bradycardia that should be considered pathologic, i.e. we
don’t have an answer as of now, whether an apnea which last 20 seconds
will have the same connotation as a pause for 40 seconds and whether
apnea which leads to desaturation to a value of 30% will differ in
neurodevelopmental outcome from an apnea which results in a oxygen
saturation levels of 80%. Apnea events exceeding 30 seconds are
occasionally seen in both healthy term and preterm infants. 2 This suggests
that apnea duration per se may not be the critical feature of altered
breathing and its relation to circulatory consequences. Lack of standardization
of this data is the most important reason for ambiguity in outcome measure
in neonatal apnea.
PATHOPHYSIOLOGY OF APNEA ......................................................

Although pathogenesis of apnea of prematurity has not been fully elucidated,
it is probably related to both the overall neurological and cardio-respiratory
immaturity of preterm babies. Apnea of prematurity results from immaturity

of brain stem respiratory control centers. As immaturity is more pronounced
with decreasing gestational age, there are more chances of apneas at
lesser gestational age. In normal individuals, the respiratory centre (situated
in the medullary region of brain stem) responds to the various signals
like increase in carbon dioxide, decrease in oxygen, and decrease in pH
by increasing the firing of respiratory neurons. This increased firing results
in increased impulses to respiratory muscles and hence results in increased
ventilation. These responses are impaired in newborns and this result in
apneas.3
• Respiratory responses to increased carbon dioxide are decreased in
preterm babies and slope of response continues to increase from 26
weeks onwards till 33 weeks and hence in face of hypoventilation
due to any reason, babies are not able to increase their respiratory
drive and land in apnea.
• Responses to hypoxia are also altered in preterm babies. In contrast
to events in older infants where hypoxia results in sustained hyper-
ventilation, preterm babies are characterized by a very brief period
of hyperventilation followed by depressed ventilation despite continued
hypoxia. Initial hyperventilation may be completely blunted in preterm
babies.
• Negative pressure in the upper airways in preterm babies can result
in inhibition of diaphragmatic contraction. In cases of mixed apneas,
the lack of airflow due to obstruction, e.g due to passive neck flexion,
results in generation of a negative pressure in airways and as a result
cause decrease in central respiratory drive. One of the mechanism
by which CPAP helps in apnea is by splinting the upper airways and
hence obviating this reflex inhibition. Also neonates are obligate nose
breather and cannot make an immediate switch to oral breathing when
nose is obstructed.
• Active or REM sleep is marked by irregularity of tidal volume and
REM sleep predominates in preterm infants. Coupled to this fact is
that chest wall compliance of premature infants is poor and hence
they have more episodes of hypoventilation.
APNEA AND NEURODEVELOPMENT ................................................

Since apnea is associated with desaturation and bradycardia, it is plausible to
think that significant episodes of apneas may have a significant impact on
neurodevelopment. However, this information at present is not clear. Earlier
reports found little evidence of any neurodevelopmental risk directly attributed
APNEA 103
to a history of apnea of prematurity or acute life threatening episode
(ALTE).4,5 Studies are few due to non standardized criteria for diagnosis and
for quantifying severity of apnea related events in NICU and also due to
variable treatment strategies. Also separating the consequences of conditions
associated with premature births like sepsis, intraventricular hemorrhage from
effects of apnea of prematurity has proven difficult.
Cheung et al6 followed 124 very low birth weight babies upto 24
months of age, to evaluate the relationship between precisely measured
pre-discharge apnea that persisted beyond 35 weeks and the neuro-
developmental outcome. They found that duration of artificial
ventilation and the grade of IVH were independent predictors of
neurodevelopmental outcome and the mean oximetry desaturation
and frequency of pre-discharge apnea correlated with mental and
motor developmental scores. Mean oximetry desaturation during apnea
was an independent predictor for both mental and motor scores in infants
with grade 3 or 4 intraventricular hemorrhage. Authors suggested that
pre-discharge respiratory recordings may be useful in predicting subsequent
neurodevelopment of high-risk preterm infants, especially those with severe
intraventricular hemorrhage. Increasing number of days on which at
least one apnea occurred also has been associated with impaired
neurodevelopemental outcome.7 In the same study, number of days
ventilation was required for apnea was also associated with poor
neurodevelopmental outcome. Even delay in resolution of apnea beyond
the 36 weeks post conceptional age has been associated with impaired
neurodevelopmental outcome.8 Apnea of prematurity has been shown
to be an independent predictor of poor early school age outcome like
cognitive functions and other neuropsychological rating.9 These events
are probably related to hypoxemia/blood flow during the episodes of
apnea. CHIME study10 also provides some insights regarding risk of
neurodevelopmental sequelae in infants with events documented using
home memory monitoring. Of the infants included in the study there
was an inverse relation between number of conventional events detected
by home monitoring and neurodevelopmental outcome. This association
was seen both in term and preterm babies. The adjusted difference in
mean MDI scores with at least five events compared to no events was
5.6 points lower in full term babies and 4.9 points lower in preterm
babies. A dose effect was also suggested by tendency for mean BSID
– II values with 1 to 4 events to be intermediate between 0 and at
least 5 events. Changes in cerebral blood flow velocity have been
documented to decrease to the level of no or minimal diastolic blood
flow during prolonged apnea.11
Although no authoritative statements can be made based on sparse

data, it may be worthwhile keeping a close check on neurodevelopment
in newborn with recurrent apneas and in whom the apneas persist
beyond term gestation. Validity of pre-discharge apnea event recording
still has to be confirmed in larger trials before it can be used as a predictive
tool for neurodevelopment in newborns.
MONITORING AND EVALUATION OF APNEA ................................

WHO ALL TO MONITOR?
All infants less than 35 weeks of gestation should be monitored
for apneic spells for at least the first week of life, because of high risk
of apneas in this group of babies. Apneic spells generally begin after
24 hours although it can begin on the first postnatal day of life also.
Progesterone (which is a known respiratory stimulant) transferred from
the mother before delivery has been suggested as the reason for the
delayed presentation of apnea. In addition term babies who have any
central nervous system disorder, systemic illness or has received
drugs, which depress respiration like narcotics etc should be
monitored for apnea.
Routine monitoring for apnea includes monitoring of heart and
respiratory rates as well as oxygen saturations, since impedance monitors
cannot detect obstructive apneas. Polysomnogram which measures cardio-
respiratory patterns, muscular activity, ETCO2, TcO2, oral and nasal flow
and chest and abdominal movements is ideal but is not routinely used
in clinical practice.
HOW LONG TO MONITOR?

Both term and preterm babies show a progressive decline in apneic episodes
over time. In an old citation involving 249 term and preterm infants,
92% had no further apnea beyond 37 weeks and by 40 weeks 98%
of the babies were apnea free.12 That study involved larger preterm babies.
In a recent study involving preterm babies between 24-28 weeks, apnea
frequently persisted beyond 36 weeks and continued beyond 40 weeks
post-conceptional age in some.13 CHIME study data showed that cardio-
respiratory events in preterm babies return to baseline normal level at
43-44 weeks post-conceptional age. Only one study till date has attempted
to answer the question of what constitutes a safe period and it concluded
8 days as a safe period but again there is paucity of data in extremely
premature babies.14
APNEA 105
Hence based on available literature, one should monitor for apnea
till at least 37 weeks gestation, but in extremely premature babies
one may have to monitor for a longer time. An apnea free period
of 8 days seems to be a reasonable period.
ROLE OF HOME MONITORING

Home monitoring has not shown to decrease the incidence of sudden
infant death syndromes (SIDS). Home monitor could be used as an
alternative to prolonged hospital stay in babies who are otherwise well
but continue to have non-life threatening apneas at the time of discharge.
Such monitoring should continue for a maximum of 44 weeks post
conceptional age as suggested by the CHIME study. Infants with frequent
events at home should be re-hospitalized and have further studies associated
illnesses have been diagnosed after admission in such babies.15
MANAGEMENT OF APNEA ................................................................

Once apnea is diagnosed, the clinician must investigate for a number
of causes while continuing to monitor and provide supportive care. In
term babies, most cases are likely to have secondary causes of apnea,
whereas in extremely premature babies, although investigations for
secondary causes must be completed, 80% of the infants would have
no identifiable cause and diagnosis is of apnea of prematurity.
Physical examination should include observation of the infants breathing
pattern and careful neurological and respiratory examination. One should
look for presence of secretions in the oropharynx which may have resulted
in occlusion of the airway. It is particularly important to rule out systemic
conditions like seizures, gastroesophageal reflux as pharmacotherapy
with methylxanthines is known to decrease the threshold for seizures
and reflux. Among the first tests to be done is blood sugar, as symptomatic
hypoglycemia is independently associated with poor neuro-developmental
outcome. Infants should be evaluated for stability of thermal environment.
Other blood tests include complete blood counts for sepsis, electrolytes
including calcium. Other test like ECG, chest radiograph, spinal fluid analysis
also may be carried out based on circumstances.
BEST PRACTICE GUIDELINES FOR THE PREVENTION AND

TREATMENT OF APNEA
Prevention of Prematurity
Since the incidence of apneas is directly related to the gestational age
at birth, decrease in incidence of premature births may offer the simplest
solution to decrease the incidence of apneas. However, this is most difficult

to achieve.
Tocolysis
Tocolysis has not been able to prolong a preterm birth for long time
in preterm labor. In fact, magnesium sulphate used for preeclampsia and
tocolysis in mother has been associated with increased risk of apneas
in neonates.16 Hypermagnesemia during parenteral nutrition has also been
a cause of apnea.17
Antenatal Steroids
Although antenatal steroids do not directly affect the maturation of respiratory
centers, it does decrease the incidence of respiratory distress syndrome
which can present as apnea in extremely premature babies.
Noxious Stimuli
Like deep suctioning, painful procedure should be avoided or done gently
as these promote a vagal inhibition of respiration.
Kangaroo Mother Care

Skin-to-skin contact, or kangaroo care, for preterm infants has been
associated with an increased occurrence of apnea, bradycardia, and
desaturation and irregular breathing; 18 this appears to be unrelated to
hyperthermia.19 The observation suggests that obstructive events may occur
during skin-to-skin contact. Recent investigators however found no adverse
events during kangaroo care.20 The disparity among the reported studies
may be related to the specific practice of skin-to-skin care in a particular
NICU or the validity of monitoring during skin-to-skin contact. Till further
data is available, given the benefits of KMC in reducing serious infections
and preventing hypothermia in preterm babies (which independently
increase the risk of apneas), KMC does hold promise in care of premature
babies.
Blood Transfusions
Classical teaching recommends red blood cell transfusions if apnea coexisted
with anemia. However, data available at present in preterm babies with
both mild (Hb 8-12 mg/dl)21 and moderate anemia (< 8 mg/dl)22 have
shown that giving transfusion to such babies does not decrease the episodes
of hypoxia/bradycardia. Given all the hazards associated with blood
transfusions in neonates, apnea of prematurity alone should not be
an indication for transfusions.
APNEA 107
Sensory Stimulation
Introduction of pleasant odour in the incubator in preterm babies who
continued to have apneas despite pharmacological therapy has been shown
to decrease the incidence of apneas by almost 30%.23 Presence of a
pleasant odor in the environment may help the infant to regulate his
physiological state, however, it is possible that vanillin used in the study
possesses pharmacological properties and therefore, has direct or indirect
effects on the respiratory centers. Since some of the odors can have negative
influence on the respiration use of this modality should wait further
trials.
CO2 Inhalation
Although one of the pathophysiological mechanisms of apnea is decreased
respiratory drive to increased CO2 in the blood, inhalation of low
concentration of CO2 has also been proposed as an effective treatment.
In one study involving 10 preterm babies with gestational age between
31-33 weeks exposure to one hour of CO2 concentration ranging from
0.5 to 1.5 percent was associated with significant decrease in the episodes
of apnea and improved oxygenation. This data however, is too limited
to recommend this therapy at this time.24
Oxygen Supplementation
Oxygen may decrease the frequency of apneas. Oxygen replaces other
gases in the functional residual space of lung ensuring that during brief
episodes of apnea there is enough oxygen in the lungs to diffuse into
the blood and avert hypoxemia. However, oxygen therapy in the neonates
is fraught with dangers of oxygen mediated free radical injury like BPD,
ROP, etc. Hence, oxygen should be used to keep the pulse oximeter
values in the 88-93% range. If a newborn requires oxygen supplemen-
tation to keep oxygen saturation in that range, then one must search
for secondary causes of apnea like sepsis, PDA, etc. and not label as
apnea of prematurity.
Temperature
Hypothermia is a known risk factor for apnea and should be avoided
or corrected before considering any further therapy. Increase in ambient
temperature to 30°C has been shown to increase the incidence of apneas
in preterm babies reaching term as compared to keeping the babies at
24°C.25 Even a slight increase in body temperature of 0.8°C increased
the indices of periodic breathing with apneic oscillations. 26 Air temperature
in an incubator should be kept near the lower end of the thermo-
neutral zone to lessen the episodes of apnea.
Position
Extremes of flexion and extension should be avoided to decrease the
likelihood of airway obstruction. Although physiologically ventilation is better
in prone position, central apneas tend to be more in prone position 27
with less arousals emphasizing the importance of recommending supine
sleeping, after neonatal unit discharge for prematurely born infants.
Kinesthetic Stimulation
Physical stimulation by nursing staff is commonly used to arouse the apneic
infant and stimulate breathing. This led people to speculate whether frequent
physical stimulation by means of oscillating mattress to provide kinesthetic
stimulation might reduce the number of apneic events. Kinesthetic stimulation
has not been shown to prevent occurrence of apnea.28 Cochrane review29
on kinesthetic stimulation to treat established apneas has shown decreased
frequency of apnea of short duration but had no impact on the clinically
significant apneas (those more than 20 seconds) in duration or those
with hypoxia and bradycardia. All the studies included in the review used
a different method of providing stimulation and because of the cross
over design, later outcomes on neurodevelopment could not be studied.
Further research with larger trials is needed with focus on
neurodevelopment before recommending this modality.
Carnitine Supplementation
Preterm infants have lower muscle carnitine reserves compared to term
infants. This is probably related to poor tissue uptake due to immaturity
of the carnitine biosynthetic pathways, reduced placental transfer and
reduced intakes from breast milk. Treatment with carnitine has shown
benefit in the respiratory status of ventilator dependent adults, as well
as stabilization of respiratory parameters and increased physical performance
in adult patients with chronic respiratory insufficiency. Cochrane review30
on carntine for apnea in neonates has shown no benefit and hence
its use at present is not recommended.
Immunization
There is an increase in adverse cardio-respiratory events following the
first dose of DTP-IPV-Hib in preterm infants. The increase in apnea has
been attributed to the whole-cell pertussis component.31 Investigators have
observed reduced morbidity with newer vaccines that contain acellular
pertussis.32 However, one recent study showed no difference between
those who received whole cell as compared to the acellular variant.33
Chronic diseases in preterm babies at the time of immunization greatly
APNEA 109
increased the risk of apneas.34 If the neonate is in the NICU for chronic
diseases at 2 months post-birth, monitoring for apnea, bradycardia
and desaturation is recommended after vaccination. Healthy preterm
infants without chronic disease and therapy seem to be less vulnerable
to such adverse effects but still should be vaccinated in hospital
settings. Acellular pertussis should be used for immunization in preterm
babies if cost is not a factor.
Pharmacological Treatment
There are no definite guidelines, when to start pharmacological therapy,
but most would start treatment when apneic spells continue despite
supportive measures or if one apneic episode was severe enough require
bag and mask ventilation.
Methylxanthines
Most commonly prescribed drug therapy for AOP.
• Caffeine citrate (not available in India at present),
• Aminophylline and its oral substitute theophylline.
Mechanisms of action of methylxanthines
• Increased response to CO2 and decreased hypoxic depression of central
respiratory drive
• Increased diaphragmatic activity
• Increased minute ventilation.
Pharmacokinetics
Theophylline: Mean half life of theophylline is approximately 30 hours
in infants. Oral theophylline is given with a loading dose of 5 mg/kg
followed by a maintenance dose of 1-2 mg/kg every 8 hours. A therapeutic
effect is seen at a plasma concentration of at least 5 mg/L, although
a target plasma concentration is around 10. Plasma concentration of
theophylline may vary widely at the same dosage levels, which necessitates
frequent monitoring and dose adjustments.35 Toxicity usually starts
after 20 mg/L but can be seen at plasma concentration of more than
13 mg/L. Side effects include tachycardia, abdominal distension, feed
intolerance, seizures, hyperglycemia and electrolyte imbalances.
Caffeine citrate can be administered either orally or intravenously. The
recommended loading dose of 10 mg/kg of caffeine (equivalent to 20
mg/kg of caffeine citrate) followed 24 to 48 hours later by a single daily
maintenance dose of 2.5 mg/kg (5 mg/kg of caffeine citrate). Caffeine
toxicity is rarely observed at plasma concentration below 50 mg/L, which
is markedly higher than the therapeutic concentration of 5-20 mg/L. Side
effects commonly seen with caffeine are jitteriness, tachycardia, and

occasionally GI intolerance.
Choice of methylxanthine therapy: Evidence suggests that caffeine is equal
in efficacy with fewer drawbacks.35 Dosing regimens of caffeine are simpler
and produce more predictable results. Moreover, caffeine has a wider
therapeutic window and required very infrequent monitoring of plasma
levels. Although caffeine at present is not available in India, given the
better profile caffeine is likely to replace theophylline once it is
available.
Reasons for concern with methylxanthines
Xanthines inhibit two (A1 and A2a) of the four known (A1, A2a, A2b
and A3) adenosine receptors and experimental evidence suggests that
non-specific adenosine receptor blockade in very preterm infants
may have detrimental effects on growth, neurological and cognitive
development and childhood behavior.
Effect on growth: Methylxanthines increase oxygen consumption 36 in
preterm babies by 20-25% and it has been shown that even a single
loading dose of theophylline 5 mg/kg can increase the energy expenditure
by15 KJ/kg/day. This data although not conclusive suggests that use of
methylxanthines may increase energy consumption and hence affect growth
of premature babies.
Effect on neurological development and behavior: Adenosine is neuro-
protective in many experimental models of hypoxia/ischemia.37 However,
the results are not consistent and Bona et al38 found that theophylline
reduced rather than increased brain injury after hypoxia–ischaemia in 7-
day old rats. Efforts to manipulate adenosine receptors in neonatal and
adult animal models of hypoxic–ischemic brain injury with specific agonists
and antagonists for the adenosine A1 and A2a receptors have yielded
complex and occasionally contradictory results. Furthermore, there is
evidence that chronic administration of adenosine receptor ligands has
different effects on hypoxic–ischemic brain injury than acute ligand
administration.39 Mice with experimental deficiency of A1 and A2 receptors
are more anxious and aggressive.40
In summary, experimental evidence of physiological and patho-
physiological roles of the adenosine receptor system in the immature brain
are complex and, as yet, incompletely understood and one cannot at
present make predictions based on experimental data. There is at present
no significant data available from randomized controlled trials in newborn
on long-term safety of methylxanthines because most of the trials have
focused on short-term benefits. Since adenosine receptors are found in
APNEA 111
all tissues, methylxanthines may have beneficial or harmful effects on
many clinically important outcomes. These include neonatal morbidities
such as necrotizing enterocolitis, retinopathy of prematurity, chronic lung
disease and ultrasonographic evidence of brain injury (which are
independent predictors of poor neurodevelopmental outcome) as well
as growth, neurological development and childhood behavior.
A large multicentric trial, caffeine for apnea of prematurity trial,41 involving
more than 2000 neonates has shown that caffeine therapy decreased incidence
of bronchopulmonary dysplasia and mean duration of mechanical ventilation
by a week. Besides, caffeine did not increase the incidence of ultrasonic evidence
of brain injury and necrotizing enterocolitis.
DOXAPRAM
Doxapram is a respiratory stimulant that acts on both peripheral chemoreceptors
and the central nervous system. Dose: 3 mg/kg bolus followed by 1.5 mg/kg/
hr as infusion. Cochrane review on doxapram (only one study) showed
decreased apnea in first 48 hours after starting the drug, but the benefit was
not sustained. No major side effects were reported. But, number of subjects
in the study was too small to make useful conclusions. Doxapram has been
shown to decrease the cerebral blood flow in preterm babies42 and even mental
developmental delay has also been associated with prolonged days of doxapram
therapy for apnea.43 Other short term side effects like hypertension, central
nervous system stimulation, gastrointestinal disturbances and even heart block
has been reported in some of the observational studies. Given that there are
no substantial data available on the benefit/side effects, doxapram use should
be restricted to scenarios where recurrent apneas are continuing despite use
of methyxanthines and facilities for ventilator support are not available.
Doxapram infusion could be used to transfer the baby to a NICU with such
facilities.
VENTILATION ........................................................................................
CONTINUOUS POSITIVE AIRWAY PRESSURE
CPAP delivered by a nasal interface is an effective treatment of apnea
of prematurity.44 Mechanisms proposed - patency of upper airways,
stabilizing chest wall, maintaining functional residual capacity. Cochrane
review45 comparing CPAP with methylxanthines suggested higher failure
rates with CPAP. The only trial included in the review, used mask CPAP
– a modality which is no longer being used. Masks require a complete
seal and improper use might have resulted in a higher failure rates. Recent
studies on VLBW babies show that early application of nCPAP and
avoidance of mechanical ventilation resulted in no adverse neurodeve-

lopment/growth.46 A significantly higher developmental quotient was found
in the nCPAP group at 18 months’ corrected age. Several trends were
also noted in the nCPAP group with a decrease of intraventricular
hemorrhage and “abnormal neurodevelopment” at 6 months corrected
age. However, these studies were not in babies having apnea. Prophylactic
CPAP has no role in prevention of apnea.
NASAL INTERMITTENT POSITIVE PRESSURE VENTILATION

If apneas continue despite CPAP and methylxanthines, intubation and
ventilation become necessary. Owing to the risks of invasive ventilation,
nasal intermittent positive pressure ventilation is an alternative worth
considering. NIPPV reduces asynchronus thoracoabdominal motion as a
result of better stabilization of chest wall.47 Two trials48,49 comparing the
NCPAP to NIPPV have shown different results – one showing no difference
whereas the more recent one49 has shown NIPPV to be more effective
in reducing apneas. Gastrointestinal perforation has also been reported
by some authors.50 Newer machines can synchronize ventilator breaths
(SNIPP) with the infant’s respiratory cycle. For practical purposes NIPPV
may be used if apneas continue despite NCPAP.
INTUBATION AND ASSISTED VENTILATION

If the infant continues to have clinically significant episodes of apnea despite
maximum pharmacological and non-invasive positive airway pressure
ventilation, intubation and assisted ventilation become necessary.
HIGH-FLOW NASAL CANNULAE

Recently it has been shown that NC can deliver positive distending pressure
(PDP) to premature neonates if the flow is increased to 1 to 2 L/min
(high-flow nasal cannulae [HFNC]). Only one study has compared nasal
cannulae (with air oxygen blender) to nasal CPAP. NC was as effective
as NCPAP in the management of apnea of prematurity with no difference
in the number of apneas, bradycardias, or desaturation during a 6-hour
period.51 This was a small study with period of observation limited to
6 hours. The nasal cannulae being inexpensive and easier to use, need
to be studied in larger trials.
FURTHER RESEARCH .........................................................................

• Understanding of the relationship of apneic episodes to oxygenation
of vital organs, particularly the brain. Defining a method for quantifying
apnea in the newborn.
APNEA 113
• Determining whether apnea has any long-term outcome consequences
independent of preterm birth.
• Determining the long-term consequences of treating apnea with
methylxanthines. Hopefully this should be answered in the CAP trial.
• Role of GABA antagonist biculline (Adenosine acts through GABA
receptors).
KEY POINTS – reducing NDD due to apnea

• There is not enough systematic information of impact of apnea on NDD
or that of various treatments. Many of very preterm babies have co –
morbidities (like IVH, hypoglycemia) that may be equally or more important.
• Hypoxemia or decreased cerebral blood flow in event of apnea is considered
as possible mechanism of brain injury.
• Outcome predictors
– Persisting apnea beyond term gestation
– Recurrent severe apnea
– Co-morbidities like IVH
– Degree of hypoxemia, number of days apnea persists, days on ventilator
– Who to monitor for apnea
– All preterm babies < 35 weeks gestation till 37 weeks corrected age
or till 8 days apnea free period.
– All term babies with encephalopathy
• How to monitor – pulse oximetry (saturation and heart rate) and respiratory
rate monitoring (impedance)
• Management of apnea
– Check air way
– Breathing pattern
– Screen for hypoglycemia, hypocalcemia
– Neurological assessment
• Caffeine is safer than aminophylline, and is equally effective
– Rule out GERD/seizure before using methylxanthine
• nCPAP with appropriate interface is as effective.
• Ventilation (or NIPPV) is resorted to, when above mentioned modalities fail
• Doxapram may be used in an emergency, if ventilation facility is not available
• Noxious stimuli, hyper/hypothermia, vaccination of chronically ill preterms
out of hospital setting must be avoided
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respiratory control, and thermoregulation. J Pediatr. Feb 2001;138(2):193-7.
19. Bohnhorst B, Gill D, Dordelmann M, et al. Bradycardia and desaturation during
skin-to-skin care: no relationship to hyperthermia. J Pediatr Oct 2004;145(4):499-
502.
20. Ludington-Hoe SM, Anderson GC, Swinth JY, et al. Randomized controlled trial
of kangaroo care: cardiorespiratory and thermal effects on healthy preterm
infants. Neonatal Netw. May-Jun 2004;23(3):39-48.
21. Poets CF, Pauls U, Bohnhorst B. Effect of blood transfusion on apnoea, bradycardia
and hypoxaemia in preterm infants. Eur J Pediatr. 1997 Apr;156(4):311-6.
22. Westkamp E, Soditt V, Adrian S, Bohnhorst B, Groneck P, Poets CF. Blood
transfusion in anemic infants with apnea of prematurity. Biol Neonate
2002;82(4):228-332.
APNEA 115
23. Marlier L Olfactory stimulation prevents apnoea in premature newborns. Pediatrics.
2005 Jan;115(1):83-8.
24. Al-Aif S, Alvaro R, Manfreda J et al. Inhalation of low (0.5%-1.5%) CO2 as a
potential treatment for apnoea of prematurity. Semin Perinatol. 2001
Apr;25(2):100-6.
25. Bader D, Tirosh E, Hodgins H, et al. Effect of increased environmental temperature
on breathing patterns in preterm and term infants. J Perinatol. 1998 Jan-
Feb;18(1):5-8.
26. Berterottière D, D’Allest AM, Dehan M, et al. Effects of increase in body
temperature on the breathing pattern in premature infants. J Dev Physiol. 1990
Jun;13(6):303-8.
27. Bhat RY, Hannam S, Pressler R, Rafferty GF, Peacock JL, Greenough A. Effect
of prone and supine position on sleep, apnoeas, and arousal in preterm infants.
Pediatrics 2006 Jul;118(1):101-7.
28. Henderson-Smart DJ, Osborn DA. Kinesthetic stimulation for preventing apnoea
in preterm infants Cochrane Database Syst Rev 2002;(2):CD000373.
29. Osborn DA, Henderson- Smart DJ. Kinesthetic stimulation for treating apnoea
in preterm infants. Cochrane Database Syst Rev 2000;(2):CD000499.
30. Kumar M, Kabra NS, Paes B. Carnitine supplementation for preterm infants with
recurrent apnoea. Cochrane Database Syst Rev 2004 Oct 18;(4):CD004497.
31. Pourcyrous M, Korones SB, Crouse D, et al. Interleukin-6, C-reactive protein,
and abnormal cardiorespiratory responses to immunization in premature
infants. Pediatrics Mar 1998;101(3):E3.
32. Ellison VJ, Davis PG, Doyle LW. Adverse reactions to immunization with newer
vaccines in the very preterm infant. J Paediatr Child Health Aug 2005;41(8):441-
3.
33. Lee J, Robinson JL, Spady DW. Frequency of apnoea, bradycardia, and
desaturations following first diphtheria-tetanus-pertussis-inactivated polio-
Haemophilus influenzae type B immunization in hospitalized preterm
infants. BMC Pediatr 2006;6:20.
34. Faldella G, Galletti S, Corvaglia L, et al. Safety of DTaP-IPV-HIb-HBV hexavalent
vaccine in very premature infants. Vaccine Jan 22 2007;25(6):1036-42.
35. Brouard C, Moriette G, Murat I, Flouvat B, Pajot N, Walti H, de Gamarra E,
Relier JP. Comparative efficacy of theophylline and caffeine in the treatment of
idiopathic apnoea in premature infants. Am J Dis Child 1985 Jul;139(7):698-
700.
36. Bauer J, Maier K, Linderkamp O, et al. Effect of caffeine on oxygen consumption
and metabolic rate in very low birth weight infants with idiopathic apnoea.
Pediatrics (2001);107:660–3.
37. Dunwiddie TV, Masino SA. The role and regulation of adenosine in the central
nervous system. Annu Rev Neurosci (2001);24:31–55.
38. Bona E, Aden U, Gilland E, et al. Neonatal cerebral hypoxia–ischemia: the effect
of adenosine receptor antagonists. Neuropharmacology (1997);36: 1327–38.
39. Von Lubitz DK, Lin RC, MelmanN , Ji XD, et al. Chronic administration of selective
adenosine A1 receptor agonist or antagonist in cerebral ischemia. Eur J Pharmacol
(1994);256:161–7.
40. Deckert J, Nöthen MM, Albus M et al. Adenosine A1 receptor and bipolar affective
disorder: systematic screening of the gene and association studies. Am J Med
Genet. 1998 Feb 7;81(1):18-23.
41. Schmidt B. Caffeine therapy for apnoea of prematurity N Engl J Med. 2006
May 18;354(20):2112-21.
42. Roll C, Horsch S. Effect of doxapram on cerebral blood flow velocity in preterm
infants. Neuropediatrics 2004 Apr;35(2):126-129.
43. Sreenan C, Etches PC, Demianczuk N, et al. Isolated mental developmental delay
in very low birth weight infants: association with prolonged doxapram therapy
for apnoea. J Pediatr. 2001 Dec;139(6):832-837.
44. Miller MJ, Carlo WA, Martin RJ. Continuous positive airway pressure selectively
reduces obstructive apnoea in preterm infants. J Pediatr. 1985 Jan;106(1):91-
94.
45. Henderson-Smart DJ, Subramaniam P, Davis PG. Continuous positive airway
pressure versus theophylline for apnoea in preterm infants. Cochrane Database
Syst Rev. 2001;(4):CD001072.
46. Wintermark P, Tolsa JF, Van Melle G, et al Long-term outcome of preterm infants
treated with nasal continuous positive airway pressure. Eur J Pediatr. 2007
May;166(5):473-83.
47. Kiciman NM, Andréasson B, Bernstein G, Mannino FL, Rich W, Henderson C,
Heldt GP. Thoracoabdominal motion in newborns during ventilation delivered
by endotracheal tube or nasal prongs. Pediatric Pulmonology 1998;25:175-81.
48. Ryan CA, Finer NN, Peters KL. Nasal intermittent positive-pressure ventilation
offers no advantages over nasal continuous positive airway pressure in apnoea
of prematurity. American Journal of Diseases of Children 1989;143:1196-8.
49. Lin CH, Wang ST, Lin YJ, Yeh TF. Efficacy of nasal intermittent positive pressure
ventilation in treating apnoea of prematurity. Pediatric Pulmonology 1998;26:349-
53.
50. Garland JS, Nelson DB, Rice T, Neu J. Increased risk of gastrointestinal perforations
in neonates mechanically ventilated with either face mask or nasal prongs. Pediatrics
1985;76:406-10.
51. Sreenan C, Lemke RP, Hudson-Mason A, Osiovich H. High-flow nasal cannulae
in the management of apnoea of prematurity: a comparison with conventional
nasal continuous positive airway pressure. Pediatrics 2001.107(5):1081-3.
Amuchou Singh Soraisham
10
Meconium Aspiration
Syndrome (MAS)
Meconium aspiration syndrome is defined as respiratory distress

associated with the passage of meconium around the time of birth with
characteristic radiological changes and without an obvious alternate etiology
for respiratory distress.1 Meconium stained amniotic fluid (MSAF) may
be a sign of fetal distress, also, meconium aspiration syndrome in
its severest form is associated with severe hypoxia, both of which may
result in brain injury.
CURRENT UNDERSTANDING OF PATHOPHYSIOLOGY AND

Meconium aspiration syndrome results from aspiration of meconium during
intrauterine gasping or at the first breath. Chronic fetal hypoxia and
acidosis may cause fetal gasping and the subsequent in utero
aspiration of meconium.
The pathophysiology of MAS is complex2,3
• Acute airway obstruction
• Chemical pneumonitis with release of vasoconstrictive and inflammatory
mediators
• Surfactant dysfunction or inactivation and
• Persistent pulmonary hypertension of newborns who have right-to-
left extrapulmonary shunting
The common disturbances of lung function in MAS are hypoxemia
and decreased lung compliance. Poor oxygenation is attributable to a
combination of ventilation perfusion mismatching, intrapulmonary shunting
related to regional atelectasis and extrapulmonary shunting related to
pulmonary hypertension. The severe form of MAS is often associated
with pulmonary hypertension and refractory hypoxemia. Hypoxic
changes in the brain are similar to what is seen in perinatal asphyxia.

But, meconium staining of amniotic fluid by itself does not predict cerebral
palsy (CP). Of the infants born through MSAF, and those who had a
low 5 minute APGAR scores (0 to 3), 94 in 1000 (9.4%),
subsequently developed CP.4 The rate of severe mental retardation
and are significantly higher among infants born through MSAF. 5,6 An
increased risk for persistent pulmonary hypertension (acute respiratory
failure) of the newborn7 is associated with cesarean delivery; late preterm
or postterm birth; being large for gestational age; and maternal
black or Asian race, overweight, diabetes, and asthma. It remains unclear
whether some of these factors are direct causes of persistent pulmonary
hypertension of the newborn or simply share common causes with it.
Survivors of MAS are at relatively high risk for CP, neonatal seizures
and adverse neurological outcome. 6,8 The babies with severest of acute
respiratory failure are referred for ECMO. In a prospective follow-up study
on 82 of the 93 ECMO survivors were classed as normal, 7 as having
“impairment”, and 4 as having “severe disability”.9
EPIDEMIOLOGY OF MAS: WHO IS AT RISK AND UNDER

WHAT CONDITIONS? ..........................................................................
MSAF is present in 10 to 15% of all deliveries,1 increasing to between
23-52% of births at > 42 weeks.10, 11 Because meconium is rarely found
in the amniotic fluid prior to 34 weeks’ gestation, meconium aspiration
chiefly affects infants at term and post-term. Intrauterine distress can
cause passage of meconium into the amniotic fluid. Factors that promote
the passage of meconium in utero include placental insufficiency, maternal
hypertension, pre-eclampsia, oligohydramnios and maternal drug abuse,
especially of tobacco and cocaine. Interestingly, MAS does not occur in
all infants born through MSAF. About 2% to 9% of infants born through
MSAF developed MAS.12 At least one third of infants with MAS require
intubation and mechanical ventilation. Factors associated with development
of MAS among MSAF include thicker consistency of meconium, non-
reassuring fetal heart tracing, fetal acidosis, cesarean delivery, meconium
below the vocal cords, infants who needed intubation at birth and low
Apgar score.12, 13 Presence of perinatal fetal compromise increases
the risk for pulmonary dysfunction 2.8 to 4.8 fold in infants born through
MSAF.14
MECONIUM ASPIRATION SYNDROME (MAS) 119
BEST PRACTICE GUIDELINES FOR THE PREVENTION OF MAS
PREVENTION OF POST TERM PREGNANCY

Since meconium staining of amniotic fluid occurs more commonly with
post term pregnancies, obstetricians should avoid post term pregnancy
by induction of labor. Gelisen et al15 reported that the frequency of
meconium-stained amniotic fluid and meconium aspiration syndrome were
significantly less with induction of labor at 41 weeks (9.3 and 1.3%) as
compare to follow up until 42 weeks.
INTRAPARTUM MONITORING
Fetal heart rate monitoring, fetal scalp pH determination and fetal pulse
oximetry16 have all been used to help decision making in timing of delivery
with the hope of improving outcome. In fetuses with IUGR, Doppler
showing absent or reversal of diastolic flow in umbilical circulation are
now generally accepted as major predictors of death and neurodeve-
lopmental disability.
AMNIOINFUSION
Amnioinfusion has been proposed to reduce the risk of MAS by diluting
the meconium, thus reducing its mechanical and inflammatory effects.
Amnioinfusion also helps by cushioning of umbilical cord, thus correcting
the recurrent umbilical compressions that lead to fetal academia.
A meta-analysis of 12 good quality studies involving 4030 pregnant
women reported that amnioinfusion was associated with an overall borderline
reduction of MAS (RR 0.47, 95% CI 0.22-0.99).17 However, in clinical
settings with standard peripartum surveillance, (10 studies, 3178
participants), amnioinfusion did not reduce the incidence of MAS (RR
0.59, 95% CI 0.28 -1.25) and did not reduce perinatal death either.
In clinical setting with limited peripartum surveillance (2 studies,
852 participants), amnioinfusion was associated with reduction in the risk
of MAS (RR 0.25, 95% CI 0.13-0.47). Amnioinfusion has been associated
with adverse events such as uterine overdistension, uterine hypertonia,
uterine rupture in association with previous scar, fetal heart rate abnormality,
umbilical cord prolapse and chorioamnionitis. Based on the current literature,
American College of Obstetrics and Gynecology (ACOG) stated that routine
prophylactic amnioinfusion for dilution of MSAF is not recommended
for prevention of MAS.18
INTRAPARTUM SUCTIONING
The goal of intrapartum suctioning before the delivery of shoulder is to
clear as much meconium as possible from airway, before infant is able
to take a breath. These practices were performed without much evidence

in the past. Vain et al19 have reported a large multicenter randomized
controlled trial comparing routine suctioning of oropharyngeal and
nasopharynx before delivery of shoulder (n=1263) or no suctioning
(n=1251). There were no difference in the incidence of MAS (4% versus
4%, RR 0.9 95%CI 0.6-1.3), need for mechanical ventilation and mortality
between suction and no suction groups. Intrapartum suctioning has potential
risks such as apnea, cardiac arrhythmias triggered by pharyngeal stimulation,
worsening hypoxia, delay in resuscitation and damage to upper airway.2,20
Currently, routine intrapartum oropharyngeal and nasopharyngeal
suctioning is not recommended for prevention of MAS in infants
born through MSAF.21
POST DELIVERY INTUBATION AND ENDOTRACHEAL SUCTIONING

Neonatal resuscitation Program (NRP) recommends intubation and direct
endotracheal suction soon after delivery for infant born with MSAF, who
has depressed respiration, depressed muscle tone or heart rate
less than 100/minute.22 Vigorous infants born through thick or thin
MSAF does not alter the incidence of MAS or mortality if they are not
intubated and suctioned at birth. Cochrane meta-analysis of four randomized
studies did not show a difference in the incidence of MAS between intubated
and non-intubated vigorous infants.23 Hence, if the baby born with
meconium-stained fluid has a normal respiratory effort, normal muscle
tone, and a heart rate greater than 100 beats per minute, direct
endotracheal suction is not recommended. Only suctioning of mouth and
nose using a bulb syringe or large bore suction catheter is indicated.
BEST PRACTICE GUIDELINES FOR MANAGEMENT OF MAS ...

VENTILATION
Approximately 40% of babies with MAS required mechanical ventilation
and additional 10% required continuous positive airway pressure.24
Conventional therapy is aimed at increasing oxygenation while minimizing
the barotrauma that lead to air leak syndromes. Pre nitric oxide era showed
great variation in management of therapies for acute respiratory failure
(PPHN) a severe complication of MAS and a major determinant of
outcomes.25 Theoretically high frequency ventilation minimizes the
barotrauma and may reduce air leak syndromes in MAS. No prospective
randomized trials have compared the conventional ventilation versus high
frequency ventilation in MAS. High frequency oscillatory ventilation
augments the response to inhaled nitric oxide therapy in PPHN associated
with MAS or diffuses parenchymal lung disease (pneumonia).26 In animal
models of MAS, partial liquid ventilation resulted in improved oxygenation
and lung mechanics.27, 28 There is no randomized clinical trial about the
use of partial liquid ventilation in human neonates.
SURFACTANT THERAPY
Evidence of surfactant inactivation by meconium led to use of surfactant
therapy in the management of MAS. Bolus surfactant therapy for MAS
has been associated with reduction in the severity of respiratory distress
and decreases the number of infants with progressive respiratory failure
requiring extracorporeal membrane oxygenation (ECMO).29 Meta-analysis
of 4 randomised trials enrolling 326 infants showed reduction in the
severity of respiratory illness and decrease in the number of infants
with progressive respiratory failure requiring extracorporeal
membrane oxygenation (RR 0.64, 95% CI 0.46-0.91).29 However, there
was no significant difference in mortality, hospital stay, length of ventilation,
duration of oxygen use, pneumothorax, pulmonary interstitial emphysema
or chronic lung disease. In animal models, therapeutic lung lavage with
surfactant has been found to be effective in clearing meconium from
the lungs and thereby improving oxygenation, lung mechanics and degree
of lung injury.30 However, clinical trials of surfactant lavage in conventionally
ventilated infants with MAS found no difference between lavage infants
and controls in terms of ECMO requirements, air leak or duration of
ventilation.31
STEROIDS
Role of steroid therapy for MAS remains to be proven. Corticosteroids
possess a potent anti-inflammatory activity by modulating the action of
inflammatory mediators and reducing the activation and recruitment of
leucocytes in the lung. Four clinical trials of steroid in MAS in neonates
have been reported with conflicting results.32-35 Two trials showed decrease
in the duration of oxygen therapy and hospital stay in steroid treated
groups.32, 33 But one study showed prolonged oxygen requirement and
respiratory distress score in infants treated with steroid.34 Wu et al35 reported
that steroid treatment in infants with MAS showed decrease in the duration
of ventilation, but no difference in chronic lung disease or duration of
oxygen therapy. There is not enough evidence to recommend use
of steroid for treatment of meconium aspiration syndrome.
ANTIBIOTICS
Routine antibiotic therapy does not affect the clinical course and outcome
related to infection in meconium aspiration syndrome in those without
any perinatal risk factors for infection.36-38 Unless there is definite risk
for infection, prophylactic use of antibiotics in MAS did not reduce infection.
If antibiotics are started for suspected infection due to perinatal risk factors,
consider to discontinue antibiotics once the blood culture results showed
negative.
NITRIC OXIDE
Severe MAS is often associated with persistent pulmonary hypertension,
resulting in severe hypoxemia. Inhaled nitric oxide (iNO) causes selective
pulmonary vasodilatation by acting directly on smooth muscle. Nitric oxide
is proven helpful in the treatment of PPHN associated with MAS. For
hypoxic respiratory failure due to MAS, infants responded well with
combined inhaled nitric oxide and high frequency ventilation (HFV) as
compared to either treatment alone.26 The response to combined treatment
with HFV and inhaled nitric oxide reflects both decreased intrapulmonary
shunt and augmented nitric oxide delivery to its site of action.
EXTRACORPOREAL MEMBRANE OXYGENATION (ECMO)

Approximately 40% of infants with MAS treated with nitric oxide or
high frequency oscillation ventilation failed to respond and required
ECMO.26 Infants with MAS form approximately 35% of the infant
population who required ECMO.39 The survival rate has gone up to 95%
with ECMO.40
SILDENAFIL
Nitric oxide is costly and may not be easily available in resource-poor
settings. Approximately 30% of patients fail to respond to iNO. High
concentrations of phosphodiesterases in the pulmonary vasculature has
led to the use of phosphodiesterase inhibitors such as sildenafil. Two
studies enrolling 37 babies were included in the Cochrane review; 41 both
from centers in resource-limited settings (no HFV or iNO) and reported
significant improvement in oxygenation in Sildenafil group. No clinically
significant side effects were reported. Long term outcomes are still not
available.
KEY POINTS – reducing NDD due to MAS
1. Some babies born through MSAF are at increased risk of CP, mental
retardation and neonatal seizures. Mere MSAF is not a predictor of NDD.
2. Perinatal asphyxia (fetal and immediately after birth may be reasons for
poor outcomes)
a. Meconium staining of amniotic fluid may be a sign of fetal distress.
Chronic fetal hypoxia and acidosis are common reasons for MSAF.
b. Of the infants born through MSAF with a low 5 minute APGAR, 9.4%
developed CP.
3. MAS is associated with severe hypoxia (acute respiratory failure/PPHN)
in its severest form. Among the babies with severest of hypoxia (acute
respiratory failure/PPHN, referred for ECMO) a good proportion had normal
outcomes.
4. Prevention of PPHN - Babies born through cesarean delivery, born late
preterm or postterm, large for gestational age and born to overweight,
diabetic, asthmatic mothers were more likely to develop PPHN.
5. Effective fetal monitoring reduces fetal mortality and likely to reduce poor
outcomes.
6. Amnioinfusion has shown benefit only in centers where intrapartum
monitoring is not easily available (resource limited) and cannot be
recommended as a routine.
7. Routine intra-partum suctioning of baby’s mouth after delivery of head is
now not recommended.
8. Resuscitation at birth includes intubation of only depressed (poor tone,
respiratory efforts or bradycardia) babies delivered through MSAF.
9. A large number of babies born through MSAF may require ventilator support.
10. High Frequency Ventilation may reduce barotraumas in babies requiring
high ventilator supports.
11. Wide variations are noted in practices (Alkali, hyperventilation, sedation
and paralysis) for management of acute respiratory failure (PPHN) indicating
that neither of them is proven superior.
12. Surfactant therapy improves respiratory outcomes of babies with MAS and
oxygen requirement >50 % on optimal ventilation.
13. There are no scientific data to endorse routine use of antibiotics or steroids
in management of MAS.
14. Newer therapies – iNO and ECMO have improved survival of babies with
severe respiratory failure and have not increased burden of handicapped
survivors.
15. Newer untested therapies like Sildenafil must be used with caution and
as a part of systematic trials recording complications and long term outcomes.
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15. Gelisen O, Caliskan E, Dilbaz S, et al. Induction of labor with three different
techniques at 41 weeks of gestation or spontaneous follow-up until 42 weeks
in women with definitely unfavorable cervical scores. Eur J Obstet Gynecol Reprod
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16. Kuhnert M, Seelbach-Goebel B, Butterwegge M. Predictive agreement between
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multicenter study. Am J Obstet Gynecol. 1998;178:330-5.
17. Xu H, Hofmeyr J, Roy C, Fraser WD. Intrapartum amnioinfusion for meconium-
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18. ACOG Committee Obstetric Practice. Amnioinfusion does not prevent meconium
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19. Vain NE, Styled EG, Prudent LM, Wiswell TE, Aguilar AM, Vivas NI. Oropharyngeal
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20. Falciglia HS, Henderschott C, Potter P, Helmchen R. Does DeLee suction at the
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22. Kattwinkel J ed. Text book of Neonatal resuscitation.5th edition Elk Grove
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24. Wiswell TE, Gannon CM, Jacob J, et al. Delivery room management of the
apparently vigorous meconium-stained neonate: results of the multicenter,
international collaborative trial. Pediatrics. 2000;105:1-7.
25. Walsh-Sukys MC, Tyson JE, Wright LL, et al. Persistent pulmonary hypertension
of the newborn in the era before nitric oxide: practice variation and outcomes.
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26. Kinsella JP, Truog WE, Walsh WF et al. Randomized, multicenter trial of inhaled
nitric oxide and high-frequency oscillatory ventilation in severe, persistent
pulmonary hypertension of the newborn. J Pediatr 1997;131:55-62.
27. Barrington KJ, Singh AJ, Etches PC, Finer NN. Partial liquid ventilation with
and without inhaled nitric oxide in a newborn piglet model of meconium
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28. Nakamura T, Matsuzawa S, Sugiura M, Tamura M.A randomised control study
of partial liquid ventilation after airway lavage with exogenous surfactant in a
meconium aspiration syndrome animal model. Arch Dis Child Fetal Neonatal
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29. El Shahed A, Dargaville P, Ohlsson A, Soll R. Surfactant for meconium aspiration
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30. Dargaville PA, Mills JF. Surfactant therapy for meconium aspiration syndrome:
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31. Wiswell TE, Knight GR, Finer NN et al. A multicenter, randomized, controlled
trial comparing Surfaxin (Lucinactant) lavage with standard care for treatment
of meconium aspiration syndrome. Pediatrics. 2002;109:1081-7.
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38. Lin HC, Su BH, Tsai CH, Lin TW, Yeh TF. Role of antibiotics in management
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Amuchou Singh Soraisham, Abbas Hyderi
11
Persistent Pulmonary
Hypertension of Newborn (PPHN)
Persistent pulmonary hypertension of newborn (PPHN) is not a disease,

rather a state with complex physiologic common end point arising from
a variety of disease processes resulting in severe hypoxemia in neonates
with a mortality of 10-20%.1 In neonates with PPHN, the severity of illness
and likely outcomes are related to the nature of the underlying disease
or abnormality and resultant pathological changes in the pulmonary
vasculature. Survivors of infants with PPHN remain at a significant risk
for neurodevelopmental impairment, cognitive delays, hearing loss
and a high rate of rehospitalization.2
CURRENT UNDERSTANDING OF PATHOPHYSIOLOGY

OF PPHN ...............................................................................................
PPHN is a state of persistent hypoxemia and cyanosis in the neonate
resulting from failure of the postnatal decline of pulmonary artery pressure
and a persistence of right to left shunting across the ductus arteriosus and
foramen ovale. PPHN is characterized by (a) severe hypoxemia shortly
after birth, (b) marked pulmonary arterial hypertension, (c) absence of
congenital heart disease and (d) vasoreactivity with extrapulmonary right
to left shunting across ductus arteriosus or foramen ovale.
To understand the pathophysiology of PPHN, one needs to know the
normal fetal and neonatal physiology. In normal fetus, pulmonary and
systemic pressures are nearly equal. The pulmonary vessels are constricted
in utero and allows only 5-10% of cardiac output to go to pulmonary
circulation, and remaining bypass the lung. The low arterial oxygen tension
in the fetus facilitates this vasoconstriction. Once the umbilical cord is clamped
and with the removal of low resistance placental circuit, systemic vascular
resistance increase. After the baby is born, pulmonary artery pressure should
PERSISTENT PULMONARY HYPERTENSION OF NEWBORN (PPHN) 127
decrease rapidly to 50% of systemic pressure and pulmonary blood flow
increases nearly tenfold to match lung perfusion with the onset of ventilation.
PPHN occurs when pulmonary vasculature resistance fails to decrease
at or shortly after birth. A high pulmonary vascular resistance (PVR),
resulting in right to left shunting of deoxygenated blood across the
patent ductus arteriosus and patent foramen ovale, is the hallmark of
pulmonary hypertension. The regulation of pulmonary vascular tone
represents a balance between the vasoconstrictor and vasodilator mechanisms.
The increased PVR is secondary to endothelial dysfunction, leading to
imbalance between the endogenous vasoconstrictors and vasodilators.
Conditions that lead to chronic hypoxia in utero or abnormal muscularisation
of pulmonary vessels can lead to persistent pulmonary vasoconstriction
and pulmonary hypertension after birth. Perinatal stressors including hypoxia,
hypoglycemia, cold stress, sepsis and direct lung injury alter the course
of normal transition. Vascular biology of pulmonary vasodilatation at birth
and pathophysiology of PPHN has been well described in the review articles
(3,4). Apart from the effects of physical and chemical (oxygen) stimuli,
the important mediators involved in the vasodilatation of pulmonary vessels
at birth are prostaglandins and nitric oxide (NO) release by pulmonary
endothelium. The influence of this dilator effect is opposed by several
vasoconstrictors such as endothelin, thromboxane and product of cytochrome
p450 pathways. Hypoxia, acidosis and alveolar atelectasis promote
pulmonary vasoconstriction and are significant contributors in the patho-
physiology of PPHN.
PPHN AND NEURODEVELOPMENTAL OUTCOME .........................

Severe hypoxia associated with PPHN can lead to brain injury. The type
of neurodevelopmental problem depends on the severity of hypoxemia
and underlying disease or abnormality. PPHN infants with severe perinatal
asphyxia have very poor prognosis for survival and long term neurodevelop-
mental problem. Similarly, infants with congenital diaphragmatic hernia
and PPHN often require ECMO and have increased risk of neuro-
developmental delay.
Apart from the hypoxia per se, various treatment modalities which
are use in the treatment of PPHN itself could be associated with
neurodevelopmental disability. High incidence of seizure and cerebral
infarction has been documented in infants with PPHN.5,6 Klesh et al6
reported 9 out of 19 (47%) infants with PPHN had cerebral infarction
whereas Oelberg et al7 documented a 40% incidence of intracranial
hemorrhage. These can be associated with cerebral palsy (CP), mental
retardation and seizures. Follow up studies on PPHN published before

1990s reported higher rates of neurodevelopmental impairment ranging
from 5% to 53%. Hyperventilation and hypocarbia for the treatment
of PPHN can cause cerebrovascular vasoconstriction with a subsequent
reduction in cerebral blood flow. One of the areas in the brain with highest
blood flow is auditory nucleus, and the high metabolic rate in this region
makes it more susceptible to a decrease in blood flow. Sensorineural
hearing loss is more common in infants with PPHN treated with
alkalosis and extracorporeal membrane oxygenation (ECMO). More
than half (53%) of surviving infants with PPHN treated with hyperventilation
and respiratory paralysis had hearing impairment. 8 Bifano and Pfannensteil
in 1988 evaluated a series of 21 infants with PPHN who were treated
with hyperventilation.9 Four infants (19%) had severe neurologic impairment;
seven babies had mild to moderate delay, and 11 babies were found
to have no abnormality. The only perinatal or treatment variable
associated with abnormal outcome is duration of PaCO2 < 25 mm
Hg after hyperventilation strategy.9 Neurodevelopmental and audiologic
impairment were seen in 46%, followed by cognitive delays (30%) and
hearing loss in 19% of surviving infants.2 Following the introduction of
inhaled nitric oxide and availability of ECMO, the neurodevelopmental
impairment were lower (15-18%).10,11
Severity of hypoxemia may be a prognostic factor. Highest alveolar-
arterial oxygen gradient (AaDO2) was a good early predictor of mortality.
AaDO2 exceeding 610 for 8 hours once maximal therapy had been offered
was associated with a 78% mortality risk, with a specificity of 71% and a
sensitivity of 94%.12 AaDO2 values of 600 mm Hg or greater were more frequent
in the nonsurvivors compared with the survivors (92% vs 37%). Air leak also
proved to be a good predictor of nonsurvival.13 The drawback of the use
of AaDO2 is that it does not account for the degree of ventilator support
required to obtained any given oxygenation value. Oxygenation index accounts
for both oxygen toxicity and barotrauma in the assessment of severity.
Oxygenation index greater than 40 on three to five arterial blood gases taken
30 minutes apart correlated with 80% mortality.14 Survivors of neonatal hypoxic
respiratory failure remain at a significant risk for neurodevelopmental and
hearing deficit and need close monitoring and follow-up.
EPIDEMIOLOGY OF PPHN ..................................................................

The incidence of PPHN is estimated to be 1.9 per 1,000 live births with a wide
variation observed among centers (0.43-6.82 per 1,000 live births).11 The
incidence is higher in pregnancies with no prenatal care and with the use of
tobacco and illicit drugs. The factors associated with increased risk for PPHN
include cesarean section deliveries, maternal black or Asian race, male
gender, high prepregnancy body mass index (BMI>27), diabetes and
asthma.15 The risk of PPHN was 7 times higher after cesarean section deliveries
than after vaginal deliveries.15 PPHN can occur in both term and preterm infants
depending on the associated illnesses.
PPHN can occur without any associated parenchymal lung disease and
are called idiopathic PPHN. Causes of PPHN are listed in Table 11.1.
Neonatal illnesses associated with increased risk for developing PPHN include
meconium aspiration syndrome (MAS), perinatal asphyxia, pneumonia,
respiratory distress syndrome, pulmonary hypoplasia, congenital
diaphragmatic hernia (CDH). Infants born to mothers who are exposed
to certain medications such as NSAID, tricyclic antidepressants during
pregnancy are also at increased risk for PPHN. In terms of frequency,
PPHN occurs most commonly in association with MAS (41%), followed
by idiopathic PPHN (17%), pneumonia/sepsis (14%), respiratory distress
syndrome (13%), congenital diaphragmatic hernia (10%) and other causes
(asphyxia, maternal diabetes, polycythemia, etc.).11
Table 11.1: Causes of persistent pulmonary hypertension of newborn

1. Idiopathic.
2. Persistent pulmonary vasoconstriction
• Asphyxia
• Meconium aspiration syndrome
• Neonatal respiratory distress syndrome
• Sepsis/pneumonia (e.g. group B streptococcal disease)
• Maternal Drugs—
a. NSAID drugs (like Indomethacin after 31weeks, Naproxen)
b. SSRI drugs (e.g. Paroxetine, Flouxetine)
c. Octreotide causes pulmonary vasospasm.
d. Diazoxide
• Others (e.g. pulmonary alveolar dysplasia)
3. Functional obstruction of pulmonary vascular bed
• Hyper viscosity secondary to polycythemia
4. Decreased pulmonary vascular bed
• Congenital diaphragmatic hernia (CDH)
• Pulmonary hypoplasia – oligohydramnios, pleural effusion, vascular
anomalies, asphyxiating thoracic dystrophy, phrenic nerve agenesis.
5. Pulmonary venous hypertension
• Total anomalous pulmonary venous return
• Left atrial or mitral obstruction
• Hypoplastic left heart syndrome
• Myopathic left ventricular disease (e.g. endocardial fibroelastosis and
Pompe disease)
• Obstruction to left ventricular outflow (e.g. aortic arch, interrupted arch,
and coarctation).
BEST PRACTICE GUIDELINES: PREVENTION OF THE RISK FACTOR,

SCREENING AND DIAGNOSIS, MANAGEMENT OF THE PPHN ..
PREVENTION OF RISK FACTOR
• Routine prenatal care and identification of high risk pregnancy
• Avoidance of using NSAID’s and SSRIs during pregnacy, if possible
• Prevention of associated illnesses (mentioned in various chapters in this
book).
DIAGNOSIS OF PPHN
PPHN should be suspected in high risk neonates with progressive cyanosis
or lability in oxygen saturation within the first few hours of life. Diagnosis
of PPHN is made from the history, physical examination, preductal and
postductal blood gases and echocardiogram.
Preductal and Postductal Oxygenation

In PPHN, the right to left shunt can occur either at patent ductus arteriosus
or at foramen ovale or both. A simultaneous preductal (right radial artery)
and postductal (umbilical artery) arterial oxygen gradient of > 20
mmHg suggest right to left shunt at the level of patent ductus arteriosus. 16
Negative test does not exclude PPHN because shunting at atrial level does
not produce ductal gradient. Simple bedside monitoring of preductal (right
upper limb) and postductal (preferably lower limb) oxygen saturation
difference of 5-10% by pulse oximetry in a high risk infant should suspect
PPHN.
Hyperoxia/Hyperventilation Test
This diagnostic test with hyperventilation to a critical PaCO2 <25 mm Hg
test is not recommended any more due to deleterious effects of hypocarbia,
barotrauma and long term neurodevelopment impairment, hence of historical
interest only.
Echocardiographic
Diagnosis of PPHN is based on presence of high pulmonary artery pressures
(more than systemic pressures) with right to left shunting through patent
ductus arteriosus and/or patent foramen ovale. Deviation of interatrial septum
into the left atrium is seen in severe PPHN. Echocardiogram also excludes
the presence of serious congenital cyanotic heart disease.
Direct Measurement of Pulmonary Pressure by Cardiac Catheterization
Direct measurement of pulmonary artery pressure seems to be the most
optimal method to diagnose PPHN. However, it is difficult and invasive
procedure and not routinely used for diagnosis.
TREATMENT OF PPHN
The goal of medical treatment of PPHN is to lower pulmonary vascular
resistance to systemic vascular resistance (PVR:SVR) ratio, reduce intracardiac
shunting and right ventricular afterload, improve postductal oxygen saturation
without systemic hypotension as well as correction of underlying cause
of PPHN.
Ten commandments of PPHN therapy are as follows:17
1. Minimal handling and maintenance of euthermia.
2. Correction of acidosis (metabolic and respiratory) and metabolic
imbalances (fluid and electrolytes).
3. Support blood pressure (e.g. plasma expanders/Inotropes).
4. Treat associated conditions (e.g. antibiotics, partial exchange
transfusion).
5. Sedation/paralysis (morphine, fentanyl, pancuronium).
6. Ventilation support.
7. Surfactant therapy.
8. Inhaled nitric oxide.
9. Extracorporeal membrane oxygenation (ECMO).
10. Other vasodilators (prostacyclin, magnesium sulfate, etc.).
Minimal Handling
Minimal handling, nursing in a quiet environment and maintenance in
thermoneutral environment is recommended. Infant should be monitored
using noninvasive monitors (transcutaneous O2/CO2 methods) and blood
gas sampling should preferably be done with indwelling arterial line.
Correction of Acidosis
Acidosis correction to achieve acceptable pH (7.35-7.45) is recommended
because acidosis is a potent pulmonary vasoconstrictor. Forced alkalosis
with sodium bicarbonate and hyperventilation were popular therapies before
nitric oxide. Extreme alkalosis and hypocarbia are not recommended as
it is associated with later neurodevelopmental deficit, including CP and
sensorineural hearing loss. Metabolic equilibrium is desired especially with
normal values of ionized calcium, lactate and glucose.
Correction of Hypovolemia/Hypotension
The goal is to correct systemic arterial hypotension and maintain adequate
systolic blood pressure (BP) to minimize right to left shunting. Aggressive support
of cardiac function involves judicious use of volumes along with inotropic agents
(dopamine, dobutamine, epinephrine and/or milrinone) to enhance cardiac
output and systemic oxygen transport. Dopamine is used frequently as the first
line but dose should be given at 2-10 mcg/kg/min to avoid alpha adrenergic
effects on pulmonary vasoconstriction and an increase in afterload. Dobutamine
is indicated in cases of poor ventricular function. Milrinone has been used to
improve inotropy and reduce afterload. Milrinone has also shown improvement
in oxygenation in severe PPHN.18
Treatment of Associated Conditions

Correction of the underlying causes of PPHN is important, if known. Broad
spectrum antibiotics are used to treat sepsis and pneumonia. Partial exchange
transfusion for polycythemia and surgery for congenital diaphragmatic hernia
are indicated.
Sedation and Paralysis

To optimize gas exchange, sedation with fentanyl or morphine is advocated
to avoid asynchrony, reflex catecholamine release and aggravation of
pulmonary vascular resistance. The use of neuromuscular blockade remains
controversial and is reserved for the infant that cannot be treated with
sedatives alone. Neuromuscular blockage can promote atelectasis of
dependent lung regions and ventilation perfusion mismatch. Neuromuscular
paralysis may be associated with increased risk of death and that exceeded
the mortality risk associated with either high frequency oscillatory ventilation
(HFOV) or ECMO.11
Mechanical Ventilation
The maintenance of adequate oxygenation is the primary goal in the
management of PPHN and mechanical ventilation is one of the treatment
modalities to achieve this goal. In the past, hyperventilation is used as
main therapy to increase blood pH, reverse ductal shunting and induce
pulmonary vasodilatation. However, it was associated with adverse
neurological sequelae. The use of gentler ventilation along with therapies
that reduce oxygen demand while maximizing oxygen delivery has been
advocated but it has been slow in becoming standard management.11
Recent management strategies usually aimed at accepting pH: 7.4-7.5,
PaCO2 at 40-60 mm Hg, PaO2 at 60-90 mm Hg to avoid barotraumas.17
Permissive hypercapnia promises to maintain gas exchanges with lower
tidal volume and thus decrease lung injury.19 High frequency ventilation
(HFV) is the alternative mode of ventilation in infants who are non-responsive
to conventional ventilator therapy.20 High frequency oscillatory ventilation
(HFOV) is the preferred mode when there is coexisting parenchyma disease
in PPHN.17 HFV is shown to improve lung inflation while decreasing the
lung injury due to volutrauma and barotrauma. HFOV has become the
mainstay of ventilating difficult PPHN with inhaled nitric oxide (iNO). HFOV
has been shown to augment an inhaled nitric oxide response by improving
lung inflation and allowing better alveolar recruitment.21,22
Surfactant Therapy
Certain causes of PPHN such as meconium aspiration syndrome, pneumonia,
respiratory distress syndrome and diaphragmatic hernia are associated with
surfactant deficiency or dysfunction. Surfactant therapy should be given
in patients with meconium aspiration syndrome and pneumonia associated
with PPHN. Surfactant therapy is found to improve oxygenation and decrease
the need for ECMO, particularly when given early in the disease in infants
with severe hypoxemic respiratory failure.23,24
Inhaled Nitric Oxide (iNO)

Inhaled nitric oxide (iNO) is the mainstay of treatment and the recom-
mended pulmonary vasodilator for PPHN. It selectively causes pulmonary
vasodilatation by relaxing the smooth muscle cells by increasing cyclic
guanosine monophosphate (cGMP) levels through the guanylate cyclase
pathway.25 iNO cause selective pulmonary vasodilatation and does not
cause systemic hypotension. Nitric oxide also causes a better ventilation
perfusion match with redistribution of pulmonary blood flow to better
ventilated alveoli. Cochrane meta-analysis of 14 randomized controlled
studies reported that inhaled nitric oxide appears to improve outcome in
hypoxemic term and near term infants by reducing the incidence of the
combined endpoint of death or need for ECMO.26 The reduction seems
to be entirely a reduction in need for ECMO; mortality is not reduced.
It is recommended to use inhaled nitric oxide in an initial concentration
of 20 ppm for term and near term infants with hypoxic respiratory failure
who do not have a diaphragmatic hernia.27 In preterm infants with PPHN;
it is suggested to start at a lower dose (usually 5-10 ppm). Low dose
inhaled nitric oxide at 5 ppm improve the oxygenation but did not affect
the rate of severity of intracranial hemorrhage or survival.28 Standard iNO
therapy is initiated when the oxygenation index (OI) is more than 25.
However, a randomized control trial of iNO given early in the respiratory
failure at an OI of 15 to 25, demonstrated that early iNO improves

oxygenation and decreases the progression to severe respiratory failure
(OI > 40) compared to standard iNO therapy initiated at an OI of 25.29
Oxygenation improves in approximately 50% of infants receiving nitric oxide.
However, strategies to optimize lung recruitment and cardiac performance
are necessary to increase the response to iNO. Nitric oxide therapy does
not consistently improve oxygenation and does not decrease the use of
ECMO/mortality in infants with congenital diaphragmatic hernia.30 Indeed
there is a suggestion that outcome may be slightly worse.
Weaning of iNO is indicated after improvement in oxygenation and
when the oxygen requirement (50-60%) is stable for at least 12 hours.
Weaning of iNO from 20 ppm is done in steps of 5 ppm if patient maintains
stable good oxygenation for about 12 hours.31 When it reaches to 5 ppm;
further weaning is slower at 1 ppm each time in a frequency of 6-12
hours. Mostly iNO can be weaned off successfully in 4-5 days. Some infants
may develop rebound hypoxemia and pulmonary hypertension when
weaning iNO. Prolonged iNO therapy may be associated with decrease
endogenous NO synthase activity32 and increased endothelin levels.33
Prolonged high dose of iNO can cause toxicity such as methemoglobinemia,
increased bleeding time, immune suppression and formation of nitrogen
dioxide or peroxynitrites.34 It is important to monitor these levels closely;
severe methemoglobinemia is an indication to stop iNO. Inhaled NO therapy
for hypoxic respiratory failure in term and near-term infants is not associated
with an increase in neurodevelopmental impairment or hearing loss at
18 to 24 months postnatal age.35,36
Extracorporeal Membrane Oxygenation (ECMO)
ECMO is the final rescue therapy in infants with refractory hypoxemia
due to reversible pulmonary or cardiac disease when all other non invasive
measures fail.18 Since ECMO is an invasive procedure; it is reserved for
infants receiving maximum ventilatory support and those that meet Barlett
criteria, (i.e. Oxygenation index > 40), which is indicative of = 80% risk
of dying.37, 38 Cochrane meta-analysis of four trials showed a strong benefit
of ECMO on mortality (relative risk 0.44, 95% CI 0.31, 0.61), especially
for babies without congenital diaphragmatic hernia (RR 0.33, 95% CI 0.21,
0.53).39 Fortunately, following the introduction of HFV, surfactant, and iNO
therapy in the early 1990s, the number of infants requiring ECMO has
decreased by more than 40% from 1992 to 2001.40 All of the decrease
has been in babies with respiratory failure due to parenchymal lung disease
and idiopathic PPHN. In a prospective follow up study of newborn infants
with acute respiratory failure treated with ECMO, 82 of 93 (88%) were
classed as normal, seven (8%) as having “impairment”, and four (4%)
as having “severe disability” at 11-19 months of postnatal age.41
Alternative Vasodilator Therapy
Nearly 30-50% of infants with PPHN do not respond to iNO therapy.
Infants who do not show initial response to iNO and those that deteriorate
subsequently while on iNO therapy continue to have significant pulmonary
hypertension and need the alternative therapy (2). Alternatives available
include: (a) Phosphodiesterase-5 inhibitors like sildenafil, (b) Prostaglandins
like prostacyclin or PGE1, (c) Tolazoline, magnesium sulfate, (d) NO precursor
L-arginine, (e) Free radical scavengers like Superoxide Dismutase,
(f) experimental agents like Bosentan (endothelin antagonist)
a. Sildenafil is a phosphodiesterase inhibitor type 5(PDE5) that has been
shown to selectively reduce pulmonary vascular resistance. Sildenafil
produces vasodilatation by increasing cyclic guanosine monophosphate
involve in the degradation of cGMP to guanosine monophosphate.42
Cochrane review included two small trials enrolling 37 infants in resource-
limited settings where iNO and high frequency ventilation are not
available.43 Both studies reported statistically significant improvement
in oxygenation (reduction in oxygenation index) in the Sildenafil group.
One study reported a strongly protective effect on mortality, (RR 0.17,
95% CI 0.03, 1.09) favoring the Sildenafil group. However, this result
needs to be replicated in larger studies. No clinically important side
effects were reported. The major concern about the use of Sildenafil
is that it can cause systemic hypotension, which can worsen the right
to left shunting and hypoxemia in PPHN.44 Although the potential adverse
effects may limit the use of Sildenafil as the drug of choice in babies
with PPHN, its use is still holds immense promise for resource limited
countries and need further randomized trials.
b. Prostacyclin (PGI2) is a potent vasodilator and its effect on vascular
tone is complementary to that of nitric oxide. Studies have shown a
potential synergistic action with combined usage with iNO due to
interaction between NO and PGI2 pathways. 45 Intravenous prostacycline
infusion has been shown to decrease pulmonary artery pressure and
improved oxygenation in neonates with PPHN in uncontrolled studies.46,47
Prostacycline infusion is shown to cause significant hypotension. Bindl
et al48 reported aerosol PGI2 improved oxygenation and decreased
pulmonary artery pressure without affecting systemic blood pressure.
Similarly Kelly et al49 has shown improvement in oxygenation by using
aerosol PGI2 along with iNO when oxygenation failed to improve with
iNO or deteriorated while on iNO. There is potential role for PGI2
in babies with hypoxic respiratory failure that failed to respond adequately

iNO or in centers where iNO is not available as a rescue therapy.
Randomized controlled trials are needed to establish safety and efficacy
of this therapy.
c. Magnesium Sulfate: Magnesium is a nonspecific vasodilator. It causes
smooth muscle relaxation by antagonizing calcium ion entry to smooth
muscle. Intravenous magnesium sulphate in a dose of 200 mg/kg given
as bolus followed by infusion of 20-150 mg/kg/hr has been found to
improve oxygenation and decreased oxygenation index in uncontrolled
trials.50-54 There are no randomized controlled trials on this agent in
the neonates. Despite low cost and easy availability, it can cause a
hypotension and central nervous system depression. Cochrane review
found no eligible randomized trials. Based on the lack of evidence,
the authors conclude the use of magnesium sulphate cannot be
recommended in the treatment of PPHN.55
d. Tolazoline: Tolazoline is a potent nonspecific vasodilator used in the
treatment of PPHN in the pre nitric oxide era.21 No randomized controlled
trials are available. Systemic infusion of tolazoline was associated with
serious adverse effects including profound hypotension, pulmonary and
gastrointestinal hemorrhage.56 Administration of tolazoline via
endotracheal route was effective in treatment of PPHN in small
uncontrolled trials without systemic hypotension.57,58
e. Arginine, adenosine and Superoxide dismutase and Bonestan (anti
endothelin I) are currently in early experimental stage.4
CONCLUSION ........................................................................................
Management of PPHN is in New Era of “HFOV and iNO, rescued by
ECMO”, with remarkable success. PPHN may be a Neonatologist’s nightmare!
A Challenge. However, there can be no better satisfaction than when a
sick PPHN baby recovers and is ready for discharge!
KEY POINTS – reducing NDD due to PPHN (severe respiratory failure)

1. PPHN is associated with severe hypoxemia and survivors of infants with
PPHN remain a significant risk for neurodevelopmental impairment, cognitive
delays, hearing loss and a high rate of rehospitalization.
2. PPHN is a complex physiologic common end point arising from a variety
of disease processes resulting in severe hypoxemia in neonates with a
mortality of 10-20%.
3. Prevention of three major illnesses (MAS, RDS and pneumonia) will decrease
the frequency of PPHN by 2/3rd.
4. Cesarean section delivery increases the risk of PPHN.
5. The type of neurodevelopmental problem depends on the severity of hypoxemia
and underlying disease or abnormality.
6. Hyperventilation strategy and hypocarbia are associated with sensorineural
hearing loss, hence, avoid hyperventilation.
7. Supportive management of PPHN includes minimal handling, correction of
temperature instability, hypoglycemia, hypocalcemia, anemia and metabolic
acidosis and hypotension.
8. Sedation is necessary but paralysis may increase the risk of death.
9. High frequency ventilation may reduce barotrauma and has become the
mainstay of ventilating difficult PPHN with inhaled nitric oxide (iNO).
10. Surfactant therapy is indicated in the management of hypoxic respiratory
failure associated with MAS, pneumonia and RDS.
11. Inhaled nitric oxide is the main stay of therapy.
12. ECMO is the rescue therapy and early transfer to ECMO centre should
be considered.
13. Other vasodilators such as Sildenafil have a promising role in resource
limited areas (HFV and NO unavailable) but larger trials are required for
safety and efficacy.
a. Magnesium sulphate therapy is used as a vasodilator, with improvement
in oxygenation, but can caused profound hypotension and CNS
depression.
b. Tolazoline and prostacyclines are non specific vasodilators and are
associated with adverse side effects and not recommended.
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24. Lotze A, Mitchell BR, Bulas DI, Zola EM, Shalwitz RA, Gunkel JH. Multicenter
study of surfactant (beractant) use in the treatment of term infants with severe
respiratory failure. Survanta in Term Infants Study Group. J Pediatr 1998; 132(1):40-
7.
25. Steinhorn RH, Millard SL, Morin FC 3rd. Persistent pulmonary hypertension
of the newborn. Role of nitric oxide and endothelin in pathophysiology and
treatment. Clin Perinatol 1995; 22(2):405-28.
26. Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at
or near term. Cochrane Database Syst Rev 2006; 18:CD000399.
27. American Academy of Pediatrics. Committee on Fetus and Newborn. Use of
inhaled nitric oxide. Pediatrics 2000;106:344-5.
28. Kinsella JP, Walsh WF, Bose CL, et al. Inhaled nitric oxide in premature neonates
with severe hypoxaemic respiratory failure: a randomised controlled trial. Lancet.
1999;354:1061-5.
29. Konduri GG, Solimano A, Sokol GM, et al. A randomized trial of early versus
standard inhaled nitric oxide therapy in term and near-term newborn infants
with hypoxic respiratory failure. Pediatrics 2004;113:559-64.
30. Inhaled nitric oxide and hypoxic respiratory failure in infants with congenital
diaphragmatic hernia. The Neonatal Inhaled Nitric Oxide Study Group (NINOS).
Pediatrics 1997; 99(6):838-45.
31. Kinsella JP, Abman SH. Clinical approach to inhaled nitric oxide therapy in
the newborn with hypoxemia. J Pediatr 2000;136(6):717-26.
32. Black SM, Heidersbach RS, McMullan DM, Bekker JM, Johengen MJ, Fineman
JR. Inhaled nitric oxide inhibits NOS activity in lambs: potential mechanism
for rebound pulmonary hypertension. Am J Physiol 1999;277:H1849-56.
33. Pearl JM, Nelson DP, Raake JL, et al. Inhaled nitric oxide increases endothelin-
1 levels: a potential cause of rebound pulmonary hypertension. Crit Care Med
2002;30(1):89-93.
34. Travadi JN, Patole SK. Phosphodiesterase inhibitors for persistent pulmonary
hypertension of the newborn: a review. Pediatr Pulmonol 2003;36:529-35.
35. Inhaled nitric oxide in term and near-term infants: neurodevelopmental follow-
up of the neonatal inhaled nitric oxide study group (NINOS). J Pediatr 2000;
136(5):611-7
36. Konduri GG, Vohr B, Robertson C, et al. Early inhaled nitric oxide therapy
for term and near-term newborn infants with hypoxic respiratory failure:
neurodevelopmental follow-up. J Pediatr 2007;150(3):235-40.
37. Kim ES, Stolar CJ. ECMO in the newborn. Am J Perinatol 2000;17(7):345-
56.
38. Perez-Benavides F, Boynton BR, Desai NS, Goldthorn JF. Persistent pulmonary
hypertension of the newborn infant. Comparison of conventional versus
extracorporeal membrane oxygenation in neonates fulfilling Bartlett’s criteria. J
Perinatol 1993;13(3):181-5.
39. Elbourne D, Field D, Mugford M. Extracorporeal membrane oxygenation for
severe respiratory failure in newborn infants. Cochrane Database Syst Rev 2002;
(1):CD001340.
40. Farrow KN, Fliman P, Steinhorn RH. The diseases treated with ECMO: focus
on PPHN. Semin Perinatol 2005;29(1):8-14.
41. Khambekar K, Nichani S, Luyt DK, et al. Developmental outcome in newborn
infants treated for acute respiratory failure with extracorporeal membrane
oxygenation: present experience. Arch Dis Child Fetal Neonatal Ed 2006; 91(1):F21-
5.
42. Turko IV, Ballard SA, Francis SH, Corbin JD. Inhibition of cyclic GMP-binding
cyclic GMP-specific phosphodiesterase (Type 5) by Sildenafil and related
compounds. Mol Pharmacol 1999;56(1):124-30.
43. Shah PS, Ohlsson A. Sildenafil for pulmonary hypertension in neonates.
Cochrane Database Syst Rev. 2007;(3):CD005494.
44. Stocker C, Penny DJ, Brizard CP, Cochrane AD, Soto R, Shekerdemian LS.
Intravenous Sildenafil and inhaled nitric oxide: a randomised trial in infants after
cardiac surgery. Intensive Care Med 2003;29(11):1996-2003.
45. de Wit C, von Bismarck P, Pohl U. Synergistic action of vasodilators that increase
cGMP and cAMP in the hamster cremaster microcirculation. Cardiovasc Res
1994;28(10):1513-8.
46. Bos AP, Tibboel D, Koot VC, Hazebroek FW, Molenaar JC. Persistent pulmonary
hypertension in high-risk congenital diaphragmatic hernia patients: incidence and
vasodilator therapy. J Pediatr Surg 1993;28(11):1463-5.
47. Eronen M, Pohjavuori M, Andersson S, Pesonen E, Raivio KO. Prostacyclin treatment

for persistent pulmonary hypertension of the newborn. Pediatr Cardiol.
1997;18(1):3-7.
48. Bindl L, Fahnenstich H, Peukert U. Aerosolized prostacyclin for pulmonary
hypertension in neonates. Arch Dis Child Fetal Neonatal Ed. 1994;71(3):
F214-6.
49. Kelly LK, Portal NF, Goodman DM, Carroll CL, Steinhorn RH. Inhaled prostacyclin
for term infants with persistent pulmonary hypertension refractory to inhaled
nitric oxide. J Pediatr 2002;141(6):830-2.
50. Chandran S, Haqueb ME, Wickramasinghe HT, Wint Z. Use of magnesium sulphate
in severe persistent pulmonary hypertension of the newborn. J Trop Pediatr.
2004;50(4):219-23.
51. Daffa SH, Milaat WA. Role of magnesium sulphate in treatment of severe persistent
pulmonary hypertension of the newborn. Saudi Med J 2002;23(10):1266-9.
52. Wu TJ, Teng RJ, Tsou KI. Persistent pulmonary hypertension of the newborn
treated with magnesium sulfate in premature neonates. Pediatrics 1995;96:
472-4.
53. Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A. Magnesium
sulphate as an alternative and safe treatment for severe persistent pulmonary
hypertension of the newborn. Arch Dis Child Fetal Neonatal Ed. 1995; 72(3):F184-
7.
54. Abu-Osba YK, Galal O, Manasra K, Rejjal A. Treatment of severe persistent
pulmonary hypertension of the newborn with magnesium sulphate. Arch Dis
Child 1992;67:31-5.
55. Ho JJ, Rasa G. Magnesium sulfate for persistent pulmonary hypertension of
the newborn. Cochrane Database Syst Rev. 2007;(3):CD005588.
56. Stevenson DK, Kasting DS, Darnall RA Jr, et al. Refractory hypoxemia associated
with neonatal pulmonary disease: the use and limitations of tolazoline. J Pediatr
1979;95(4):595-9.
57. Welch JC, Bridson JM, Gibbs JL. Endotracheal tolazoline for severe persistent
pulmonary hypertension of the newborn.Br Heart J 1995;73(1):99-100.
58. Parida SK, Baker S, Kuhn R, Desai N, Pauly TH. Endotracheal tolazoline
administration in neonates with persistent pulmonary hypertension. J Perinatol.
1997;17(6):461-4.
Section 6
Perfusion
Problems
12. Neonatal Shock
13. Neonatal Sepsis
Gurdev Chowdhary
12
Neonatal Shock
Shock is a clinical syndrome characterized by inadequate tissue and

organ perfusion. When this occurs, inadequate amounts of oxygen and
nutrient substrate are delivered to body tissues, and removal of metabolic
waste products is inadequate. This results in cellular dysfunction, which
may eventually lead to cell death. Failure of perfusion may involve isolated
organs or the entire organism. Hypotension (i.e. lower than expected
blood pressure) frequently, but not always, accompanies shock.
NORMAL BLOOD PRESSURE ............................................................

WHAT IS NORMAL BLOOD PRESSURE?
Epidemiology: The ‘normal’ blood pressure limits have been defined as
the gestational and postnatal-age dependent blood pressure values between
the 10th and 90th percentiles (Fig. 12.1).1 A linear relationship exists
between blood pressure and both gestational age or birth weight
and postnatal age. The statistically defined lower limits of mean BP
during the first day of life are approximately numerically similar to the
gestational age of the infant. However, by the third day of life, most preterm
infants, even with 24-26 weeks’ gestation, have a mean BP of 30 mm
Hg or greater. The increase in blood pressure with advancing gestational
and postnatal age is clearly developmentally regulated. In the absence
of a PDA and past the immediate newborn period, cardiac output is similar
in both term and preterm infants. Therefore, the increase in BP is primarily
the result of increase in SVR. Maturation of vascular smooth muscle,
changes in the expression of vascular angiotensin II receptor subtypes and
maturation of the central autonomic and peripheral nervous system play
a significant role in increasing vascular tone and therefore, SVR with increasing
gestational age.2
Fig. 12.1: Gestational and postnatal-age-dependent normogram for mean BP values

in neonates during the first wks of life. Each line represents the lower limit of
80% CI of mean BP for each gest. age gp (Nuntnarumit et al1)
PHYSIOLOGY
In terms of physiology, the normal range for blood pressure is best defined
by the presence of intact organ/issue perfusion. However, the lower and
upper limits of this physiologic blood pressure range have not been
determined in the newborn. In clinical situations, decision to treat a
hypotensive newborn on the basis of “numbers” is without proven physiologic
relevance.
PHASES OF NEONATAL SHOCK ......................................................

Shock presents in distinct phases of advancing severity characterized by
specific pathological alterations in cardiovascular and renal function. 3 In
the initial compensated phase of shock, vital organ function and blood
pressure are maintained by neurohormonal compensatory mechanisms.
However, especially in the immediate postnatal period in the preterm infant,
the associated changes in cardiovascular and renal function are difficult
to assess and the compensated phase of shock frequently goes undetected.
With progression of the condition, shock enters its uncompensated phase.
In this phase, failure of the neurohormonal compensatory mechanisms
results in the clinically recognizable symptoms of systemic hypotension and,
with further progression of the process, the development of metabolic acidosis.
Thus, in the preterm infant, shock is most frequently recognized
in its uncompensated phase.
NEONATAL SHOCK 145
ETIOLOGY OF SHOCK IN NEONATE ...............................................
Adequate tissue perfusion depends on
• Cardiac output
• Integrity and maintenance of peripheral vascular tone
• Blood volume
• Oxygen carrying capacity.
In neonates, abnormal peripheral vasoregulation with or without
myocardial dysfunction is the most frequently encountered primary
etiological factor of shock.4-6 In most of the cases of shock in neonates
like sepsis, asphyxia, NEC, etc. the culprit is abnormal peripheral vaso-
regulation with or without myocardial dysfunction.
Studies showing lack of relationship between blood volume and BP
in neonates7,8 and the finding that dopamine is at least twice as effective
in normalizing blood pressure as compared to volume administration9 strongly
support the view that absolute hypovolemia is a less frequent primary
cause of neonatal hypotension. However, if evidence of acute blood
loss, excessive transepidermal water loss or excessive urine output is there,
absolute hypovolemia should be considered as the primary cause.
CEREBRAL BLOOD FLOW (CBF)

CBF is obviously the most physiological and reliable indicator of cerebral
perfusion. A major problem in exploring the relation between early changes
in the CBF and brain injury in newborns is how to measure it. BP gives
only a loose indication of systemic blood flow and the effect of shunting
at PDA on left ventricular output and of atrial shunts on right ventricular
output can cause either of these measures to overestimate the real systemic
(cerebral) blood flow. The flow returning to the heart via the superior
vena cava (SVC) offers a solution to this problem in that it represents
flow to the upper body, approximately 80% of which goes to the brain.10
Kluckow M et al11 assessed SVC flow together with right ventricular
output and atrial or ductal shunting. Normal range was established in 14
infants born after 36 weeks gestation and 25 uncomplicated infants born
before 30 weeks. It was found that in term babies median SVC flow rose
from 76 ml/kg/min on day 1 to 93 ml/kg/min on day 2 and in preterm
infants, it rose from 62 ml/kg/min at 5 hours to 86 ml/kg/min at 48 hours.
RELIABILITY OF CLINICAL PARAMETERS IN ASSESSMENT

OF CEREBRAL BLOOD FLOW IN PRETERM BABIES
SVC flow measurement or near infrared spectroscopy (NIRS) may not
be possible in all settings, thus it is important to know whether clinical
parameters like BP, capillary refilling time (CRT) or central-peripheral
temperature difference (CPdT) can detect low systemic/cerebral blood flow

states. In clinical practice during the first postnatal day, lower limit of normal
mean arterial pressure (MAP) is considered to be equal to baby’s
gestational age. However, physiology studies of CBF have found that
the lower limit of the auto-regulatory BP range is around
30 mm Hg even in the 1-day-old extremely low birth weight (ELBW)
neonate. Loss of autoregulation does not necessarily result in cerebral
injury unless significant swings in systemic blood pressure occur and/or
hypotension reaches the ischemic threshold14 (Fig. 12.2).
Fig. 12.2: The flat portion represents the autoregulatory plateau. The upper
threshold is not known. Below the lower threshold (30 mm Hg), blood flow falls
more in proportion to BP. The critical closing pressure (CrCP) depends on arterial
elasticity and intracranial pressure. The ischemic threshold is assumed to be
around 50% of resting CBF but the BP at that point is not known14
In the ELBW infant in the immediate postnatal period11,15 (on the

first day of life), blood pressure in the normal range may not
always guarantee normal vital organ (brain) blood flow. The reason
for this finding is not known. However, by the second postnatal day, normal
blood pressure is highly likely to be associated with normal brain and
systemic blood flow 15. In another study of premature babies, cerebral blood
flow assessed by NIRS was not significantly different16 in he groups with
MAP <30 mm Hg and MAP >30 mm Hg.
In a prospective, study of infants born at < 30 weeks gestation, Invasive
BP, CRT and CPTd (center peripheral temperature difference) and SVC
flow were measured at three, 5–10, and 24 hours after birth. CPTd did
not detect infants with low flows, CRT > 3 seconds had 55%
sensitivity and 81% specificity, mean BP < 30 mm Hg had 59%
sensitivity and 77% specificity for detecting low SVC flow. Combining
NEONATAL SHOCK 147
a mean BP < 30 mm Hg and/or central CRT > 3 seconds increases
the sensitivity to 78%. Thus the conclusion was that these clinical
parameters are likely to miss unacceptably high number of preterm
babies with low cerebral blood flow on first day of life.17
HYPOTENSION AND CNS MORBIDITY/NEURODEVELOPMENTAL

OUTCOME
Several studies have found an association between hypotension and
central nervous system morbidity (IVH, PVL) and neurodevelopmental
outcome.18-26 However, it is important to note that very little data are
available demonstrating a causative relationship among these factors.
MAP and IVH/PVL: In a study recording hourly blood pressures in 131
very low birth weight infants in intensive care during the first 4 days of
life, cranial ultrasound evidence of intraventricular hemorrhage
correlated well with periods of hypotension however, ischemic lesions
did not correlate with hypotension.19 Another similar study using computerized
continuous measurement of MAP and serial cranial ultrasonography in
33 infants of less than 31 weeks gestation showed that a MAP of
< 30 mm Hg for over an hour was significantly associated with
severe hemorrhage, ischemic cerebral lesions, or death within
48 hours. No severe lesions developed with a MAP =30 mm Hg.20 Bada
et al21 noted microcomputer-derived, minute-to-minute MAP values during
the first 48 hours of life in 100 preterm VLBW babies. In 72 babies with
no IVH or grade 1 IVH, the MAP values increased during the study period,
but in infants with grades 2 to 4 IVH (n = 28) consistently lower MAP
values were recorded. In a 5 year retrospective study on 232 VLBW babies
assessing association between intra-arterial MAP in first 7 days of life and
morbidity, it was found that IVH was predominantly associated with
a low and variable MAP on the day IVH was noted or the day before.
PVL and ROP were not associated with blood pressure.22
MAP and cerebral fractional oxygen extraction (CFOE): CFOE is also used
as a surrogate for CBF because these two are inversely related. Two recent
studies evaluating relationship between CFOE and MAP had apparently
contrasting results. Tsuji et al18 used NIRS to determine quantitative changes
in cerebral concentrations of oxygenated hemoglobin (HbO2) and deoxy-
genated hemoglobin (Hb) in VLBW infants. Impaired cerebrovascular
autoregulation was observed in 17 (53%). Eight of the 17 infants (47%)
developed severe IVH or PVL or both. Of the 15 infants with apparently
intact autoregulation, only 2 (13%) developed severe ultrasonographic lesions.
Thus, 8 of the 10 with severe lesions exhibited high correlation between
MAP and HbD.
Another study showed no relationship between MAP and CFOE.23,24

MAP and Long term outcome: Long term outcome is considered to be
the best yardstick against which all neonatal problems, their treatments
and interventions are weighed. In a study examining influence of acidosis,
hypoxia and hypotension on neurodevelopmental outcome, 191 VLBW
babies were enrolled and parameters like the type of acidosis (metabolic
or respiratory) present, duration of single and cumulative episodes of acidosis,
hypoxia and hypotension were measured. At 6 months, both respiratory
and metabolic acidosis as well as the total duration and longest single
episode of acidosis were significantly correlated with cognitive, motor, and
neurologic outcome (P < .0001). By 24 months, only the metabolic
component of acidosis had any significant association with all three outcome
measures. Duration of hypotension independently correlated with outcome
at both testing periods (P < .002) but isolated hypoxemia did not. The
metabolic component of acidosis and isolated hypotension contri-
buted significantly to adverse outcomes – abnormal neurological
examination and Bayley scores at 6 and 24 months (P < .05).25
Another study enrolled, 98 newborns, less than 34 weeks at birth to
examine the relationship between newborn hypotension and hypoxemia
and brain damage. Heart rate, blood pressure and oxygen saturation were
recorded continuously during the 96 hours following delivery. Outcome
measures included neuropathology in children who died, and motor and
cognitive development at one year corrected age in children who survived.
There were 22 children with a minor and 27 with a major abnormal outcome.
There was a relationship between newborn hypotension, newborn hypoxemia
and low birth weight, and a major abnormal outcome. The probability
of a major abnormal outcome increased from 8% in newborns
with no hypotension or hypoxemia, to 53% in children with both
hypotension and hypoxemia.26
LOW CEREBRAL BLOOD FLOW AND CNS MORBIDITY/

NEURODEVELOPMENTAL OUTCOME
Low CBF and IVH: Low or fluctuating cerebral blood flow is considered
to be one of the most important pathophysiological basis of IVH. 27 The
relation between CBF on the first day of life and the severity of any subsequent
IVH was investigated by Meek et al.28 CBF was measured in 24 babies
during the first 24 hours of life using NIRS. Infants were classified as:
normal scan, minor IVH or severe IVH. CBF was significantly lower
in the infants with IVH than those without hemorrhage, despite no
difference in carbon dioxide tension and a higher MAP. On subgroup
analysis, those infants with severe IVH had the lowest cerebral
blood flow.
NEONATAL SHOCK 149
In another study15, SVC flow was used as a surrogate for CBF11 in
babies born before 30 weeks gestation. SVC flow below the range recorded
in well preterm babies11 was common in the first 24 hours (38%) babies,
becoming significantly less common by 48 hours (5%) babies. 13 of 14
babies with grade 2 to 4 IVH had SVC flow below the normal range
before development of an IVH. Two of 4 babies with grade 1 IVH also
had SVC flow below the normal range before developing IVH. In all,
IVH was first seen after the SVC flow had improved, and the grade of
IVH related significantly to the severity and duration of low SVC
flow.
Another study by same authors on risk factors of IVH in premature
infants prospectively followed 2 cohorts of 126 (1995-1996) and 128 (1998-
1999) infants born <30 weeks gestation. It was found that early IVH
was associated with vaginal delivery and possibly low APGAR
scores and low SVC flow was the only independent risk factor for late
IVH in both cohorts (1995-1996 adjusted OR: 20.39; 1998-1999 adjusted
OR: 5.16).29 On comparing the SVC flow disturbances and middle cerebral
artery (MCA) indices for strength of association with IVH 30, it was found
that after controlling for gestation, there was a highly significant
association between lowest SVC flow and subsequent IVH but
no association between IVH and lowest MCA mean velocity, estimated
diameter, pulsatiIity, or MAP.
LOW CBF AND LONG TERM OUTCOME31-33

A prospective observational study was performed on a cohort of 126 babies
(<30 weeks) who had serial measurement of SVC flow, during the first
48 hours after birth. Neurodevelopmental follow-up data was available
for 93% of this cohort at 3 years of age. After controlling for confounding
variables, average SVC flow over the first 24 hours of life was significantly
associated with the primary outcome of death or survival with any disability
(P = .004) and with the secondary outcome of abnormal developmental
quotient (P=.006). A greater number of low SVC flow readings during
the first 24 hours were significantly related to death and adverse
developmental outcome, but the individual lowest SVC flow was not,
suggesting the importance of duration of low SVC flow. After
adjustment, there was no significant association between average mean
blood pressure over the first 24 hours and abnormal developmental outcome,
whereas, the proportion of mean blood pressure readings less than
the gestational age showed a trend toward an association with death
and any disability.32
TREATMENT OF SHOCK AND NEURODEVELOPMENTAL OUTCOME

Hypotension may cause brain injury and other serious problems and treatment
aims to maintain blood flow to brain and other vital organs by using
fluids or drugs.
VOLUME EXPANSION
Products used—albumin, blood or blood substitute or salt solutions. Osborn
et al34 reviewed the evidence from various trials on the subject and performed
a meta-analysis to study whether volume expansion is effective and what
type of fluid is most effective. Seven studies were included.35-42 Five studies,
four with data for mortality, compared volume to no treatment. Two studies,
comparing different types of volume expansion enrolled very preterm infants
with hypotension.
One study examined the effect of volume expansion on blood flow
but in normotensive very preterm infants. Comparing volume and no
treatment, 4 studies with a total of 940 very preterm infants reported no
significant difference in mortality (RR 1.11, 95% CI 0.88, 1.40). The large
NNNI 199641 study reported no significant difference in severe disability
(RR 0.80, 95% CI 0.52, 1.23), cerebral palsy (RR 0.76, 95% CI 0.48,
1.20) and combined death or severe disability (RR 1.00, 95% CI 0.80,
1.24). No significant difference was reported in grade 3-4 P/IVH and
combined death or grade 3-4 P/IVH. One study (NNNI 199641) reported
no significant difference in the incidence of hypotension.
Comparing albumin and saline in hypotensive infants, one study (Lynch
200240) reported a significant increase in mean BP and reduced incidence
of treatment failure (persistent hypotension). The other study (So 1997 42)
and the meta-analysis of the two studies found no significant difference
in treatment failure (RR 0.75, 95% CI 0.53, 1.06) or in any other clinical
outcome. They concluded that there is no evidence to support the
routine use of early volume expansion in very preterm infants
without cardiovascular compromise. There is insufficient evidence
to determine whether infants with cardiovascular compromise
benefit from volume expansion. There is insufficient evidence to
determine what type of volume expansion should be used in preterm infants
(if at all) or for the use of early red cell transfusions.
VOLUME EXPANSION VERSUS INOTROPES

A meta-analysis of trials comparing volume expansion and inotropes was
done.43 Two small studies39,44 comparing volume expansion, using albumin,
with dopamine were included. Both studies were adequately randomised,
NEONATAL SHOCK 151
unblinded studies of albumin versus dopamine with no losses to follow
up and analysed by intention to treat. Data for clinical outcomes were
available from one study in hypotensive preterm infants on the first day
of life.44 In this study, albumin had a higher failure rate for correcting
hypotension than dopamine (RR 5.23; 95% CI 1.33 to 20.55). As 49%
of these infants had already been given volume, the question of which
treatment should be given first was not answered. A second study39 compared
albumin with dopamine in preterm infants with a normal mean blood
pressure at a mean age of 32 hours. Dopamine produced a significant
increase in mean blood pressure when compared to infants who received
albumin or no treatment, although the difference between the dopamine
and albumin groups did not reach significance. No difference was found
in mortality (RR 1.45; 95% CI 0.53 to 3.95) or morbidity including any
P/IVH, chronic lung disease or retinopathy. There was a higher rate of
grade 2-4 P/IVH of borderline statistical significance in infants who received
albumin in one study (RR 1.47; 95% CI 0.96 to 2.25: RD 0.27, 95%
CI 0.00 to 0.54). No data were available for neurodevelopmental outcomes.
The conclusion was that dopamine was more successful than albumin
in correcting low blood pressure in hypotensive preterm infants,
many of whom had already received volume. Neither intervention has
been shown to be superior at improving blood flow, or in improving mortality
and morbidity in preterm infants.
INOTROPES (DOPAMINE VERSUS DOBUTAMINE)

Inotropes, including dopamine and dobutamine, are commonly used to
increase blood pressure. However, the safest and most effective drug for
treating hypotension in preterm babies has been unclear. There are multiple
trials on this subject but only five satisfied the inclusion criteria of Cochrane
meta-analysis.45 There was no evidence of a significant difference
between dopamine and dobutamine in terms of neonatal mortality
(RD 0.02 95% CI –0.12 to 0.16), incidence of periventricular leukomalacia
(RD –0.08, 95% CI –0.19 to 0.04), or severe periventricular hemorrhage
(RD –0.02, 95% CI –0.13 to 0.09). Dopamine was more successful than
dobutamine in treating systemic hypotension, with fewer infants having
treatment failure (RD –0.23, 95% CI –0.34 to –0.13; NNT = 4.4, 95%
CI 2.9 to 7.7). Treatment with dobutamine was associated with a significantly
greater increase in left ventricular output in the single study reporting that
outcome. There was no evidence of a significant difference between the
two agents with respect to the incidence of tachycardia (RD –0.06, 95%
CI –0.25 to 0.14). None of the studies reported the incidence of adverse
long term neurodevelopmental outcome. Dopamine is more effective
than dobutamine in the short term treatment of systemic

hypotension in preterm infants. However, in the absence of data confirming
long term benefit and safety of dopamine compared to dobutamine, no
firm recommendations can be made regarding the choice of drug to treat
hypotension.
CORTICOSTEROIDS
In most hypotensive preterm infants, cautious and limited volume
administration and the early use of dopamine are effective in improving
the cardiovascular status and renal function. However, a subgroup of
hypotensive preterm infants do not respond even when treatment is escalated
and aggressive volume resuscitation and dopamine doses well beyond the
conventional (2–20 μg/kg/min) dose range are used. In these patients with
volume- and pressor-resistant hypotension, several therapeutic
approaches have been attempted including additional escalation of dopamine
treatment, addition of epinephrine or nor epinephrine and more recently,
initiation of steroid administration. 51-55 Cochrane meta-analysis on this topic
identified two small studies and it was not considered appropriate to perform
a meta-analysis.56
Thus, there is no evidence linking various treatment modalities of shock
to the neurodevelopmental outcome.
TREATMENT OF LOW SVC FLOW AND

NEURODEVELOPMENTAL OUTCOME ...............................................
Osborn et al57 performed a two-center, randomized, double-blind study.
Infants (n = 42) with low SVC flow (<41 ml/kg/min) in the first 12 hours
were randomly assigned to receive 10 ml/kg normal saline solution, followed
by 10 μg/kg/min of dobutamine or dopamine. If low flow persisted or
recurred, the inotrope was increased to 20 μg/kg/min, with crossover to
the other inotrope if treatment failed to maintain flow. It was found that
volume produced a more significant increase in SVC flow than dopamine
(+43%). At the highest dose, dobutamine resulted in a significantly
greater increase in SVC flow than dopamine (mean, +9.9 vs
–3.2 ml/kg/min, P = .02). Dopamine resulted in a significantly greater
increase in blood pressure. Forty percent failed to increase or
maintain SVC flow in response to either inotrope. No significant
differences in mortality or morbidity were found.
The surviving babies of the above study were followed up by blinded
neurodevelopmental assessments at corrected ages of 1 and 3 years.58
No significant differences were found in clinical outcomes, except for reduced
NEONATAL SHOCK 153
rates of late severe periventricular/intraventricular hemorrhage in the
dobutamine group. At 3 years, infants in the dopamine group had significantly
more disability and a lower Griffiths General Quotient. At the latest time
measured, however, combined rates of death or disability were similar.
KEY POINTS – reducing NDD due to neonatal shock

1. Neonatal shock is a major outcome determinant in sick neonates – in preterm
babies major NDD increased from 8% in newborns with no hypotension
or hypoxemia, to 53% in children with both hypotension and hypoxemia.
2. A MAP of < 30 mm Hg for over an hour was significantly associated with
severe IVH and ischemic cerebral lesions.
3. IVH was predominantly associated with a low and variable mean arterial
pressure on the day IVH was noted or the day before.
4. In VLBW, metabolic acidosis and isolated hypotension contributed significantly
to adverse outcomes – abnormal neurological examination and Bayley scores
at 6 and 24 months.
5. On the first day of life, in VLBW babies, clinical tools used to measure
systemic perfusion like invasive BP, CRT and CPTd (center peripheral
temperature difference) are highly likely to miss cerebral hypoperfusion.
6. SVC flow is probably the best available tool to assess cerebral perfusion.
Highly significant association is observed between lowest SVC flow and
subsequent IVH.
7. Hypovolemia is not a common mechanism of shock in VLBW babies.
Fluid boluses have not shown to be useful in management of shock in
VLBW.
8. There is no demonstrable difference between dopamine and dobutamine
in clinically relevant long-term outcomes.
9. Dopamine is more effective than fluid boluses and dobutamine in treatment
of hypotensive (low blood pressure) preterm babies. Dobutamine is associated
with greater increase in tissue perfusion.
10. There are not good studies to comment on use of steroids in volume and
inotropes resistant shock.
11. Best evidence is still not available on what is the end point (measurement
parameter) to assess therapies. Even babies in whom SVC flows (currently
considered best measure of physiology) were compared as outcome
of therapy, no differences could be demonstrated in long term out-
comes.
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NEONATAL SHOCK 155
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John BM, Daljit Singh
13
Neonatal Sepsis
Neonatal sepsis can cause devastating damage to developing brain.

While the term neonate is affected only when there is direct brain
involvement particularly with meningitis, the scenario in preterm VLBW/
ELBW babies is more complex and sinister.
PATHOPHYSIOLOGY AND IMPACT ON NEURODEVELOPMENT ..

Inflammatory cytokines released in sepsis can cause increased per-
meability of blood brain barrier, disturb cerebral auto-regulation
mediate release of free oxygen radicals and many other cytotoxic products.1-
9
In intrauterine infection, clinical and/or histologic chorioamnionitis,

is associated with cerebral white matter injury and subsequent
neurodevelopmental impairment.10-14 A key role for an inflammatory response
by the fetus as well as the mother in the pathogenesis of brain injury
has been postulated.15-17 Proinflammatory cytokines in amniotic fluid
and in fetal or neonatal blood appear to increase the risk for neonatal
brain injury and adverse long-term outcome.
In neonates, inflammatory cytokines may be neurotoxic in vitro and
in vivo and may increase the permeability of the preterm blood-brain
barrier.18-22 Although it appears that the inflammatory cytokine response
precedes and contributes to brain injury, a cytokine response may also
be the result and/or marker of damaged white matter. Efforts to reduce
the inflammatory responses of the neonate with infection might reduce
the risk of brain injury associated with infection.23,24
Neonates with infection are at risk for circulatory and/or respiratory
insufficiency with decreased systemic blood pressure, hypoxemia, and
pathologic alterations in cerebral blood flow. A maturation-dependent
impairment in regulation of cerebral blood flow in preterm infants
increases the risk of ischemic injury.25 The long-term impact of cerebral

ischemia–reperfusion precipitated by sepsis-related cardiovascular instability
is unclear. Volpe and others have shown that oligodendroglial precursor
cells, the major cellular target in the pathogenesis of white matter injury/
PVL, are particularly vulnerable to free radicals that are generated in
response to ischemia-reperfusion. The role of infection and cytokines in
the pathogenesis of PVL might be related to effects on cerebral hemo-
dynamics, to the generation of reactive oxygen species/free radicals, or
to direct toxic effects on vulnerable oligodendroglial precursors.26-28
Babies with meningitis are noted to have motor deficits, seizures,
hydrocephalus, vision, hearing and cognition problems. Neonatal meningitis
can have severe long-term sequelae (CP, significant learning problems
(IQ < 55), global delay, need for special education) in 12–29% of survivors
and milder impairment (abnormality that impairs function without
significant intellectual or developmental impairment: mild CP, mild learning
problems (IQ 55–69)) of neurological function occurs in another 15–38%.
In VLBW infants this number increases to 40-50%. A recent report
from the United Kingdom noted a 4-fold increase in CP among VLBW
infants with a history of neonatal sepsis compared with infants with
no history of neonatal infection.9 Similar outcomes were demonstrated
in a large cohort study by Stoll et al involving more than 6000 ELBW
neonates. Infected ELBW infants are associated with poor neuro-
developmental and growth outcomes in early childhood-CP, low Bayley
Scales of Infant Development II scores on the mental development index
and psychomotor development index and vision impairment. Infection in
the neonatal period was also associated with impaired head growth, a
known predictor of poor neurodevelopmental outcome.32 Hearing impairment
was more frequent among children who survived neonatal sepsis or sepsis/
NEC, especially if they were infected with gram-negative agents or had
polymicrobial bacteremia or multiple infections.
Outcomes in relation to organisms have not been consistent. A few
studies have shown poorer outcome in gram negative infections as compared
to GBS.
EPIDEMIOLOGY OF SEPSIS1-5 ....................................................................................

The term neonatal sepsis is used to describe a disease of infants who
are younger than one month of age, are clinically ill, and have positive
blood cultures. The presence of clinical manifestations differentiates this
condition from the transient bacteremia observed in some healthy neonates.
Neonatal sepsis is the largest cause of morbidity and mortality in newborns
NEONATAL SEPSIS 159
particularly in the preterm/low birth weight babies. The incidence is 1-
5/1,000 live births in term babies and increases by 3-10 folds in preterm. It
is complicated by meningitis in many neonates and the incidence of
meningitis is 0.2-0.4/1,000 births in term neonates and much higher in
preterms. The data from our own country as published in National Neonatal
Perinatal Database reflects a much higher incidence of neonatal sepsis.
DIAGNOSIS ............................................................................................
In early onset sepsis, the maternal history may provide important information
about maternal exposure to infection, maternal colonization and obstetric
risk factors (prematurity, prolonged ruptured membranes, maternal
chorioamnionitis). The signs and symptoms of neonatal late onset sepsis
are often nonspecific,1-5 and sepsis should be considered in any sick neonate.
INVESTIGATIONS ..................................................................................
No single laboratory test has been found to have sufficient specificity and
sensitivity and therefore, laboratory information must be used in conjunction
with risk factors and clinical signs.1-5
MICROBIOLOGIC TESTS: CULTURES

Blood
• It is the gold standard for the diagnosis of septicemia. Definitive diagnosis
of neonatal sepsis can be made only with a positive blood culture.
• Minimum one, but ideally >1 blood culture. Blood cultures should
be obtained from peripheral skin punctures.
Cerebral Spinal Fluid (CSF)
• Meningitis can be often missed clinically. Consider performing
a lumbar puncture if there are any signs of sepsis in a neonate.
• Repeat lumbar puncture at 24-48 hours.
Complete 2 weeks of antibiotics in gram-positive meningitis and 3 weeks
in gram-negative infection after CSF is sterile.
Blood cultures may be sterile in 10-15% of infants with early onset
and in one-third of infants of VLBW with late-onset meningitis. Lumbar
puncture (LP) is indicated in all cases with positive blood culture
and symptomatic (stable) neonates being started on antibiotics
on strong clinical suspicion.
CSF should be obtained before starting antibiotics and sent for cell
count, differential count, and chemistry determinations as well as for
Gram stain and culture. CSF culture is the only reliable diagnostic
marker of meningitis. In a study in VLBW babies with meningitis, spinal
fluid abnormalities were sparse, regardless of etiologic organism. Of
38 non-bloody spinal fluid taps (<1,000 erythrocytes/mm3), only 6 had
>30 leukocytes/mm3, 5 had protein >150 mg/dl%, and 6 had glucose
<30 mg/dL (1.67 mmol/L). Only 10 infants (26%) had 1 or more of
these spinal fluid abnormalities. “Meningitis” survivors as determined
by CSF culures, had a higher rate of major neurologic abnormality (41%
vs 11%, p<0.001) and subnormal (<70) Mental Development Index (38%
vs 14%, p<0.001) than non-meningitis survivors.80
Other Cultures
Other cultures (urine, pus, limited utility for ET, catheter tip cultures) should
be obtained as indicated by clinical findings. One must also check maternal
cultures before and after delivery.
OTHER LABORATORY TESTS

Excluding cultures, none of the laboratory tests when used alone are sensitive
or specific enough to diagnose or exclude neonatal sepsis. Many investigators
have evaluated the predictive values of panels (combination) of tests for
diagnosing sepsis.
Leukocyte Counts
The ratio of immature to total neutrophils (I/T ratio) is 0.16 at birth and
declines to a peak value of 0.12 after 72 hours of age. I/T ratio of >0.20
is suggestive of infection. Total WBC less than 5,000/mm3, absolute neutrophil
count less than 1,000/mm3 and bands/ polymorphonuclear ratio greater
than 0.2 have been shown to have good predictive accuracy and sensitivity
for sepsis.
Acute-Phase Reactants34-52
Of the many different acute phase reactants C reactive protein has been
most extensively used and investigated. Serial determinations of CRP at
12-hour intervals after the onset of signs of sepsis has been found to increase
the negative predictive value of CRP, in excluding sepsis. Nonbacterial
infections can have a variable CRP response. CRP has a low positive
predictive value and should not be used alone to diagnose sepsis. 34-47
Serum procalcitonin has been claimed to be superior to other acute phase
proteins, including CRP, with sensitivity and specificity ranging from 87
to 100%.48-52
NEONATAL SEPSIS 161
Cytokines53-66
Cytokines are the chemical mediators of inflammatory pathway and are
detectable long before acute phase reactants or hematological changes
occur in response top bacteremia. They have been extensively studied
in the last decade—IL-6,53-55 IL8,56,57 CD64,58-61 CD11b,62-66 and many
others. They all suffer from limitations of use in clinical settings, and more
importantly have not been able to improve accuracy of diagnosis of sepsis
to the clinicians needs.
DETERMINANTS OF OUTCOME—NEONATAL MENINGITIS ...........

A retrospective study of 101 cases of neonatal bacterial meningitis admitted
between 1979 and 1998 identified early predictors of adverse outcome
at 1 year of age (death or moderate/severe disability). Twelve hours after
admission the important predictors of adverse outcome were presence of
seizures, presence of coma, use of inotropes, and leucopenia
5000 × 109 (sensitivity 68%, specificity 99%). Ninety six hours after admission,
predictors of adverse outcome were seizure duration of >72 hours, coma,
use of inotropes, and leucopenia (sensitivity 88%, specificity 99%). There
was no difference in outcome by pathogen, consistent with other reports.
The study excluded infants <35 weeks of gestation and infants with criteria
for intrapartum asphyxia, and thus cannot be used in assessing the risk
of disability in such infants. Prospective validation of the model is required.
A retrospective study assessed the value of the electroencephalogram
(EEG) in cases of neonatal meningitis. Infants who had normal or mildly
abnormal EEG backgrounds had normal outcomes (at a mean of 34 months),
whereas those with notably abnormal EEGs died or had severe
neurological sequelae.
TREATMENT ...........................................................................................
Early recognition and treatment of neonatal sepsis and supportive
therapy probably account for recent improvements in outcome and survival.1-
5 When a toxic newborn or young infant presents with fever and
lethargy or irritability, it is important to consider the diagnosis of meningitis

even if the classic localizing signs and symptoms are absent. Cerebrospinal
fluid should be obtained (unless lumbar puncture is clinically contraindicated)
to enable initial therapy to be planned. Initial results of cerebrospinal fluid
testing may not conclusively differentiate between aseptic and bacterial
meningitis, and antimicrobial therapy for all likely organisms should be
instituted until definitive culture results are available. Comprehensive therapy,
including antibacterial and antiviral agents, should continue until a
cause is identified and more specific therapy is initiated, an etiology is

excluded or the patient improves considerably and the course of antimicrobial
therapy is completed.
TREATMENT SUMMARY ......................................................................

ANTIBIOTIC THERAPY
Empirical antibiotic therapy should be instituted immediately after
obtaining samples for culture rather than waiting for the culture results.
The choice of empirical therapy should be based on several factors: the
timing and setting of the disease, the microorganisms most frequently
encountered, the susceptibility profile for these organisms, the site of the
suspected infection and the penetration of the specific antibiotic to that
site and the safety of that antibiotic.
• Empirical therapy for meningitis after the first week of life
• Repeat lumbar puncture at 24-48 hours
• Continue antibiotic therapy (intravenously) for at least two weeks (GBS
and Listeria) or three weeks (Gram-negative bacteria) after sterilization
of CSF cultures
• Consider longer duration of therapy if focal neurological signs persist
at two weeks, if >72 hours required to sterilise CSF, or if obstructive
ventriculitis, infarcts, encephalomalacia, or brain abscesses are found
by neuroimaging studies. A repeat lumbar puncture may help guide
duration of therapy in these circumstances.
B. Supportive care of the sick neonate has an equally important if not
more than antibiotics and adjuncts.
C. Immunotherapy
Currently there is insufficient evidence to support the routine administration
of exchange transfusion, granulocyte transfusion, granulocyte colony
stimulation factor and intravenous immunoglobulin (IVIG) in treatment or
prevention of neonatal sepsis. Pentoxifylline, a phosphodiesterase inhibitor
has been found to reduce mortality in preterm neonates with suspected
late onset sepsis.
IMAGING
If CSF culture positive at 48-72 hours and/or suspicion of neurological
complications perform cerebral ultrasound and/or computed tomography
Neuroimaging is recommended to detect the complications of meningitis.
Complications should be suspected when the clinical course is characterised
by shock, respiratory failure, focal neurological deficits, a positive CSF culture
after 48-72 hours of appropriate antibiotic therapy, or infection with certain
NEONATAL SEPSIS 163
organisms. Citrobacter koseri and Enterobacter sakazakii meningitis, for
example, are frequently associated with the development of brain abscesses,
even in infants who have a benign clinical course.The most useful and
non-invasive method early in the course is ultrasonography, which will provide
information regarding ventricular size and the presence of haemorrhage.
Computed tomography will be useful in detecting cerebral abscesses and
later in the treatment course in identifying areas of encephalomalacia that
may dictate prolonged therapy.
MANAGEMENT PRACTICES IN A NEONATE WITH SUSPECTED

SEPSIS ...................................................................................................
While the treatment of the sick/symptomatic neonate is less controversial,
the same cannot be said for the asymptomatic baby. Currently, decision
to initiate treatment and selection of antibiotic are both empirical. Protocols
may be devised for the unit and audited for utility (e.g. Perinatal risk
score by Bhakoo et al).
PREVENTION OF NEONATAL SEPSIS

Antibiotics given to mother with pre-labor rupture of membranes reduces
the risks of infection in mother and baby (ORACLE trial), the choice of
antibiotic may be decided on local epidemiology of the unit. Some antibiotics
may be associated with increased risks, e.g. amoxicillin-clavulonate is
associated with risk of NEC after birth.
Each unit will have to evaluate practices and develop stringent protocols
for prevention of sepsis, e.g. Kilbride et al have commented on evaluation
and development of potentially better practices to prevent neonatal
nosocomial bacteremia.67 These include:
• Reducing line and line connections (hubs) contamination will decrease
risk of bacterial entry and nosocomial bacteremia.
• Hand hygiene is the primary means to limit potential colonization and
nosocomial infections in high-risk newborns.
• Standardized assessment of nosocomial infections will limit unnecessary
antibiotic treatment of contaminated blood cultures (False positives).
• Use maximal barrier precautions for insertion of central catheters.
• Selected use of topical application of preservative-free ointment in preterm
infants.
• Decrease the number of skin punctures.
• Reduce the duration of IV lipid use.
• Limit the number of days that percutaneous deep lines are in place
to 21.
ADJUNCT THERAPIES
Discussed elsewhere in the book.
KEY POINTS – reducing NDD due to sepsis

1. Sepsis mediates NDD by meningitis (loss of cerebral blood flow auto-
regulation, increased permeability of BBB, direct cytotoxic injury) and indirect
effects—hypoxia and perfusion problems. In VLBW and ELBW babies, sepsis
without meningitis also increases risk of NDD (mediated by inflammatory
cytokines). In intrauterine infection, chorioamnionitis is associated with white
matter injury in preterm.
2. As many as one-third of term babies and half of VLBW babies with meningitis
have serious NDD.
3. Lumbar puncture (LP) is indicated in all neonates with positive blood culture
and symptomatic (but medically stable) neonates being started on antibiotics
on strong clinical suspicion.
4. CSF should be obtained before starting antibiotics. CSF culture and Gram
stain are the most reliable tools in diagnosis of meningitis, especially in
VLBW.
5. Seizures, duration of coma, need for inotropes, leucopenia and delayed
sterilization of CSF are predictors of NDD.
6. EEG— A normal or mildly abnormal EEG is a predictor of good outcome
in meningitis.
7. Neuroimaging is recommended to detect the complications of meningitis.
Complications should be suspected when the clinical course is characterized
by shock, respiratory failure, focal neurological deficits, positive CSF culture
after 48–72 hours of appropriate antibiotic therapy, or infection with certain
organisms- Citrobacter koseri and Enterobacter sakazakii.
8. Screening and treatment of asymptomatic neonates at risk of infections
is currently empirical, algorithms/protocols may be devised for the unit.
9. Diagnosis—Cultures are the only definitive diagnostic tools for sepsis, all
other lab tests are not sensitive/specific to be used alone, and mostly tests
are combined as panels.
10. Management—If a neonate presents with encephalopathy, the baby must
be started on appropriate broad spectrum antibiotics in anti-meningitic doses
until the diagnosis of sepsis – meningitis is excluded. If viral infections
are likely, antiviral drugs may also be started, till CSF viral studies are
available.
11. Supportive care and adjunct therapies must be initiated as appropriate.
12. Prevention of sepsis—Strict hygiene and house keeping protocols must
be adhered to, and regular monitoring of cultures for nosocomial infections
is necessary.
FAQ’s68-79 .........................................................................................................................................
Q-1. What is the role of vancomycin for prophylaxis against sepsis

in preterm neonates?
A-1. The limited data available suggests that the use of prophylactic
vancomycin in low doses reduces the incidence of nosocomial sepsis in
the neonate with insufficient evidence to ascertain the risks of development
NEONATAL SEPSIS 165
of vancomycin resistant organisms. However, the current consensus
does not recommend routine antibiotic prophylaxis.
Q-2. What is the status of use of topical ointment for preventing
infection in preterm infants?
A-2. The rationale for this practice is that topical emollient therapy decreases
dermatitis and fissuring, thus decreasing the entry of bacteria into the
bloodstream. Randomized, controlled trials of emollient application have
demonstrated improved skin grading scores and decreased numbers of
bacteria cultured from the skin. However, the practice of routine ointment
application remains controversial because a more recent randomized trial
demonstrated an increase in CONS in preterm infants who received twice-
daily petrolatum ointment application. The routine application of emollients
may actually increase colonization, with no added benefit for patients who
have intact skin. The group consensus is that emollients have a place
in maintaining skin integrity, but routine application
for intact skin is unnecessary and the risks may outweigh the
benefits.
Q-3. Is there a difference of prophylactic versus selective antibiotic
use for term asymptomatic babies born to mothers with risk
factors?
A-3. There is insufficient data from randomized controlled trials to guide
clinical practice. A large randomized controlled trial is needed in asymptomatic
term infants born to mothers with risk factors for infection in their babies,
which compares the effect of prophylactic versus selective antibiotics on
morbidity, mortality and costs.
Q-4 What is the role of prophylactic intravenous antifungals to
prevent fungal infections in preterm VLBW babies?
A-4. Recent meta-analysis found some evidence that prophylactic intravenous
fluconazole reduces mortality prior to hospital discharge in very low birth
weight infants. The meta-analysis suggests that there will be one fewer
death in every nine infants treated with this intervention, but the 95%
confidence interval around this estimate of effect is wide. The longer term
neurodevelopmental consequences for infants exposed to this intervention
remain to be determined. It will be important to identify any subgroups
of very low birth weight infants that receive the most benefit from this
intervention. There is also a need for further data on the effect of the
intervention on the emergence of organisms with stable antifungal resistance.
Q-5. Is there a role of prophylactic antibiotics to reduce morbidity

and mortality in neonates with umbilical venous/arterial catheters?
A-5. There is insufficient evidence from randomized trials to support or
refute the use of prophylactic antibiotics when umbilical venous catheters
are inserted in newborn infants. There is no evidence to support or refute
continuing antibiotics once initial cultures rule out infection in newborn
infants with umbilical venous catheters.
Q-6. Are there any vaccines which can be given to the mother
to prevent neonatal infection?
A-6. There are trials going on in early phases with GBS vaccines .There
are also trials with pneumococcal vaccine to prevent pneumococcal infection
in neonates. Currently, there is insufficient evidence to support pneumococcal
vaccination during pregnancy to reduce infant infections.
Q-7. Vaccination after birth.
A-7. Besides routine vaccination, Hemophilus influenzae B vaccine and
pneumococcal conjugate vaccines given after birth reduce the risk of
meningitis in early infancy.
Q-8. What is the role of pentoxyfylline in neonatal sepsis?
A-8. Current evidence suggests that the use of pentoxifylline as an adjunct
to antibiotics in neonatal sepsis reduces mortality without any adverse effects.
But the number of neonates studied has been small. Hence, these results
should be interpreted with caution. Researchers are encouraged to undertake
large well-designed trials to confirm or refute the effectiveness of pentoxifylline
to reduce mortality and adverse outcomes in neonates with suspected or
confirmed neonatal sepsis.
Q-9. What is the role of IVIg in neonatal sepsis?
A-9. There is insufficient evidence to support the routine administration
of IVIg preparations investigated to date to prevent mortality in infants
with suspected or subsequently proved neonatal infection.
Q-10. Is there any role of IVIg in preventing sepsis in preterm
infants?
A-10. Recent meta-analysis showed that IVIg administration resulted in
a 3% reduction in sepsis and a 4% reduction in any serious infection,
one or more episodes, but was not associated with reductions in other
important outcomes: sepsis, NEC, IVH, or length of hospital stay. Most
importantly, IVIg administration did not have any significant effect on mortality
from any cause or from infections. Prophylactic use of IVIg is not associated
with any short term serious side effects. From a clinical perspective a 3-
4% reduction in nosocomial infections without a reduction in mortality
NEONATAL SEPSIS 167
or other important clinical outcomes is of marginal importance. The decision
to use prophylactic IVIG will depend on the costs and the values assigned
to the clinical outcomes.
Q-11. What is the current evidence on use of granulocyte
transfusions in neonatal sepsis?
A-11. Currently, there is inconclusive evidence from RCTs to support or
refute the routine use of granulocyte transfusions in neonates with sepsis
and neutropaenia to reduce mortality and morbidity.
Q-12. What is the role of various colony stimulating factors in
management of neonatal sepsis?
A-12. There is currently insufficient evidence to support the introduction
of either G-CSF or GM-CSF into neonatal practice, neither as treatment
of established systemic infection to reduce resulting mortality, nor as
prophylaxis to prevent systemic infection in high risk neonates. No toxicity
of CSF use was reported in any study. The limited data suggesting that
CSF treatment may reduce mortality when systemic infection is accompanied
by severe neutropenia should be investigated further in adequately powered
trials which recruit sufficient infants infected with organisms associated with
a significant mortality risk.
WEB LINKS ...........................................................................................

1. http://www.cochrane.org/reviews/
2. h t t p : / / w w w . g f m e r . c h / G u i d e l i n e s / M a t e r n a l_ n e o n a t a l _ in f e c t io n s /
Neonatal_infections.htm
3. http://www.neonatology.org/neo.clinical.html
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Section 7
Interventions
14. Pain and Analgesia
15. Neonatal Transport
16. Perinatal Steroids
17. Mechanical Ventilation
Jaikrishan Mittal
14
Pain and Analgesia
Pain is defined as ‘an unpleasant sensory and emotional experience

associated with actual or potential tissue damage’. Neonates endure many
painful procedures during their stay in the neonatal intensive care unit
(NICU). The use of pain relieving interventions has been sparse due to
the misconception that neonates do not feel pain. There is now
sufficient evidence that neuro-anatomical and neuro-endocrine systems
in a viable fetus are sufficiently mature for transmission and perception
of painful stimuli.1-4
PATHOPHYSIOLOGY ............................................................................
Nociceptive pathways develop very early in fetal life. As early as 6 weeks
gestation, dorsal horn cells in the spinal cord form synapses with the
developing sensory neurons. These sensory neurons grow peripherally
to reach the skin of the limbs by 11 weeks, the rest of the trunk by
15 weeks and the remaining cutaneous and mucosal surfaces by 20 weeks.
At full term, the density of nociceptive nerve endings in the newborn
skin is at least as great as that of the adults. Myelination of nociceptive
thalamo-cortical radiations is complete by 37 weeks. In contrast, descending
inhibitory tract, which suppress the transmission of noxious stimuli, are
not fully functional at term. The lack of descending inhibition from
higher centers increases afferent nociceptive transmission in the spinal cord.
Although nociceptive connections are immature in the preterm, the larger
receptive fields, the immaturity of the descending inhibitory pathways,
and the ability of “non C nerve fibers” to transmit nociceptive inputs
into the dorsal horn (facilitated by “sub-threshold C-nerve fibers”) results
in under damped, poorly discriminated and exaggerated responses.
This concept is derived from Fizgerald’s observations on the cutaneous
withdrawal reflex.5
WHAT ARETHE COMMON PAINFUL PROCEDURES IN NEONATAL PERIOD?

Painful procedures commonly performed in the neonatal intensive care
unit are:
Diagnostic
• Arterial puncture
• Heel lancing
• Lumbar puncture
• Retinopathy of prematurity examination
• Suprapubic bladder tap
• Venipuncture
• Bronchoscopy
• Endoscopy.
Therapeutic
• Bladder catheterization
• Central line insertion/removal
• Chest tube insertion/removal
• Chest physiotherapy
• Dressing change
• Feeding tube insertion
• Intramuscular injection
• Peripheral venous catheterization
• Mechanical ventilation
• Postural drainage
• Removal of adhesive tape
• Suture removal
• Tracheal intubation/extubation
• Tracheal suctioning
• Ventricular tap
Surgical
• Circumcision
• Other surgical procedures.
HOW DOES A NEONATE REACT TO PAINFUL STIMULI?
Both term and preterm neonates exhibit physiologic and hormonal responses
to painful stimuli - increased sympathetic activity, increased catecholamine
production, hyper dynamic circulation, increased oxygen demand,
insulin resistance, increased gluconeogenesis, and a catabolic
state. The responses may be exaggerated when compared with older
PAIN AND ANALGESIA 177
children and adults. Major stress e.g. surgery without analgesia can result
in serious complications and contribute to surgical mortality.
Acute Effects of Pain
The acute effects of nociception are
• Hemodynamic response: Rise in mean arterial pressure
• Rise in intracranial pressure
• Hormonal responses
• Greater nitrogen loss, post surgery: Delayed post-operative recovery.
Long-term Effects of Pain
• Post-injury hyperalgesia
• Allodynia
• Persistence of immature pain response.
Immediate Neurological Consequences of Pain

Acute hemodynamic changes caused by painful or stressful stimuli are
implicated in causation or subsequent extension of early intraventricular
hemorrhage (IVH) or the ischemic changes leading to periventricular
leukomalacia (PVL).6
Long-term Consequences of Pain
There is evidence that untreated pain experienced in early life may lead
to an exaggerated response to subsequent painful episodes. Infants circum-
cised without anesthesia demonstrate exaggerated response to vaccination.
This hypersensitivity may be a consequence of painful stimuli during critical
period of brain development, leading to structural and functional changes
in the nervous system.
Non-noxious stimuli during these periods of hyperalgesia increase painful
experiences. Long-term follow-up of preterm neonates may substantiate
the preliminary data associating repetitive painful experiences with
neurobehavioral and developmental sequelae.
ASSESSMENT OF PAIN IN NEONATES ..........................................

Pain assessment tools in neonates depend on subjective evaluation
of physiological and behavioral responses. (Table 14.1)
PREVENTION AND MANAGEMENT OF PAIN IN

NEONATES—PRINCIPLES ...................................................................
1. Pain in newborns is often unrecognized and under-treated. Neonates
do feel pain, and analgesia should be prescribed when indicated.
Table 14.1: Commonly used methods for assessment of pain in newborn

Premature Neonatal facial Neonatal Infant CRIES score
Infant Pain Coding Scale Pain Scale
Profile (PIPP) (NFCS) (NIPS)
Variables Gestational age Brow bulge Facial expression Crying
assessed Behavioral state Eye squeeze Cry Requires
Heart rate Naso-labial furrow Breathing patterns Increased
Oxygen saturation Open lips Arms oxygen demand
Brow bulge Stretch mouth Legs Expression
Eye squeeze Lip purse State of arousal Sleeplessness
Naso-labial furrow Taut tongue
Chin quiver
Tongue
protrusion
Reliability data Inter-rater and Inter-rater and Inter-rater Inter-rater

intra-rater intra-rater reliability >0.92 reliability >0.72
reliability >0.93 reliability
> 0.85
Forms of Face, content, Face, content, Face, Face, content,

validity construct (in construct, and construct, and discrimnant,
established preterm and convergent concurrent and concurrent
term neonates) (r = 0.89) (r = 0.53-0.84) (r = 0.49-0.73)
Clinical utility Feasibility and Feasibility Not established Nurses

utility established at preferred
established at bedside CRIES over
bedside another scale
2. If procedure is painful in adults, it should be considered painful in

newborns, even if they are preterm.
3. Compared with older age groups, newborn may experience a greater
sensitivity to pain and are more susceptible to the long term effects
of painful stimulation.
4. Adequate treatment of pain may be associated with decreased clinical
complications and decreased mortality.
5. The appropriate use of environmental, behavioral, and pharmacological
interventions can prevent, reduce, or eliminate neonatal pain in many
clinical situations.
6. Sedation does not provide pain relief and may mask the neonate’s
response to pain.
7. Health care professionals have the responsibility for assessment,
prevention, and management of pain in neonates.
8. Clinical units providing health care to newborns should develop written
guidelines and protocols for the management of neonatal pain.
TREATMENT MODALITIES FOR PAIN

1. Pharmacological
a. Opioids: Morphine, fentanyl, codeine
b. Non opioids: Paracetamol, sucrose, midazolam
c. Anesthetic agents: EMLA, lidocaine, ketamine, thiopental.
2. Environmental
a. Minimizing painful interventions
b. Clustering of painful interventions
c. Decreased handling
d. Reducing ambient noise and light
e. Establishing day – night cycle.
3. Behavioral
a. Gentle sensory stimulation of visual, tactile, auditory, and taste
sensation
b. Oral sucrose
c. Kangaroo mother care.
Pharmacological Treatment Modalities (Table 14.2)

Morphine: Morphine, fentanyl and codeine are the most commonly used
opioids in NICU. Morphine is the historical gold standard against which
other analgesics are compared.
• Evidence: Cochrane review7 on opioids for neonates receiving
mechanical ventilation. Thirteen studies, 1505 infants. Infants given
opioids showed reduced premature infant pain profile (PIPP) scores
compared to the control group (weighted mean difference –1.71; 95%
confidence interval –3.18 to –0.24). However the studies were significantly
heterogeneous. Meta-analysis of mortality, duration of mechanical ventilation,
and long and short term neurodevelopmental outcomes showed no
significant differences. Very preterm infants given morphine took significantly
longer to reach full enteral feeding than those in control groups.
• Short term neuro-developmental outcome: Only one study6 assessed
the neurodevelopmental outcome at 36 weeks corrected age using
neurobehavioral assessment of the premature infant (NAPI score). After
adjusting for differences in neonatal medical index (sickness score) and
gestational age, no significant differences were noted in the NAPI score,
between the morphine and placebo group.
• Long term neuro-developmental outcome: When assessed at 5-
6 years age, there were no significant differences in the morphine
and non-morphine groups in disability, combined death and disability
rates, intelligence, motor impairment or behavioral problems.
• Incidence of IVH: A meta-analysis showed no significant difference
(relative risk 0.84; 95% confidence interval 0.60 to 1.17) in the incidence
of “all grades of IVH” between morphine and placebo groups. The
lone study on very preterm infants,6 also showed no significant effect
of analgesia on the incidence of “any grade IVH”. The meta-analysis
did not find a difference in incidence of “severe IVH” between morphine
and placebo groups.
• Incidence of PVL: A meta-analysis of studies including very preterm

babies, showed no significant difference in incidence of PVL between
morphine and placebo groups.
• Conclusion: There is insufficient evidence to recommend routine use
of opioids in mechanically ventilated newborns. Opioids should be
used selectively, as indicated by clinical judgment—pain scales.
• Doses: In ventilated babies, an intravenous loading dose (50-150
microgram/kg) is required to achieve effective analgesia, followed by
an infusion rate between 5 and 20 microgram/kg/hour. However, as
tolerance develops, the infusion rate may need to be increased.
Morphine should be given with caution in the spontaneously breathing
neonate.
• Unanswered questions: need for further research on long term neuro-
developmental consequences of morphine. Currently, no recommen-
dation can be made on its routine use.
Midazolam: Midazolam is a short acting benzodiazepine. It is preferred
over other benzodiazepines because of its water solubility and rapid
clearance. The safety and effectiveness of intravenous midazolam as a
sedative in critically ill neonates is not well established.
The Cochrane review 8 showed higher level of sedation in the midazolam
group compared to the placebo group, although there was no difference
in sedation level between midazolam and morphine. Jacqz-Aigrain found
lower blood pressure in babies receiving midazolam than in placebo group. 9
Anand et al showed a higher incidence of adverse neurological events
(death, grade III-IV IVH, PVL) in the midazolam group compared
with placebo and morphine group. 6
• Conclusion: There are insufficient data to promote the use of

intravenous midazolam infusion as a sedative for neonates in intensive
care units. If sedation is required, morphine is safer than
midazolam.
• Further research: effectiveness and safety of midazolam in neonates.
Sucrose: The administration of sucrose with and without non-nutritive
sucking (pacifiers) is the most studied non-pharmacological intervention
for relief of procedural pain in neonates. The effects of sucrose are thought
to be mediated by both the endogenous opioids and non-opioid systems.
These mechanisms may be additive or synergistic but most likely depend
on normal functioning of central nervous system.
In Cochrane review, sucrose, used in a wide range of dosages, was
found to improve physiologic (heart rate) and behavioral (the mean percent
time crying, total cry duration, duration of first cry, and facial action)
pain indicators and composite pain scores in neonates undergoing heel
stick or venepuncture. Premature infant pain profile was significantly reduced
in infants who were given sucrose compared to the control group. Long
term neuro-developmental outcomes were not reported in any of the
study.10
• Conclusion: Sucrose is safe and effective for reducing procedural
pain from single painful events (heel lance, venepuncture).
• Doses: there is an inconsistency in the dose of sucrose that is effective,
in available studies (dose range 0.012 g to 0.12 g). There is a dose
dependent effect, but optimum dose is not known.
• Unanswered questions: The effect of repeated administration of
sucrose in neonates need to be investigated, also, the right dose needed
when combined with behavioral (e.g. facilitated tucking, kangaroo care)
and pharmacologic (e.g. morphine, fentanyl) interventions. Efficacy
in very low birth weight neonates who are unstable and/or ventilated
also needs to be studied.
Breastfeeding or breast milk: There are several proposed mechanisms by
which breast milk or breast feeding acts as an analgesic-presence of a
comforting person (mother), physical sensation (skin to skin contact with
comforting person), diversion of attention and sweetness of breast milk.
Compared to artificial formulas, breast milk contains a higher concentration
of tryptophan, a precursor of melatonin. Melatonin is shown to increase
the concentration of beta endorphins and could possibility be one of
the mechanisms for the nociceptive effects of breast milk.
In a systemic review by Shah et al,11 neonates in the breastfeeding group
were found to have lesser increases in the heart rate and reduced proportion
of crying time compared to swaddled group or pacifier group. Neonates in the
breastfeeding group had a significant reduction in duration of crying compared
to fasting (no intervention group), but there was no significant difference when
compared to glucose group. PIPP scores were significantly different between
the breastfeeding group when compared to placebo group and the group
positioned in mother’s arm. However these scores were not significantly different
in the breastfeeding and glucose group.
• Conclusion: If available, breastfeeding or breast milk should be used
to alleviate pain in neonates undergoing a single painful procedure.
• Further research: The effectiveness of breast milk for repeated painful
procedures is not established and further research is needed.
Kangaroo mother care (KMC): In a clinical trial by Ludington-Hoe SM

et al,12 heart rates and length of cry in response to pain were significantly
reduced during Kangaroo Care as compared to when infants were in
the warmer. In another study by Johnston CC et al.13 Premature Infant
Pain Profile scores across the first 90 seconds from the heel-lancing
procedure were significantly lower during KMC.
EMLA and pain relief for circumcision: EMLA is a water-based cream
that contains 2.5% lidocaine and 2.5% prilocaine. The efficacy of EMLA
in treatment of procedural pain in children and adults is well established.
Apprehension in using EMLA in neonates is due to risk of
methemoglobinemia from prilocaine metabolites (oxidize hemoglobin).
Preterm infants may be at greater risk of toxicity because of immaturity
of skin that enhances percutaneous absorption of drugs.
In the Cochrane review,14 EMLA was compared with dorsal penile
nerve block (DPNB) and placebo for circumcision. Compared to placebo/
no treatment, DPNB demonstrated significantly lower heart rate, decreased
time crying and increased oxygen saturation. EMLA also demonstrated
significantly lower facial scores, decreased time of crying and lower heart
rate. Erythema and mild skin pallor were observed with the use of EMLA.
Methaemoglobin levels evaluated in two trials of EMLA were within normal
limits. Conclusions; DPNB was the most frequently studied intervention
and was the most effective for circumcision pain. Compared to placebo,
EMLA was also effective, but was not as effective as DPNB. Both
interventions appear to be safe for use in newborns. None of the studied
interventions completely eliminated the pain response to circumcision.
EMLA for lumbar puncture: A randomized controlled trial from Delhi.15
compared EMLA with placebo for pain relief in lumbar puncture. When
compared with placebo, EMLA significantly attenuated the pain
response, as shown by a lower heart rate, a lower behavioral score
particularly at needle insertion and needle withdrawal. Conclusion:
Lumbar puncture in newborns is associated with pain. Eutectic mixture
of local anesthetics is an efficacious agent for reducing the pain associated
with needle insertion and withdrawal during lumbar puncture in
newborns.
EMLA vs sucrose for venepuncture: A randomized controlled trial by Abad
F et al16 found that 24% oral sucrose solution compares favorably
with EMLA cream as a safe and cheap analgesic procedure to decrease
pain responses to venepuncture in newborns. There was no added
advantage of EMLA cream over sucrose solution.
Venepuncture versus heel lance for blood sampling in term neonates:
Heel lance has been the conventional method of blood sampling in neonates
for screening tests or measurement of serum bilirubin or glucose. Sick
neonates admitted to neonatal intensive care units undergo this procedure
repeatedly as part of routine care. A systematic review compared pain
associated with heel lance and venepuncture. 17 All included studies showed
statistically significant lower pain scores for venepuncture as compared
to heel lance. A meta-analysis of the NIPS scores during the first minute
of the procedure was statistically significantly lower in the venepuncture
group compared to heel lance group. The study concluded that,
venepuncture, when performed by a skilled phlebotomist, appears
to be the method of choice for blood sampling in term neonates.
Pre-medication for Endotracheal intubation: Most NICUs do not have
a policy on pre-medication for intubation. The systemic review by Shah
et al 2002 concluded that wake intubation is probably inappropriate in
most newborn infants.18
Table 14.2: Recommended analgesia in neonates19

Agent Intermittent dose Infusion dose Local/ Topical
Opioid analgesics
Morphine sulfate 0.05-0.1 mg/kg IV 0.01-0.03 mg/kg/hr ……..
0.5-2 µg/kg/hr
Fentanyl citrate 0.5-3 µg/kg IV ……..
Anesthetic agents
Lidocaine …………….. …………….. 2-5 mg/kg IV
(local/topical) 0.5-1 mg/kg
endotracheally
EMLA(local/topical) 0.5-2 mg/kg IV 0.5-1 mg/kg per 0.5-2 g under occlusive
hour dressing 1 hour before
the procedure
Ketamine 2-5 mg/kg IV ………….
hydrochloride
(Systemic)
Other agents
Acetaminophen 10-15 mg/kg orally; …………… ………………..
20-30 mg/kg rectally
Sucrose 12%-24% solution ……………… ………………..
given orally 2 min
before the procedure,
2 ml for term neonates
and 0.1-0.4 ml for
preterm neonates
FURTHER RESEARCH .........................................................................

1. Long term neurodevelopmental assessment of neonates undergoing
painful procedures and receiving various pharmacological and non
pharmacological interventions is still not available and further research
is required.
2. Environmental interventions for reduction of pain, e.g. clustering of
painful interventions, decreased handling, reducing ambient noise and
light and establishing day night cycle has not been studied in detail
and requires further research.
KEY POINTS – reducing NDD related to pain and adverse effects of analgesia
1. Neonates have pain sensation – they have functional neuro anatomic and
neuro endocrine pain pathways at very early gestations.
2. Preterm babies may have exaggerated pain sensation; their descending
pain suppressing pathways may not be mature, although the pain sensing
ones are.
3. Pain causes several physiologic and hormonal responses - increased
sympathetic activity, hyper dynamic circulation, increased oxygen demand,
insulin resistance, increased gluconeogenesis, and a catabolic state.
4. Painful stimuli are implicated in causation and extension of IVH and PVL
in preterm babies.
5. Repeated painful experiences modify subsequent reaction to pain. Pain
may have a role in modifying neurological and behavioral outcomes.
6. There are not enough studies on long term outcomes of medication/non
pharmacological methods used for analgesia in painful procedures.
7. Morphine is considered safer than midazolam if analgesia is necessary.
But, even morphine should be used sparingly in very preterm babies and
babies already in shock.
8. Ideally pain assessment should guide need for analgesia and routine use
is not currently recommended. Pain assessment scales combine physiologic
and behavioral parameters.
9. Sucrose, breast milk, Kangaroo Mother Care and non-nutritive suck are
effective non-pharmacologic methods that reduce pain.
10. Venepuncture by trained personnel is associated with less pain than heel
lance.
11. Local application of EMLA reduces procedure related pain – canulation,
lumbar puncture etc.
12. A consistent effort must be made to reduce, club painful procedures and
use appropriate pharmacological and non pharmacological measures.
REFERENCES ........................................................................................
1. Anand KJ, Hickey PR. Pain and its effects in the human neonate and fetus.
N Engl J Med 1987;317:1321-9.
2. Fitzgerald M, Millard C, Mcintosh N. Cutaneous hypersensitivity following
peripheral tissue damage in newborn infants and its reversal with topical
anaesthesia. Pain 1989;39:31-6.
3. Fitzgerald M, Anand KJS. Developmental neuroanatomy and neurophysiology
of pain. In: Schechter NL, Berde CM, Yaster M editor(s). Pain in infants, children
and adolescents. Baltimore: Williams and Wilkins, 1993:11-32.
4. Giannakoulopoulos X, Sepulveda W, Kourtis P, Glover V, Fisk NM. Fetal plasma
cortisol and beta endorphin response to intrauterine needling. Lancet 1994;
344:77-81.
5. Andrews K, Fitzgerald M. The cutaneous withdrawl reflex in human neonates:
sensitization, receptive fields, and the effects of contralateral stimulation. Pain
1994; 56:95-101.
6. Anand KJ, Barton BA, McIntosh N et al. analgesia and sedation in preterm
neonates who require ventilatory support:results from the NOPAIN trial. Neonatal
Outcome and Prolonged Analgesia in Neonates. Archives of Pediatrics and
Adolscent medicine 1999;153:331-8.
7. Bellu R, de Waal KA, Zanini R. Opiods for neonates receiving mechanical
ventilation. Cochrane Database of Systemic Reviews 2005, Issue 1. Art No.:
CD004212.
8. Ng E, Taddio A, Ohlsson A. Intravenous midazolam infusion for sedation of
infants in the neonatal intensive care unit. Cochrane Database of Systemic Reviews
2003, Issue 1. Art. No. CD002052.
9. Jacqz-Aigrain E, Daoud P, Burtin P, Desplanques L, Beaufils F. Placebo-controlled
trial of midazolam sedation in mechanically ventilated newborn babies. Lancet
1994;344:646-50.
10. Stevens B, Yamada J, Ohlsson A. Sucrose for analgesia in newborn ionfants
undergoing painful procedures. Cochrane Database of Systemic Reviews 2004,
Issue 3. Art. No. CD001069.
11. Shah PS, Aliwalas LL, Shah V. Breastfeeding or breast milk for procedural pain
in neonates. Cochrane Database of Systemic Reviews 2006, Issue 3. Art. No.
CD004950.
12. Ludington-Hoe SM, Hosseini R, Torowicz DL. Skin-to-skin contact (Kangaroo
Care) analgesia for preterm infant heel stick. AACN Clin Issues 2005;16:373-
87.
13. Johnston CC, Stevens B, Pinelli J, Gibbins S, Filion F, Jack A, Steele S, Boyer
K, Veilleux A. Kangaroo care is effective in diminishing pain response in preterm
neonates. Arch Pediatr Adolesc Med 2003;157:1084-8.
14. Tadddio A, Ohlsson K, Ohlsson A. Lidocaine-prilocaine cream for analgesia during
circumcision in newborn boys. Cochrane Database of Systemic Reviews 2000
Issue 2. Art. No. CD000496.
15. Kaur G, Gupta P, Kumar A.. A randomized trial of eutectic mixture of local
anesthetics during lumbar puncture in newborns. Arch Pediatr Adolesc Med 2003;
157:1065-70.
16. Abad F, Diaz-Gomez NM, Domenech E, Gonzalez D, Robayna M, Feria M. Oral
sucrose compares favorably with lidocaine-prilocaine cream for pain relief during
venepuncture in neonates. Acta Paediatr. 2001; 90:160-5.
17. Shah V, Ohlsson A. venepuncture versus heel lance for blood sampling in term
neonates. Cochrane Database of Systemic Reviews 2007, Issue 4. Art. No.
CD001452.
18. Shah V, Ohlsson A. The effectiveness of premedication for endotracheal intubation
in mechanically ventilated neonates: A systematic review. Clin Perinatol 2002;
29:535-54.
19. Anand KJS, and the International evidence based group for neonatal pain.
Consensus statement for the prevention and management of pain in the newborn.
Arch Pediatr Adolesc Med 2001; 155:173-180.
20. KJS Anand, R Whit Hall. Controversies in An Introduction. Seminars in
Perinatology. Pain. Volume 31, Issue 5, October 2007, Pages 273-74.
21. Witt, catherine L. Are we doing enough for neonatal pain management? advances
in neonatal care. 7(3):109-110, 2007.
22. Prakesh S. Shah, Lucia Aliwalas, Vibhuti Shah. Breastfeeding or Breast milk
to Alleviate procedural pain in neonates: A systematic review. Breastfeeding
medicine. 2007;2(2):74-82.
Dinesh Kumar Chirla
15
Neonatal Transport
Sick neonates are transported routinely after birth from the maternal unit
(labor room) to the neonatal facility (intra-hospital transfer). Sometimes,
inter-hospital transport, from a primary hospital (level 1) to a better-
equipped center (level 2/level 3 units) immediately after birth and later
when the neonate is seriously sick, becomes necessary. The commonest
reasons for transport are respiratory distress, perinatal asphyxia, seizures,
preterm delivery and a newborn needing surgery.
IN–UTERO TRANSPORT1-11 ............................................................................................

Transferring women at risk of very preterm birth, or previously identified
complication of pregnancy, that necessitates better care for the neonate,
decreases neonatal mortality.3,8 The National Neonatal-Perinatal Database
(NNPD) for the year 2002–2003 showed a striking 6.7 fold higher risk
of death in extra-mural neonates (born outside and referred to tertiary
facility), as compared to NICU babies are born in the tertiary institute
(intra-mural). This does not include those infants who do not reach the
regional center. In-utero transport decreases major neonatal complications
and hence, short term (grade III and IV intra-ventricular hemorrhage)
and long-term neuro-developmental disabilities are fewer.2
IMPACT OF NEONATAL TRANSPORT ON OUTCOMES ...............

Higher risk for grade-III or IV intra-ventricular hemorrhage have
been documented in VLBW infants born at level-I hospitals and transported
to the tertiary care center, as compared with those born at the level-
III facility.10 In a study reported from Canada, infants delivered at the
community hospitals had a higher prevalence of neuro-sensory impairments
compared with infants delivered at the tertiary care center (37% vs 14%,
NEONATAL TRANSPORT 187
p<0.05). Countries like UK, Australia, Canada, Ireland and Norway have
established national neonatal transport programs and have demonstrated
dramatic improvements in clinical outcome, as well as reduction in infant
mortality.
The reason for better outcomes include better
• prenatal care (e.g. antenatal steroids)
• resuscitation at birth
• access to specialist support
• infra-structure including safer intra-hospital transfer.
The type of tertiary facility to which the infants are transferred
may influence outcomes. For example, Shah et al9 demonstrated that
Canadian, out-born, premature (<32 weeks) infants admitted to perinatal
centers had a lower risk of death, compared with those admitted to free-
standing pediatric hospitals (adjusted odds ratio 2.25;95% CI 1.20–4.20);
staff and management policies in such facilities may not be equipped or
accustomed to the needs of premature infants. After birth, out-born infants
may be compromised by the speed and efficiency with which eventual
transfer to an appropriate tertiary center is accomplished.
NEONATAL TRANSPORT ....................................................................

In India, most of the time, it is the distressed parents who transport their
sick newborns in an auto-rickshaw, bus, car and if lucky in a private
ambulance with just an oxygen source at the best. The following are
crucial for improving outcomes of transported neonates.
EARLY RECOGNITION
A delay in management of illness – hypoxia, hypo perfusion, metabolic
problems like hypoglycemia and jaundice, all can cause increased risk
of disability. Units must have simple and easy to follow guidelines to
recognize severity of illness and facilitate early and safer transfer.19
PATIENT SELECTION
It may not be beneficial to transfer all babies, difficult to manage at the
primary level, to a referral centre. Babies likely to have poor outcomes,
e.g. extreme preterm babies, severe incurable malformations, HIE grade-
III, etc. may not benefit by transfer. For example only infants weighing
more than 800 gm at birth showed a significant improvement in disabilities
at 3 years corrected age (49% vs 22%, p<0.001).7
RESPONSIBILITIES OF REFERRING CENTER

Parents should be counseled about the need for transport and the risks
involved and consent be taken. Document the mother’s and infant’s case
histories and investigations (including radiograph plate) should be made
available to the transport team. All referring hospitals should have facilities
for resuscitation and initial stabilization of critically ill, newborns.
STABILIZATION BEFORE TRANSFER

There is no need to rush the baby from the referring hospital. This increases
the risk of physiological deterioration during the transport. Keeping the
baby warm at birth and before transport is the responsibility of the referring
clinician. In the community skin-skin to contact is effective (if warmers
not available). The newborn should be given oxygen, IV glucose and
appropriate antibiotics if required.
LOGISTIC ISSUES IN TRANSFER OF NEONATES–DURATION OF

TRANSPORT
In a study from India,12 showed that neonates with a long duration of
transport had 79% higher odds of death than those transported for a
short duration, even after adjusting for confounders of the 4966 neonates
those transported for >90 minutes had more than twice the rate of neonatal
death (RR 2.26, 95% CI: 1.26-4.04), and evidence that those transported
for between 60 and 90 minutes had an 80% higher rate of neonatal
death (RR 1.81, 95% CI: 1.07-3.06) as compared with those transported
for between 30 and 60 minutes.12
MONITORING DURING TRANSFER

In unorganized transport or self-transport, by the time the neonate reaches
referring hospital he is cold, hypoglycemic, poorly perfused, cyanosed
and acidotic. Even babies transported by paramedics were unstable,
half the time, showing that in the absence of sensitization to newborn
care, babies may be transferred sub-optimally. When the baby is being
transferred (intra or inter hospital), there should be good monitoring
and appropriate interventions to prevent hypothermia, hypoglycemia,
hypoxia, hypo-perfusion, all of which have implications on long-term
morbidity and developmental outcome.
NETWORKING
Organization of referrals based on availability of beds (networks) improves
outcomes of extreme preterm babies.
COMMUNICATION
Between parents, referring specialist and referral unit can minimize medical
and social issues.
REVERSE TRANSFER
This feedback will improve the neonatal care practices of referring unit.
It also takes care of a major inhibition for transport and referral i.e. loss
of patient confidence in referring unit.
STANDARD PROTOCOLS FOR NEONATAL TRANSPORT

There is a need for protocols on safer transport and this must also cover
legal issues. The National Neonatology Forum of India has developed
a module for training on neonatal transfer.
ETHICS
It is very important to avoid criticizing the management of referring hospital.
Also it is important to speak to the parents before you start any procedures
on the baby.
DOCUMENTATION
Documentation of clinical status on leaving the referring hospital, during
transport and arrival is very important.
ORGANIZATION OF A NEONATAL TRANSPORT SERVICE .........

NEONATAL TRANSPORT TEAM
Transport of sick, newborn infants is a challenging job and should not
be left to the most junior member of team. The transport team should
consist of; (i) a specially trained doctor, (ii) an experienced nurse and
(iii) a trained ambulance driver. The doctor and nurse should be able
to recognize and initiate treatment of complications, administer required
medications, resuscitate, keep stable, and maintain communication with
team leader (Neonatologist).
TRANSPORT AMBULANCE
Ideally should be able to house and stabilize transport incubator. There
should be source of oxygen, enough light, back up energy source, etc.
Power source should be compatible with the medical transport equipment.
EQUIPMENT
Equipments and drugs for transport should be kept in state of readiness.
Equipment should be regularly checked to ensure that batteries are charged,
gas supplies are adequate and emergency drugs and disposables present.
There should be a checklist, which the transport nurse uses before going
for transport services. Transport incubator with transport ventilator would
have:
• Monitor: Multi channel monitor with ECG, NIBP with cuff, SpO2
monitoring, Thermometer, Stethoscope
• Airway: Self inflating bag and mask (all sizes), Endotracheal tubes
(all sizes), 2 Laryngoscopes, Oxygen cylinders, suction catheters and
portable suction device, nasogastric tube, chest drain, etc…
• Circulation: Intravenous syringe pump, IV catheter, tubing and
connectors, Three way taps, IV solutions, Umbilical catheter, syringes
• Others: Sterile gloves, cleaning solutions, IV cut down pack, suture
materials.
DRUGS
Resuscitation drugs, Adrenaline 1:10,000, Calcium gluconate 10% solution,
Dextrose 10% solution, Phenobarbitone, Phenytoin; Cardiovascular drugs,
Dopamine, Dobutamine, Adenosine, Frusemide, Prostaglandin E2, Antibiotics
– Ampicillin, Amikacin, Cefotaxim, Metronidazole; Sedatives/muscle relaxants
– Morphine, Midazolam; Others – Vitamin K, Heparinized saline.
CARE DURING TRANSPORT ..............................................................

RESPIRATORY CARE
We need assess the neonate’s ability to maintain airway during the transport.
Anticipate physiological deterioration during transport. Clear airway secretions
and position the baby with slight neck extension. Neonates who have mild
distress can be managed with an oxyhood. All infants with significant respiratory
distress should be intubated, before transfer is very difficult to intubate in
the ambulance. To prevent long-term consequences the neonate should be
adequately oxygenated and if ventilated, they should have adequate sedation
and analgesia to prevent the baby from fighting ventilator, tube dislodgement,
hypoxia, risk of intra-ventricular hemorrhage (preterm) and PPHN (Term
Meconium Aspiration syndrome). Check for pneumothorax at all times.
Emptying the stomach before transport reduces the risk of aspiration.
CIRCULATION
Check heart rate, capillary refill, quality of peripheral pulses, color, temp
of skin. If perfusion is poor or blood pressure is low give 10 ml/kg of
normal saline and repeat if necessary. Start inotropes if required. See
that the newborn is normotensive before you start the journey and through
transport.
THERMAL CARE
Minimize draughts and keep ambulance warm (25°C). Wrap the baby
in cling wrap and cover with blanket. If skin temperature is below 36°C,
then re-warm the baby before transport either in the radiant warmer
if available in the hospital or shift to transport incubator. Avoid opening
the transport incubator canopy and maintain incubator temperature in
thermo-neutral range. Hypothermia can lead to hypoxia and hypoglycemia.
Neonates who are hypothermic are at risk of developing necrotizing
entero-colitis and pulmonary hemorrhage. In the community setting
temperature maintenance could be achieved by skin to skin contact
(kangaroo mother care), using warm blanket, cotton wool, hot water
bottle in a carrycot (avoid direct touch or leakage), thermocol box with
holes, etc.
BLOOD SUGAR
Check heel-prick blood sugar, commence IV infusion with a syringe pump.
From sub-centers and PHC if IV access is difficult give 10 ml/kg of EBM
or 5–10% dextrose orally. Infants who have altered level of
consciousness or seizures with low blood glucose level are at risk
of adverse long-term neurological outcome. In case of suspected sepsis,
antibiotics need to be started after collecting blood culture. Delay in
antibiotics with progression of sepsis into septic shock or meningitis have
long-term implications in terms of neurological outcome.
KEY MESSAGES – reducing NDD by appropriate neonatal transport
1. In-utero transport is safer; recognize high-risk pregnancy, and transfer mother

to tertiary care before delivery
2. Early recognition and referral of sick neonate, before they are too sick for
safe transfer
3. Appropriate patient selection, avoid referral of babies unlikely to benefit from
transfer
4. Stabilization before transfer, Monitoring during transfer
a. Airway and oxygenation
b. Perfusion
c. Euglycemia
d. Thermal regulation
5. Communication between referring, receiving team and parents is crucial
6. NNF module on neonatal transport need to be followed and regularly
upgraded by experiences from different centers.
FURTHER READING .............................................................................

1. Neonatal transferal and Transportation: NNF training module.
REFERENCES ........................................................................................
1. Kollee LAA, Verloove-Vanhorick PP, Verwey RA, Brand R, Ruys JH. Maternal
and neonatal transport: results of a national collaborative survey of preterm and
very low birth weight infants in the Netherlands. Obstet Gynecol. 1988;72:729-
32.
2. Towers CV, Bonebrake R, Padilla G, Rumney P. The effect of transport on the
rate of severe intraventricular haemorrhage in very low birth weight infants. Obstet
Gynecol. 2000;95:291-95.
3. Bucher HU, Fawer CL, von Kaemel J, Kind C, Moessinger A. Intrauterine and
postnatal transfer of high risk newborn infants: Swiss Society of Neonatology.
Schweiz Med Wochenschr. 1998;128:1646-53.
4. Simpson JM, Evans N, Gibbard RW, Heuchan AM, Henderson-Smart DJ. Analysing
differences in clinical outcomes between hospitals. Qual Saf Health Care.
2003;12:257-62.
5. Kitchen W, Ford G, Orgill A, et al. Outcome of extremely low birth-weight infants
in relation to the hospital of birth. Aust NZ J Obstet Gynaecol. 1984;24:1-5.
6. Truffert P, Goujard J, Dehan M, Vodovar M, Breart G. Outborn status with a
medical neonatal transport service and survival without disability at two years:
a population-based cohort survey of newborns of less than 33 weeks of gestation.
Eur J Obstet Gynecol Reprod Biol. 1998;79:13-8.
7. Saigal S, Rosenbaum P, Hattersley B, Milner R. Decreased disability rate among 3-
year-old survivors weighing 501 to 1000 grams at birth and born to residents of
a geographically defined region from 1981 to 1984 compared with 1977 to
1980. J Pediatr. 1989;114 :839-46.
8. Chien LY, Whyte R, Aziz K, Thiessen P, Matthew D, Lee SK. Improved outcome
of preterm infants when delivered in tertiary care centers. Obstet Gynecol.
2001;98:247-52.
9. Shah PS, Shah V, Qiu Z, Ohlsson A, Lee SK, Canadian Neonatal Network.
Improved outcomes of outborn preterm infants if admitted to perinatal centers
versus freestanding pediatric hospitals. J Pediatr. 2005;146:626-31.
10. Towers CV, Bonebrake, Padilla G, Rumney P. The Effect of Transport on the
Rate of Severe Intraventricular Hemorrhage in Very Low Birth Weight Infants.
Obstetrics and Gynecology 2000;95:291-5.
11. Clark CE, Clyman RI, Roth RS, Sniderman SH, Lane B, Ballard RA. Risk factor
analysis of intraventricular hemorrhage in low-birth-weight infants. J Pediatr
1981;99:625-8.
12. Mori R, Fujimura M, Shiraishi, Evans B, et al. Duration of inter-facility neonatal
transport and neonatal mortality: Systematic review and cohort study. Pediatrics
International 2007;49(4):452–8.
13. Kitchen, W.H., Callanan, C., Doyle, L.W, et al. Improving the quality of survival
for infants of birth weight < 1000 g born in non-level-III centers in Victoria.
Med. J Aust 1993;158:24–7.
14. Leslie, A.J. and Stephenson, T.J. Audit of Neonatal intensive care transport. Arch.
Dis. Child. 1994;71,F61-66.
15. Neonatal Transport. Journal of Neonatology. 19, 2005.
16. Cloherty JP, Stark AR. Manual of Neonatal Care. 4th Ed. Philadelphia: Lippincott-
Raven; 2004:151–57.
17. David Field, Neonatal Transport. In :Janet Rennie, Roberton’s, Textbook of
Neonatology, 4th edition, 2005:242–46.
18. Yu VYH, Dunn PM. Development of regionalized perinatal care. Sem Neonatol
2004.
19. Reddy MH, Bang AT. How to identify Neonates at risk of death in rural India.
Clinical criteria for risk approach. J Perinatol 2005.
Ravishankar K
16
Perinatal Steroids
Premature infants are treated with a number of drugs in the NICU despite
a lack of long-term studies proving their safety, especially on the developing
brain. Of particular recent concern is the data that the use of postnatal
dexamethasone in VLBW infants is associated with abnormal neurodeve-
lopmental outcome.
Chronic lung disease (CLD) in preterm infants including the previously
commonly used term bronchopulmonary dysplasia (BPD), is an important
cause of mortality and is associated with long-term morbidity, including
delayed growth, recurrent respiratory infections, impaired pulmonary function,
and neurodevelopmental delay. In the past, several randomized trials have
demonstrated the usefulness of postnatal dexamethasone in short-term
respiratory outcomes, although there was no actual impact on the survival
(Table 16.1). These have included early extubation and baby going off
oxygen earlier. Unfortunately long courses of very high dose dexamethasone
had been used for years despite the lack of follow-up studies on the safety
of such a potentially risky drug. Initial short-term studies have shown poor
weight gain and poor head growth in neonates treated with early postnatal
dexamethasone. The results of larger long-term follow up studies have,
now, conclusively proved that use of postnatal dexamethasone is
strongly associated with neuromotor delay (upto 40%), cerebral
palsy (CP) (2 fold) and PVL (Table 16.2).
The early (<96 hours) regimen of dexamethasone was associated
with greater risk of neurodevelopmental problems than moderately
early (7–14 days) or delayed (> 3 weeks) regimens. The mechanism
of injury could be dexamethasone-induced suppression of the release of
brain-derived neurotrophic factor, which is vital for neuronal development.
Apart from having direct neuronal toxicity, dexamethasone may also impair
mechanisms that protect against hypoxia and hypoglycemia. It is possible
PERINATAL STEROIDS 195
Table 16.1: Benefits of postnatal corticosteroids
Outcome Timings RR(95% CI) NNT(95% CI)
CLD at 28 days E 0.85 (0.79, 0.9.2) 14 (9, 25)

M 0.87 (0.81, 0.94) 9 (6, 20)
CLD at 36 weeks corrected age E 0.69 (0.60, 0.80) 11 (8, 20)
M 0.62 (0.47, 0.82) 4 (3, 8)
D 0.76 (0.58, 1.00) 6 (3, 100)
Mortality at 28 days E 1.05 (0.90, 1.22)
M 0.44 (0.24, 0.80) 17 (10, 50)
Mortality before discharge E 1.02 (0.90, 1.17)
M 0.66 (0.40, 1.09)
D 1.03 (0.71, 1.51)
Failure to extubate at 7 days E 0.76 (0.66, 0.88) 8 (6, 17)
M 0.62 (0.46, 0.84) 3 (2, 7)
D 0.69 (0.58, 0.82) 4 (3, 7)
PDA E 0.75 (0.68, 0.83) 10 (7, 14)
D = delayed (>3 weeks); E = early (<96 hours); M = moderately early (7–14 days);
NNT = number needed to treat.
Table 16.2: Adverse effects of postnatal corticosteroids

Outcome Timings RR(95% CI) NNH(95% CI)
Hyperglycemia E 1.36 (1.23, 1.51) 9 (7, 13)

M 1.51 (1.20, 1.90) 8 (6, 20)
Hypertension E 1.84 (1.54, 2.21) 10 (8, 14)
M 2.73 (1.25, 5.95) 20 (13, 100)
D 2.61 (1.29, 5.26) 17 (10, 50)
Hypertrophic cardiomyopathy E 4.33 (1.40, 13.40) 3 (2, 6)
M 3.29 (1.50, 7.20) 5 (3, 11)
GI hemorrhage E 1.90 (1.35, 2.66) 17 (11, 33)
M 1.74 (1.02, 2.98) 17 (9, >200)
Infection M 1.35 (1.06, 1.71) 11 (7, 50)
Growth failure E 6.67 (2.27, 19.60) 2 (1, 2)
Abnormal neurological exam E 1.81 (1.33, 2.47) 10 (7, 20)
CP E 1.69 (1.20, 2.38) 17 (9, 50)
Death or CP E 1.16 (1.00, 1.34) 17 (8, >200)
D = delayed (>3 weeks); E = early (<96 hours); M = moderately early (7–14 days);
NNH = number needed to harm.
that dexamethasone is uniquely neurotoxic amongst the corticosteroids,

maybe contributed partly by the preservatives used. People have used
later, shorter and smaller doses of dexamethasone in evolving BPD, however
clear cut evidence of long term benefits or safety has not been studied.
Steroids other than dexamethasone have been studied that could provide
pulmonary benefits without harming the developing brain. Betamethasone,
methylprednisolone, inhaled steroids and hydrocortisone has been found
to be safer, but efficacy and follow up studies are awaited.
It therefore appears that there is little role of postnatal steroids and
should be used as a part of studies where neurodevelopmental outcome
is the primary endpoint. Dexamethasone should not be used in the

first 4 days and very limited steroid use may still be justified later in life-
threatening situations, to improve lung inflammation and improve lung
function.
The European association of perinatal medicine has recommended:
1. Corticosteroids should be avoided
2. No indication to give postnatal dexamethasone in the first 3–4 days
of life
3. Spontaneously breathing neonates should not be given steroids
4. Corticosteroids might be indicated for very ill, ventilator dependent patients
5. The lowest possible dose for the shortest possible duration should be
used.
It has been suggested that dexamethasone could be started at doses
as low as 0.2 mg/kg/day initially for 2 days and later tapered to
0.1 mg/kg/day and 0.05 mg/kg/day for 3 days each. The greatest
benefit of steroids is seen when used in 2nd week of life. Babies exposed
to steroids should have RBS and BP monitored and should have
neurodevelopmental follow up.
Compared to postnatal steroids, single course of antenatal steroids is
of great benefit in reducing the incidence of IVH and improving
neurodevelopmental outcome. Antenatal steroids are widely recognized for
their ability to increase maturity of the fetal lung. But as the improvements
in lung function were not sustained beyond a week, multiple courses of
antenatal steroids were given to the mothers. However, mounting evidence
suggests that repeated courses of antenatal steroids given to stimulate
lung maturity is physiologically (poor lung growth) and
developmentally (poor brain growth and adverse neurodeve-
lopmental outcome) hazardous to premature infants. Therefore
Table 16.3: 2000 NIH consensus statement recommendations

on antenatal corticosteroids
• All pregnant women between 24 and 34 weeks gestation who are at risk
of preterm delivery within 7 days should be considered candidates for treatment
with a single course of Antenatal corticosteroids.
• Standard treatment consists of 2 doses of betamethasone ,12 mg, intramuscularly
24 hours apart or 4 doses of 6 mg of dexamethasone intramuscularly 12
hours apart
• As a result of insufficient scientific data from randomized clinical trials (RCTs)
regarding efficacy and safety, other regimens and repeat courses of
corticosteroids should not be used routinely, but reserved only for patients
enrolled in RCTs.
PERINATAL STEROIDS 197
repeated courses of antenatal steroids are unproven and potentially harmful.
The NIH guidelines are given in Table 16.3.
However in a recent study from chandigarh, multiple doses of antenatal
steroids resulted in improved NICU survival, without any endocrine, somatic
or neurodevelopmental adverse outcomes in babies followed till 22 months
(Table 16.4).
Table 16.4: Long-term outcomes of antenatal steroids—Chandigarh study

Multiple courses single course
(n=25) (n=28) P
Mean age at follow-up 21.1 months 23 months 0.08
Neurological outcome
suspect 6 4 0.37
Abnormal 2 0 0.12
BSID scores-abnormal MDI 2 2 0.91
weight <5th centile 16 19 0.77
length<5th centile 4 10 0.1
OFC<5th centile 5 12 0.08
In general, drugs in the NICU should be used judiciously, after carefully

reviewing the literature and consensus statements. Periodic drug updates
are published in peer reviewed journals and one should keep abreast of
this. An effort should be made to follow the babies treated with potentially
risky drugs for their developmental outcome. Minimizing interventions, gentle
brief ventilation, developmentally supportive care and intensive monitoring
would definitely decrease the need for drugs in NICU.
BIBLIOGRAPHY .....................................................................................
1. Assisted Ventilation of Neonate, Goldsmith. 4th edition. Chapter Central Nervous
System Morbidity. P 429-448.
2. Follow-up at 15 Years of Preterm Infants From a Controlled Trial of Moderately
Early Dexamethasone for the Prevention of Chronic Lung Disease Steven J.
Gross, Ran D. Anbar and Barbara B. Mettelman Pediatrics 2005;115;681-7.
3. Management of BPD; guidelines for corticosteroid use. David G. Grier and Henry
L. Halliday. Drugs 2005:65(1);15-29.
4. Multiple courses of antenatal steroids. Sandesh Kiran, Dutta Sourabh, Narang
Anil et al. Indian J of Pediatrics. Vol 74, May 2007.
5. Perinatal Corticosteroids: A Review of Research Part 2: Postnatal Administration
Isabell B. Purdy. Neonatal Network VOL. 25, NO. 2, May/June 2004.
6. Perinatal Corticosteroids: A Review of Research Part I: Antenatal Administration.
Isabell B. Purdy,Dorothy J. Wile. Neonatal Network VOL. 23, NO. 2, March/
April 2004.
Ashish Mehta
17
Mechanical Ventilation
Availability of newer and better machines for ventilation and better care
of sick neonates has resulted in a great improvement in survival of ventilated
neonates. Ventilation strategies are currently targeted at minimizing lung
injuries. There is a paucity of data on neurodevelopmental implications
of different ventilation strategies.
HOW INAPPROPRIATE VENTILATION CAN CAUSE BRAIN INJURY?

The cause of brain injury in ventilated neonates is multifactorial but
perturbations in cerebral blood flow are considered to be of central
importance.11,15,16 Cerebral circulation is very sensitive to changes in PaCO 2
and pH. Babies on mechanical ventilator are vulnerable to both insufficient
corrections of homeostasis and also to inadvertent “over-ventilation”.
FACTORS IN MECHANICAL VENTILATION THAT AFFECT

NEURODEVELOPMENTAL OUTCOMES ............................................
PaCO2
CO2 extremes result in changes in cerebral blood flow. Low CO2 decreases
cerebral blood flow and high CO2 increases cerebral blood flow.
Studies on hypocapnea and preterm brain injury: In a study monitoring
PaCO2 levels, extremely low PaCO2 levels (<17 mm Hg) during first three
days of life were associated with significantly increased risk of moderate
to severe periventricular echodensities, large periventricular cyst, grade
III or IV intracranial hemorrhage and cerebral Palsy (CP).1
In another study, a lowest PaCO2 of > 20 mm Hg was not associated
with an increased risk of adverse neurological out come. In this study,
there was no correlation between CO2 changes beyond the third
day of life and brain injury (neurosonographic or neurodevelopment
MECHANICAL VENTILATION 199
abnormalities). In the absence of perinatal complications (like APH, asphyxia)
there is strong correlation between severe hypocapnea (PaCO2
<20 mm Hg) and cystic PVL.2
The duration as well as the severity of hypocapnea has been associated
with adverse neurodevelopment outcome. A retrospective study comparing
preterm infant with cystic PVL with matched controls showed that, infants
with cystic PVL had both lower mean PaCO2 levels and longer period
with PaCO2 levels < 25 mm Hg.4
High frequency jet ventilation (HFJV) places the baby at high risk
of hypocarbia. Wiswell prospectively evaluated preterm infants undergoing
HFJV with serial neurosonograms, and assessed the cumulative effect of
hypotension, acidosis, hypoxia and hypocarbia. Using logistic regression
analysis it was found that infants with cystic PVL were more likely to
have cumulative hypocapnea below a threshold level of 25 mm Hg
during the first day of life. However in a prospective randomized
controlled trial performed by the same investigator in which HFJV was
compared to conventional ventilation in preterm infant with RDS,
hypocapnea was not found to independently predict an adverse outcome.3,5
Permissive Hypercapnea
The association between hypocapnea and adverse neurodevelopmental
morbidity has resulted in greater interest in the practice of allowing higher
PaCO2. Data available from the two studies in the Cochrane review do
not support the use of permissive hypercapnea to prevent morbidity/
mortality in ventilated new born infants. There are no serious adverse
effects reported with permissive hypercapnea (minimal ventilation
strategies) in the studies included. Therefore, it can be concluded that
hypercapnea at least in the range targeted (up to 60 mm Hg) is not
harmful in the short term. Long term neurodevelopmental evaluation
is yet to be seen. Gentler ventilation strategies are likely to result in shorter
duration of ventilation and lesser lung and possibly other organ injuries. 6
Until more evidence to support the safety and benefit of hypercapnea
strategy is available, it would seem wise to avoid exposure of ventilated
newborns to either severe hypocapnea (<20 mm Hg) or hypercapnea
(>55 mm Hg).
pH
Sensory neural hearing loss is more common in infants with PPHN
treated with alkalosis and extracorporeal membrane oxygenation
(ECMO). More than half (53%) of surviving infants with PPHN treated
with hyperventilation and respiratory paralysis had hearing impairment.7,19
Metabolic acidosis may be an indicator of tissue hypoxia and should

be corrected by treating the appropriate cause. The use of sodium
bicarbonate to treat even the severest of acidosis (except in select
circumstances) is considered harmful. Respiratory acidosis, high CO2 is
associated with increased cerebral perfusion and risk of IVH.
PaO2
Hypoxia
It would be unethical to have studies comparing outcomes of babies with
hypoxia and those with appropriate therapy. It is still not known as to
how low levels of PaO2 would definitely be associated with brain injury.
Indirect evidence of tissue hypoxia (metabolic acidosis, lactate, etc). may
be a guide to oxygenation status at tissue level.
Hyperoxia
ROP awareness has mandated closer monitoring of oxygenation. With
continuous pulse oxymetry monitoring and judicious use of blood gases
low/high PaO2 can be avoided. Keep saturations between 87–93 % in
preterm babies. PaO2 should be between 60–80, use minimum FiO2 to
achieve above targets. Although direct brain injuries are not described,
hyperoxia is associated with ROP and BPD/CLD.
MEAN AIRWAY PRESSURE AND OPTIMAL LUNG VOLUME

Hypoxia and acidosis are understandably responsible for poor neuro-
developmental outcomes. Delay in ventilation, or conservative ventilation
strategies (under-ventilation) and consequent hypoxia/hypercapnea and
low pH can be detrimental to brain. The initial trials on HFV that used
conservative mean airway pressures resulted in increased IVH and that
too severe grades. Recent optimal lung volume strategies employing higher
mean airway pressures have supported both elective and rescue HFV.
In an event of hypoxemic brain injury, body compensates by increasing
cerebral perfusion, and hence, severity of brain injury is minimized. Overzealous
ventilation to improve oxygenation will lead to high mean airway pressures
or tidal volumes. This increases intra-thoracic pressure and results in decreased
venous return and filling pressures in the heart.9
Current ventilation targets “optimal lung volumes” and avoids
complications of under/over ventilation. It is mandatory to observe central
venous pressure (CVP) and invasive blood pressure in a sick baby
requiring high airway pressures on ventilator. Lack of such close monitoring
and dependence on clinical observations for hemodynamic status of
a baby may result in poor neurological out come.
ASYNCHRONOUS BREATHING
Asynchrony during ventilation of a preterm baby with RDS can result
in fluctuating cerebral blood flow which is a precursor of IVH.10 Increased
respiratory efforts cause fluctuations affecting both systolic/diastolic
components of perfusion. To avoid arterial blood pressure fluctuations,
synchrony needs to be achieved. This can be achieved by increasing
ventilator support, use of synchronized mechanical ventilation, or sedation
and muscle paralysis.
Synchronized Ventilation
Use of SIMV and SIPPV especially after the acute phase (in weaning)
reduces duration of ventilation and oxygen dependency.
Neuromuscular Paralysis
Cochrane review has shown that paralyzing with pancuronium reduces
the incidence of IVH in babies fighting the ventilator. But paralysis is
known to adversely affect other aspect of ventilation and long term outcomes
have not been addressed in these studies. Currently, paralysis is not
routinely recommended.12
Sedation
Morphine: Neo pain trial suggested that pre-emptive morphine infusions
do not reduce IVH among mechanical ventilated babies. Morphine use
in extreme preterm babies and babies with poor perfusion are
at increased risk of disability.13
Midazolam: Studies, where midazolam was used for sedation of sick
ventilated babies, showed statistically increased incidence of adverse
neurological events (death, grade III/IV IVH and PVL). Cochrane systemic
review concludes insufficient evidence for the use of midazolam: lack of
clinical benefit and increased risk of poor neurological out come.
NURSING ISSUES
Both, Tracheal suctioning and chest physiotherapy are considered
risk factors for IVH. Vigorous deep tracheal suctioning produces fluctuations
in blood pressure leading to risk of IVH.
DURATION OF VENTILATION
There is a documented relationship between number of days on the
ventilator and adverse developmental outcomes.
ACUTE COMPLICATIONS—PNEUMOTHORAX
Results in sudden and severe fluctuations in cerebral circulation. In preterm
and unstable neonates, pneumothorax increases risk of IVH.8
CLD/BPD
Longer duration of ventilation and oxygen dependency increases risk of
NDD in preterm babies. Currently the effect of ventilation strategies, fluid,
nutrition, adjunct therapies like steroids, vitamin A, aerosolized and systemic
diuretics on incidence and severity of CLD and consequent NDD are
inconclusive.
VENTILATION STRATEGIES
a. nCPAP—a less invasive form of ventilation, reduces the number of
days baby remains intubated. Currently, not enough data to show
difference in neurodevelopmental outcomes on nCPAP vs conventional
ventilation
b. HFV—There were initial concerns of increased IVH with HFV. With
use of optimal lung volumes, HFV is now considered safe and a preferred
mode of ventilation when high mean airway pressures are required
on conventional ventilation
c. Volume targeted ventilation—with improving ventilators, it is now possible
to fine tune the targeted tidal volume at each breath and thus possibly
keep the CO2 tightly controlled. Duration of ventilation and incidence
of pneumothorax is reduced.17,18
ADJUNCTS—SURFACTANT
Although drop in pulmonary pressure and increased cerebral perfusion
have been demonstrated, no increase in IVH rates and incidence of disability
are noted on long term follow up. Improved survival of smaller babies
(due to surfactant and ventilation) has not added to a greater proportion
of handicapped babies. It is only logical that reduced severity of lung
disease, less air leaks and shorter ventilation would indirectly act through
several mechanisms and reduce NDD.14
SUGGESTIONS TO MINIMIZE VENTILATION ASSOCIATED

BRAIN INJURIES ..................................................................................
1. Use antenatal steroids in preterm labor. This reduces incidence and
severity of RDS and hence, need for ventilation. ANS also decreases
NDD through several other mechanisms
2. Appropriate use of Surfactant will reduce severity of lung disease and
need for ventilation
3. Monitor oxygenation – avoid hyperoxia, keep saturations between 87–
93% in preterm babies. PaO 2 should be between 60–80, use minimum
FiO2
4. Avoid hypocarbia – gentler ventilation, early extubation, use of nCPAP,
5. nCPAP – non invasive ventilation, early extubation are lung friendly,
but neurodevelopmental outcomes are not reported
6. Permissive hypercapnea – allowing CO2 to rise above previously targeted
“normal ranges” is not tested enough to be recommended
7. Volume targeted ventilation, although new, promises to control CO 2
tightly and optimize ventilation
8. Synchronized ventilation is likely to reduce ventilator associated lung
injury, duration of ventilation and reduce fluctuations in cerebral
circulation.
REFERENCES ........................................................................................
1. Greziani: Mechanical ventilation in preterm infant- neurosonographic and
developmental study. Pediatrics 1992;90:515-22.
2. Fujimoto S, Togari H, Yamaguchi N, et al. Hypocarbia and cystic periventricular
leukomalacia in premature infants. Arch Dis Child 1994;71:F107-F110.
3. Calvert: Etiologic factors associated with development of PVL in preterm infants
Acta Pediatr Scand 1987, 76:254-259
4. Wisewell, et al. Effect of Hypocarbia on development of cystic PVL in preterm
infants treated with HFJV. Pediatrics 1996;98:918–24 and 1035-43.
5. Greisen G, Munck H, Lou H. Severe Hypocarbia in pretem infants and
neurodevelopmental deficit. Acta Pediatr Scand 1987;76:401-04.
6. Woodgate PG, Davies MV. Permissive hypercapnea for the prevention of morbidity
and mortality in mechanically ventilated newborn infants- Cochrane systemic review
7. Hendriks-Munoz KD, Walter JP. Hearing loss in infants with persistent fetal
circulation. Pediatrics 1988;81:650-56.
8. Hill A, perlman JM, volpe J. Relationship of pneumothorax to the occurrence
of IVH in prematured new born. Pediatrics 1982;69:144-9.
9. Mirro R, Busija D, Green R, Leffler CB. Relationship between mean airway
pressure, cardiac output and organ blood flow with normal and decreased
respiratory compliance. J Pediatr 1987;111:101-06.
10. Perlman JM, McMenanim JB, Volpe JJ. Fluctuating cerebral blood flow velocity
in respiratory distress syndrome: relationship to subsequent development of IVH.
N Eng J med 1983;309:204-09.
11. Perlman JM, volpe JJ. Are venous circulatory changes important in the patho-
genesis of Hemorrhagic and/or ischemic cerebral injury ? Pediatrics 1987;80:705-
11.
12. Cools F, Offringa M. Neuromuscular paralysis for new born infants receiving
mechanical ventilation. Cochrane database syst Rev 2005(2):CD 002773.
13. Anand KJ, Hall RW. Desai N, et al. Effects of morphine analgesia in ventilated
preterm neonates, Lancet 2004;363(9422):1673-82.
14. Suresh GK, Soll RF. Current surfactant use in premature infants. Clin Perinatol
2001;28(3):671-94.
15. Volpe JJ. Neurology of the new born. Fourth ed. Philadelphia:W.B. Saunders
company, 2001.
16. Deorari A, Chawla D, Maria A. Preterm brain injury. Journal of Neonatology;
20,(2)140-46.
17. Greenough A, Sharma A. What is new in ventilation strategies for the neonate?
European Journal of Pediatrics. 2007;166(10):991-6.
18. Mathur NB, Bhatia V. Effect of Stepwise Reduction in Minute Ventilation on
PaCO2 in Ventilated Newborns. Indian Pediatrics 2004;41:779-85.
19. Hendricks-Munoz KD, Walton JP. Hearing loss in infants with persistent fetal
circulation. Pediatrics. 1988;81(5):650-6.
Section 8
Neurodevelopmental
Assessment
18. Risk Stratification for Neurodevelopmental
Disability
19. Clinical Examination Protocol
20. Screening Protocol
INTRODUCTION .....................................................................................
Optimal perinatal care is the most important determinant of
neurodevelopmental outcomes.
Appropriate follow up of these high risk neonates after discharge
from NICU is another “opportunity” to modify outcomes.
The understanding of neurodevelopment assessment has made
significant advances. But, the lack of a “user friendly standard-protocol”
that can be practiced at all levels of care has been the limiting factor
to “best-clinical practices”. This chapter attempts to organize currently
available knowledge on neurodevelopmental follow up – who should be
assessed, how, when, what to look for and who would be responsible.
OBJECTIVES OF A FOLLOW UP PROGRAM ................................

Reduction of childhood disability by:
• Providing anticipatory guidance to parents/families of high-risk
infants
• Guiding pediatricians/primary care physician on “assessment and
follow up”
• Provide simplified algorithms on assessment, follow-up and referral
• Providing developmental experts with best practices and integrating
follow up with medical care
• Quality assurance—assign responsibilities at various levels of care
The risk stratification, clinical examination, screening, follow-up, early
stimulation and specific interventions (next section) are detailed in a sequence
in the book for purpose of easy reading. But, in clinical practice many
of the processes are simultaneous and may be in a sequence as determined
by the pediatrician of the baby.
18
Risk Stratification for
Neurodevelopmental Disability
Throughout this chapter,

Green color represents babies at minimal risk of NDD,
Yellow color represents babies at moderate risk of NDD and
Red color represents babies at high risk of NDD.
NEED FOR RISK STRATIFICATION ..................................................

ANTICIPATORY GUIDANCE TO PARENTS
Plotting of risk factors of the high risk neonate on the color chart forms
an easy-to-understand visual display of the babies “risk” that can guide
parents at various stages, e.g. before birth, at admission to NICU, at
occurrence of risk events, a discharge and so on. For example
< 2500 gm < 1500 gm < 1000 gm
Risk of CP (%) 0.8-1.4 6-14 9-17

Risk of MR (%) 0.8-1.4 2-8 22.3-37
Risk of CP in general population is 0.02%. It is evident that a baby

born at <1000 gms is at a greater risk.
ASSIGNING LEVEL OF FOLLOW UP

All babies need to be assessed for their growth and development. This
is the primary responsibility of a pediatrician/any primary care physician
who cares for children.
In order to optimize utilization of available resources it is necessary
to identify babies/infants at increased risk of neurodevelopmental disabilities
(NDD) and stratify their assessment, follow up and intervention based
on expected outcomes. The perinatal risk factors for NDD have been
detailed in the previous chapter. The previous chapters on high risk newborn
are summarized in the Table 18.1.
Table 18.1: Risk stratification (encircle risk factors), chose the column of
maximum severity as indicated by risk factors
Mild risk for NDD Moderate risk for NDD High-risk for NDD
Antenatal risk factors Fetal growth abnormalities Fetal distress
Prelabour ROM, Outborn/Sub-optimal Sub-optimal Neonatal

prolonged labor Perinatal care transfer/care
Preterm Gestation < 33 weeks < 28 week
< 2500 Gm Birth weight < 1500 gm < 1000 gm, preterm
with SFD, 10th centile
> 1 abortion, infertility Multiple births Metabolic disorders, Intra-
treatment (twins/triplets) uterine infections,
congenital anomaly
(nervous system/ multiple),
teratogens exposure
Perinatal asphyxia/mild NE Moderate Neonatal Severe NE ** – Levene

encephalopathy (NE) Grade 3,
Levene grade 2 Prolonged encephalopathy
> 2 weeks, multi organ injury
Transient hypoglycemia Hypoglycemia, blood sugar Symptomatic hypoglycemia,

< 25 mg/dL, > 3 days seizure
Suspect sepsis Sepsis (culture +ve/ Meningitis

(screen negative) clinical and screen +ve)
Neonatal jaundice Neonatal jaundice leading Kernicterus

needing phototherapy to Exchange transfusion
IVH grade 1 or 2, Intraventricular Hemorrhage Ventriculomegaly and/or
no abnormality at (IVH) > grade 2 on Neuro- cystic periventricular
40 weeks sonogram leukomalacia (at 40 weeks),
hydrocephalus
NICU admission Complex medical course – Severe hypoxia (ventilation

NEC and PDA (needing > 7 days, apnoea requiring
surgery), CLD resuscitation), hypotension
Normal neurologic Severe/prolonged Abnormal neurologic

exam at discharge encephalopathy examination at discharge/
Any cause Suspect finding on
neurodevlopental Follow Up
Good home + follow up Sub-optimal Home Parent/physician concern

Environment for NDD
(Parent coping poor/
low socio-economic)
CLINICAL EXAMINATION PROTOCOL 209
19
Clinical Examination Protocol
PHYSICAL EXAMINATION—POINTERS TO NDD (RED FLAGS) ...

MAXIMAL OCCIPITO FRONTAL CIRCUMFERENCE (OFC)
(HEAD CIRCUMFERENCE)
One of the Best Studied/Simple Tools in NDD Prediction
Measure OFC—Use a narrow tape with a small metallic end. Measure
OFC by “overlap” technique to avoid the artifact produced by the non
pliable metallic end.
Measure length—Use an infantogram.
Plot OFC and length on standard growth charts; compare centiles
of OFC in relation to length (In low birth weight babies use special growth
charts, and use corrected age on standard charts after the preterm babies
cross the expected date of delivery).
Exclude familial variations in OFC (measure maternal/other family
members OFC before labeling abnormal).
Exclude measurement errors when looking at serial OFC—try and
use the same tape/infantogram.
Microcephaly
• OFC centile << length centile
• Static/dropping OFC centile (in relation to length centile) on serial follow-
up
Macrocephaly
• OFC centile >> length centile
• Increasing OFC centile (in relation to length centile) with/without
hydrocephalus
ASSESS GROWTH
Measure weight and length; plot on appropriate growth chart and compare
centiles.
• Poor growth— weight << length centile
• Growth centiles less than expected for gestation/dropping on serial follow
up
• Severe growth retardation (symmetric) with dysmorphism points to
genetic origin
• Poor growth may point to medical problems that can affect
Neurodevelopment
• Poor growth may be seen in babies with NDD as the feeding is
not optimal
COMPLETE HEAD-TO-TOE EXAMINATION (FOR ABNORMALITIES

THAT MAY POINT TO NDD)
a. Dysmorphic facies (Chromosomal anomalies)
Slant of eye, placement of ears, and philtrum of upper lip etc. may
be morphologically different and point to specific syndromes/chromosomal
anomalies. Do not commit on dysmorphic facies on first day
of life (effect of delivery process) and without seeing the face of
parents/family members. Preterm babies may appear dysmorphic.
It would be appropriate to wait and reassess before diagnosis are made.
b. Abnormal Dermoglyphics (chromosomal anomalies)
c. Neuro cutaneous markers (NCM)
In dark skinned babies a careful search may be necessary in-order to
not miss these NCM. For the same reason the newborn period (while
the skin is still not fully pigmented) is the best to make a note of
café-au-lait spots.
d. Examine for murmurs
e. Abnormal genitalia
f. Intra-uterine infections markers—IUGR, congenital heart disease,
hepatosplenomegaly, cataract, petechiae (thrombo-cytopenia), micro-
cephaly
g. Sacral dimple/midline defect (above level of natal cleft)—for occult
spinal defects.
HIP EXAMINATION FOR DEVELOPMENTAL DYSPLASIA OF HIP (DDH)

a. Desirable—to screen all neonates/infants for DDH
Perform clinical examination of hips on first 2 days of life and all
immunization/well baby visits till 1 year for signs of DDH. If—
i. Ortolani/Barlow positive or asymmetry or suspect click-clunk on
assessment—retest at 2 weeks.
ii. Refer to orthopedician by 2 weeks—USG at 3 to 4 weeks of life
(X-ray if greater than 4 months age).
b. Risk group—breech, girl, family h/o. Consider need for routine Ultrasound
screening.
NEUROBEHAVIOR .................................................................................
In neonates, predictive power of isolated neurological signs is not great.
An overall impression of suspicious/abnormal neurological status is more
useful—tone, suck, feed, cry and activity (movements)—5-fold increase
in incidence of CP.
An overall impression of abnormal/suspicious neurobehavior is very useful
in prediction of (neurodevelopmental) outcomes.
Neurological signs in neonate (mostly term) Increased risk of CP
Abnormal Tone—limb, neck, trunk 12-15 fold
Diminished cry for > one day 21 fold
Weak or absent suck 14 fold
Need for gavage or tube feeding 16-22 fold
Diminished activity > one day 19 fold
Collaborative Perinatal Project of National Institutes of Health
Important—neonate should not be sedated, should be medically stable

at time of examination.
NEUROBEHAVIORAL ASSESSMENT
Neurobehavioral assessment is a useful tool for assessment of young infants—
from preterm (> 32 weeks) to one month corrected age
• Research tools for assessment of neurobehavior
• NAPI (Neurobehavioral Assessment of Preterm Infants)
• APIB (Assessment of Preterm Infants Behavior)
• BNBAS (Brazelton Newborn Behavior Assessment Scale)
• Simple clinical tools assessment of neurobehavior
• Levene’s Grading for encephalopathy (for term babies) (Table 19.1)
• Simple KIMS* score
NAPI (Neurobehavioral Assessment of Preterm Infants)

Research tool for assessment of neurobehavior. Can be used for babies
between 32 weeks gestation and term. Requires training. It includes assessment
of—
* Kerala Institute of Medical Sciences
• Motor development and vigor

• Scarf sign
• Popliteal angle
• Alertness and orientation
• Irritability
• Vigor and crying
• Percentage sleep ratings
Also score rating scales for quality of spontaneous movements,
crying and visual behavior.
VLBW and ELBW babies who had CP, had low scores of NAPI.
Table 19.1: Perinatal asphyxia—Levene’s modification

of Sarnat and Sarnat score#
Grade 1 Grade 2 Grade 3
No seizure Seizure Prolonged seizure
Irritable Lethargy Comatose
Hypotonia mild Marked tone abnormal Severe hypotonia
Poor sucking Requires tube feed Needs ventilation##
# Levene MI, Lornberg J, Williams THC. The incidence and severity of post-
asphyxial encephalopathy in full term infants. Early Human development 1985;
11:21-26.
## Fails to maintain spontaneous respiration
Simple KIMS Score**

Lethargic baby defined as
• Decreased spontaneous movements
• Decreased tone
• Poor responsiveness to touch
• Poor cry
If the baby is lethargic (abnormal signs mentioned above) for more
than 24 hours—consider HIE, meningitis, IVH—do Neuro imaging, CSF
analysis. In sick babies, lethargic for more than 24 hours, there is an increased
risk of adverse outcomes (death/NDD) by 13 times.
*Constantinou JC, Adamson- Macedo EN, Mirmiran M, Ariagno RL, Fleisher BE.
Neurobehavioural Assessment predicts differential outcome between VLBW and ELBW
preterm infants. J Perinatol 2005;25(12):788-93.
** Naveen Jain. Predictors of adverse outcomes in sick neonates, abstracts. Neocon
2004.
NEUROLOGICAL EXAMINATION ........................................................
a. Optimality score has made neurological examination of newborn easy
and objective. (The neurological assessment of the preterm and full
term newborn infant, 2nd ed. Clinics in Developmental Medicine Series,
vol. 148. Dubowitz LMS, Dubowitz V, Mercuri E).
b. Some abnormal signs that point to NDD are cited in Table 19.2.
Table 19.2: Abnormal neurological examination findings in newborn

Item Abnormal
Head size </> 2SD
Fontanel Wide
Pupils Asymmetric, slow reaction
Position of eyes Strabismus, nystagmus, sun-setting
Fixation and horizontal tracking
(30 degree) No
Acoustic response No eye open/frighten
Glabellar tap Weak/asymmetric
Posture Lies flat on table, hands closed
Spontaneous movements Decreased/increased
Tremors Fine in hands, chin, coarse limb
Muscle tone (rest) Asymmetric, decreased
Muscle tone (against resistance) Increased/decreased
Traction response Head lags, flaccid, arms fully
extended (no flexion at elbow)
Palmar/plantar grasp Absent, interrupted, tremor
Knee/ankle/biceps jerk Exaggerated/absent
Moro stage 1 Absent, exaggerated
(full extension)
(Normal - extension of elbows)
Moro stage 2 Absent adduction, flexion of elbows
Cry Weak/groaning/high pitch
Asymmetry Present
Cranial nerve Abnormality
Responsiveness Diminished/hyper excitable
NEUROIMAGING ....................................................................................
May be done as Initial assessment of neurodevelopment (Before discharge/
first assesment of a young infant)/or decided on follow up based on abnormal
clinical findings.
NEUROSONOGRAM
Indications
• Preterm < 32 weeks gestation, < 1500 grams weight at birth
• Preterm with abnormal Neurobehavior/examination—seizures, lethargy,
apnoea, sudden onset pallor, bulging anterior fontanel, tight popliteal
angles.
Protocol—1st assessment at 3 to 5 days (desirable), 2nd assessment
at 40 weeks corrected gestation (mandatory).
Look for evidence of brain atrophy as in ventriculomegaly/cystic Peri-
Ventricular Leukomalacia (PVL)—white matter disease (WMD)
CT SCAN
Indications
• Moderate (Grade 2, Levene)/prolonged or unexplained encephalopathy
• Encephalopathy and Seizures
1st scan as clinically indicated (1st 2 weeks of life, before discharge),
2nd at 2 to 6 weeks age (more useful for prognostication)
Look for Marked diffuse hypo density or major intra cerebral hemorrhage/
calcification/malformations/evidence of strokes (infarcts)
CT is not superior to Neurosonogram in picking up PVL.
• In sick preterm infants, neurosonogram is preferred, as it is portable,
can come to NICU, rather than baby move, and can be repeated serially
without risk of radiation hazards (in contrast to CT).
MAGNETIC RESONANCE IMAGING (MRI)

The neuro-radiologist interpreting newborn MRI must be aware of milestones
of myelination on the MRI.
Advantages
Sensitivity of MRI in diagnosis of brain atrophy in preterm neonates is
higher than neurosonogram (specificity similar). Diffusion weighted MRI
can prognosticate outcomes early (within minutes after the asphyxial insult)
in perinatal asphyxia. MRI is generally superior to CT in delineation of
many pathologies; but CT is superior to MRI in delineation of intracranial
calcification.
Practical Difficulties
Deep sedation needed for MRI, difficulty in monitoring (metal incompatibility
of MRI) makes it unsafe in these at-risk babies.
EEG
The EEG of a baby must be evaluated keeping in mind the gestation;
EEG maturation and changes have been demonstrated at various gestations.
Always include a quite sleep EEG in evaluation of newborns; abnormalities
may be apparent only in this period.
Impairment of EEG developmental maturation persisting for more than
3 weeks of life (often associated with major EEG abnormalities) is predictive
of abnormal outcomes.
Major EEG abnormalities
• Disordered development
• Depression/lack of differentiation
• Burst suppression pattern
• Electro cerebral silence
• Unilateral depression of background activity
• Periodic discharges
• Multifocal sharp waves
• Central positive sharp waves
• Rhythmic generalized/focused alpha activity
• Hypsarrhythmia
PHYSIOLOGICAL BRAIN IMAGING

Positron emission tomography (PET) provides information regarding cerebral
blood flow, oxygen and glucose consumption, also the spatial distribution
and also quantitative details. Currently this is a research tool.
20
Screening Protocol
RETINOPATHY OF PREMATURITY (ROP) SCREENING ...............

For Preterm Infants (before discharge/on follow-up if discharged before
screening complete).
INDICATIONS—WHO TO SCREEN?
Preterm baby < 33 weeks gestation/<1500 gm birth weight (some Indian
studies have reported ROP at older gestation/weights—the protocols may
be modified at individual centers, based on local experience. Most Indian
experts suggest < 34 weeks).
Any preterm baby with severe cardio-respiratory compromise.
WHEN TO SCREEN?
Start at 4 weeks of life or after 31 weeks gestation (which ever is later)
Screen 1/2/3 weekly as per ICROP guidelines and more frequently if
“plus disease” noted.
HOW OFTEN TO FOLLOW-UP?—FOLLOW-UP AFTER

• 1-week or less, if
Stage 1 or 2 ROP: zone I, stage 3 ROP: zone II
• 1 to 2-week, if
immature vascularization; zone I—no ROP, stage 2 ROP: zone II,
regressing ROP: zone I
SCREENING PROTOCOL 217
• 2-week follow-up
stage 1 ROP: zone II, regressing ROP: zone II
• 2- to 3-week follow-up
Immature vascularization: zone II—no ROP, stage 1 or 2 ROP: zone
III, regressing ROP: zone III
WHAT TO LOOK FOR?

Severe ROP—for laser photocoagulation/cryotherapy.
WHEN CAN THE BABY BE DISCHARGED FROM ROP SCREEN?

No risk of ROP needing treatment.
Findings that suggest that examinations can be curtailed include the
following:
1. Zone III retinal vascularization attained without previous zone I or II
ROP (if there is examiner doubt about the zone or if the postmenstrual
age is less than 35 weeks, confirmatory examinations may be warranted);
2. Full retinal vascularization;
3. Postmenstrual age of 45 weeks and no pre-threshold disease (defined
as stage 3 ROP in zone II, any ROP in zone I) or worse ROP is
present; or
Regression of ROP (care must be taken to be sure that there is no
abnormal vascular tissue present that is capable of reactivation and
progression).
WHO CAN SCREEN?

• Indirect ophthalmoscopy by trained ophthalmologist, after pupillary
dilation using binocular indirect ophthalmoscopy to detect ROP
(desirable).
• Direct ophthalmoscopy by trained pediatrician (in absence of trained
ophthalmologist).
WHEN TO TREAT?
The presence of “plus disease” (defined as dilation and tortuosity of the
posterior retinal blood vessels) in zones I or II suggests that peripheral
ablation, rather than observation, is appropriate.
Threshold ROP, as defined in the Multicenter Trial of Cryotherapy for
Retinopathy of Prematurity, may no longer be the preferred time of
intervention.
Treatment may also be initiated for the following retinal findings:
1. Zone I ROP: any stage with plus disease
2. Zone I ROP: stage 3—no plus disease
3. Zone II: stage 2 or 3 with plus disease
Treatment should generally be accomplished, when possible, within 72

hours of determination of treatable disease to minimize the risk of retinal
detachment.
ROP—Policy Statement
Screening Examination of Premature Infants for Retinopathy of
Prematurity.*
ROP is a pathologic process that occurs in immature retinal tissue and
can progress to a tractional retinal detachment, which can result in functional
or complete blindness. Peripheral retinal ablative therapy using laser
photocoagulation has resulted in the possibility of markedly decreasing
the incidence of this poor visual outcome, but the sequential nature of
ROP creates a requirement that at-risk preterm infants be examined at
proper times to detect the changes of ROP before they become
permanently destructive.
“The International Classification of Retinopathy of Prematurity Revisited”
(Arch Ophthalmology 2005) should be used to classify, and record retinal
findings at the time of examination.
The schedule of follow up is determined by stage of disease, plus
disease and zone.
HOW DO WE DILATE?
The recommended eye drops are tropicamide 0.5-1% with phenylepherine
2.5%. Two to three instillations of each of these drops, five minutes apart
are usually sufficient to dilate the pupils in 15-20 minutes; and the effect
remains for 30-45 minutes. Cyclopentolate 0.5% to 1.0% can also be
used safely. Care should be taken to wipe (with sterile cotton/tissue) any
eye drops that spills onto the cheeks, as they can be absorbed from
the skin of the babies and cause increased heart rate. It is not advisable
to use 10% phenylepherine or atropine (drops or ointment) in premature
babies for screening, as severe tachycardia, and fatal hyperthermia and
dehydration can occur due to systemic absorption. Use of any dilating
eye drops (or even antibiotic or corticosteroid eye drops) in premature
babies can be life threatening and should not be taken casually.
[Note: In India only 10% (and sometimes 5%) phenylepherine is available
commercially. A 10% solution needs dilution in 1:4 ratio. To prepare 2.5%
solution, dilution can be done with methylcellulose eye drops or
commercially available distilled water.]
———
*Section of Ophthalmology American Academy of Pediatrics; American Academy of
Ophthalmology; American Association of Pediatric Ophthalmology and Strabismus.
AAP policy statement: Screening Examination of Premature Infants for Retinopathy
of Prematurity. Pediatrics 2006;117(2):572-6
SCREENING FOR HEARING IMPAIRMENT ** .................................
WHO TO SCREEN?
Desirable—all neonates, mandatory—all babies admitted to NICU/risk factors
for hearing impairment (see overleaf).
WHEN TO SCREEN?
Desirable—before discharge from NICU, Mandatory—within 3 months of
life.
Hearing Assessment—Risk Group

• Craniofacial anomalies • Asphyxia
• Family h/o of hearing impairment • Meningitis
• Intracranial hemorrhage • Ventilated
• Neonatal Jaundice (needing exchange) • < 1500 gms
• Amino glycosides, frusemide • IU infections
Babies who have risk factors for hearing loss should have a diagnostic
hearing test at 1 year chronological age (even if passed the screening test).
HOW TO SCREEN?
Oto-Acoustic emissions (OAE)—for all babies
Brainstem Evoked Response Audiometry (BERA)—babies who fail repeat
OAE.
Babies at high risk of hearing impairment must undergo both (OAE
misses sensory-neural hearing impairment).
WHO CAN SCREEN?

Any trained personnel can do OAE.
BERA must be done and interpreted by an audiologist.
If hearing impairment is detected, the infant should have
intervention for hearing impairment before 6 months of age to optimize
language development.
OAE
Evoked otoacoustic emissions (OAE) are acoustic signals generated from
within the cochlea that travel in a reverse direction through the middle
ear space and tympanic membrane out to the ear canal. These signals
are generated in response to clicks or tone bursts. The signals may be
detected with a very sensitive microphone/probe system placed in the
external ear canal. The OAE test allows for individual ear assessment,
** Michael Cunningham, ND and Edward O. Cox MD. The committee on practice

and ambulatory Medicine and the section on otolaryngology and Bronchoesophagology.
Hearing Assessment in infants and Children: Recommendations Beyond Neonatal
Screening Pediatrics 2003;111(2):436-40
is performed quickly at any age, and is not dependent on whether the

child is asleep or awake. Motion artifact does not interfere with test results.
The OAE is an effective screening tool for inner and middle ear
abnormalities. At hearing thresholds (30 dB), there is no OAE response.
The OAE test does not further quantify hearing loss or hearing threshold
level. The OAE also does not assess the integrity of the neural transmission
of sound from the eighth nerve to the brainstem and, therefore, will
miss auditory neuropathy and other neuronal abnormalities. Infants with
such abnormalities will have normal OAE test results but abnormal BERA
test results.
BERA
BERA is an objective means of evaluating hearing. This instrument measures
evoked responses in response to sound clicks at frequencies greater than
1000 Hz. The automated screener provides a pass-fail report and no
test interpretation by an audiologist is required. Automated BERA can
test each ear individually and can be performed on children of any age.
Motion artifact interferes with test results. For this reason, the test is
performed best in infants and young children while they are sleeping
or, if necessary, sedated.
The BERA and OAE are tests of auditory pathway structural integrity
but are not true tests of hearing. Even if BERA or OAE test results are
normal, hearing cannot be definitively considered normal until a child
is mature enough for a reliable behavioral audiogram to be obtained.
Behavioral pure tone audiometry remains the standard for hearing evaluation.
Children as young as 9 to 12 months can be screened by means
of conditioned oriented responses (CORs) or visual reinforced audiometry
(VRA).
SCREENING FOR CONGENITAL HYPOTHYROIDISM*** .................

WHO TO SCREEN?
Desirable: screen all neonates, Mandatory: screen at least babies at risk
of NDD.
WHEN TO SCREEN?
Beyond day 3 and before 1 week of life.
If discharged earlier, take samples before discharge from hospital
***American Academy of Pediatrics; Rose SR; Section on Endocrinology and Committee

on genetics, American thyroid Association; Brown RS; Public Health Committee, Lawson
Wilkins Pediatric Endocrine Society; Foley T, Kaplowitz PB, Kaye CI, Sundarrajan S,
Varma SK. Update of Newborn Screening and therapy for Congenital Hypothyroidism.
Pediatrics 2006;117(6):2290-2303.
HOW TO SCREEN?
Desirable method: TSH and Free T4, Mandatory: at least TSH alone
(cost-effective, can miss some cases).
WHAT TO LOOK FOR?

TSH > 20 in 1st 2 weeks of life, TSH > 10 after 1st 2 weeks of life
are abnormal.
(If the screening test is suggestive, full work up should be completed
and treatment started within 2 weeks).
Congenital Hypothyroidism (CH)

The overall incidence of CH ranges from 1 in 3000 to 1 in 4000
newborn infants. Newborn screening and thyroid therapy started within
2 weeks of age can normalize cognitive development.
Initial dosage of 10 to 15 μg/kg levothyroxine (LT4) is
recommended. The goals of thyroid hormone therapy should be to maintain
total/free thyroxine in the upper half of the reference range during
the first 3 years of life and to normalize the serum thyroid-stimulating
hormone concentration.
The goal of therapy is to normalize T4 within 2 weeks and TSH
within 1 month.
Although T3 is the more biologically active Thyroid Hormone (TH),
most brain T3 is derived from local monodeiodination of T4, so T3 should
not be used.
The pill should be crushed and suspended in a few milliliters of formula,
breast milk, or water. Care should be taken to avoid concomitant
administration of soya milk, fiber, iron supplements, or anticonvulsants;
During TH therapy, 4 or more episodes of insufficiently suppressed
TSH (>5 mU/L) after the age of 6 months were the most important
variables associated with school delay.
A failure of the serum free T 4 concentration to increase into the upper
half of the reference range by 2 weeks and/or failure of the TSH
concentration to decrease to less than 20 mU/L within 4 weeks after
initiation of L-T4 administration should alert the physician that the child
may not be receiving adequate L-T4 regularly.
Infants need to undergo frequent laboratory and clinical evaluations
of thyroid function, growth, and development to ensure optimal Free
T4 dosage and adherence to their therapy regimen. Serum Free T 4 and
TSH measurements should be performed: at 2 and 4 weeks after the
initiation of L-T4 treatment, every 1 to 2 months during the first 6 months
of life; every 3 to 4 months between 6 months and 3 years; every 6
to 12 months until growth is completed; and at more frequent intervals

when compliance is questioned, abnormal values are obtained, or dose
or source of medication has been changed; FreeT 4 and TSH measurements
should be repeated 4 weeks after any change in L-T4 dosage.
The aim of therapy is to ensure normal growth and development
by maintaining the serum total T4 or Free T4 concentration in the upper
half of the reference range in the first year of life.
SCREENING FOR METABOLIC DISORDERS ..................................

WHO SHOULD BE SCREENED FOR METABOLIC DISORDERS?
Desirable—All neonates. Mandatory—All neonates at risk of NDD.
POINTERS TO METABOLIC DISORDER

• Unexplained encephalopathy.
• “Sepsis like picture” with labs not supporting—cultures and sepsis screen
and response to antibiotics not suggesting sepsis.
Baseline Tests
Serum ammonia, blood gas analysis (for anion gap acidosis), urinary ketones.
Special Test
Serum, urine (stored cold during transfer), CSF for biochemical analysis
to metabolic lab.
Section 9
Neurodevelopmental
Follow-up
21. Discharge Protocol
22. Follow-up Protocol
23. Organization of Neurodevelopmental
Follow-up
21
Discharge Protocol
DISCHARGE PLANNING ......................................................................

ROLE OF TREATING PEDIATRICIAN/NEONATOLOGIST
• Plan discharge well ahead; document all risk factors for NDD, clinical
course in NICU and interventions
• Identify a local primary care physician for purpose of follow-up and
communicate effectively
• Involve the development therapist in pre–discharge counseling
• Co-ordinate multi-specialty consults
• Integrate follow-up with medical follow-up
• Communicate with family, specialists and primary care physician.
ROLE OF DEVELOPMENTAL THERAPIST

• Babies at moderate/high risk of NDD should be initiated on an early
stimulation program before discharge.
ROLE OF PRIMARY CARE PHYSICIAN

• Counseling parents educating/guiding on need for follow-up
• Link between specialists and family
– Co-ordinate appointments—tests, interventions
– Conveniences of family (family friendly)
– Periodic preventive assessments with medical visits.
CHECK LIST BEFORE DISCHARGING A HIGH RISK NEONATE

1. Summary of baby’s neonatal hospital course (copy to primary physician)
• Date of birth and expected date of delivery
• Gestational age at birth

• Birth weight
• Risk factors for NDD
– Antenatal risk factors
– Neonatal risk factors (diagnosis, medications/interventions, referrals)
• Discharge weight (and weight gain over last week), approximate
1% of birth weight per day
• Discharge OFC (growth over last week), 0.75 to 1.25 cm/week for
preterms till term, 0.5 cms per week there after (and for term babies)
• Date and results of
– last metabolic screen (Ca, P, ALP)
– last hematology assessment (Hb)
– last ROP check
– hearing screen (if done)/proposed date of test if not done before
discharge
– last neurosonogram report
~ worst/significant abnormality on USG
• Dietary intake at discharge (breast milk/formula/other supplements,
as per medical prescription)
• Immunization status
• Environment assessment (HSQ) (assess parent preparedness/socio-
economic).
2. Risk stratification for NDD based on risk factors and initial assessment
of neurodevelopment
• In-clinic FU (low/no risk)
• Developmental unit (Moderate risk)
• Child development center (high-risk).
3. Pre-discharge counseling
• Danger signs- how to contact in case of emergency?
• Need for neurodevelopmental follow-up
• Plan of follow-up till one year
• Role of parents in stimulation of child
• Parent observed development assessment (e.g. development obser-
vation card, DOC).
4. Follow-up appointments
• ROP
• Appointment for hearing screen (if not done)
• Newborn unit (medical)
• Lab tests
• Neurodevelopmental assessments.
5. Immunization.
DISCHARGE PROTOCOL 227
CHECK LIST OF NDD WITH DEFINITIVE THERAPY
(Make sure these are not missed, these are definite opportunities to improve
babies outcomes)
• ROP treatment—laser photocoagulation/cryotherapy
• Squint correction/surgery/refractory error correction
• Hearing intervention—hearing aid/speech therapy/cochlear implant
• Hypothyroidism treatment with L—thyroxine
• Seizures medications, hypertonia medications
• Developmental stimulation
• Physical and occupational therapy
• Pediatric surgery interventions—hernia, GERD surgeries
• Ortho consults
• Hydrocephalus shunt
• ENT consult—swallowing, oro-motor problems.
DDST—report as normal—review after 3-6 months, abnormal—state
interventions, questionable—repeat after 3-4 weeks.
DASII—report as DQ and score—If more than 85 reviews after 3-
6 months. If less than 85—repeat after 3-4 weeks and intervention.
Neuro exam—report as normal tone/hypertonia/hypotonia/
patterns—diplegia, quadriplegia, hip shoulder girdle hypotonia, hemiplegia.
REASSESS—IF NO DEFINITE OPINION POSSIBLE

Hearing—a baby passing a hearing test states hearing is normal on that
day, acquired hearing loss can result in hearing impairment later.
Parents to note. Each of the tests takes a lot of time and hence,
tests may not be possible without prior appointment. Parents also
need to confirm availability of the appointment one-day prior, as
appointments are made well ahead and unforeseen situations may make
a particular service unavailable on that day. A good mood of the baby
is essential for all tests/sedation may be required for some—hence
completion of test is subject to cooperation/sedation.
A normal report indicates that no abnormality is detectable on that
day. Brain of babies is still acquiring complex functions and hence, the
future course cannot be predicted by these tests—and are not guarantees
of normal future and hence, repeated testing—surveillance is necessary,
the tests only help to plan any interventions on that day. The parents
are the best development specialists and if they note any unusual behavior
they may report to the development unit. Plan of follow-up after 1-
year age will depend on the baby’s development assessment.
KIMS –CDC follow-up schedule

Name Hospital No.
DATE OF BIRTH EDC
Corrected age Term 1 month 2 months 4 months 8 months 12 months

DATE (CA)
Growth (weight,
OFC for length,
corrected age)
Neurobehavior/
personal social
(DDST)
Neurologic exam
(Amiel Tison)
Limited utility
Gross motor (DDST)
before 3 months
Use DDST for
Fine motor (DDST)
moderate risk (done
by developmental
Language (DDST)
pediatrician)
Use DASII for high-
DASII score
risk done by
MoDQ
developmental
DASII score therapists
MeDQ
CDC grading
NB: some centers prefer to follow a schedule of 3, 6, 9 and 12 months
Corrected age
DATE Term 1 month 3 months 12 months
Ear (OAE/BERA) * * * (repeat in

risk high)
Labs (Hb, Ca, P, * * Calcium MV till (3.5- Clinical and lab Iron
ALP), 4.5kg) assessment for iron-
deficiency anemia
Eye (ROP/squint 4 weeks As per ophthalmologists 45 WEEKS/ 9-12 months–

nystagmus/ after birth/ advice—1/2/3 weekly or completed Refraction/
refraction) 31 weeks more frequently in plus vascularization squint
DATE (if later) disease
By ophthalmologist
ASSESSMENT OF THE CHILD’S HOME ENVIRONMENT .............

Assessed at all visits to neurodevelopment clinic.
WHAT IS HOME ENVIRONMENT?

Assessment of parents/extended family - coping/parenting skills/opportunities
for stimulation of infant.
DISCHARGE PROTOCOL 229
TOOLS
• Social environment scale
The social status of the family is a simple measure of environment,
but not a completely reliable predictor of the outcomes in an at-risk
infant.
• HOME inventory
Objective tool for assessment of home environment in relation to baby’s
development.
• Home screening questionnaire
Simpler to do in clinical practice.
HOME (Home Observation for Measurement of Environment)

Bettyle M Caldwell, Robert H Bradley
Objective method of describing the quality of home environment.
The inventory scores the environment on following areas:
• Emotional and verbal responsivity
• Acceptance of child behavior
• Organization of physical and temporal environment
• Provision of appropriate play materials
• Parent involvement with the child
• Opportunities for variety in daily stimulation.
Dr Anand Pandit et al, clearly demonstrated that the intelligence quotient
(IQ) of LBW and VLBW decreased (more so in later) with decreasing
maternal education—demonstrating the effect of environment on neuro-
developmental outcomes.
22
Follow-up Protocol
If the infant is being assessed for the first time beyond neonatal period
please check whether initial assessment is complete.
INTRODUCTION—CONCEPT OF CORRECTED AGE .....................

For assessment of “milestones” in preterm infants, there is unsettled
controversy of whether to “correct for prematurity” and if so how
much to correct (full or half) and till what age?.
If correction is not made for prematurity, an extreme preterm infant
may miserably fail all developmental tests in early infancy. On the other
hand, correction overestimates childs cognitive abilities (especially important
<35 weeks) and may fail to identify infants who would benefit from
early interventions.
It appears that earlier exposure to extra-uterine environment may have
greater effect on language (component of cognition) than on motor
development. Preterms with language and cognitive abilities consistently
below their age corrected for prematurity should be evaluated and initiated
on early intervention.
Most developmental experts agree to correct for prematurity
till at least two years of age.
Correction for prematurity—full correction: calculate the infants age
from the “expected date of delivery” (for the purpose of neurodevelop-
mental follow-up), rather than from the actual date of birth.
GROWTH, NUTRITION AND MEDICAL ASSESSMENT ..................

• Head circumference should be plotted at every health maintenance
visit until the age of 2 years (LOE 2).
• Height and weight should be measured and plotted at regular intervals.
FOLLOW-UP PROTOCOL 231
A poor weight gain <20 gm/day during the first month after discharge
should be investigated.
Use preterm growth charts for preterm babies.
NUTRITION
Encourage breast-feeding even in VLBW, ELBW babies. There is no
evidence to recommend fortified formula over breast-feeding, if breast
milk is available sufficiently
• Mothers must express breast milk for the sick preterm baby from as
early as possible (breast pumps may be used).
• Even in very preterm (< 32 weeks corrected age)—practice non-
nutritive sucking and kangaroo mother care.
All preterm infants (<35 weeks) should receive supplements
• Iron - starting at 4-6 weeks (can start at 2 weeks) till 1-year of age
(3 mg/kg/day of elemental iron)
• Calcium (as phosphate salt) - start when on full feeds—150 mg/kg/
day of elemental calcium till term
(Monitor Hb, Ca, P, alkaline phosphatase, nearing 40 weeks corrected
age)
• Multi-vitamin supplementation till approximately 3.5 kg (approximate,
expert opinion)
• Protein supplementation -using human milk fortifiers or special formula
for preterms has demonstrated only short term growth advantages,
the advantage of supplementation does not carry into childhood
(Indication—poor linear growth poor and by medical prescription only).
Weaning may start early (at 4 months corrected age) in preterm
babies.
GENERAL CARE/MEDICAL ISSUES

• Advice on thermoregulation (kangaroo mother care)
• Advice on prevention of infections (hand wash, avoid visitors)
• Schedule of feeding (demand feeding even for VLBW once stable
enough to discharge)
• Immunization—BCG, OPV can be given after discharge from NICU
(after 34 weeks gestation), hepatitis B—if mother recorded HBsAg
negative, immunize as per national schedule starting with first DPT
(can be given if baby ready for discharge and gaining weight). In
case the mother is Hep B positive, or status unknown, Hep B vaccine
can be administered even in extreme preterms immediately after birth.
Other vaccines as per chronological age (from actual date of birth,
not expected date of birth)
• Constipation—common in preterms, may use lactulose

• Inguinal hernia—advice surgical consult/umbilical hernia reassure
• Examine for murmurs after 2-3 weeks of life on a regular basis (Left
to right shunts manifest earlier in preterm)
• Watch for hepatosplenomegaly, cataract, (IU infection)
• Repeat any abnormal lab tests till normal (e.g. hemoglobin, platelet
count, renal and liver function tests).
NEUROLOGICAL EXAMINATION ........................................................

A structured, age-appropriate neuro-motor assessment should be performed
and assessed by corrected age
• at least once during the first 6 months
• once during the second six months
• and once between ages 1 and 2, 2 and 3 and 4 and 5 years (LOE 3).
ASSESSMENT OF PASSIVE TONE

Assessment of passive tone (Amiel Tison, Infant Motor Screen) in the
first year of life is a useful tool for early detection of motor developmental
disability (Reported even better than BSID at 3, 6, 9 months).
Test schedule –desirable: 3, 6, 9, 12 months (some prefer 2, 4, 8,
12), mandatory - 3 months, 12 months.
Adductor and popliteal angles are best studied. Adductor and popliteal
angle are measured with a goniometer.
Months 3 6 9 12
Adductor angle 40-80 70-110 100-140 130-150
Popliteal angle 80-100 90-120 110-160 150-170
Word of Caution
It has been seen that, tight angles at 4 months (<2000 gm birth weight)
do not always predict abnormal outcome, many of which become normal,
where as persisting hypertonia at 8-12 months is associated with poor
outcomes.
What to look for

a. Tone abnormalities
• Normal tone
• Hypotonia (mild/severe)
• Hypertonia (mild/severe).
b. Pattern of tone abnormalities
• Diplegia
• Quadriplegia
• Hemiplegia.
c. Look for asymmetry.
d. Serial assessment of tone abnormalities
• Transient
• Persistent.
ACTIVE TONE
There should be no head lag at 3 months of age, should be possible
to pull to sit by 6 months and pull to stand by 9 months age.
ABNORMAL NEUROLOGICAL SIGNS ON NEWBORN

Explained in previous chapters.
PRIMITIVE REFLEXES AT 3 MONTHS

• Palmar grasp
• Automatic walking
• Moro reflex
• Asymmetric tonic neck reflex.
All disappear by 3 months in Indian infants.
Primitive reflexes are difficult to interpret even by experts. In infants
with diffuse bilateral cerebral injuries, stronger, sustained reflexes with no
signs of habituation (stereotyped, not decreasing with repeated elicitation)
are obtained.
POSTURAL REFLEXES AT 9 MONTHS

• Parachute
• Lateral propping
Postural reactions are relatively easier to interpret, and a slow appearance
indicates delay in acquiring postures and hence, CNS injury. Vojta’s system
of kinesiological diagnosis (based on the evaluation of 7 postural reactions)
enables one to identify infants at risk for neurodevelopment delay as
early as 3 months of age with 100% accuracy when 3 reactions were
abnormal.
CRANIAL NERVE EXAMINATION

Refer text of pediatric neurology.
RED FLAGS
• Frog legs—hypotonia
• Scissoring—hypertonia
• Early rolling 1-2 months (hypertonia)
• Persistent fisting at 3 months of age
• Pulling directly to stand at 4 months (instead of to a sit)
• Delay in appearance of postural reactions
• Hand dominance prior to 18 months.
DEVELOPMENTAL ASSESSMENT .....................................................

Developmental assessment is defined as obtaining information about the
skills and potentials of individuals (next section for details).
RECOMMENDED SCHEDULE
For Babies at Mild Risk of NDD/All Babies
• Trivandrum Development Screening Chart (TDSC)
• Development Observation Card (DOC), Schedule: 2, 4, 8, 12 months
at well baby/immunization visits.
For Babies with Moderate Risk Factors for NDD

Mandatory:
A multidimensional development-screening test (Denver Development
Screening Test (DDST/Denver II) should be documented using standar-
dized instruments (LOE 3)
• At least once during first 6 months
• At least once during next 6 months
• Once every year till 5 years.
Desirable
Formal developmental evaluation (Development Assessment Scale for Indian
Infants –DASII) be performed (limited utility before 6-8 months corrected age)
• At least once between 9 and 15 months
• At least once between 21 and 30 months corrected age
• Within 2 months of a abnormal/questionable DDST.
For Babies with High Risk Factors for NDD

• Mandatory—DDST every 3-4 months
• Desirable—DASII every 3-4 months by developmental therapist.
BEHAVIORAL PROBLEMS/LEARNING DISORDERS .......................

These disabilities result in poor adaptation to society and poor self-esteem.
• There is an increase in the psychological problems. Attention Deficit
Hyper kinetic Disorder (ADHD) and only awareness of the problem
can result in early diagnosis and intervention
• It is recommended that all babies < 28 weeks, < 1000 gms undergo
a psycho-educational assessment between the ages 3 and 5 (LOE 3)
• Learning problems (borderline IQ) is a great area of concern as unlike
the major disabilities, they are often not recognized and result in poor
school performances and behavioral problems.
FUNCTION ASSESSMENT ...................................................................

For the purpose of rehabilitation—assessment of functional loss/adaptation
is more useful than diagnosis of Neurodevelopmental disability. An example
is—
1. Walks without restrictions; limitations in more advanced gross motor
skills.
2. Walks without assistive devices; limitations walking outdoors and in the
community.
3. Walks with assistive mobility devices; limitations walking outdoors and
in the community.
4. Self-mobility with limitations; children are transported or use power
mobility outdoors and in the community.
5. Self-mobility is severely limited even with the use of assistive technology.
23
Organization of
Neurodevelopmental
Follow-up
Infants should be assigned to risk groups (mild, moderate or severe) based

on severity of perinatal problems, the interventions received in NICU and
assessment of family preparedness.
FOR BABIES AT LOW RISK OF NDD ............................................

It is sufficient to follow-up in the usual well baby clinic – “In Clinic” follow-
up.
Objective: Screening for growth and development deviation and referral.
Provider: All pediatricians/primary care physicians (level 1 care).
Prerequisites
• Familiarity with growth charts, TDSC
• Aware of indications to seek NDD consult.
FOR BABIES AT MODERATE RISK OF NDD ................................

It would be appropriate to follow-up such babies in a specially planned-
“Developmental unit”
Objective: Comprehensive ND FU, early developmental stimulation and
referral.
Provider: all centers with NICU (level 2 care).
Prerequisites
• Pediatrician familiar with good clinical practices in neonatology
• Developmentally sensitized pediatrician (knowledge of special growth
charts, protocols for neurodevelopmental follow-up)
• Developmental therapist trained in DDST (or equivalent development
screening test), Amiel Tison (equivalent neurological examination)
ORGANIZATION OF NEURODEVELOPMENTAL FOLLOW-UP 237
• Early stimulation program
• Radiologist (familiar with neurosonography of preterms)
• Trained ophthalmologist for ROP screens
• Audiologist/ENT specialist (OAE)
• Physical and occupational therapist
• Social worker.
FOR BABIES AT HIGH RISK OF NDD ...........................................

These babies are a serious risk of disability and screening would be
inappropriate. They should have follow-up at a multi-specialty diagnostic
and intervention center—“Child development center”.
Objective: Serial comprehensive NDFU: Diagnostic tests and interventions.
Provider: tertiary care centers.
Prerequisites: (desirable)
• Neonatologist (uses standard risk definitions for NDD)
• Developmental pediatrician (uses special growth charts, formal neurologic
examination), developmental therapist trained in DASII (or equivalent
formal development tests), DDST (or equivalent development screening
test), Amiel Tison (equivalent neurological examination screening test),
early stimulation program
• Counselor for genetic disorders (familiar with dysmorphology)
• Pediatric neurologist
• Radiologist (trained in neurosonogram CT, MRI and EEG in newborn/
preterm)
• Trained ophthalmologist/retina expert
• Audiologist/ENT specialist (OAE, BERA)
• Endocrinologist (familiar with management of congenital hypothyroidism)
• Metabolic disorders expert (tandem mass spectroscopy)
• Physical and occupational therapist
• Psychologist for behavioral problems
• Expert in learning disability management
• Neurosurgeon, pediatric surgeon
• Social worker
BIBLIOGRAPHY .....................................................................................
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Committee on Genetics, American Thyroid Association; Brown RS; Public
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Screening and Therapy for Congenital Hypothyroidism Pediatrics 2006;
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4. Bailey, et al. First Experiences with Early Intervention: A National Perspective.
Pediatrics 2004;113(4):887.
5. Bear LM. Early identification of infants at risk of development disabilities,
Pediatr Clin N Am 2004;51:685-701.
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study—cognitive abilities and educational performance at twelve years. Indian
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8. Committee on Children With Disabilities American Academy Of Pediatrics
Developmental Surveillance and Screening of Infants and Young Children
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BE. Neurobehavioral assessment predicts differential outcome between VLBW
and ELBW preterm infants. J Perinatol 2005;25(12):788-93.
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AA. Treated hypotension is associated with neonatal morbidity and hearing
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J. Ability of neonatal head circumference to predict long-term neuro-
developmental outcome. Rev Neurol 2004;39(6):548-54.
12. Girolami GL, Campbell SK. Efficacy of a neurodevelopmental treatment
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Therapy. 1994; 6:175-84.
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B, Breart G. A new and improved population-based Canadian reference
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Neurodevelopmental problems at preschool age, Academic dissertation,
University of Helsinki 2002.
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mance in infants born preterm. Aust J Physiother 2001;47(3):169-76.
17. Levene MI, Lornberg J, Williams THC. The incidence and severity of post-
asphyxial encephalopathy in full term infants. Early human development
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of the infant. J Child Adolesc Psychopharmacol 2005;15(2):240-8.
19. Maiya PP, Samtha S. Predicting neuro-developmental outcome at 3 months
of age in babies with hypoxic ischemic encephalopathy by Vojta’s
neurokinesiological examination. Indian Pediatrics 1999;36:171-3.
20. Michael Cunningham, MD and Edward O. Cox, MD the Committee on Practice
and Ambulatory Medicine and the Section on Otolaryngology and
bronchoesophagology Hearing Assessment in Infants and Children:
ORGANIZATION OF NEURODEVELOPMENTAL FOLLOW-UP 239
Recommendations Beyond Neonatal Screening Pediatrics 2003;111(2):436-
40.
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Pediatrics 2005; 42:985-988.
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2004; 41:1201-02.
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nnf India, IAP.
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Annual convention of NNF 2004.
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Academy of Ophthalmology; American Association for Pediatric
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Pediatrics 2006;117: 2080-92.
Section 10
Developmental
Evaluation
24. Developmental Evaluation
Babu George, Narayanan Potti, MKC Nair
24
Developmental Evaluation
Developmental assessment is defined as obtaining information

about the skills and potentials of individuals.
THE PURPOSES OF ASSESSMENT ..................................................

Assessment of individual children might serve one of the following
purposes:
1. To determine the existence of a developmental delay
2. To identify strengths and needs
3. To develop strategies for intervention
4. To determine progress on significant developmental achievements
5. To serve as a basis for reporting to parents
WHAT IS DEVELOPMENTAL ASSESSMENT ...................................

• Every baby follows his or her own unique schedule of development
within fairly broad limits
• Assessment may take on special significance in a suspected
developmentally abnormal infant.
• The score obtained is not an IQ score, but rather a relatively short-
term, best estimate of developmental progress.
• It can prove useful in detecting the precursors of later impairment.
• Despite limitations assessment techniques continue to be effective means
of identifying infants at risk for developmental disabilities.
• Identification of risk status can lead to early intervention services aimed
at prevention and amelioration of potential problems.
• Infant assessors must be well trained professionals who not only have
a sound background in child development but have training in the
use of the measures and understand their strengths and limitations.
DEVELOPMENTAL ASSESSMENT — BELOW 2 YEARS ..............

TEN COMMANDMENTS IN ASSESSMENT
1. Assessment must be based on an integrated model of child
development, which includes developmental domains and child’s
functional capacities. It is necessary to observe the child over a time
period and in different contexts.
2. Assessment involves multiple sources of information and multiple
components.
• Developmental history
• Parents perceptions of child’s strengths and needs
• Direct observation of the child, including interactions with caregiver
• Observations and interaction with the family regarding family’s
needs and capabilities. Focused observation of the child in different
areas of functioning is a must.
3. Assessment should follow a certain sequence.
• Build an alliance with the parent/caregiver
• Obtain developmental history
• Observe the child in the context of unstructured play with caregivers
• If appropriate, observe child in play with evaluator/clinician
• Conduct specific assessments of individual functions
• Integrate all the data to create picture of the whole child, and
convey assessment findings in the context of an alliance with the
parents.
4. The child’s relationship and interactions with his or her caregiver
should form the cornerstone of the assessment. Children will generally
reveal their highest level of skills in the context of spontaneous,
motivated interactions with caregivers. The evaluator can build on
these interactions by coaching the parent to elicit certain competency
or by joining in the interaction.
5. An understanding of the sequences and timetables in typical
development is essential as a framework for the interpretation of
developmental differences among infants and toddlers. Given the
considerable variation in the normal range of development during
the early years, professionals must have sound knowledge in the
typical sequence and timetable for different areas of development.
6. Assessment should emphasize attention to the child’s level and pattern
of organizing experience and to functional capacities, which represent
an integration of emotional and cognitive functioning. The basic
capacities of relating, interacting and thinking will directly have impact
on the specific developmental skills under consideration. It is not
DEVELOPMENTAL EVALUATION 245
just a question of whether a particular skill exists or not, but how
does the environment support the child’s developmental functioning.
7. The assessment process should identify current competencies and
strengths, as well as identify the next step in the developmental
sequence in order to facilitate growth. It is more useful to think
about how to build on the child’s current capacities, than to merely
describe deficits or lags in development. Too often an assessment
focuses on the delay in development.
8. Assessment is a collaborative process. Building an alliance with the
primary caregivers is essential to the process. All the professionals
involved with the child have an important role to play in the evaluation.
9. Assessment should be viewed as the first step in a potential intervention
process. The process of screening and assessment has an impact
on the family and child regardless of whether intervention services
will be provided. It is important to recognize the impact of the process
on the family.
10. Reassessment should occur in the context of daily family or intervention
activities. Formal reassessment should occur in the context of the
child’s daily activities and be conducted by those who are working
with the family and child.
TOOLS AND TECHNIQUES IN DEVELOPMENTAL ASSESSMENT

The large majority of developmental delays in the first year could be
identified by using cut off points for four simple motor developmental
milestones namely, social smile, head holding, sitting and standing.
The major tools and techniques that can be used for developmental
screening are:
1. Trivandrum Developmental Screening Chart (TDSC)
2. Developmental Assessment Scale for Indian Infants (DASII)
3. Denver Developmental Screening Test (DDST)
4. Neurological evaluation—Amiel-Tison Passive Angles method
5. CDC grading for motor milestones
6. Developmental Observation Card (DOC)
7. Assessment of Vision Impairment in Early Infancy
8. Assessment of Hearing Loss in Early Infancy
TRIVANDRUM DEVELOPMENTAL SCREENING CHART (TDSC)

What is TDSC?
This is a simple developmental screening test designed and validated at
the Child Development Centre, Trivandrum. There are 17 test items in
the chart, carefully chosen after repeated trial and error. The age range
for each test item is taken from the norms given in the Bayley Scales
of Infant Development (BSID).
Age range—0-2 years.
Test Material
TDSC is a simple tool which doesn’t require a developmental kit. A pen
and a bunch of key are probably the things required.
Who can do it?

The Trivandrum Developmental Screening Chart is a simple tool that can
be administered by anganwadi workers or any person with minimal training.
There is an over representation of items near one year of age because
one year is an ideal age for formal developmental assessment in a community
setting.
Through the Integrated Child Development Scheme (ICDS) routine
developmental assessment of infants of children less than two years of
age is routinely done in Kerala using Trivandrum Developmental Screening
Chart (TDSC), a simplified form of Bayley Scales of Infant Development.
Since the norms for TDSC is taken from Bayley Scales, the universally
accepted developmental scale for children below 30 months, TDSC may
be used in other states also.
DEVELOPMENTAL ASSESSMENT SCALE FOR

INDIAN INFANTS (DASII)
Age Range-till 2.5 Years
DASII developed by late Ms. Pramila Phatak, Baroda University based
on Bayley Scales of Infant Development (BSID). Bayley Scales are designed
to provide a tripartite basis for the evaluation of a child’s developmental
status in medical, psychological and social aspects in the first two and
half years of life.
DASII consists of 2 scales viz; mental scale and motor scale.
i. The mental scale: This is designed to assess sensory-perceptual acuities,
discrimination and the ability to respond to these, the early acquisition
of ‘object constancy’ and memory, learning and problem solving
ability; vocalizations and the beginnings of verbal communications;
and early evidence of the ability to form generalizations and
classifications, which is the basis of abstract thinking. Results of the
administration of the mental scale are expressed as a standard score,
the MDI, or Mental Development Index.
ii. The motor scale: This is designed to provide a measure of the degree
of control of the body; coordination of the large muscles and finer
manipulatory skills of the hands and fingers. As the motor scale
is specifically directed toward behaviors reflecting motor coordination
and skills, it is not concerned with functions that are commonly
thought of as ‘mental’ or ‘intelligent’ in nature. Results of the
administration of the motor scale are expressed as a standard score,
the PDI, or Psychomotor Development Index.
Denver Developmental Screening Test–II

Age range : 2 weeks to 6 years
Purpose : A screening tool to detect developmental delays
Publication dates : 1967-1990
Publisher : Denver Developmental Materials, Inc.
Description
This instrument was designed to be a quick and simple screening tool
to be used in clinical settings by people with little training in developmental
assessment. The test is comprised of 125 items, divided into four categories:
• Gross Motor
• Fine Motor/Adaptive
• Personal Social
• Language
The items are arranged in chronological order according to the ages
at which most children pass them. The test is administered in 10–20
minutes and consists of asking the parent questions and having the child
perform various tasks. The test kit contains a set of inexpensive materials
in a soft zippered bag, a pad of test forms, and a reference manual.
The manual includes instructions for calculating the child’s age, administering
and scoring each item, and interpreting the test results.
The test items are represented on the form by a bar that spans the
age at which 25%, 50%, 75%, and 90% of the standardization sample
passed that item. The child’s age is drawn as a vertical line on the chart
and the examiner administers the items bisected by the line. The child’s
performance is rated Pass, Caution, or Delay depending on where the
age line is drawn across the bar. The number of Delays or Cautions
determine.
Neurological Evaluation
Generally in children who present with symptoms of CP, the earliest
manifestation is the abnormalities in the muscle tone. It may be either
hypertonia or hypotonia. The variations in tone can be picked up early

by the method of evaluation devised by Amiel-Tison. It has simplified
the approach to motor difficulties, grouping them within a simple framework
with a dual goal: to simplify the explanations to the family who want
to understand, for example, why cerebral damage would lead to orthopedic
treatment of the hips; the second, to simplify the classification of motor
problems for the doctor and the physiotherapist. Repeated neuro-
developmental assessments at 2 years, 3 years, 5 years, 7 years etc. only
can give the complete picture of all possible abnormalities including problems
at school.
The major advantage of following the method of Amiel-Tison in
preference to other neurological evaluation techniques is that there is
an individual objective for each of the baby in terms of monthly evaluations
and corrective therapy. At the end of one year no attempt is made to
give any score. The babies are grouped into:
i. Normal babies.
ii. Babies with patterns of transient abnormalities.
iii. Babies with patterns of persistent abnormalities.
AMIEL-TISON Passive Angles Details

i. Adductor angle: With the infant lying supine, the legs are extended
and gently pulled as far apart as possible. The angle formed by
the legs at this point is called the adductor angle. Asymmetry between
the right and left leg should be noted.
ii. Heel to ear: With the infant lying supine, the legs are held together
and pressed as far as possible towards the ears. The pelvis must
not be lifted from the table. The arc extending from the infant’s
heel to the table represents the angle. Increased resistance on one
side is an indication of asymmetry, but it might be difficult to apply
equal pressure to both sides.
iii. Popliteal angle: The thighs are flexed laterally at the hip along both
sides of the abdomen. While holding the infant in this position, the
examiner presses the lower leg as far as possible towards the thigh.
The popliteal angle, which is formed by the calf and the thigh is
estimated in both legs simultaneously. In contrast to the maneuvers
described above, it is easier to apply equal pressure to both sides
when examining the popliteal angle; therefore, estimation of asymmetry
is more objective. Significant asymmetry is indicated by a difference
of 10 to 20 degrees between the right and left angles.
iv. Dorsiflexion angle of the foot: The examiner holds the infant’s leg
straight and flexes the foot towards the leg. This is accomplished
by applying pressure with the thumb to the sole of the foot. The
dorsum of the foot and the anterior aspect of the leg form the
dorsiflexion angle.
v. Scarf sign: The infant is held in a semi reclining position supported
by the examiner’s palm. At the same time, the examiner takes the
infant’s hand and pulls the arm as far as possible across the chest
towards the opposite shoulder. Four positions are possible in describing
the position of the elbow in relationship to the umbilicus.
1. The elbow does not reach midline (not cross)
2. The elbow across the midline (cross)
3. The arm encircles the neck and the elbow reaches axilla
4. The arm encircles the neck like a scarf and elbow is beyond
axilla.
CDC GRADING FOR MAJOR MOTOR MILESTONES

The grading for 3 major motor milestones developed by CDC is widely
used for developmental assessment.
Grading—for what ?
• To form a common opinion about the developmental status of the
child.
• Make out the improvements in the therapy procedures.
– To convince the mother about the improvements in the development
of her child.
Head Holding: Completed 4 Months

Grade 0 : No head holding at all
Grade I : Head erect and steady momentarily
Grade II : Dorsal suspension—lifts head along with body
Grade III : Prone position—elevates on arms, lifting chest
Grade IV : Holds head steady while mother moves around
Grade V : Head balanced at all times.
Sitting: Completed 8 Months

Grade 0 : No sitting at all
Grade I : Sit momentarily
Grade II : Sit 30 seconds or more leaning forward
Grade III : Sit with the child’s back straight
Grade IV : While sitting, can turn around and manipulate a toy
Grade V : Raises self to sitting position
Standing: Completed 12 Months

Grade 0 : Not standing well
Grade I : Stands holding onto a furniture momentarily
Grade II : Take few steps with both hands supported
Grade III : Can stand alone with legs apart
Grade IV : Come to standing position with support of a stool
Grade V : Without support takes few steps.
Interpretation of CDC Grading

Grade 0, I, II - abnormal for that age
Grade III, IV, V - normal for that age
Grade 0 means poor developmental status
Grade V means better developmental status.
If a baby has apparently Grade-III head holding (only lifting head
without raising on arms) without Grade-II, this is to be considered abnormal,
because this may be due to neck extensor hypertonia. Occasionally it
may be possible that Grade-IV standing is achieved before the child is
able to stand alone (Grade-III) and this is not abnormal.
DEVELOPMENTAL OBSERVATION CARD (DOC)

Developmental disabilities are often seen in infants with no apparent risk
factors. Hence it is ideal to have some sort of developmental evaluation
for all babies. This is now possible using Developmental Observation Card,
a self explanatory and simple card that can be used by the parents.
The DOC developed at Child Development Centre,Thiruvananthapuram
is now being used in our developmental screening clinic. The large majority
of developmental delays could be identified using cut off points for 4
simple developmental milestones. Developmental Observation Card
developed at Child Development Centre (CDC) Kerala could be used
effectively by distributing the same in postnatal wards.
DOC—Major Milestones
Social Smile - achieved by completed 2 months.
(Baby smiling back in response to your smile)
Head holding - achieved by completed 4 months
(Keeping head steady when baby is held upright)
(Lifts head and shoulder supported on fore arm
in prone position)
Sitting alone - achieved by completed 8 months.
(Baby is able to sit alone with back straight, no
support).
Standing alone - achieved by completed 12 months.
(Baby is able to stand bearing weight on both
legs with minimal or no support).
Make sure that the child can see, hear and listen. Those who fail
these simple milestones must have a formal developmental assessment.
ASSESSMENT OF VISION IN EARLY INFANCY ............................

Early detection of visual and hearing problems is not a special service
to be offered by ophthalmologists and ENT surgeons. Anybody and
everybody who comes in contact with the baby, especially the mother
should be encouraged to make sure that the baby can see, hear and
even more important can listen. If an adult becomes blind or deaf he
can cope with the situation because his brain has already developed and
matured and he has had all life’s experiences.
An infant with visual and hearing impairment from birth unless supported
adequately may develop developmental delay due to a lack of orientation,
mobility and experiences. Significant visual and hearing impairment will
affect all areas of development because the child’s awareness of environment
and the ability to interact with it are limited and different from their
normal counter parts.
VISUAL DEVELOPMENT
• At birth—babies show visual perception and will follow a moving person
with his eyes. Baby can follow a dangling ring with difficulty.
• 3-4 weeks—will watch mother intensely as she speaks to him, fixating
on her face.
• 4 weeks—can follow in a range of 90 degrees.
• 4-6 weeks—begins to smile at mother’s face.
• 3 months—can follow a range of 180 degrees and can fixate well
on near objects.
• Before 6 weeks there is little convergence.
• 4 months—can fix his eyes on a half-inch brick.
• The eyes of the newborn tend to move independently. Binocular vision
begins at 6 weeks and is well established by 4 months
• 12-20 weeks—hand regard starts as he lies on his back
• 5 months—excited when his feed is being prepared.
– 6 months—adjusts his position to see objects. Bending back to see
things he is interested in also starts at this age.
VEP (Visual Evoke Potential)

VEP is electrical response to a standardized visual stimulus. The test is
used for assessing visual acuity and visual processing disorder.
Method—it is recorded by putting electrodes over occipital scalp. Visual
stimulus is given by a light flash through red light emitting diodes in
goggles placed over infants eyes. An alternative or generally preferable
stimulus is given by shift or reversal of checkerboard pattern.
Response
• First negative wave is seen at the age of 24 weeks of gestation.
• The positive wave appears between 32-35 weeks of gestation.
• The completely defined pattern is seen by 40 weeks of gestation.
• The latencies of both positive and negative waves decreases in linear
fashion with increasing maturation.
• Waking and sleep states may alter the latency of VEP.
• Testing is recommended in quiet sleep and can be done as early as
3 months.
Role of VEP in Newborn
Experience is limited, because obtaining data requires newborn to fix
eyes on visual display.
Clinical condition Response
1. Severe hypoximia in PT Loss of VEP (response is
regained on normalization of gases)
2. Asphyxia in term Impaired VEP (severity of abnormality
correlates well with poor
neurological outcome)
3. Posthemorrhagic Abnormal response
hydrocephalus (due to dilatation of occipital horn.
Improvement seen follow V-P shunt.)
4. PVL Abnormal response seen.
Role in Children
1. To determine prechiasmal, chiasmal and postchiasmal lesion.
2. Demyelinating disorder of visual pathway.
3. Monocular VEP can be of help in evaluation of visual acuity and
refraction.
ASSESSMENT OF RETINOPATHY OF PREMATURITY (ROP)

It is a postnatal multifocal vasoproliferative retinal disorder. It affects eyes
of certain premature babies. It is a preventable cause of blindness.
Incidence
80–90% less than 1000 gm birth weight
50–65% 1000-1250 gm birth weight.
Incidence and severity increases with decreasing gestational age and
birth weight. Onset of ROP correlates well with postconceptional age rather
than chronological age. The mean age of onset of ROP is around 34
week’s postconceptional age.
ASSESSMENT OF HEARING LOSS IN EARLY INFANCY

Hearing Development
The ear is fully developed at birth and sound perception is possible in
utero. Recognition of voice and speech perception is present shortly after
birth. Language development begins at birth. It is known that babies
learn to speak by mimicking what they hear.
This sequence of development of sound localization (according to
Murphy) is described when a sound is made approx. 18 inches from
the ear. It is as follows.
• 3 months—the infant turns his head to the side to which the sound
is heard.
• 3-4 months—the infant turns his head towards the sound and the
eyes look in the same direction.
• 5-6 months—turns his head to one side and then downwards if the
sound is made below the ear.
• About 6 months—he turns his head to one side and then upwards,
when the sound is made above the level of the ear.
• 6-8 months—turns his head in a curving arc towards the sound source.
• 8-10 months—the head is diagonally and directly turned towards the
sound (correctly localizes).
A baby may initiate sounds by 6 months. By 7 months he may respond
to his name. By the age of 9-12 months he knows the meaning of several
words. From about 9 months the baby learns to control and adjust his
response to sound. By the first year the ability to localize a sound source
is almost as good as in older children and adults. He may listen to hear
sounds again and not attempt to localize it.
Although infants can locate sounds their skill at doing so is somewhat
limited. Experts suggest that infants have a natural preference for females—
that is high-pitched human voices. In fact it is more accurate to say that
infants prefer sound in the middle range of pitch, which is the range
most similar to human voices—male or female.
Points to be Remembered
• Babies cannot speak if they cannot hear
• If the problems of hearing are undetected it will cause problems with
speech, language and cognitive development
• It is important to have the baby’s hearing tested as early as possible,
if there are risk factors for a hearing abnormality
• Hearing loss may not be apparent until children show signs of
developmental delay, often in their speech and language.
Early Detection of Hearing Abnormalities

Check whether the baby is progressing as per the normal speech, language
and hearing developmental stages. Ensure that the baby is acquiring these
milestones.
Around 2 months of age
• Starttls to loud noises
• Quiets to familiar voices
• Makes vowel sounds like “ohh” and “ahh”
• Looks for sounds with his eyes
• Starts babbling
• Uses a variety of voice sounds, such as squeals, whimpers and chuckles.
• Turns head toward sound
• Begins to imitate speech sounds
• Babbles (ba-ba and ga-ga)
• Imitates the speech sounds of others
• Understands “no-no” and “bye-bye”
• Turns his head towards soft sounds
• Correctly uses “ma-ma” or “da-da”
• Gives a toy when it is asked for
• Responds to singing or music
• Locates sound in all directions
Simple Ways to Check for Hearing Impairment

The best age for a formal hearing test is at 8-10 months and not before
6 months or after 15 months. All babies should have a formal hearing
test at 8 months of age.
AUDIOMETRY AND BERA
Audiogram
Incidence of bilateral hearing loss is around 1.5-2.0/1000 children under
six years of age, in developed countries. In India the incidence is believed
to be still higher than that. Early detection and treatment is critical to
speech, language and cognitive development. The most efficient combina-
tion for early detection of hearing loss is OAE & BERA. Audiogram provides
only fundamental description of hearing sensitivity.
Indications for Audiometry
Age Speech
1 year No vocal imitation or babbling.
1.5 year No use of single word.
2 year Single word vocabulary less than
PURE TONE AUDIOMETRY (PTA)

Method
The air conduction is tested by delivering pure tones ranging from 250-
8000 Hz through an ear phone. The bone conduction is tested by an
oscillator placed on mastoid or forehead.
Interpretation
1. Air and bone conduction threshold are same in normal ear and in
ear with sensory neural deafness.
2. In conductive hearing loss there is difference between air and bone
conduction threshold.
3. In mixed hearing loss both air and bone conduction thresholds are
abnormal.
4. In children with functional hearing loss the test is not valid.
Visual Reinforcement Audiometry

The test is useful in children between 5 months to 2.5 years. The technique
incorporates head turning response with activation of a machanical toy
reinforcer. It does not provide ear specific information.
Behavioral Observation Audiometry

This test is useful in children below 5 months of age. It tests unconditioned
reflexive response to complex test sound (noise, speech, music etc).
Response varies widely within and across infants. Test is less sensitive
therefore mainly used as a screening test.
BRAINSTEM EVOKED RESPONSE AUDIOMETRY (BERA)

The test is useful in diagnosis of auditory dysfunction and other disorders
of auditory pathway.The electrical response is recorded by putting two
electrodes across mastoid and vertex. The test can be performed under
sedation or anesthesia.
There are total seven waves, which represents different areas of auditory
pathway.
Wave I Eighth nerve
Wave II Cochlear nucleus
Wave III Superior olivery nucleus
Wave IV Lateral lamniscus
Wave V Inferior colliculus
Wave VI Thalamus
Wave VII Thalamic radiations
Developmental Changes
Waves I, III and V are better featured at birth.
Wave I stabilizes by 3 months and wave V by 1.5 years.
With age, amplitude of wave increases while threshold decreases.
The time difference between wave I and wave IV-V complex is dependent
upon transmission through brainstem auditory pathway.
Character of BERA Site of disorder

Periphery Brainstem
Wave I (threshold) Elevated Normal
Wave I (latency) Prolonged Normal
Wave V (latency) Prolonged Prolonged
I-V Interval Normal Prolonged
Section 11
Early
Developmental
Stimulation
25. Early Stimulation in NICU
26. Early Stimulation after Discharge
27. Early Stimulation Protocol
Prasanna GL, Rajeev K, MKC Nair
25
Early Stimulation in NICU
By early ‘infant stimulation’ programs we mean early interventional therapy

for babies at-risk for developmental delay and periodic developmental
assessment, in motor development, cognitive functioning, language
development or adaptive functioning.
WHY IS EARLY STIMULATION IMPORTANT IN TODAY’S WORLD?

1. All parents want their infants to develop to their maximum potential.
2. Nowadays advanced perinatal care have improved chances of survival
of newborns who would otherwise have succumbed. These survivors
are identified with problems later on. Often such problems are identified
quite late, may be at school age, when only some rehabilitation measures
can be taken which do not necessarily bring out the best in the
child.
3. Parents are adapting small family norms and every child is precious
and they want a high degree of quality in their child. Planned and
highly individualistic intervention programs after a detailed develop-
mental assessment is the answer to this.
AIMS OF EARLY STIMULATION ........................................................

1. Stimulating the child through the normal developmental channels
2. Prevention of developmental delay
3. Prevention of asymmetries and abnormalities.
• to prevent atrophy of muscles
• to prevent fixity of joints
• to prevent contractures of the joint
• to decrease the tone of the muscle
• to prevent tightening of tendons
4. Detection of transient abnormalities and minimization of persistent

abnormalities.
IMPORTANCE OF EARLY STIMULATION .........................................

Early stimulation is important both for the growing brain and body.
Adequate nutrition and the presence of both parents during the early
years are also crucial to a child’s well being. All these factors contribute
towards a normal healthy adult. The stimulation the child receives depends
on life at home and the family structure.
A newborn baby’s life may appear to be nothing but a cycle of sleep
and feedings. From this age itself, a baby’s personality begins to evolve.
Some babies are very lively, others are slow to react. But all need to be
cuddled, spoken to gently and stimulated. Stimulation plays an important
part in child development. Various easily available age appropriate toys are
advised and the optimum time for stimulation is when the child is most active
and playful. Stimulation should be given to normal babies as well.
Proponents of early interventional therapy are suggesting that
multidisciplinary structured intervention by highly trained interveners should
be provided for infants who are at risk for neuromotor disorders as soon
as possible to minimize future handicaps and successfully rehabilitate the
child. Early stimulation and early intervention can be applied remarkably
to infants in order to arouse their actions and feelings ultimately giving
them a normal experience of development.
Parents of newly diagnosed children with mental retardation often refuse
to accept that their child is not “normal”. This leads to a delay in instituting
early therapy and often results in the child developing some set patterns,
which are difficult to change. Therefore special schools prefer to start
a program by age 3 or 4 and may not accept children at ages above
6 or 7. The need therefore is to approach institutions in your vicinity
at the earliest.
Unlike a normal baby a brain damaged baby is an at risk baby requires
more attention of the family members in an effort to prevent mental
subnormality setting in, by anticipatory action.
These goals rest on the delivery of developmentally supportive
individualized care geared to enhance the strengths of each infant and
family. This alliance listens to the language of the infant’s behavior and
uses the dialogue between the infant, family and the professional caregiver
to guide care.
Early intervention improves not only medical outcome but also
neurodevelopment outcome by preventing active inhibition of the central
EARLY STIMULATION IN NICU 261
nervous system pathways due to inappropriate input, and supporting the
use of modulating pathways during a highly sensitive period of brain
development. Developmentally supportive care may be associated with
improved cortical and specifically frontal lobe development from early
on. This may begin to explain the positive lasting effects into school age
that are beginning to be documented in preterm children who received
developmental care.
EARLY INTERVENTION AND PARENTS ...........................................

• Increasing the knowledge, skills and experience of parents by improving
parental perceptions of their infant’s abilities and by improving parenting
skills.
• Parents can utilize the developmental care framework long after the
child has been discharged from the neonatal intensive care unit.
• Parents need the skills to understand and interact with their small infant
appropriately.
• Longer term positive effects have been seen on the ways that mothers
may interact with their infants and on the infants cognitive development.
• Interventions require individualized care plans centred on the infant’s
behavioral organization, the mother-child interaction, and the parent’s
needs.
• Parent participation in decision-making and actual hands-on experience
in caring for their child in preparation for their role as full-time parents
is recommended as essential and is the key to successful developmental
intervention.
WHO NEEDS EARLY STIMULATION .................................................

ALL BABIES
Need stimulation to grow physically and even more for cognitive and
intellectual development by arousing their feelings.
ALL AT RISK BABIES

It is compulsory to provide early stimulation for at risk babies in a planned
and systematic manner in order to arouse their feelings, through interaction
with the mother and the environment and to prevent mental sub normality
setting in-by anticipatory action.
At risk babies are babies who have had problems during the pre-
natal, natal and postnatal period i.e. before, at or after birth and are
at risk for developing some sort of developmental problems later on.
The problems may be pre-maturity (born < 37 weeks of gestation), low

birth weight (<2.5 kg at birth), birth asphyxia (lack of oxygen at birth),
septicemia (infection of the blood), seizure (fits) etc. An at risk baby needs
more attention from the family members with the aim of trying to prevent
mental sub normality setting in- by anticipatory action. For them it has
to be started from the NICU (Neonatal Intensive Care Unit). There should
not be over stimulation. Studies have shown that babies did better with
less stimulation in NICU.
OVER STIMULATION ...........................................................................

• Babies cannot comfortably handle different modes of stimulation all
at once.
• For all babies their neural system has to be mature to receive the
stimulus given to them. While giving stimulation it should be essential
to note that the stimulation is not beyond their capacity. There are
cues to watch for the baby might
– Just close his eyes and try to go to sleep.
– May start to stick out his tongue as an aversion response, then
yawn
– And finally, start to show agitation by his body movements; arching
his back, squirming to get away, fussing, crying etc.
• Playing with one’s baby in ways that both parent and child enjoy
is the best way to stimulate his senses and thinking. How much the
parent enjoys the activities shared with the baby is the best stimulation
for the child. When the parent is emotionally involved in the play,
and not feeling bored or dutiful or anxious, the infant will be more
involved too.
PRECAUTIONS .......................................................................................
THINGS TO BE REMEMBERED WHILE GIVING STIMULATION
• Monitored stimulation with an awareness of and willingness to decrease
environmental hazards is necessary.
• The stimulation provided has to be developmentally appropriate.
• The smallest babies need the quietest of places that can be provided.
• The quality of stimulation given is more important than the quantity
of time spent.
• Stimulation should be introduced gradually followed by a developmental
assessment.
EARLY STIMULATION IN NICU 263
• The younger the infant, the more disorganized his neurological systems
are and the less likely he will be able to process stimulation, whether
positive or negative.
SAFETY MEASURES TO BE TAKEN WHILE GIVING STIMULATION

• Stimulation should be given only under strict supervision.
• Care should be taken to prevent the baby from swallowing any of
the small things used during stimulation.
• Avoid giving paint coated toys, it may be toxic if swallowed.
• Avoid toys with sharp edges and those which are fragile.
NEWBORN STIMULATION IN NICU ..................................................

Early stimulation should start as early as possible in the NICU with a
special emphasis on incorporating both the parents and medical people.
There should be programs designed to increase parental awareness of
infants abilities and individuality patterns. Stimulation given in NICU should
be neither over stimulating nor under stimulating.
Infant has limited, individual but improving capacity for input filtering
and perceptual analysis and state control. In NICU the child experiences
often painful procedure, handling, noises, lack of contingent responses,
irregular, inconstant social contact, and unstable comforting mechanisms.
Infants toleration of and need for different modalities of stimulation can
be estimated sequentially and it should be individualized and changed
over time.
MODIFICATIONS THAT CAN BE MADE IN NICU

• Individual lightening units can be dimmed and adjusted to reflect the
cycles of the days (specially during night).
• Reduce unnecessary noises from the neonatal environment. Heartbeat
sounds, mother’s voice and music can be recorded and the tape played
near the baby at a low volume.
• Gentle massage and soft bedding promote tactile stimulation.
• Try to promote bonding whenever possible through kangaroo method.
• Rocking and oscillating waterbeds can be introduced in order to stimulate
the kinesthetic/vestibular senses.
• Passive exercises for the joints in order to prevent muscle spasm.
• Each individual has his own individual reactions and a multi-sensory
combination all the above can be applied accordingly.
Sunitha RM, Lakshmi MA, Babu George
26
Early Stimulation after Discharge
THE WAITING GUEST .........................................................................

Bringing the baby home from hospital is a time that the mother, the
family and friends have been waiting for. However, it is important to
remember that all this attention and love can be overwhelming.
BABIES NEED PEACE AND QUIET ..................................................

Babies may exhibit distress when they are being overwhelmed. It can
be difficult to explain to those who wish to see the baby, after weeks
and months in hospital, that the baby may become tired very quickly.
However, it is important that the mother and the baby are given a chance
to truly get to know each other.
BABIES NEED ‘WALLS’ AROUND THEM .........................................

After discharge from the nursery, babies may be fussy and difficult to
settle. Full term babies in the womb spend a lot of time curled up in
a ball, legs and arms tucked in. If one’s child is agitated, one can put
him on his tummy on one’s shoulder, and help get his legs and arms
tucked in, his hands to his mouth, and wrap him in a blanket.
UNDERSTAND HER ‘CUES’ ................................................................

At home the mother should be able to recognize additional individual
signs of stress or distress. Being able to recognize and respond appropriately
to these cues will help the mother become closer to her baby. It will
also be very useful should the baby need to go back into hospital, as
she will then have this extra knowledge about caring for her baby.
EARLY STIMULATION AFTER DISCHARGE 265
NEWBORN STIMULATION AT HOME ...............................................
KEEP IN MIND THAT
• Newborn babies are surprisingly alert. When the tummy is full, the
bottom is dry and the body rested, newborns are busy looking, listening,
and learning about their new world.
• Babies are hard-wired to learn. If parents understand the wiring a
little better, they can target early play to help their newborns learn
and develop. Keep the play gentle and the playtime short — just
a few minutes at a time is probably plenty.
• Subtle environments; pastel colours, a feather on a string spinning
in the breeze, a fish tank to watch, curtains blowing, lying under a
tree, a candle flame, these foster deep attentiveness, long curious staring
and wondering, which is good for development.
The following are some ways to begin playing with a newborn.
Remember though that it is easy to over stimulate a newborn.
VISION
• Vision is one of the most primitive senses at birth-newborns can only
focus about 8 inches away, and their sight is two dimensional. Because
vision develops so quickly and so dominates the human sensory
experience, it soon becomes the major means through which children
learn about the people and properties of their world. The following
are some ideas to stimulate the baby’s developing sense of vision.
BOLD PATTERNS WITH STRONG CONTRAST

• Newborns are attracted to the edges of patterns where light and dark meet.
• Babies tend to look at the edges of shapes, so a baby is likely to
scan one’s hairline rather than gaze into one’s eyes.
• Start with simple shapes-squares, circles, and bold black and white
face shapes. Paste these shapes by the changing table, or cut them
out and make a “Nursery Novel,” a little book made up of different
patterns. The newborn’s eyes examine the edges and his brain learns
to process simple visual information.
MAKING FACES
• The most intriguing object for newborns is the mother’s or father’s
face.
• Try to catch the baby’s attention and make a face— one can stick
out the tongue, make an ‘O’ with one’s lips, or raise and lower one’s
eyebrows.
• Newborns can mimic expressions.

• Remember to vary the expression: new babies have very short
attention spans.
MOVING OBJECTS
• Vision involves the complex process of tracking objects as they move
through space.
• Lay the baby on the lap. Take a toy, small picture, or one’s hand
and slowly move it in an arc from your baby’s left to right, and then
back again. Newborns cannot track the object as it moves across their
centre line—this will develop in the first few months.
HEARING ................................................................................................
• At birth the sense of hearing is considerably more advanced than
vision. Although it is more advanced, hearing develops gradually.
PLAYING MUSIC
• Music stimulates more than just the auditory brain centers and connects
powerfully to the baby’s emotions.
• Test how music affects the baby-play a lively, fast-paced song, then
a slow, soothing song.
• Babies have an innate response to music, which can be very useful
when trying to soothe an overtired, over stimulated, or colicky newborn.
• Classical music is particularly good for the baby’s developing brain;
it is closely linked with an improved ability to solve spatial problems.
Playing classical strains to the newborn could help lay down important
spatial reasoning pathways, as well as connections within the auditory
system.
TALKING AND IMITATION

• Language development begins from the moment the baby first hears
voices.
• Talk to the baby often — when changing him, feeding him, or walking
with him. Listen carefully to his little noises and repeat them; one
can have baby ‘conversations’ this way, each taking a turn.
• Read to the baby — look for books with rhythmic, rhyming language.
• Even tiny babies will listen attentively to the sing-song cadences of
poems and nursery rhymes.
TOUCH ....................................................................................................
Every time a baby is touched or cuddled, it shapes his growing brain.
Touch experience is essential not only for the development of touch sensitivity
but for general cognitive development as well.
BABY MASSAGE
The purposive, non-repetitive contact with human hands on the baby’s
bare skin is a soothing way to stimulate the baby’s sense of touch. Routine
massaging the baby is essential for her optimum growth and development.
Ideally it should be done by the mother, father or grand parents. The
masseur should be relaxed and unhurried and won’t be interrupted. Don’t
massage the baby when he is hungry or full of stomach.
SETTING
Mother sit relaxed on the floor with baby on a towel or rubber sheet.
Newborns like massaging for about 2-5 minutes and children over 2
months of age will like even more time.
TECHNIQUE
Application of oil before massaging reduces friction. Gentle firm strokes
can be used. Apply at least 12 strokes to each area. Do not kneed or
squeeze. The stroke should not be too light or else they will cause a
tickling sensation to the baby that may be discomforting.
• Make tiny circles on the face, then smooth the baby’s forehead with
both hands at the centre, gently press outside as if stroking the pages
of a book. Make small circles around the baby’s jaw, massaging around
the baby’s mouth may comfort him during teething.
• Rub the hands to make them warm and gently stroke the baby’s
chest as if stroking the pages of a book.
• Stroke each arm alternately from central outwards, open the palms
and massage each finger separately.
• Massage the tummy from baby’s right side to the left in a clockwise
direction.
• Stroke and massage each leg and foot separately.
• Stroke the baby’s back— first back and forth across, then in long, sweeping
lines from shoulders to feet. Always keep one hand on the baby.
• Stroke the buttocks in a circular motion.
• Gentle passive exercises can be given in the joints of both hands and
legs by bending and stretching. Make sure the baby is enjoying the
stimulation. Reassure him if he cries or protests and restart again.
Continue massaging according to his wish and end up with a kiss.
ROCKING, WALKING AND SWINGING

• Why is it that babies calm down when they are rocked or gently
bounced? Closely related to the sense of touch, the baby’s vestibular
system tells the baby where his body is in space—if he is reclining,
sitting upright or moving.
• Every time the baby is walked, rocked, or swung, the vestibular system
is stimulated.
• Infants who are comforted through vestibular stimulation show greater
visual alertness than babies comforted in other ways. It’s during these
periods of quiet alertness that babies do their best learning, when
they can most effectively absorb information about the world around
them.
Baby swings are a good way to stimulate the vestibular system. If
the baby is in a sling or front carrier, the natural motion provides plenty
of vestibular stimulation. Sometimes the motion will help a baby to sleep,
but often the baby will become quiet and watchful. This is an excellent
time to talk or sing to the baby.
TOUCH THERAPY—WHAT IS IT? .....................................................

Touch therapy is purposive, repetitive, non-medical contact with human
hands on an infant’s bare skin administered with a view to stimulating
nature and stimulating normal growth and development. It is recommended
that mothers and fathers participate for best results. In its broadest sense
it involves massage (tactile-kinesthetic stimulation), non-nutritive sucking
and skin-to-skin contact in any form. It is an appealing, pleasurable, culturally
acceptable easily taught and understood form of interventional stimulation
to the preterm infant but can be administered to term infants equally
effectively and there is no cost involved.
WHY TOUCH
Touch is the natural extension of stimulation as it is an extension of what
the baby has experiences in utero. Nature intended development to occur
in an environment filled with stimulation and sensations. Tactile kinesthetic
stimulation is continuously provided in utero as the mother moves, walks,
sits and bends, the amniotic fluid creates a whirlpool like milieu which
as both stimulating and protective to the actively developing fetus. Since
the fetal volume increases and amniotic fluid decreases as the pregnancy
near term, the opportunities for touch and contact with the placenta,
uterine surfaces and the fetus, own body becomes greater in the last
part of the pregnancy.
This constant tactile— kinesthetic stimulation has been shown to be
essential for the developing brain in terms of positive feedback messages.
TOUCH-EFFECT ON INFANTS
• Non-nutritive sucking for LBW babies are associated with better
oxygenation during feeding.
• Improves weight gain—by increasing growth hormones or better
utilization of nutrients due to better production of gut hormones.
• Effect on neurodevelopment.
Resmi VR, Latha S, MKC Nair
27
Early Stimulation Protocol
Early stimulation can be applied remarkably to infants at-risk during infancy

itself, in order to arouse their actions and feelings, ultimately giving them
a normal experience of development through interaction with the mother
and environment. Unlike a normal baby a brain damaged baby has acquired
inability to send adequate signals to the mother and the people around,
for them to respond normally and adequately. This then means that an
at-risk baby requires more attention of the family members in an effort
to prevent mental subnormality setting in, by anticipatory action.
THE 0-2 MONTHS PERIOD ................................................................

Babies will usually put their both hands to mouth in order to organize.
If your child isn’t doing this, help her; gently to hold her hands together
and then put them to mouth. This is calming and organizing, thereby
creating neural pathways in her brain that will be the building blocks
for future complex activities.
AUDITORY
• Make the child listen to different sounds such as squeeze toy, rattle,
bell, music, high pitched and low pitched human sounds etc.
• Always humming in a soft low voice.
VISUAL
• Hang brightly colour clothes (red/orange/fluorescent), shining mobiles,
colour balls; B & W striped clothes etc across the crib. Don’t interchange
them frequently.
• Put the baby in a well-ventilated room having good light.
EARLY STIMULATION PROTOCOL 271
TACTILE
• Frequently change child’s position. Put the child on his sides, on his
back, on his tummy etc.
• Put the baby in different surfaces like soft mattresses, form rubber
mat, on soft clothes, on mother’s lap etc.
VESTIBULO/KINESTHETIC
• Gently rock the child, avoid fast changes of position
• Avoid sudden jerky movements, always support his head.
ACTIVITIES
• Always try to maintain eye-to-eye contact while communicating with
the child.
• Cuddle the baby closely, making it a joyous interaction with the mother
and the baby.
• Talk and sing to baby when you bathe him, dress him, and when
you feed or rock him.
• Encourage and help the baby to turn his head towards the source
of sound and sights.

AUDITORY
• Sound producing toys are suitable for this age. Noisy toys/squeaky
rubber toys etc. can be given.
• Parents should spend more time with child, keep on talking with the
child, pointing out the name of objects shown will help the child to
use more words when he starts talking.
VISUAL
• Hang brightly colored objects/shiny mobiles about 12-15 inches above
the crib, this will enable the child to watch it constantly and slowly
starts to babble.
• Maintain eye contact while talking with the child
• Show brightly colored clothes when the child is awake.
TACTILE STIMULATION
• Give the child various things to bite and suck and paper to crumble.
• Give your child the experiences of soft, hard, rough, cold, warm etc.
• During daytime place the child on a foam rubber mat on the ground
and allow him to move freely.
GENERAL STIMULATION
• Always hold the baby at shoulder
• Child should be carried straight at shoulder with hand supported, on
both sides (right and left) after the attainment of head control, he
can be carried crossed astride the hips on both sides.
• Place the child on his tummy, with both hands supported. Shake a
sound making rattle in front of his head and gently lift the rattle just
a little to encourage the child to lift the head and upper chest. Make
sure that the baby is watching the rattle.
• Rub small toys or rings across the palm of the baby’s hand to help
him to grasp it. As he wraps his fingers around the toy, let him hold
it. This will promote the child to grasp things.
• Place things just out of reach of baby’s hands. Stimulate him to reach
out and grasp it.
• When talking the baby crossed astride the hip some babies have the
tendency to turn their head towards one side only. Play with the child
or show colourful toys or make noises from the opposite side. This
will promote the child to turn head towards the desired side.

• At this age children like imitation and they learn a lot from that.
Stimulation programme at this age should be based in this. They need
a variety of stimuli, and the parents pay attention to organize the
environment in such a way that it is stimulating for the child. They
love to see their own images at mirrors and will look at this for a
long period. Expose the child to outside people, siblings etc.
AUDITORY STIMULATION
• Babies will turn their head towards the source of sound at this age.
Shake a bell or a squeaky toy over his head. Then slowly shake it
near to the side of his head. Encourage him to turn his head and
find the sound. Repeat on the other side also.
GENERAL ACTIVITIES
• Place the child flat on his back on the ground over a soft blanket.
Sit near to him/her, showing a colorful toy, slowly turn him/her by
flexing the far away leg, and assist him to turn over to her tummy.
Repeat it on both sides.
• Sit the baby on your lap and gently bounce your knees, by singing
songs. This will promote child’s ability to locate sounds almost he bounce
himself.
• Encourage reaching by showing an attractive toy, just out of reach
of child’s hands. With this increased interest the infant moves his hands
towards it.
• Strengthen the leg muscles: put your hands under child’s feet and
move her legs up and down as if she were pedalling a bicycle. Stimulate
her to push on your hands with her feet.

Keep your child in a safe area near to your work place, so that you
can have a close watch at her and can communicate with her frequently.
A childproof room, if possible can be arranged at home where the child
can move freely and explore. Let the child sleep on foam rubber mat
on the ground during daytime.
GENERAL ACTIVITIES
• Start calling the child by his name. He should be spoken to quite
often. Banging toys such as drums, pans or pots can be given at
this age.
• The child can be carried crossed astride at this age.
• Give the baby pieces of paper to tear. The paper can be made attractive
by changing colors and textures. Talk with baby about what she is
doing, how it feels and how it looks.
• As long as possible make the child sit; a walker can be used and
the child can be made to sit comfortably.
• Lay the baby back on the floor over a mat. Show him attractive
toys on one side. Encourage him to roll over on his tummy. Then
stimulate him to roll on his back by gently pushing back the child’s
shoulder by folding the hand under his chest towards which he is
turned and showing a colorful sound producing toy from front to
back.
• Make the child on his tummy and put a roll under his chest. By
showing a colorful toy above his head, stimulate him lift his head
and rise up on his hands.
• Child lying flat on his back. Stabilize the legs by pressing the knees.
Raise the child’s right shoulder (directing the movement over to the
left). Let him lean on his left shoulder, then on his elbow, then his
hand, till finally he is able to sit. To make him lie down again, lean
him on his hand, elbow and left shoulder. Repeat the same movement
on other side also.
• Help the child to sit on the ground by giving support on his pelvis.
• Child can be made to sit on small chairs with hand rest on the sides
so he can sit comfortably.
• Put the child in all fours over a roll. Gently move the roll from front
to back, making the child lean alternating on his knees and hands.
After a very short time, he will make active use of his hands and
knees. This will stimulate him to rise on his knees.
THE 8-10 MONTHS PERIOD ..............................................................

Provide safe and hygienic objects for the child to play and handle. Family
members should participate in his play and he enjoys such companies.
Play peek-a-boo with the child.
ACTIVITIES
• Encourage the child to stand on by hold on furniture
• Put him in all fours on the ground. Bring the child’s buttocks on
to his heels with the upper part of his body erect. Show him a toy
at shoulder level so that he turns from one side to the other. This
will allow the trunk independent of the legs and also stimulate him
to rise on his knees erect.
• Mother sit on the chair, make the child stand on mother’s knees and
bounce her legs gently up and down. Stimulate the child to support
as much of her weight as she can help to strengthen her leg muscles.
• Encourage the child to clap hands by demonstrating while listening
to music. Give him some banging toys and help him to bang it so
as to produce sound.
• Give him a small container and encourage him to drop small thing into it.
• Encourage the child to produce monosyllables.
• Show him/her picture books of birds/flowers/animals and assist to turn
the pages of books. The pages of the books should be harder enough
for the baby to turn it.
THE 10-12 MONTHS PERIOD ............................................................

At this age the child understand instructions. Acts of daily life can be
made stimulating for the child by pointing out things with the aid of
simple but exact words.
ACTIVITIES
• Allow the child to play with other children.
• Balls with different sizes, dolls, puppets, push and pull toys, rocking
toys, small containers, pegboards, etc. can be used.
• Allow the child to move freely on the ground.
• Naming the body parts can be done while bathing the baby.
• Child can be carried out for a walk and different animals and birds
can be shown on the way.
• Lightweight toys, colour balls, squeaky toys, mirror etc. can be given.
• Do simple actions in front of the child and encourage copying the
actions like clapping hands, tilting head throwing ball, waving bye-
bye.
• Encourage the child to crawl over and stimulate him to crawl over
moving things by pulling a toy.
• Stimulate the child to stand up by keeping his favourite toy on as
low stool. Encourage him to pull to stand by holding on the stool.
• Give toys with large holes to poke and to feel with fingers. Care should
be taken to avoid dangers on fingers.
THE 12-15 MONTHS PERIOD ............................................................

Provide opportunity for the toddler to explore and understand the world
surrounding him. In this stage of exploration basic concepts such as ‘in’
and ‘out’ will be learned.
• Give baby picture books that have heavy, thick cardboard pages. As
you look at each picture, talk about what you see and then let the
baby turn the pages. You may have to help him turn the pages one
at a time.
• The baby can be stimulated to see, hear and smell things.
• Dressing time can be made fun by pointing to the body parts, counting
to her. Numbers can be emphasized while stimulating child to stack
blocks, putting things into containers etc.
• Look out of the window. If the window is low enough, help the baby
pull up to stand so that he/she can see. Talk about what the weather
is like.
• Make the child sit in front of a mirror so that she can see herself.
Sit behind her and start to sing about her eyes, nose, mouth and
hair. Pat your nose and see if baby will copy you. If she doesn’t
help her to move her hand so that she pats her nose while you
sing. Sing the song a few more times and change the body part each
time. This stimulate child to copy a few simple actions and also to
know body parts.
• While the baby stands holding on to a support, encourage him to
stoop or bend over by dropping a noise-making toy on to the floor
beside him and pick it up.
• Encourage the baby to stand up holding to a walker (three wheeled)

and to walk by calling him in front.
• While the baby is watching, hide a favourite small toy under a cloth.
Encourage the baby to grab the cloth, pull it away, and find the
hidden toy.
• Cut and mount toy pictures from picture book that looks similar to
child’s own toys.
• Give the baby two or three blocks of different sizes to stack and knock
down. Hand him the blocks one at a time and help him to pile them
on top of each other. Make a game out of playfully knocking them
down and laughing as you build them up again.
• Give the baby a fat crayon and some paper.
• Encourage the child to scribble by drawing a few lines while she is
watching. Assist her scribble on her own. If she does not, gently hold
hand and help her scribble.
• Encourage the baby to place things into a wide mouth jar and them
to take things out of a container.
• Finally stimulate the child to gradually achieve independence in all
areas. Let him make his own decisions and take his own time.
Section 12
Developmental
Therapy
28. Motor Stimulation in Early Infancy
29. Vision and Hearing Stimulation in Early Infancy
Jyothi R, Deepa Jayaprasad, MKC Nair
28
Motor Stimulation in
Early Infancy
Various physical therapy techniques have been used all over the world
for children with motor delay with encouraging results but not supported
by randomised controlled trials. But what has been clinically observed
is that child’s potential to achieve motor milestones, even if late by months
or years is prevented by late onset of therapy and stimulation.
INTERVENTION FOR HEAD CONTROL ............................................

While giving intervention for head control delay, in prone position, concentrate
on the following abilities.
• Raise the head
• Hold it for sometimes
• Turn the head to both sides.
1. Place the child in prone across your lap. To encourage the child
to raise his head, attract his attention with brightly colored objects
that make strange or pretty sounds (At first use toys in the centre
and progress to each side of the child and move them slowly from
center to side and from side to side)
2. If he does not lift his head, gently stroke downwards over the neck
muscles.
3. Bring his shoulders back and inwards towards the spine (retraction
of the shoulder girdle). This provokes him to raise head.
4. The child flat on his stomach, head and shoulders reaching out over
the edge of the table. With one hand, hold the child’s buttocks, with
other hand, support him under his forearms. Gradually, remove the
support from under his arms.
5. If the child turns his head to one side only, do weight bearing exercises
for the upper limb on the other side. Always approach the child
from that side towards which the baby does not turn.
6. Place the child in supine position. Encourage the child to lift and
hold his head by pulling him to sitting position, holding under the
axilla and supporting the neck only if needed. Gradually, bring him
to sitting position and then slowly put him back to lying position.
7. Place the child over a soft roller. Gently tilt the roller to and fro.
8. Encourage the child to hold his head steady by carrying him in an
upright position (supporting the head only as needed).
9. Make the child sit over his mother’s lap. Mother tilts her leg up and
down so that the child tries to balance his head.
10. If the baby makes almost no efforts to lift or hold his head, when
you feed him, instead of putting the nipple or food into his mouth,
barely, touch his lips with it and make him come forward to get
it.
11. Place the child over a bed with 4-inch thickness with hand supported
on the floor.
12. The child must be made to lie on his stomach and is guided on
his elbows (a roll can be used if necessary). Encourage the child
to lift and hold his head by showing a colorful toy. The head holding
can then be maintained as long as the child enjoys and then gradually,
the child is stimulated to rotate the head laterally by moving the
toy.
13. Encourage the child to lift and hold head by pulling him to sitting
position in a playful manner and then gradually, putting him back
to lying position.
14. Hold the child at a distance from our body by placing one hand
under his knee and other on the chest. Stand near to a mirror and
encourage him to raise his head and shoulder.
15. Hold the baby crossed astride, give support to the neck if needed.
16. Weight bearing on forearms will also help the child’s head control.
Use visual and auditory stimuli in these positions. Check that the child’s
forearms are well away from the body, with elbows at right angles to
the body (Place a roll of towels between his body and upper arms) and
if possible, hands open.
INTERVENTION TO PROMOTE ROLLING .........................................

If the child is very stiff, first help to relax him by swinging his legs back
and forth
1. Attracts the child’s attention by holding a rattle or toy in front of him.
Then move the toy to one side, so the child turns her head and shoulders
to follow it. Encourage him to reach sideways for the toy.
MOTOR STIMULATION IN EARLY INFANCY 281
2. Bring one of his arms over to the opposite side with palm of his hand
facing forward his face; or offer him a toy on the opposite side; this
may lead to roll over.
3. Place the child on his back on a blanket. Hold each end of the blanket,
(two adult may be needed) and suspend the child in the blanket just
off the ground. Tip the child gently from side to side, waiting for him
to complete his roll over. Do not do this with a child arches backwards.
4. Child in supine on a soft rubber mattress or inflatable bed. Press down
on one side of his body, so that he tips over towards you and rolls.
5. Make an incline with pile of mattresses or sponge rubber and left gravity
help the child roll downhill on his own.
6. Child lying on his back. Bend one hip and knee well over to the opposite
side and wait for him to complete the roll over. Stretch the child’s
underneath arm out and upwards, if it gets ‘caught’. Praise him each
time he makes an effort.
7. Child lying on his back. Bend one hip and knee well over to opposite
side, while holding his upper shoulder back. Release his shoulder for
him to complete the roll. This treats the ‘rolling in one piece’ as in
the neck righting reaction.
CREEPING ..............................................................................................
If the child can lift her head well when lying on his stomach, encourage
her to begin creeping.
1. Put a toy or food the child likes just out of reach and encourage the
child to move towards it.
2. If the child cannot bring her leg forward to creep, help her by lifting
the hip.
INTERVENTION TO PROMOTE CRAWLING ......................................

1. Place the child on hands and knees over or your arms and when
possible let him balance on his own. Encourage the child to balance
with one limb off the ground using toys.
2. Suspend the child in a blanket. Hold each end of the blanket and
tip the child in it so that his weight is taken more on one side releasing
the other side for a step forward.
3. Child in prone position, bend the child’s one leg and place it under
his stomach. Raise the pelvis on the opposite side. The child begins
to bear weight on the bent knee and moves the other knee forwards.
Repeat this on other side also.
4. Child flat on his stomach. Bend one leg brings it forward and move
the opposite side upper arms forwards. Repeat on the other side also.
5. Once the child have started crawling, encourage him to crawl on all
surfaces.
INTERVENTION TO PROMOTE SITTING ...........................................

1. Make the child sit leaning over one hand with his elbow straight.
Stabilize his elbow and hand by holding firmly over his elbow and
wrist (hands should remain open). Gently tip the child to this side
so that his body weight is taken through his elbow and wrist. Hold
it for about 10 seconds and release. Repeat the same over the other
side also.
2. Make the child sit while stabilizing his pelvis if needed
3. Make the child sit across your knee. Raise the knees up and down
alternatively, so he has to balance.
4. Make the child sit. Encourage the child to twist and reach side wards
for toys.
5. Make the child sit. Just tilt the child forward, backward and sideways
so that he begins to catch himself.
6. Once the child had attained sitting balance, make him sit on a tilting
board.
7. Place the child on hands and knees over rolls or your arms. Encourage
the child to maintain this position for sometime. Then slowly guide
him to kneel sitting and then to side sitting position.
8. Mother sit with her legs straight and back supported against a wall.(long
sitting). Place the child prone across her lap (hands on one side
and legs on the other side). With one hand hold the child’s both
knee and help him to attain quadriped position. Repeat this by placing
the child on the other side also.
9. Child lying on his back. Encourage him to attain sitting position by
gently pulling on of his hand diagonally across the opposite side.
Child comes to sitting bearing weight on the other hand. While doing
this if the child’s knees flex excessively, keep them straight by pressing
over the knees with one hand.
10. Encourage the child to sit by putting him in an armchair in a sitting
position supporting him with pillows as and when possible. This position
can also be used during feeding.
11. While playing and talking with the child, encourage the child to sit
with a wide base supported at the pelvis. If necessary help the child
to maintain this erect sitting position by showing a colorful toy. Gradually
he can be stimulated to turn to either side by moving the toy and
also to reach out.
12. During play child can be encouraged in side sitting position on both
sides by supporting himself on the hand to the side, which he is
sitting. For example, if right side then right hand can be used as
the support.
13. Guide the child to support on his hands and knees (four point kneeling/
quadruped positions) during play. A roll or pillow can be used if
necessary. Help the child to maintain this position by encouraging
him through play. If needed minimal support can also be given. Then
slowly guide him to sitting on one of his sides, supporting on that
particular hand. Help the child to maintain this position for a while.
Then guide him again on to his hands and knees and then gradually
to side sitting on the other side.
14. Baby walker can also be used to stimulate and improve sitting. (under
supervision).
INTERVENTION TO PROMOTE STANDING .......................................

While giving therapy for standing, note
a. Bears weight equally over both legs
b. Deformities are corrected
c. Gradually withdraw support and encourage independent standing
d. Encourage walking by shifting weight from one leg to the other.
1. Guide the child on to his both knees (upright kneeling) during play
time. Finally support him at the pelvis, if necessary even give support
to the upper part of his body. Gradually, the support can be withdrawn
and the child can be made to support himself by holding on to
a low stool. This position can be maintained by directing the child’s
attention to any play activity.
2. From the lying on the back (supine position), stimulate the child to
pull to sit and gradually to the standing position during play time.
3. First guide the child on to his knees supporting on a low stool with
both hands, while directing his attention to a colorful toy through
play. Slowly help him to raise one of his legs so as to stand on
one foot and the other knee (Half-standing position.) Help the child
to maintain this position while playing and talking with him. This
position can be repeated on other side also. Meanwhile depending
on the child’s ability stimulate him to pull to standing position by
himself, supporting on the stool.
4. Make the child stand leaning against a wall. Give support on knees
if needed.
5. Make the child stand with support on both hands and then to one
hand.
6. Place the child on kneel standing holding to a support. Gradually
bring one of his feet forward and place it in front, thus bring him
to half kneeling position. Do the same on the other side also.
7. Make the child kneeling holding on to a support. Encourage the child
to ride up to standing position, holding on to the support. If needed,
help him by supporting his pelvis, while he attempts to stand.
8. Child stands first with and then without support. Just push him forwards,
backwards and laterally. Encourage him to catch himself.
9. Help him too balance on an inclined surface.
10. Encourage him to stand on one leg with support on both hands.
11. Gradually, withdraw the support.
12. Help him to walk with support on both hands.
13. Encourage him to walk on a parallel bar.
INTERVENTIONS FOR DEVELOPMENT OF HAND FUNCTION ....

HAND REGARD AND BRINGING HANDS TO MIDLINE
Place the child in a half-lying or supported sitting position with arms held
forward. The child should be made aware of his hands by your talk,
shining a torch on them, putting sticky things like a jam or honey or
playing with his figures.
OPENING OF HAND
1. Stroke the outer edge of hand from little finger to wrist.
2. Press the heal of his hand on a firm surface while keeping his shoulder
and elbow straight.
3. Open hands when the child is leaning on hands while in prone, sitting
or standing positions. Pull the thumb or fingers out from the base and
not from there.
4. Once the hands are open, help the child to rub his palms together,
touch his face and body and later clasp and unclasp hands.
HAND GRASP
1. Place an object in his hand, and bend his fingers around it. Be sure
the thumb is opposite the figures. Gradually, twist the object from side
to side and let go off hand. The object should be of a size that fit
into the whole palm of his hand. Avoid toys that can be squeezed.
Use objects of different shapes and textures (wooden, metal and plastic
objects, sand, dough, clay, etc).Name the textures for him as he feels
it.
2. Encourage the child to reach and grasp an object that just touches
his fingertips. First touch the back of his hand and then place it below
the fingertips.
3. Hang interesting toys, bells and rattles around large hands grips, bars,
handlebars of a cycle, etc.
PINCER GRASP
Begin with large objects. Then progress to smaller ones. Thumb and all
finger tips are used first before thumb and index finger are used.
1. Use child’s index finger to press in to sand. Later make lines and scribbles
in sand.
2. Put paint on the child’s fingertips and encourage him to make dots
and scribble.
3. Encourage the child to pick up small objects like buttons or pebbles
and place them in a container.
4. Make the child hold thick pencils or chalk for making marks on a
paper.
5. Encourage the child to hold a small cup handle for drinking.
6. Use toys, which have buttons and knobs to press and turn.
7. Allow the child to attempt the activities on his own. If he cannot manage
to isolate his index finger, hold his little, ring and middle finger flexed
for him until he can do this alone.
TOYS TO ENCOURAGE STIMULATION .............................................

• In the first few years babies learn to use his hands and develop eye-
hand co-ordination by simply watching and moving his own hands
and fingers. Good and age-appropriate toys will help practice and perfect
these newly acquired skills.
• When you are making or buying toys to encourage your child tolearn
things, follow the BBC code, i.e. big, bright and colorful.
• Big toys are easier for young babies to see. Older children can use
magnification of small objects.
• Bright means presenting toys and play materials in the best possible
light,
Colorful means choosing toys with good strong contrasting colours and
making sure they do not merge into the background. Putting a nappy
or a cot sheet over a heavily patterned carpet may be useful. Some children
find shiny surfaces attractive, others prefer mat colors. Children usually
show by their reaction, which they prefer and will not be bothered with
a toy if they do not find it interesting.
POINTS TO REMEMBER DURING THE SELECTION OF TOYS

• Toy should be age appropriate
• Toys should be safe – no sharp points and cutting edges
• Colored toys—the paint should be non-toxic
• Components of the toy should not be so small that the baby is able
to push them into the mouth, nose and ears
• The child’s interest, needs and abilities should be considered
• Washable and sturdy enough to withstand rough handling.
Mini AO, Rekha S, MKC Nair
29
Vision and Hearing Stimulation
in Early Infancy
The term ‘early intervention’ encompasses a wide variety of medical, educational,

and psychological treatments for an at-risk baby or one with neurodevelopment
abnormalities as well as socioeconomically disadvantaged children. The
parents need to provide stimulation for their children that would otherwise
have been missed, by giving emotional support, sensory input and by
play methods. Encourage the mothers to show love, to handle and talk
to their children more, to help the children to acquire independence
all of which help to improve language and communication later on.
VISION ....................................................................................................
WHY IS VISION IMPORTANT?
There are some assumptions that are basic to an understanding of how
the visual system contributes to early development and that must be
understood if a foundation for stimulation is to be established.
Vision is the Primary Data—Gathering System of the Human Organism

Of all the senses, vision provides the most information to the brain. It
is both a near and distance sense, and can integrate the information
it gathers. Only vision can perceive shape, size, color, distance and spatial
location— all in one glance. The other senses together cannot provide
equal information to the brain.
Vision is the Feedback System for all Other Developing

Systems in the Young Child
An infant’s early development depends on vision, since all the other systems
require visual feedback for practice and refinement. When the visual system
is impaired or dysfunctional, the other systems do not have a monitoring
tool to assure their smooth and timely development.
We Cannot Wait Until a Loss of Vision has

Caused a Development Delay
Early Stimulation may be based on a deficit model. The time to intervene
is before delay occurs; the goal is to prevent the delay, if possible;
Vision Happens in the Brain Not in the Eyes

It takes both eyes and brain for vision to occur. When either system
is dysfunctional or defective, the visual system becomes impaired and
cannot provide adequate visual information to the infant. The two systems
are interrelated, interconnected and interactive. This basic concept is essential
to early stimulation.
Do not Conserve Vision by Not Using It

Vision must be used to be effective and we cannot “save” vision. Moreover,
it must be practiced to become most efficient.
EARLY DETECTION OF VISUAL ABNORMALITIES IN YOUNG CHILDREN

• Check for eye fixation—note whether the baby is watching when one
is looking at his face and when one talks or plays with him.
• Hold the baby in such a way that the baby faces the window, and
then slowly turn him towards the darkest side of the room. Observe
whether the baby is turning his head towards the window.
• Observe whether the baby’s eyeball wanders from one corner of the
eye to the other while awake (after 6 weeks).
• Check for cataract (a white spot seen in the pupil).
• Note whether the baby has a strong family history of visual problems.
• Be cautious if a squint persists even after 6 months of age.
• Holding objects very close to the face while examining or looking
at something is a warning sign.
VISUAL STIMULATION—WHY EARLY?

• Visual impairment affects the development of the brain. If vision is
not dominant as the avenue of information, it does not get its normal
representation in the brain cortex.
• Visual stimulation seems to be more useful during infancy and very
early childhood.
• It may be more helpful to children with certain cases of blindness
than for other children.
• Pairing the visual stimulation with other experiences is more useful.
Incorporation of all the senses (touch, hearing, and smell) into visual
experiences helps the child make better sense of visual images.
VISION AND HEARING STIMULATION IN EARLY INFANCY 289
• The ultimate goal of visual stimulation is to motivate the child to make
the best use of the vision he has and to identify those situations when
the use of another sense would be more efficient.
By early stimulation of vision it means use of strong visual stimuli
to make an infant or child aware of vision, since these children usually
have very limited visual capabilities and no visually guided functions. Tactile
and visual stimuli can be used simultaneously. If the infant gets strong
visual input and at the same time tactile information is used to explore
the surface qualities and form of the object, there is hope that the two
different types of information can be integrated.
Visual stimulation is an integral part of play and therapy situations.
The content of the stimulation is the same as for normally sighted children
but the visual information is clearer with a good contrast so that it can
be used for eye-hand coordination, eye-foot coordination, and development
of spatial relationships. In these training situations the visually impaired
infants often use tactile information for quite some time to explore the
surface qualities and form of an object. Picture perception is one of the
most difficult concepts to develop in a visually impaired child.
In some visually guided motor functions the child may not reach the
usual milestones so these motor functions need special training. Visual stimulation
and training are integrated in the child’s early stimulation program.
STIMULATION TECHNIQUES FOR VISUALLY IMPAIRED CHILDREN

All children need to be encouraged to use their eyes and to think about
what they see. For those who find it difficult to concentrate, or those
who appear to take little interest in their environment, a special effort
must be made to provide them with things they will really want to look
at, as well as interesting things they need time to explore.
Many a child has natural curiosity. When he is shown a pretty thing
which may be precious or old, has been taken to visit an interesting
place, or simply has his attention drawn to a spectacular sunset, he may
be building associations and memories which might influence his life more
than can perhaps be imagined.
Techniques
Arrange a room that is bright, stimulating, and colorful—full of toys and
materials that are both interesting and attention grabbing. Some decorative
items for a room are helpful for increasing visual awareness.
Intervention to Promote Eye Focus and Following

Place the child supine. Help him to keep his head in the midline. Hold
both his shoulders forward. Place shiny, colorful, noisemaking toys or
a torch light close to the child’s eye. The mother can attract his attention
by face-to-face singing or talking
Senses as Learning Tool

• In a visually impaired child other senses are potentially at a maximum
(touch, taste, smell, and hearing). So, provision of an environment
where the child can explore things and utilize his existing good senses
is very important.
• Provide opportunities for the child to grasp information by touching
with his hands and skin, hear a lot using his ears, to smell using his
nose and to taste with his tongue.
• A blind child needs to be taught a lot. A child with partial visual
impairment can perceive a whole lot of unclear images, but in a child
with complete visual impairment the stimulation is very difficult.
• The child learns about his world through talking and touching mainly. ‘What
is the object made of? What is it for? How is it ….? What happens if ……?’—
he learns through hearing information related to it.
• Shake the baby’s arms and legs and keep repeating the name of
the parts you touch.
• Music boxes or wind up toys coming toward the child from a distance
may help perk-up attention to an approaching object. Balls with electronic
sounds that do not roll very far are available. A ball with a sound
that continues to play is very helpful for seek-and-find.
• A toy that rolls away should have a sound so the child can remember
where it went.
• Toys with music and sounds activated by pushing a button are useful.
• Allow the baby finger play with dough.
• Place the baby on different surfaces, hold him frequently, lay him
on the ground, over a mat—all these help.
• Hang small bells around the crib.
• Textured balls, large push and bump toys like cars, trucks and walking
push toys can be made use of.
• All young children with some vision enjoy mirror play, but watch out
for glare. Use them in diffused lighting.
• Provide him with opportunities for hearing other people’s speech also.
Put the baby on his mother’s lap while she is communicating with
others.
• Spread sound making toys in the sound proof room where he is
playing?
• Provide the child with the sensation of different textures. Make the
child walk barefoot on grass, on gravel, on sand, on the road, etc.
VISION AND HEARING STIMULATION IN EARLY INFANCY 291
ENCOURAGING EXPLORATION
• Gently guide the baby’s hand towards the sound of a toy and keep
decreasing the amount of help offered.
• Use toys that light up or objects with reflective surfaces if light perception
is present.
• Change the position of the baby frequently, put him on his back,
turn him onto his sides, on his tummy, etc.
• Don’t put the baby always in the crib.
• Hung strings of Christmas lights in baby’s room to encourage visual
attention.
• Hang noisy toys over the crib and guide his hands towards it. Assist
him to reach for and then grasp it.
• Ask the mother to keep the child at her side and to keep on talking
to him as she does her work.
• Attach different textures on the lower portion of walls to encourage
the child to explore the walls.
• Make the child sit on a rocking horse or rocking chair.
BODY IMAGE
• Draw the child’s attention to different body parts. Place a small pillow
over his legs and encourage him to knock it off.
• Place an over sized plastic ring on the baby’s wrist or ankles and
encourage him to remove the ring.
• Guide the baby’s hand to each part of the body as related nursery
rhymes are sung.
OBJECT PERMANENCE
• Help the baby hold on to the spoon while feeding, this will help
him to learn to hold it and feed by himself later.
• Guide the baby’s hand to a hidden toy or tap the toy on the floor
to give him a clue.
• Peek-a-boo games, pulling a scarf off a hidden musical toy, etc. can
be made fun.
• Encourage independent mobility at home.
HEARING
EARLY STIMULATION FOR HEARING IMPAIRMENT
Without adequate sound stimulation in infancy and early childhood, speech
and language development will be compromised. Later treatment may
never fully compensate for this early deprivation. The critical period for
language and speech development is the first 2 years of life.
TECHNIQUES
• Encourage him to produce new sounds by imitation or by continuous
repetition of words
• Maintain face-to-face conversation while talking to him.
• The child could sing thorough a mouthful of cereal—‘mum-mum-
mum’ and think that he is at least saying Mom. The mother could
reward him with a smile and cuddles
• Make a variety of sounds in the environment—patting plastic chairs,
banging a wooden table, banging the rattle across the wall, banging
a cup and spoon together. The child will gradually begin to associate
certain sounds with a sequence of events.
• The ding-dong of the doorbell, the sound of the bath water running,
noises of family pets—such sounds will contribute to the baby’s idea
of home and security
• Provide plenty of noisemakers for the baby to shake, bang, kick, hit
or drop
• Have a code sound for a certain activity—e.g.using a little rattle to
announce mealtime, or splashing a hand in the water before bathing.
• Speak to the baby as much as possible. All young babies need to
listen to speech for many months before they can sort out and imitate
the sound of words. With a hearing-impaired child this listening stage
often lasts for a long time and because the child does not appear
to respond, it can be very easy to forget to talk to him.
• Make the child listen to record players, the radio and the TV, etc.
• Making sound pictures—first think of a situation and then create the
appropriate noises, which will conjure up that image. An easy one
is ‘a walk down the street’. This includes traffic noises, scraps of
conversations, footsteps of different people, a police siren, sounds from
different shops, supermarkets, etc.
GENERAL ACTIVITIES
• Do not overprotect the child. Treat him like a normal child.
• The anticipatory movements should be accurate. For example, call
the baby to lift his head while holding his shoulders and axilla.
• Encourage moments of experimentation in every day situations, which
create sounds and sensations.
Section 13
Prenatal
Strategies
30. Prenatal Risk Factors
31. Multiple Fetal Pregnancies
32. Assisted Reproductive Technique—Is It Safe?
Archana P. Bilagi, Ranjan Kumar Pejaver
30
Prenatal Risk Factors
During the last two decades, the improved neonatal care in our country
has resulted in increasing numbers of high risk neonates surviving and
being discharged from neonatal intensive care units (NICU). However,
the quantum of neurodevelopmental disability (NDD) noted at follow-
up has not decreased; reasons for this vary from poor implementation
of potentially best practices (PBPs) in neonatal care to insufficient attention
to a crucial period of brain development—prenatal period.
Intra-partum and neonatal events are just a continuation of the
antenatal life of the fetus. Several antenatal factors influence the well
being of the baby and the neurodevelopmental outcome is dependent
on these factors that operate during the prenatal period.
RISK FACTORS
1. Prematurity
2. Growth restriction
3. Maternal nutrition
4. Intrauterine infections
5. Maternal diseases
6. Maternal factors
7. Teratogens.
PREMATURITY ......................................................................................
The risk of NDD in newborns is inversely proportional to their gestational
age. The gestation represents a composite of all the morbidities likely
to occur after birth. Babies born before 28 weeks gestation have been
observed to have some degree of neurodevelopmental compromise even
when the NICU stay has been “uneventful”. 2 Despite description of several
antenatal strategies, only one strategy has proven benefit.
ANTENATAL STEROIDS (ANS)

A single course of antenatal glucocorticoids has been shown in several
elegant randomized controlled studies and meta-analysis to decrease the
incidence of mortality, respiratory distress syndrome, intraventricular
hemorrhage and necrotizing enterocolitis.11,12 It is now the standard of
care and is routinely administered in suspected preterm delivery prior
to 34 weeks gestation with few exceptions. Several randomized controlled
studies have studied repeated weekly courses of antenatal steroids. Adverse
long term neurodevelopmental outcome are feared in babies who received
repeated courses.13,19 Decrease in head circumference, increased rate of
cerebral palsy (CP), cognitive and motor deficits, delayed psychomotor
development and behavioral problems are some of the adverse outcomes
that were noted. Hence, the current recommendation is a single course
of antenatal steroids in women at risk for preterm delivery. Repeated
or multiple courses of steroids is recommended to be used only in
randomized controlled studies settings. Betamethasone is preferred over
dexamethasone as dexamethasone was found to be associated with
increased incidence of periventricular leukomalacia.
GROWTH RESTRICTION—BABIES WHO ARE SMALL FOR

GESTATION, EITHER TERM OR PRETERM ...................................
In India nearly two thirds of the newborn babies are small for gestation
(SGA). A study done by Bhargawa et al revealed that among the 150
LBW infants followed up, 7.0% had developmental delay, 4% had CP
and 10% had transitory dystonia.22 Many more of these babies scored
much less than the controls on the developmental scales.
In many babies born SGA, growth in utero is impaired and such
babies are higher risk of perinatal mortality and morbidity. Many others
are constitutionally small and not short of their best potentials, and at
no increased risk of perinatal problems.
GROWTH RESTRICTION AND NEURODEVELOPMENT—

WHAT HAPPENS?23-25
Some of the IUGR babies have increased risk of minor motor dysfunction
(not CP)30, 31 impaired speech and language development but most have
only behavioral problems and attention deficit disorders in their
later years.
PRENATAL RISK FACTORS 297
The key factor is the malfunction of the placental unit resulting in inadequate
supply of nutrients and oxygen. This malfunction could be due to maternal
factors like systemic illness, teratogens or placental circulation being affected
as in pregnancy induced hypertension, or an abnormal placental unit. Babies
with bad dopplers are at increased risk of IVH.25
Schreuder and colleagues32 reported no significant differences between
the children who had forward flow in the umbilical artery. Those with
absent EDF, those who had reversed EDF did worse on tests of general
conceptual ability and spatial/pictorial ability. There were more children
with severe visual deficits in the groups with reversed EDF than in
the absent EDF group. Furthermore, children with reversed EDF scored
higher on assessments of hyperactivity and peer problems than the
group with forward flow. However, 50% of the children from the reversed
EDF group were doing well in normal school without any additional help.
Brain—sparing hemodynamics (fetal hemodynamic adaptation—
the U/C ratio, comparing umbilical artery and Middle Cerebral Artery
(MCA) Pulsatality Indices.33,34
At 5 years of age, 54% of children with a raised umbilical/cerebral
or U/C ratio were functioning below the expected level, compared to
20% of children born with normal U/C ratios. Children born after raised
U/C ratios had a 9-point lower IQ score at 5 years of age compared
to those who had normal U/C ratios. ‘Brain-sparing’ may be protective
against gross neurological abnormalities in early childhood, but these
adaptations may predispose the infant to later cognitive
problems.33,34
IDENTIFYING PREGNANCIES AT RISK OF IUGR

A combination of maternal risk factors and screening tools are use. The
purposes of early detection of IUGR are two
• Interventions to improve fetal circulation, e.g aspirin if detected
very early
• Timing of delivery.
Maternal History
Previous pregnancy IUGR, advanced maternal age, maternal medical
illnesses—SLE, bowel, renal, cardiac, obstetric—PIH, GDM, maternal
habits—smoking, alcohol, maternal nutrition, socioeconomic status, etc.
Biochemical Screening
The OR for delivering an SGA infant for women with a low PAPP-A
level at 8-14 weeks gestation was 2.8 (with 95% CI 2-4) and when levels
of alpha fetoprotein (AFP) were also elevated at 15 -21 weeks in the

same pregnancy, the OR for SGA rose to 8.5. (95% CI 3.6-20).29
Ultrasound Screen
Uterine artery Doppler done at 23 weeks identifies those pregnancies
at high risk of adverse obstetric outcomes, with a high positive predictive
value for early delivery.
DO BABIES BENEFIT BY EARLY DELIVERY IF IUGR IS SEVERE?

Babies may have to be delivered preterm if the in utero growth restriction
is very severe. Studies have shown that babies should not be delivered
before 26 weeks gestation and estimated fetal weight of 600 grams for
IUGR. Best predictors of intact outcome were gestation > 29 weeks and
weight > 800 grams.
MATERNAL NUTRITION AND BRAIN DEVELOPMENT .................

Many nutrient deficiencies, particularly macronutrients, can have profound
effects on the neuroanatomy, neurochemistry, and neurophysiology of
the developing brain. Affected brain structures include neurons, progenitor
cells, and supporting cells such as oligodendrocytes, astrocytes, and microglia.
Depending on the timing and duration of restriction, neuronal division,
growth, and complexity can be affected, with attendant deficits in neuronal
number, size, dendritic arbors, and synapses. Earlier restriction (prior to
24 weeks post-conception) is more likely to affect neuronal number; later
fetal and postnatal restriction tends to affect size and complexity.
The effect of malnutrition on the supporting cells of the central
nervous system should not be underestimated. Oligodendrocytes are
glial cells that produce myelin and depend on macronutrient substrate
for their own energy metabolism and for fatty acids to be incorporated
into myelin. Astrocytes serve multiple functions, including nutrient delivery.
Microglia is a macrophage derived cell that serves an important role in
neuronal migration prior to 24 weeks post-conception. Therefore, restriction
of macronutrients can result in hypomyelination, further reductions in
nutrient delivery, and migration abnormalities during early brain
development. These alterations subsequently could cause behavioral
abnormalities characterized by reduced speed of processing,
reduced synaptic efficacy, and potentially a predisposition to later
developmental psychopathologies (e.g. schizophrenia, depression, or
autism).
Neurochemical effects of protein-energy malnutrition include altered
synthesis of neurotransmitters, their postsynaptic receptors, and their
pre-synaptic reuptake transporters. Protein-energy malnutrition could affect
neurophysiology, defined as the ability of neurons to work in an electrically
optimal way, by directly altering neuronal metabolism or by indirectly
altering neuronal structure or neurotransmitter homeostasis.
INTRAUTERINE INFECTIONS
Intrauterine infections that involve the fetal central nervous system result
in devastating neurological sequelae. Most infections occur during the first
and second trimesters with some exceptions. Etiological agents are popularly
remembered by the acronyms TORCHS (toxoplasmosis, others, rubella,
cytomegalovirus, herpes, syphilis) or SCRATCHES (syphilis, cytomegalovirus,
rubella, AIDS or HIV infection, toxoplasmosis, chickenpox, herpes, entero-
viruses).
These infections are often missed during pregnancy as maternal infections
can be asymptomatic or can cause just mild mononucleosis-like symptoms.
Route and timing of transmission are shown in the Table 30.1. Severity
of CNS involvement can vary with the timing of transmission.
Table 30.1: Route and timing of transmission of intrauterine infections

Major route of Predominant period of
transmission transmission
Cytomegalovirus Transplacental First and second trimesters
Toxoplasmosis Transplacental First and second trimesters
Rubella Transplacental First trimester
Syphilis Transplacental Second and third trimesters
Human immunodeficiency Transplacental First and second trimesters,
virus birth
Herpes Ascending, Birth
parturition
Varicella Transplacental Peripartum, first 20 weeks of
gestation
Enterovirus Contact, Postpartum, birth
parturition
The IU infections are often asymptomatic in the newborn period. Certain

clinical signs and symptoms can raise suspicion of these infections. CMV
and toxoplasmosis can cause intrauterine growth restriction, preterm birth,
microcephaly, hepatosplenomegaly, anemia, cutaneous petechial rash,
pneumonitis or hyperbilirubinemia. Chorioretinitis is a prominent feature
in CMV and toxoplasmosis infections; the latter tending to involve the
macular region. Rubella can cause ‘blueberry-muffin’ cutaneous lesions,
ocular or cardiac defects. Congenital varicella can present with cutaneous

depressed scars in a segmental distribution, muscle or limb hypoplasia.
Congenital syphilis is likely to present with symptoms and signs only after
2 weeks of age, involve the skin and reticuloendothelial and skeletal systems.
Coxsackie B infection causes myocarditis and fever. Progressive neurological
disease in congenital CMV infection can manifest in the months to years
following birth; progression of hearing loss during childhood has been
reported.
NEUROPATHOLOGY
Intrauterine central nervous infections are characterized primarily by
inflammatory and destructive processes. Meningoencephalitis can involve
all cellular elements of the brain parenchyma resulting in necrosis and
reactive gliosis. Multicystic encephalomalacia, porencephaly and hydrancep-
haly can result. Microcephaly is the result of these multifocal necrotizing
lesions as well as inhibition of neural proliferation. Delayed myelination
may also be seen. Intracerebral calcifications are seen in 51-75% of
symptomatic CMV infections and in 15% of toxoplasmosis infections;
calcifications tend to be periventricular in the former as compared to
the diffuse calcifications in the latter. Herpes simplex meningoencephalitis
can be devastating with serious consequences. Microcephaly is seen in
infections acquired during early pregnancy; other features include
chorioretinitis, microophthalmia, multicystic encephalomalacia and cerebral
calcifications.
Hydrocephalus is commoner in toxoplasmosis; it can result from
occlusion of the aqueduct with periventricular inflammation and thrombosis
with resultant infarction. Migrational disorders such as lissencephaly,
polymicrogyria, pachygyria and schizencephaly have been described in
congenital CMV infection thus giving it a teratogenic potential. The early
stage of congenital syphilis is characterized by acute and subacute
meningitis, hydrocephalus, cranial neuropathies and cerebrovas-
cular infarcts. Optic atrophy and auditory nerve injury, juvenile
general paresis and tabes dorsalis are seen in the late stage of congenital
syphilis. HIV differs in that the neuropathology is more related to the
immune response of the host. Cerebral atrophy and resultant microcephaly
is a prominent feature resulting from loss of neurons and myelin. Entero-
viruses cause primarily meningoencephalitis. Neuropathological features
in congenital varicella infection include meningoencephalitis, myelitis,
dorsal root ganglionitis and denervation atrophy of muscle in segmental
distribution.
Cytomegalovirus26 (CMV)
Congenital CMV infection is a leading cause of hearing loss and
neurodevelopmental disabilities, and of the common IU infections. Of
those children with congenital CMV, 80-90% have a normal developmental
outcome. One third of children with symptomatic congenital CMV infection
are normal.
Infection in early gestations results in neuronal migrational disorders,
whereas later gestations produce only myelination defect. Microcephaly
and abnormal neuroradiologic imaging are associated with poor
neurodevelopmental outcomes and the normal head circumference and
normal neuro—imaging favors good prognosis. Neuroradiological findings
include multifocal lesions predominantly involving deep white matter,
ventriculomegaly, intracranial calcification, and brain atrophy, destructive
lesions, with or without gyral abnormalities. The presence of abnormalities
in the anterior part of the temporal lobe, increases the likely hood
of CMV infection. Based on a data from MacDonald (80 infants), the
outcome correlates with the presence of symptoms at birth. In the
symptomatic group, with overt neurological disease with microcephaly,
calcifications or chorioretinitis, almost 95% exhibited major neurological
sequelae or died.
If systemic signs without neurological involvement were present, almost
50% of these infants were normal and 16% exhibited major neurological
sequelae or died. Major neurological sequelae included mental retardation,
seizures, deafness or motor deficits.
In the asymptomatic group, sensorineural hearing impairment was seen
to progress during early childhood underlying the importance of evaluating
these infants periodically (can be as late as 6 years of life). In studies,
11% developed bilateral hearing loss with moderate to severe loss noted
in 6%.
Visual impairment and strabismus are common due to chorioretinitis
and involvement of other eye structures. It is unusual to have eye
involvement in children who were asymptomatic neonates.
Infection acquired during breastfeeding and delivery is not associated
with neurodevelopmental sequelae.
IgM test is useful when it is done 3 weeks after birth. It is positive
in only 70% cases. Ideal diagnosis is by demonstration of virus in urine
or saliva.
Currently there is no evidence to suggest antiviral therapy for
congenital CMV. In an RCT, 6 weeks of Ganciclovir at a dose of 6
mg/kg/day resulted in improved hearing compared to controls at 6 months
follow up. In addition 68% in untreated group had deterioration of hearing
function at 1 year follow up as compared to 21 % of the group not

treated. Viral excretion decreases in the treatment period, but, only
temporarily. There are only single case reports of improvement in cholestasis
and retinitis.
Preventive strategies—hand washing after contact with saliva, urine in
day care centers/centers for disabled. Early studies on intravenous human
immunoglobulin to pregnant mother with primary CMV have claimed
decrease in transmission, but further evaluation is necessary.
Toxoplasmosis27
About 20-25% of infants will be affected if maternal infection occurs during
the first or second trimester. In maternal infections during the third trimester,
about 65% of infants will be affected. Although the risk of transmission
is higher later in pregnancy, the severity of fetal involvement is greater
in early pregnancy and can involve the ocular and CNS systems. Treating
the mothers decreases the risk of transmission and severity of the
intracranial lesions, but has no impact on eye involvement.
Reduction in maternal—fetal transmission requires treatment within 3
weeks of infection in mother.
Affected newborns are mostly asymptomatic. In symptomatic infants,
two-thirds can have neurological signs. Chorioretinitis mainly involving
the macular region is seen in 90% of these infants. Microcephaly
is seen in 10% of cases. Infants with neurological involvement have a
poor outcome, with only 9% normal on follow up. Major neurological
sequelae include visual loss.
In systemic syndrome with predominantly signs referring to the
reticuloendothelial system, approximately two-thirds will have chorioretinitis.
Neurological involvement is less prominent. 50% are normal on follow
up and severe visual impairment is seen in 40%. Asymptomatic cases
can also develop chorioretinitis and eventually visual loss; neurological
deficits and hearing loss may also result.
Early treatment of toxoplasmosis can result in better outcome. Treatment
for 3 months seems to be as effective as longer courses pf 6-12 months.
Spiramycin was effective in reducing mother to baby transmission; there
is no evidence for efficacy of sulfa, pyrimethamine.
Currently, there are no recommendations on screening of pregnant
women for toxoplasma infections.
Rubella28
The risk of transmission and severity of infection is greatest during early
pregnancy. CNS, ocular involvement, and hearing loss are seen in infections
acquired during the first two months; these are not seen in maternal
infections after the fourth month of pregnancy.
Two-thirds of infants can be asymptomatic in the newborn period.
Neurological involvement is seen in 50-75% of cases. Prolonged
progressive infection occurs during early childhood. Hearing loss can
be detected later during childhood. A great number of cases will have
major neurological sequelae.
Syphilis
CNS involvement occurs in a majority of cases if untreated. 65-90% of
cases are asymptomatic in the newborn period. Symptoms may be seen
in the first two years of age in the early stage of congenital syphilis.
Neurological signs are seen rarely although abnormal CSF findings
can be seen in most of the cases in symptomatic disease.
CNS involvement in the late stage of the disease is characterized by
optic atrophy, auditory nerve injury, tabes dorsalis and general paresis
presenting at 10-15 years of age.
The prognosis in congenital syphilis depends on the severity of
neurological injury. Symptomatic newborns have a worse prognosis than
asymptomatic cases. Neurological sequelae can be prevented by early
adequate treatment.
Herpes Simplex
The risk of transmission during primary infection in the presence of visible
lesions is almost 50% if the infant is born vaginally. Ascending infection
during labor can also occur especially if the duration of rupture of
membranes is more than 6 hours.
Most of the affected cases are symptomatic in the newborn period.
Disseminated disease almost always involves the CNS although overt
neurological signs may not be seen in one third of the cases. Left untreated,
the mortality rate is as high as 80% and 50% of the survivors have
severe neurological sequelae. Even with early recognition and antiviral
treatment, the mortality rate is high at 60% and only 10-20% normal
on follow up.
Localized disease may involve the CNS in as many as 30-60% of
cases. These usually present in the second or third week of life with
neurological signs. Mucocutaneous lesions may be absent. If untreated,
the mortality rate is about 60-80%; almost all the survivors exhibit significant
neurological sequelae. With early recognition and antiviral treatment, the
mortality rate is 15% with only 30-40% normal on follow up. In muco-
cutaneous localized disease, progression to involve the CNS can occur.

The mortality is almost zero with 90-100% normal on follow up in localized
mucocutaneous form of disease.
Human Immunodeficiency Virus

HIV infection affects the CNS with clinical features seen months to years
after birth. Neurological signs in the newborn period are rare; onset
of these occurs in about 20% of infected infants and are usually seen
between 2 months and 5 years of age. Progressive encephalopathy
can develop with spastic motor deficits, microcephaly and extrapyramidal
signs developing in a rapid or subacute fashion. The median age of survival
after onset of these features is 14 months. Static encephalopathy occurs
in 20-25% of cases and is characterized by cognitive problems and motor
dysfunction. About 75% survive to the age 6 years; approximately 25%
will have mild cognitive and motor deficits. Survival rate at 10 years is
60%; approximately 25% will need special education.
Varicella
Two syndromes are recognized: congenital varicella syndrome and prenatal
varicella infection. The former occurs with transplacental transmission during
the first 20 weeks of pregnancy. The risk of fetal infection is reported
to be about 0.4% during the first 12 weeks and 2% during 13-20 weeks
of pregnancy. CNS involvement is significant. Seizures, muscle weakness
and bulbar signs manifesting as difficulty swallowing may be seen in 26-
50% of cases. Retarded neurological development may be seen in 51-
75%. Ocular abnormalities occur in 76-100% of cases and include
chorioretinitis, cataracts, Horner’s syndrome or optic atrophy.
Perinatal varicella results when infection is transmitted close to or at
the time of delivery and is clinically apparent in the infant within 10
days of delivery. CNS involvement is rare.
Enterovirus
Most of these infections occur postnatally. Transmission may occur during
delivery. Transplacental transmission can occur near the time of delivery
if maternal viremia is present. Coxsackie B infection can result in serious
involvement of the CNS along with myocarditis. CNS signs may be seen
in only about 25% of cases. Prognosis with coxsackie B infection is generally
good; exception being those cases with encephalitis. They may develop
neurological or cognitive deficits.
Chorioamnionitis
Chorioamnionitis has emerged as an important risk factor for adverse
neurodevelopmental outcome in both term and preterm infants.
Chorioamnionitis can be overt or subclinical. Overt infection is manifested
by well known clinical features like maternal fever associated with fetal
or maternal tachycardia, uterine tenderness, or foul-smelling amniotic fluid.
Eastman et al reported in the 1950s that intrapartum fever occured
7 times more common in mothers of infants with CP.3 Nelson et
al analyzed characteristics of a population registry of infants with CP and
reported that a clinical or histologic diagnosis of chorioamnionitis was
associated with an 8-fold increased risk of CP. Several studies have
noted an association between placental infection/inflammation in term infants
and the development of CP in early childhood.7-10
A significant number of cases of preterm labor with premature rupture
of membranes may be accompanied by sub-clinical microbial invasion
of the amniotic fluid producing a condition called sub-clinical chorioamnio-
nitis. This condition is associated with increased fetal and amniotic fluid
cytokines such as interleukin-6, interleukin-8, interleukin-1-beta, and tumor
necrosis factor-alpha. Interleukin-6 in particular, is a pro-inflammatory
mediator produced in response to infection and can elicit various bio-
chemical, physiologic and immunological host responses that can then
result in a condition called fetal inflammatory response syndrome (FIRS).
Funisitis is considered a hallmark feature of FIRS. FIRS can progress on
to septic shock, multiple organ dysfunction, encephalopathy and death.
IL-6 has been shown to be increased in FIRS. It can directly or indirectly
(by producing systemic hypotension) produce white matter lesions in the
brain that can result in periventricular leukomalacia. PVL has been linked
in several studies to the later development of CP.
MATERNAL DISEASES ........................................................................

Main mode of causing NDD is by restricting the growth of the fetus and
or resulting in preterm birth.
• Risk of LGA, jaundice, breast trauma, respiratory distress
• Hypertension
Risk of SGA in mild chronic hypertension varied from 8.0 to 15.5%
• Previous affected pregnancy( which has resulted in SGA babies)
20% recurrence risk, depending on persistence of risk factors
• Smoking
Reduction in average birth weight of 458 g in smokers of 20 cigarettes/
day
• Renal disease
women with moderate (defined as serum creatinine concentration of
124-220 mm/L) and severe renal impairment (defined as serum
creatinine concentration >220 mm/L), 37% of births were SGA (<10th
centile birth weight).
• Connective tissue disease
Incidence of growth restricted fetus 28.5% in women with active systemic
lupus erythematosus, but 7.6% in those with inactive lupus.
• Thrombophilia
Although there is evidence for adverse pregnancy outcome with
antiphospholipid syndrome, with IUGR occurring in around 30%, the
risks for other thrombophilias are less clear. A systematic review concluded
that women with poor obstetric outcomes (such as IUGR) are more
likely to test positive for thrombophilia, but routine screening currently
not be recommended.
• Cardiac disease
A prospective study of over 500 women (with heterogeneity of cardiac
disease) found significant maternal morbidity or mortality in up to
13% of pregnancies. In this series, the incidence of a <10th centile
SGA birth weight was not significantly higher than in controls (4%
versus 2% in controls). However, there was a significantly increased
risk of fetal death, premature delivery and respiratory distress syndrome.
Maternal condition prior to the pregnancy appears to predict to some
extent the maternal and possibly fetal outcome.
• Smoking, alcohol and caffeine use
Many studies report a reduction in birth weight at term of around
150-330 g in smokers compared with non-smokers. Comparisons have
been made of anthropometric measurements of infants born to women
who continued to smoke (>1 cigarette/day) throughout pregnancy,
with those that stopped after the booking visit. There is an association
between continued smoking and reductions in birth weight, head
circumference and crown-heel length, with more pronounced effects
in heavier smokers (>10 cigarettes/day).
Alcohol at low doses (less than 1 unit/day) translate to an odds ratio
(OR) of delivering an infant below the 10th centile for gestational age
of 1.1 (95% confidence interval (CI) 1.00-1.13). With consumption of 1-
2 units a day, the corresponding OR is 1.62 (95% CI 1.26-2.09) and
with 5 units a day, the OR is 1.96 (95% CI 1.16-3.31).
Caffeine: The effects of reported caffeine consumption on birth weight
in over 2000 women in Connecticut and Massachusetts showed small
observed reductions in birth weight. At high doses (600 mg/day) caffeine
reduced mean birth weight by the equivalent of smoking about 10 cigarettes
a day. However, when smoking was controlled for, moderate intake seemed
to have little effect on the risk of birth weight under the 10th centile.
Drugs of abuse: Most studies report a high incidence of IUGR in opiate
users but multiple confounders exist. The most likely drug with a particular
effect is cocaine because of its associated constrictor effects, although in
a review of 200 babies born to women using drugs of abuse, 11% were
found to be SGA (under 10th centile), which suggests the effects may
not be as great as commonly thought.
Prescribed drugs: The fetus may be exposed to drugs during pregnancy
because of pre-existing maternal problems or complications of pregnancy
itself, such as hypertension, or anticipated preterm delivery. Beta-blockers
(including labetolol), for example, do appear to be associated with an
increased risk of a SGA infant when used to treat hypertension.
MATERNAL FACTORS ........................................................................

Assisted conception: In 307 in vitro fertilization (IVF) pregnancies, 16.2%
of babies had a birth weight below the 10th centile compared with 7.9%
of controls. A recent meta-analysis found an OR of 1.6 (95% CI 1.3-
2.0) for a birth weight <10th centile for singleton pregnancies conceived
by IVF compared to spontaneous conceptions.
Age: There is no association between SGA and low maternal age,28 but
there is with older mothers.29 In the London perinatal database of 385,120
singleton pregnancies, an OR of 1.28 for a birth weight <5th centile
was reported in women aged >35 and an OR of 1.49 for women aged
>40.
Body mass index: Obesity is not associated with the birth of a SGA
fetus, whereas maternal ‘underweight’, i.e. a BMI <20, increases the risk
of both preterm delivery and birth weight <5th centile.
TERATOGENS .......................................................................................
There are two important mechanisms by which drugs affect the developing
CNS: teratogenic effects and passive addiction. Teratogenic effect refers
to the effects of any agent that causes a structural abnormality following
Table 30.2: List of well known teratogens that affect the fetal CNS
Drug Fetal effects of intrauterine exposure
Phenytoin 1. Fetal hydantoin syndrome (craniofacial dysmorphology especially
ocular hypertelorism, hypoplastic distal phalanges and nails, growth
retardation, delayed neurological development and cardiac defects.
2. Intracranial bleed (hemorrhagic disease of newborn)
3. Cleft lip/palate, cardiac defects
Phenobarbital 1. Dysmorphic features, growth retardation
3. Cleft lip/palate, cardiac defects
4. Passive dependence (withdrawal symptoms)
Valproic acid 1. Dysmorphic features
2. Cardiac defects
3. Neural tube defects especially myelomeningocele (risk 1-2%)
Carbamazepine 1. Craniofacial defects
2. Neural tube defects especially myelomeningocele (risk 1-2%)
3. Developmental delay
Trimethadione 1. Impaired growth
Paramethadione 2. Craniofacial dysmorphology (v-shaped eyebrows, malformed ears,
cleft lip/palate)
3. Microcephaly, mental retardation, developmental delay
Alcohol 1. Fetal alcohol syndrome (impaired growth, microcephaly, developmental
delay, facial abnormalities: low nasal bridge, midface hypoplasia, long
featureless philtrum, small palpebral fissures and thin upper lip; cardiac
defects, hearing loss, optic nerve hypoplasia)
2. Cognitive and behavioral deficits
Isotretinoin 1. Craniofacial dysmorphology (malformed ears, atretic ear canals,
microtia)
2. Cleft palate
3. CNS defects (hydrocephalus, migration defects, cerebellar and brain
stem abnormalities)
4. Cardiac defects
Cocaine 1. CNS defects (Micrencephaly, migration disorders, callosal agenesis,
neural tube defects)
2. Microcephaly
3. Cerebral infarction, intracranial hemorrhage
4. Neurobehavioral abnormalities
5. Abnormal EEG and brainstem auditory evoked responses
Warfarin 1. Facial dysmorphology (nasal hypoplasia, depressed nasal
(coumadin) bridge)
2. Severe mental retardation, seizures, microcephaly, hydrocephalus
3. Stippled bone epiphysis
4. Growth retardation
Methotrexate 1. Facial dysmorphology
2. Microcephaly
3. Growth retardation, talipes equinovarus
Radiation Microcephaly, growth restriction, mental retardation
Lead Spontaneous abortion, neurological abnormalities
fetal exposure during pregnancy. Passive addiction of the fetus is the
physical dependence that occurs due to maternal exposure to the drug.
The teratogenic effect of agents depends on dose of the agent, timing
and duration of exposure to the agent, genotype of the pregnant woman,
genetic susceptibility of the fetus, physical characteristics of the agent
including size, solubility and polarity. In general, the embryonic stage (first
trimester) is more vulnerable than the fetal period (second and third
trimesters) (Table 30.2). The embryonic period, from 18 to 54-60
days after conception, the period of organogenesis is the period
of maximum risk of teratogenicity. Since teratogens are capable of
affecting many organ systems, the pattern of anomalies produced depends
upon which systems are differentiating at the time of teratogenic exposure.
Teratogen exposure during the fetal phase, from the end of the embryonic
stage to term which is the period of growth and functional maturation,
will affect fetal growth (e.g., intrauterine growth retardation), the size of
a specific organ, or the function of the organ.
KEY POINTS
Strategies to prevent or decrease the risk of fetal abnormalities include: use
of the lowest dose possible, the avoidance of combination drug therapies (for
the treatment of seizure disorders), the use of a different agent (heparin instead
of coumadin for thrombophlebitis), the avoidance of first trimester exposures
(preconception diabetes or PKU control), and folic acid supplementation.
TEAM APPROACH IN MANAGEMENT OF THE MOTHER AND

THE BABY FOR REDUCING NDD
1. There should be a close liaison between the obstetric and
pediatric colleagues in managing high risk and for that matter all
pregnancies. Appropriate consultation with other specialists like
physicians, cardiologists, nephrologists may be needed depending on
the maternal/fetal condition
2. Ultrasonography plays a major part, not only in visualizing the growth
of the fetus and the anatomy, but also in assessing the well being
of the fetus by assessing the fetoplacental circulation.
3. Considering various factors like the lung maturity, facilities for Intensive
care, etc. optimum mode of delivery at the appropriate time
should be planned.
4. In utero transfer is the most desirable practice. Uterus is the best
incubator known to mankind. High risk pregnant ladies should be
transferred to tertiary centers with adequate facilities to look after the

preterm/sick baby. This minimizes the morbidity associated with the
transport of an unstable neonate. The outcome is much better in
babies who were transferred in utero as compared to sick unstable
babies transferred after delivery. It is essential that every level 3 NICU
build an efficient transport team for these purposes.
5. High risk pregnancies with compromised fetus, warrant a trained
neonatal resuscitation team. A protocol for prompt resuscitation
and transfer if needed of such babies to higher centers should have
been put in place before the delivery.
If the child is damaged, the family is affected and the society suffers.
Long term care of the high-risk infant is a multi specialty commitment
small beginnings, great expectations.
REFERENCES ........................................................................................
1. Volpe JJ. Neurology of the newborn (4th edition). Philadelphia: WB Saunders,
2001.
2. Fanaroff AA, Martin RJ. Neonatal-Perinatal medicine (7th edition). St Louis:
Mosby, Inc, 2002.
3. Eastman NJ, De Leon M. The etiology of Cerebral Palsy. Am J Obstet Gynecol
955;69:950–8.
4. Wu Y, Colford J. Chorioamnionitis as a risk factor for Cerebral Palsy: A meta-
analysis. JAMA 2000;284:1417-24.
7. Grether JK, Nelson KB. Maternal infection and Cerebral Palsy in infants of normal
birth weight. JAMA 1997;278:207–11.
8. Roberto Romero, Tinnakorn Chaiworapongsa. Preterm Labor, Intrauterine
Infection, and the Fetal Inflammatory Response Syndrome. NeoReviews, May
2002;3:73-85.
9. Leviton A, Paneth N, Reuss ML, et al. Maternal infection, fetal inflammatory
response, and brain damage in very low birth weight infants. Pediatr Res 1999;
46:566–75.
10. Naccasha N, Hinson R, Montag A, Ismail M, Bentz L, Mittendorf R. Association
between funisitis and elevated interleukin-6 in cord blood. Obstet Gynecol 2001;
972:220–4.
11. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation
for women at risk of preterm birth. Cochrane Database of Systematic Reviews
2006, Issue 3. Art. No.: CD004454. DOI: 10.1002/14651858.CD004454.pub2
12. Alan H Jobe. Prenatal Corticosteroids: A Neonatologist’s Perspective. NeoReviews
2006;7:e259-e67.
13. Crowther CA, Doyle LW, Haslam RR, Hiller JE, Harding JE, Robinson JS. The
ACTORDS Study Group. Outcomes at 2 Years of Age after Repeat Doses of
Antenatal Corticosteroids. NEJM 2007;357:1179-89.
14. Wapner RJ, Sorokin Y, Mele L, Johnson F, Dudley DJ, Spong CY, Peaceman
AM, Leveno KJ, Malone F, Caritis SN, Mercer B, Harper M, Rouse DJ, Thorp
JM, Ramin S, Carpenter MW, Gabbe SG. The National Institute of Child Health
and Human D. Long-Term Outcomes after Repeat Doses of Antenatal
Corticosteroids. NEJM 2007;357:1190-8.
15. Guinn DA, Atkinson MW, Sullivan L, et al. Single vs weekly courses of antenatal
corticosteroids for women at risk of preterm delivery: a randomized controlled
trial. JAMA 2001;286:1581-7.
16. French N, Hagan R, Evans S, Godfrey M, Newnham J. Repeated antenatal
corticosteroids: size at birth and subsequent development. Am J Obstet Gynecol
1999;180:114-21.
17. Smolders-de-Haas H, Neuvel J, Schmand B, Treffers P, Koppe J, Hoeks J. Physical
development and medical history of children who were treated antenatally with
corticosteroids to prevent respiratory distress syndrome: a 10-12 year follow-
up. Pediatrics 1990;86:65-70.
18. Esplin M, Fausett M, Smith S, et al. Multiple courses of antenatal steroids are
associated with a delay in long-term psychomotor development in children with
birth weights grams. Am J Obstet Gynecol 2000;182:S24.
19. Baud O, Foix-L’Helias L, Kaminski M, et al. Antenatal glucocorticoid treatment
and cystic periventricular leukomalacia in very premature infants. N Engl J Med.
1999;341:1190-96.
20. Volpe JJ. Neurology of the newborn (4th edition). Philadelphia: WB Saunders,
2001.
21. Cloherty JP, Stark AR. Manual of neonatal care (3rd edition). Boston: Little Brown
and Company, 1991.
22. Bhargava SK, Kumari S, Pandit N, et al. Outcome of low birth weight children.
IAMS 1975;11:77-99.
23. Saigal S. Follow up of very low birth weight babies to adolescence. Semin Neonatl
2005;5(2);107-18.
24. Perlman JM. Neurobehavioural deficits in premature graduates of NICU. Pediatrics
2001;108:1339-48.
25. Breez ACG, Lees CC Prediction and Perinatal outcomes of fetal growth restriction.
Sem Neonatal Med 2007;12,383-97.
26. Malm G, Engman ML. Congenital cytomegalovirus infections. Seminars in fetal
and neonatal medicine 2007;12:154-9.
27. Petersen E, Toxoplasmosis. Seminars in fetal and neonatal medicine 2007;12:
214-23.
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29. Smith GCS, Shah I, Crossley JA, et al. Pregnancy associated plasma protein—
A and alpha- fetoprotein and prediction of adverse perinatal outcome. Obstet
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30. Baschat AA, Cosmi E, Bilardo CM, et al. Predictors of neonatal outcome in early-
onset placental dysfunction. Obstet Gynecol 2007;109(2):253-61.
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preterm small for gestational age infants: the first nine years of life. Br J Obstet
Gynaecol 1998;105(2):162-8.
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33. Scherjon SA, Oosting H, Smolders-DeHaas H, et al. Neurodevelopmental outcome
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2000;105(2):385-91.
Arvind Shenoi, Mohan BK
31
Multiple Fetal Pregnancies
About 3% of human pregnancies are multiple, and natural occurrence

rate of dizygotic twins is about 1.7%. With the use of fertility drugs the
incidence of multiple gestations could be as high as 25%.
IMPACT ON NEURODEVELOPMENT1 ...................................................................

Multi Fetal Pregnancies (MFP) are associated with a variety of adverse
outcomes, including delayed development, impaired sensor-motor function,
and cerebral palsy. The reported increase in risk of CP in MFP is similar
from studies in different geographic areas of the world. Incidence of
cerebral palsy in twins as compared to singleton was 7.4 versus 1 in
1,000 survivors at 1 year and 6.7 versus 1.1 in 1,000 survivors at 3
years of follow-up. The risk in triplets was even higher 28 vs. 7.3 vs.
1.6 in triple, twin and singleton pregnancies followed for 1 year.2 The
reasons attributing to the increased risk of CP in MFP are prematurity,
low birth weight, abnormal presentation, monochorionicity, death of a
fetus, and placental vascular anastomoses.
This increased risk of CP is probably related to the incidence of preterm
and low birth weight deliveries in MFP being much higher than singleton
pregnancies. When data for incidence of CP in singleton and MFPs
is stratified by birth weight, there is a significant increase in CP in MFPs
with birth weight 2500g or more; as compared with no significant increase
in risk for CP for infants of low birth weight (<2500g).3 The third factor
in MFP is the chorionicity with incidence of adverse neurodevelopmental
outcome being associated with mono-chorionicity. A further confounder
is the association of adverse outcome associated with death of one of
the fetuses in a MFP. Co-twin survivor after the death of a twin in utero
or at infancy has a much greater risk for cerebral palsy than if both
twins remain alive through infancy. However, when both twins remain
MULTIPLE FETAL PREGNANCIES 313
alive, the overall risk for cerebral palsy in normal birth weight twins is
greater than the risk for singletons, with a trend toward a higher prevalence
in like than unlike twins.4
Is the increase in CP in MFP due to prematurity and LBW alone?
Yokoyama and coworkers found that the risk of CP in multiple births
was 20 times higher in births before 32 weeks’ gestation than at > 36
weeks’ gestation. A strong correlation between the risk of CP in twins
and gestational age at birth was also found by Williams and colleagues.
Although, LBW and preterm are apparently the most significant risk factor
for CP, the disadvantage of twin pregnancies becomes evident near term.
When comparing twin with singleton births, the relative risk of CP was
greatest and significant, only for twins delivered at more than 37 weeks’
gestation. This probably implies that “term” occurs earlier in twins and
it may be advisable to deliver them before 38 weeks.
Low birth weight is an important determinant of CP in MFP. But,
the relative risk (in comparison to singletons) of CP was greatest (4.5-
fold) among twins weighing >2499 g. Grether and colleagues and Pharoah
and Cooke showed a comparable risk for CP among VLBW twins and
singletons, whereas twins weighing > 2500 g had a higher risk (3-4 times)of
CP than singletons of similar weight.
FACTORS IN PREGNANCY AND LABOUR

MFPs are associated with adverse perinatal outcomes due to higher risk
of premature onset of labor, IUGR, and difficult presentations. Hence,
increased fetal surveillance has been advocated for twins and multiple
gestations. Close antenatal fetal surveillance of MFPs to reduce or obviate
these factors should be performed, irrespective of chorionicity.5
ASSISTED REPRODUCTIVE TECHNOLOGY (ART)3

There is an invariable rise in incidence of MFPs as a result of ART. The
risk of CP is much higher after ART transfer of 3 embryos (16.8), transfer
of 3 and reduction to 2 (10.3), than two embryos (8.7) in contrast to
spontaneous twins (2.7) per 1000 births. This may in part be explained
because IVF twin pregnancies are at greater risk for obstetric complications
and adverse neonatal outcome in comparison with naturally conceived
twin gestations.6 Monozygous (MZ) division occurs more frequently in
ART (1.2%) than in spontaneous conceptions (0.45%). Babies born as
a result of IVF (in-vitro fertilization) had same neurologic risks as those
born as a result of ICSI (Intracytoplasmic sperm injection).7
MONOCHORIONIC TWIN PREGNANCY

Monozygotic twins comprise of one-third of spontaneous twins and 1in
10-15 of ART twins. Two-thirds of monozygotic twins are monochorionic.
Monochorionic twins are at further risk of perinatal complications, i.e.

Twin-twin transfusion syndrome (TTTS) and death of single or both fetuses.
Data suggest that the risk of occurrence of co-twin sequelae is 3-fold
greater in MC pregnancies complicated by twin–twin transfusion syndrome
(TTTS).5 The risk of perinatal death / neurological sequelae is 3-4 folds
greater in monochorionic pregnancies than dichorionic pregnancies. Ante-
partum death of a single fetus complicates 2.5-5% of twin pregnancies
and may be associated with a significant morbidity and mortality in the
surviving co-twin. Perinatal outcome of a surviving twin in twin pregnancy
depends upon several factors involving the placenta.8,9
TWIN TO TWIN TRANSFUSION SYNDROME (TTTS)

Evidence suggests that the placental vascular anatomy plays a significant
factor in influencing the neurological outcome in multiple pregnancies.
Information which is helpful in determining the likelihood of sequelae
in surviving twin are placental histology such as chorionicity, marginal
or velamentous cord insertion and the type of vascular anastomosis and
in the babies - growth restriction, hydrops, pallor, congestion and
cardiomegaly. Recently studies have shown that TTTS is caused by the
presence of a unidirectional deep arteriovenous (AV) shunt with paucity
of superficial anastomoses.9, 10-13 The incidence and severity of TTTS
increases with the intra-uterine fetal death (IUFD) of one twin. it has
been suggested that it is the superficial anastomoses which are responsible
for acute transfusional complications following intrauterine fetal death (IUFD)
of one of the twins.14 Risk to the surviving MC co-twin may depend
upon the type and the size of the vascular shunts.
GROWTH DISCORDANCE
There is inconclusive information on effect of relative growth restriction
of one twin as compared to other. Some considered it a reassuring
sign in twins and explained it a natural mechanism to reduce total uterine
volume and prolong pregnancy. Others suggest that growth discordance
possibly reflects a hostile intrauterine environment at least to the smaller
twin. The outcomes are related to birth weight in the absence of
monochorionicity and TTTS. Consequently, increased surveillance of
discordant twins is commonly practiced.
INTRA-UTERINE DEATH OF ONE TWIN

Two theories have been suggested for the demise or neurological sequelae
in twin/ multiple pregnancies complicated with IUFD.
• Thrombotic theory: Passage of thrombotic or necrotic material from
the dead to healthy twin along the placental vascular shunts can lead
to vascular insults in the healthy twin resulting in cerebral necrosis.15
The incidence of fetal thrombosis in monochorionic-twin pregnancies
was significantly higher than that of dichorionic-twin and singleton
pregnancies. In monochorionic twins, fetal thrombosis was associated
with co-twin fetal death, but in dichorionic twins no correlation was
identified. Microscopically, fetal vessel thrombosis in twin placentas was
associated with vascular cushions (fibrous hyperplasia of fetal vessel).
The validity of this idea has been questioned recently because of the
normal coagulation status and anemia in the survivors.16
• Hemodynamic theory: The vascular anastomosis can be superficial/
deep, AA/VV/AV/VA anastomosis, unidirectional or bidirectional. In the
presence of superficial AA anastomoses, a massive transfer of blood
can occur, from the live to the dead twin. This may cause brain damage
or fetal demise of the surviving twin simply because of severe
haemodynamic imbalance. Placental anastomoses allow transfer of
blood from the surviving twin to the dead co-twin, giving rise to periods
of hypoperfusion resulting in neurological changes.17
Following the demise of one twin, a massive blood transfusion can
occur from the survivor’s arterial to the dead twin’s venous circulation
(AV). In the dead twin, this may lead to a rise in the systemic filling
pressure which then in turn can initiate the flow along the VA
anastomoses with the establishment of an intertwin circulation. In this
cohort, it is theoretically possible that thrombotic material generated
in the dead twin may reach the circulation of the viable fetus. However,
the normal outcome in eight cases with no evidence of neurological
handicap argues against the thromboembolic episode as the cause for
co-twin sequelae.6 Antenatal cerebral white matter necrosis occurs
relatively frequently in monochorionic twins. It is proposed that placental
artery-to-artery or vein-to-vein anastomoses may predispose twin fetuses
to hemodynamic instability. Fluctuations in blood pressure or blood
volume may then result in cerebral necrosis, without requiring the
death of one twin or transfer of a blood-borne factor from one twin
to the other. The twin survivor with cerebral palsy can display a wide
variety of anatomic abnormalities, especially if the co-twin’s death occurs
in utero. The defects include white matter infarction, hydrocephalus,
multicystic encephalomalacia, cortical atrophy, ventriculomegaly,
holoprosencephaly, polymicrogyria and periventricular heterotopia. 17,18
Adverse neurologic effects are not limited to pregnancies in which
when one co-twin dies in utero. Long term poor neurologic outcomes
are also seen in live-born twins when one of the twins subsequently
dies in infancy. This implies that monochorionic placentation is responsible
for cerebral lesions, not necessarily in-utero death of co-twin.19 In

pregnancies where both twins are still viable, an alternative option such
as the occlusion of the umbilical cord of the recipient twin is a distinct
possibility.19,20
FETAL REDUCTION AND VANISHING TWIN SYNDROME

Studies have shown serious increase in risk of CP when fetal reduction
was done. Conversely there are studies that report the contrary – and
hypothesize that decrease in prematurity and low birth weight should
improve outcomes. In spontaneously disappearing twins, there is no clear
information on expected outcomes.3,21
Mode of delivery
Caesarian delivery offered no advantage in VLBW, ELBW babies even
when fetal presentations and growth concordance by more than 1 kg
were taken into consideration.22
KEY POINTS–Reducing NDD due to multiple gestations1,3,22
1. MFP are associated with an increased risk of CP. There is an exponential
increase in risk of CP with increase in number of fetuses. Quadruplets have
a poorer outcome than triplets and triplets do poorer than twins.
2. Low birth weight and prematurity are commoner in MFP.
3. The true difference in NDD between singleton and MFP becomes evident
nearing term gestation. The risk of CP is higher for twins delivered after
37 weeks or later as compared to singletons.
4. As complications of pregnancy and delivery in MFP are higher, closer fetal
monitoring is recommended.
5. Risk of CP is lower in spontaneous MFP as compared to product of ART
with transfer of more than one embryo.
6. The surviving twin, in case of demise of other monochorionic twin, has higher
risk of CP.
7. Monochorionic twins, are at higher risk of CP than dichorionic twins even
when both are live born.
8. In TTTS there may be an increased risk of CP, even if both twins survive
and TTTS is treated.
9. There is not clear data on vanishing twin and fetal reduction, but may increase
NDD. Concerns are expressed on fetal reduction.
10. Caesarian delivery does not reduce NDD in twin term / preterm pregnancies.
11. There is no significant difference on the occurrence of CP in MFP caused
by in vitro-fertilization or intra-cytoplasmic injection of sperm.
UNANSWERED QUERIES / FURTHER RESEARCH

In multiple pregnancies the development of newer techniques to map
the vascular anatomy of MC placentae accurately in vivo are much
awaited. The availability of such information during the antenatal period
is likely to influence the clinical management and may reduce the
neurological handicap in some of the surviving co-twins. The challenge
in multiple pregnancies is to understand the close interaction between
placenta, multiple fetuses and the intra-uterine environment.
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Problems and outcome with conservative management. Br. J. Obstet. Gynaecol.,
1990;97(6):511–6.
15. Benirschke, K. Intrauterine death of a twin: mechanisms, implications for surviving
twin, and placental pathology. Semin. Diagn. Pathol. 1993;10(3):222–31.
16. Okamura K, Murotsuki J, Tanigawara, S et al. Funipuncture for evaluation of
hematologic and coagulation indices in the surviving twin following co-twin’s
death. Obstet. Gynecol 1994;83(6):975–8.
17. Bajoria R. and Kingdom, J. A case for routine determination of chorionicity and
zygosity in multiple pregnancies. Prenat. Diagn., 1997;17 (13),1207–25.
18. Bebbington MW, Wilson RD, Machan, L., Wittmann BK Selective feticide in twin
transfusion syndrome using ultrasound-guided insertion of thrombogenic coils.
Fetal Diagn. Ther., 1995;10(1):32–36.
19. Deprest, J.A., Evrard, V.A., Van Schoubroeck, D. and Vandenberghe, K..
Endoscopic cord ligation in selective feticide. Lancet, 1996;348 (9031):890–1.
20. Gonen R. The origin of brain lesions in survivors of twin gestations complicated
by fetal death. Am J Obstet Gynecol 1991;161:1897-8
21. Gonen R, Heyman E, Asztalos EV et.al the outcome of triplet, quadruplet, and
quintuplet pregnancies managed in a perinatal unit: obstetric, neonatal, and follow-
up data. Am J Obstet Gynecol 1990;162(2):454-9.
22. Rand L., Eddleman KA, Stone J. Long-term outcomes in multiple gestations.
Clin Perinatol 2005;32:495-13.
ASSISTED REPRODUCTIVE TECHNIQUE—IS IT SAFE? 319
Sathy M Pillai
32
Assisted Reproductive
Technique—Is It Safe?
The most important outcome of any Assisted Reproductive Techniques

(ART) should be the well being of the babies thus conceived. In the
three decades, since the birth of Louise Brown in 1978 ART practice
has changed hugely. Modifications in ART procedures such as embryo
and oocyte cryopreservation, Intra Cytoplasmic Sperm Injection (ICSI),
assisted hatching and extended culture techniques have been introduced
ignoring the risks to the child. Even newer procedures Trans-epididymal
Sperm Aspiration (TESA) and testicular biopsy have resulted in a less
naturally selective form of reproduction. Newer techniques in in-vitro
fertilization (IVF) are constantly being introduced, such as in vitro maturation
(IVM) and vitrification.
In the early days, there was little awareness about the safety
of IVF. The procedures were sporadic, so there was not enough human
data to report safety. First clinical reports of increased risk of congenital
anomalies in babies born of IVF appeared in the literature from Australia.1
Sub-fertile parents who conceived by IVF in its various forms are per
se a skewed population of individuals, whose offspring may well be
at-risk of problems because of their parent’s genetic nature, rather than
the procedures for treatment of sub-fertility themselves. The overall
impression from the literature concerning the risk of congenital anomalies
suggests a higher risk of anomalies after ICSI and any ART, but
that risk is modest.2 Since the advent of ICSI even couples with severe
male factor infertility are able to conceive and some of then clearly have
known genetic defects (in non-obstructive oligozoospermia or obstructive
azoospermia).
Other possible factors that may increase risks from ART are culture media.
Recently an increased risk of genomically imprintable disorders
after ART has been described such as Beckwith-Wiedemann syndrome.
COMPLICATIONS DUE TO MULTIPLE PREGNANCIES .................

The short-term risk to children born after ART, are largely but not entirely
due to the risk of high order births. As failure rates of IVF treatment
were high, IVF clinics remained focused on efficacy than on safety. Efforts
were concentrated on ways and means to increase efficacy. The most
important option was by increasing the number of embryos placed. Success
rate of IVF was expressed as the proportion of pregnancies per embryo
transfer. As a result proportion of multiple births also increased. Wramsby
in 1987 reported a multiple birth rate of 14% when transferring five
embryos and this was seen as a success rather than a problem.3
As assisted reproductive techniques improved, the proportion of multiple
births increased to appalling levels sometimes even exceeding 30%. 4 These
IVF children were siblings in sets of twins, triplets and even of higher
order. Some 50% of twins are born at less than 2500 grams and 50%
are born at less than 38 weeks gestation.5 The extremely high levels of
multiple pregnancies led to a very high proportion of prematurity (five-
fold or more) causing increased risks of morbidity and mortality among
the newborns.6 The relative importance of birth defects was masked
by the iatrogenic problems following multiple pregnancies.
EFFICACY VS SAFETY .......................................................................

Today, there is a transition towards reporting the success of ART as benefit
rather than efficacy. Benefit is the balance between efficacy, safety, quality,
cost and time. Safety includes risk of birth defects, low birth weight
and prematurity. Genuine efforts are being taken today to reduce High
Order Multiple Pregnancy (HOMP) by practicing elective Single Embryo
Transfer (SET) embryo cryopreservation and Frozen Embryo Transfer
(FET). In the new era of “SET as the norm” several countries (e.g. Sweden,
Finland, Norway, Belgium, Denmark, Australia) the problem of prematurity
(iatrogenic part) and related problems following IVF multiple pregnancies
will obviously be reduced, although not completely eliminated.5 In India,
the ICMR in its guidelines for ART clinics has restricted the number of
embryos transferred to three or less.
Over 3 million IVF children have been born in the world and only
a very small proportion have been followed-up for outcomes. Some
countries have high quality national registration of birth defects, whereas
others do not. Other problems are issues on definitions, coverage, lost
to follow-up, validation and control groups. There is heterogeneity in
selection of patients, drugs, laboratory and clinical procedures. Reporting
of registered data on birth defects takes several years. Therefore, continuous
early screening of birth defects reporting is an indispensable part of high
quality birth defect registers. Assessment of health of children born after
successful pregnancies can be divided into health at birth, at one year
and health of older children. We can also investigate congenital anomalies
in ART babies.
MALFORMATIONS IN DIFFERENT ORGAN SYSTEMS .................

There is evidence from Bonduelle’s work that congenital urogenital
malformations are more common in ICSI than in IVF. This seems
logical in view of the parental genetic background and the increased risk
of male sub-fertility when there are genitourinary defects in the father.
5% of all IVF children had a relatively severe birth defect compared to
3% in the general population. Some diagnoses had a stronger association
than others; neural tube defects, atresias and cardiovascular defects.
No difference was noted between the risk after standard IVF and after
ICSI, with the exception of hypospadias, which was more frequent after
ICSI. The risk increase was the same whether the embryos were fresh
or frozen.7
EVALUATION OF PUBLISHED STUDIES (CONGENITAL ANOMALIES)

• IVF compared with general population
Hansen’s study showed an increased risk with an odds ratio of 2 even
after adjusting for maternal age, parity and sex.2 Others, felt that risk
of anomalies disappeared after adjusting for confounders.8-10
• ICSI compared with the general population.
Retrospective Studies
In the Australian study of Hansen and colleagues concerning congenital
malformation at 1 year of age the odd’s ratio remained 2 after adjusting
for confounders.2 In two other Swedish retrospective studies by Wennerholm
and Ericson and Kallen, there was an increase in congenital malformations
in ICSI and IVF.9,11 But adjustment for maternal age and other confounders
showed no increased risk.
Prospective Studies
In one prospective control study by a German group, 3372 ICSI children
were compared with a control group of 8,016 children from natural
conception. The major malformation rate was 8.7% (295/3372) for the
ICSI group and 6.1% (488/8016) for the population based control cohort.
Even after adjusting for confounding factors, the risk was still slightly higher
(1.24) than that of the natural population.12
ICSI Compared with IVF

Bonduelle found no differences in malformations rates between ICSI and
IVF children. This was the largest cohort studied with 2995 IVF versus
2889 ICSI children.13 But specific types of defects were more likely after
ICSI. There is serious concern on risk of anomalies following ART.14,15
Developmental Outcome Studies of IVF/ICSI Children

ICSI-CFO is an international collaborative study of intracytoplasmic sperm
injections—child and family outcomes. This is the largest follow up
study on IVF-ICSI children; 5 European countries participated.16 Approxi-
mately 500 ICSI singletons, 500 IVF and 500 naturally conceived children
aged 5 years were each assessed with observer blinding to conception
status. All children were singletons born after 32 weeks and matched
for sex and social class and race. The study showed no effect of conception
status on neurodevelopment. The ICSI and IVF children were not found
to be physically different from normal class children with the exception
of congenital anomalies.16
Bowen and colleagues in 1998 studied developmental outcomes in
ICSI conceived children, conventional IVF children and naturally conceived
controls. They found an increase in mild developmental delay using
Bayley Scales of infant development. But the study used comparison of
children, who were already enrolled in a separate study and there was
no blinding of assessors. The ICSI children and controls differed in
demographic data.17
Several other workers have also studied ICSI and IVF children. They
have not found marked differences in developmental outcome between
the two groups and also when compared to naturally conceived children.
However, there was a greater use of health care services by ICSI and
IVF children when compared to normal class children.
NEUROLOGICAL PROBLEMS
A Swedish study has shown that children born after IVF have an increased
risk of developing neurological problems particularly cerebral palsy (CP). 26
There was a 4 fold increase in CP in these children compared with matched
cohorts (OR 3.7). The risk in singletons was nearly 3-times (OR 2.8).
After adjusting for birth weight and a gestation of more than 37 weeks
the risk remained with an OR 2.5. However, Sutcliffe noted that the
study used proxy measures for disability and it was unexplained why
CP seemed higher in the singleton group than the IVF group, in
contradiction to the entire twin literature!
RETINOPATHY OF PREMATURITY
HOMP and premature births related to assisted conception has led to
an increase in retinopathy, because of early birth and low birth weight.
Anteby and colleagues reported that 26% of children (out of a small
cohort of 47 children studied) born after IVF had major ocular malforma-
tions. The defects included congenital cataract, optic atrophy and
retinoblastoma.21
GROWTH
Saunders and colleagues studied children conceived by ART and found
that physical outcomes, weight, head circumference and malformation
rates were not different between groups. The IVF group had a greater
mean length centile. The twins in each group had poorer physical outcomes,
with an increase in prematurity and low birth weight, and reduced height
and weight at age two when compared to singletons.20 The ICSI-CFO
study also showed that the growth standard deviation scores (SDS) for
both IVF and ICSI are higher than for naturally conceived children.16
USE OF MEDICAL SERVICES

IVF and ICSI children are more likely to need neonatal care mainly because
of prematurity due to multiple pregnancies, pregnancy induced hyper-
tension (PIH), intra-uterine growth retardation (IUGR), diabetes and pre-
term delivery. ICSI-CFO has shown higher use of medical resources among
IVF/ICSI children including surgery. There are other studies which suggest
that IVF children did not require extra medical attention after the neonatal
period.18,19
CHILDHOOD CANCER
The UK Medical Research Council (MRC) working party and a Swedish
national cohort study of IVF children found no increase in cancer rates
in children conceived through ART. But the power of the studies was
limited by too small a number.22,23
Similarly an Australian study, and more recently Klip and associates
found no increase in cancer risk in IVF/ICSI children.24 But Doyle and
colleagues estimated that 20,000 ART children would be required to observe
a doubling or halving of the risk of childhood cancer.25
GENOMIC IMPRINTING ........................................................................

In ART and imprintable disorders (ARTID)27 four conditions known to
be imprintable in man were surveyed—Beckwith-Wiedemann syndrome
(BWS), Prader Willi syndrome (PWS), Angelman syndrome (AS) and

transient neonatal diabetes (TNDM). They confirmed an association between
ART and BWS, showing that epigenetic changes caused by ART can lead
to human disease. Epimutations are a rare cause of AS. ART related
BWS and AS may be specially associated with maternal allele ICR
methylation loss. The cause of the association between ART and loss of
maternal allele ICR methylation in humans is uncertain, but two hypotheses
have been proposed.28 In vitro embryo culture may predispose to the
mutations. Alternatively, there may be an increased risk of an imprinting
disorder because of an association with infertility per se rather than with
in vitro embryo culture. They did not find evidence of an association
between ART, PWS and TNDM. But TNDM is a very rare disorder and
this was the smallest patient group available for study.
KEY POINTS—safety in ART

1. The highest risks from ART are from prematurity (mainly from twins and higher-
order births); therefore, single embryo transfer, at least in the first cycle, is
recommended.
2. Term babies are healthy and not at long-term health risk as a consequence
of mode of conception.
3. There is probably a higher risk of congenital anomalies after ART. In ICSI
children there is specifically a higher risk of genitourinary (GU) anomalies
marginal increase over general population.
4. ART neonates, however, do increase the health resource needs.
REFERENCES
1. Lancaster P. Congenital malformations after in vitro fertilization. Lancet 1987;2
(8572):1392-3.
2. Hansen , Kurinczuk JJ, Bower C, Webb S. The risk of major birth defects after
intra-cytoplasmic sperm injection and in vitro fertilization. N Engl J Med 2002;
346(10):725-30.
3. Wramsby H, Sundstrom P, Liedholm P. Pregnancy rates in relation to number
of cleaved eggs replaced after in vitro fertilization in stimulated cycles monitored
by serum levels of oestradiol and progesterone as sole index. Hum Reprod
1987;2(4):325-8.
4. Adamson D, deMouzon J, Lancaster P, Nygren KG, Sullivan E, Zegers-Hochschild
F. World collaborative report on in vitro fertilization. Fertility Sterility 2006;85:
1586-1622.
5. Sutcliffe AG. Health risks in babies born after assisted reproduction. Br Med
J 2002;325:117-8.
6. Bergh C. Single embryo transfer: A mini review. Hum Reprod 2005;20: 323-
7.
7. Nygren KG. Is there an association between ART and birth defect?—An appraisal
of outcome data and their clinical implications. Kruger TF, van der Spuy ZM,
Kempers RD (eds.). In: Advances in fertility studies and reproductive medicine
IFFS 2007; published by Juta and Co. Ltd.
8. Westergaard HB, Johansesn AM, Erb K, Andersen AN. Danish National In-Vitro
Fertilization Registry 1994 and 1995: A controlled study of births, malformations
and cytogenetic findings. Hum Reprod 1999;14(7):1896-1902.
9. Ericson A, Kallen B. Congenital malformations in infants born after IVF : A
population based study. Hum Reprod 2001;16:504-9.
10. Anthony S, Buitendijk SE, Dorrepaal CA, et al. Congenital malformations in
4224 children conceived after IVF. Hum Reprod 2002;17(8):2089-2095.
11. Wennerholm U-B, Bergh C, Hamberger L, et al. Obstetric outcome of pregnancies
following ICSI classified according to sperm origin and quality. Hum Reprod
2000;15(5):1189-94.
12. Katarlinic A, Rosch C, Ludwig M. Pregnancy course and outcome after ICSI:
A controlled prospective cohort study. Fertil Steril (in press).
13. Bonduelle M, Liebaers I, Deketelaere V et al. Neonatal data on a cohort of
2889 infants born after ICSI (1991–1999) and of 2995 infants born after IVF
(1983–1999). Hum Reprod 2002;17(2):671–94.
14. Orstavik KH, Eiklid K, van der Hagen CB, Spetalen S, Kierulf K, Skjeldal O,
Buiting K. Another case of imprinting defect in a girl with Angelman syndrome
who was conceived by intracytoplasmic semen injection. Am J Hum Genet 2003;
72(1):218–19.
15. Powell K. Fertility treatments: Seeds of doubt. Nature 2003;422:656–58.
16. Barnes J, Sutcliffe AG, Kristoffersen I, et al. The influence of assisted reproduction
on family functioning and children’s socio-emoitonal development: Results from
a European study. Hum Reprod 2004;19:1480-7.
17. Bowen JR, Gibson FL, Leslie GI, Saunders DM. Medical and developmental
outcome at one year for children conceived by intra-cytoplasmic sperm injection.
Lancet 1998;351:1529-1534.
18. Sutcliffe AG, Sebire NJ, Pigott AJ, et al. Outcome for chidren born after in utero
laser ablation therapy for severe twin-to-twin transfusion syndrome. Br J Obstet
Gynaecol 2001;108(12):1246-50.
19. Sutcliffe AG, Taylor B, Saunders K, et al. Outcome in the second year of life
after in-vitro fertilization by intra-cytoplasmic sperm injection: A UK case control
study. Lancet 2001;357:2080-2084
20. Saunders K, Spensley J, Munro J, Halasz G. Growth and physical outcome of
children conceived by in vitro fertilization. Pediatrics 1996;97:688-692.
21. Anteby I, Cohen E, Anteby E, BenEzra D. Ocular manifestations in children born
after in-vitro fertilization. Arch Ophthalmol 2001;119(10):1525-9.
22. Lerner-Geva L, Toren A, Chetrit A, et al. The risk for cancer among children
of women who underwent in-vitro fertilization. Cancer 2000;88:2845-7.
23. Bergh T, Ericson A, Hillensjo T, et al. Deliveries and children born after in-vitro
fertilization in Sweden 1982 to 1995: A retrospective cohort study. Lancet 1999;
354:1579-85.
24. Bruinsma F, Venn A, Lancaster P, et al. incidence of cancer in children born
after in-vitro fertilization. Hum Reprod 2000;15:604-7.
25. Doyle P, Bunch KJ, Beral V, Draper GJ. Cancer incidence in children conceived
with assisted reproduction technology. Lancer 1998;352:452-3.
26. Stromberg B, Dahlquist G, EricsonA, et al. Neurological sequelae in children
born after in-vitro fertilization: A population based study. Lancet 2002;359:
461-5.
27. Sutcliffe A, Peters C, Bowden S, et al. ART and imprintable disorders: British
Isles survey. Human Reprod 2005;20(suppl.1).
28. Maher ER. Imprinting and assisted reproductive technology. Hum Mol Genet
2005;14(spec no.1):R133-8.
Section 14
Unexplored
Territories
33. Nutrition, Fluid and Electrolytes
34. Follow-up Research—Some Methodological
Issues
Pankaj Garg, Manoj Modi
33
Nutrition, Fluid and
Electrolytes
Nutrition, fluid and electrolytes are very important components of daily

management of a sick neonate and in volve close monitoring and titrating.
Currently, immediate end points are known but, there is a paucity of evidence
on long-term neurodevelopmental consequences.
PRINCIPLES OF FLUID AND ELECTROLYTE MANAGEMENT ......

1. Maintenance of normal tonicity and intravascular volume.
2. Glucose homeostasis
3. Prevention and correction of dyselectrolyemia
4. Nutrition
a. enteral
b. parenteral.
MAINTENANCE OF NORMAL TONICITY AND

INTRAVASCULAR VOLUME .................................................................
PERINATAL CHANGES IN TBW
Total body water (TBW) is 75% of birth weight at term and even more
in preterm infant (>75-80%). A greater proportion of this is extracellular
fluid (ECF). During the first 7-10 days of life, the newborn baby must
lose weight; decrease in weight is secondary to water losses from the ECF.
Term babies may lose up to 7-10% and preterm up to 10-15% (as preterm
infants have more ECF).1
INSENSIBLE WATER LOSS (IWL)

Water is lost as urine, stool, used for metabolism and insensible water
loss (IWL), i.e. via evaporation from the skin (2/3rd) and the respiratory
tract. IWL is the most variable component, and relates inversely to gestational
age IWL increases with environmental temperature and relates inversly to

relative humidity of nursing environment. A 26 week/ELBW baby under
a radiant warmer on day 1 may lose over 150 ml/kg/day as against
< 30 ml/kg/day in a term baby. Insensible losses decrease after first few
days, as skin matures to its full layers (thickness).
In clinical practice, measurement of IWL is only based on surrogate
parameters and empirical fluid plans are proposed as a starting point-
Suggested fluid rates as per BW on day 1 of life.
Weight (gm) <750 750-1000 1000-2500 >2500
Fluid (cc/kg/d) 120 100 80 60
Common Clinical Conditions Affecting IWL

• Increased IWL: Prematurity, high ambient temperature, low humidity,
mechanical ventilation without humidification of gases, omphalocele,
gastroschisis, burns, phototherapy, skin damage, myelomeningocele,
encephalocele
• Decreased TWL: Thermo-neutral environment, incubator with humidity
control, incubator vs open care, double walled vs single walled, PVC
Film cling wrap, plastic shield.
FLUID REQUIREMENT
Goals
• Prevent dehydration or hypervolemia
• To allow 1-2% daily weight loss during first week (up to 7-10% in
term and 10-15% in preterm infant).
The accurate assessment of hydration status in term babies is based
on clinical perfusion, serum osmolarity, serum sodium, blood urea nitrogen,
hematocrit, blood gases and electrolytes, urine output and urine specific
gravity , daily weights (and more frequently in smallest babies), and hepatic
size and edema. In preterm and more so in extreme preterm babies none
of the above said tools individually remain reliable and an attempt to
homeostasis is the only end point.
Maintenance fluid (1st week): Urine output + Insensible

losses—2% wt loss
1. Increase total fluid intake by 20 cc/kg/d each day until day 5-6 (or
as guided by perfusion and assessment of hydration). This is inresponse
to improvement in GFR (Glomerular filtration rate).
2. If under a radiant warmer, add 20 ml/kg/day.
NUTRITION, FLUID AND ELECTROLYTES 331
3. If under phototherapy, add 20 ml/kg/day.
4. Very preterm infants should be placed in humidified incubators in a
neutral thermal environment as soon as practical after birth.
Decrease in total fluids may be necessary in renal failure, CHF, respiratory
disease, PDA and SIADH, and increase in fever, increased losses (stool/
urine, 3rd spacing).
Restriction of Fluids
Preterm babies: High fluid intake may be associated with higher incidence
of NEC and symptomatic PDA,2,3 which may lead to prolongation of
ventilation and associated neurologic morbidity. The most prudent prescription
for water intake to premature infants would seem to be careful restriction
of water intake so that physiological needs are met without allowing significant
dehydration.4
Perinatal asphyxia: Although a convention, there is no evidence from
randomized, controlled trials to support or refute that the practice of fluid
restriction in neonates following perinatal asphyxia affects mortality and
morbidity.5
Ventilated neonates: In ventilated, VLBW babies, fluid restriction in the
perinatal period is proposed to reduce CLD. Colloid infusion, however,
is associated with increased duration of oxygen dependency.6
Dehydration and Hypoperfusion

Suboptimal fluid intake can lead to dehydration and under perfusion of
body organs. Severe dehydration can also lead to increased risk of shock,
acidosis and when less severe, relative polycythemia and thrombo-embolism
with can be associated with poor neurological outcome. The pathophysiology
relevant to neonatal dehydration is related to hypernatremic states and
to problems resulting from the intravenous fluid correction of such states.
The common adverse effects of dehydration are mild cognitive, behavioral,
or motor impairment; these are unlikely to occur in the type of dehydration
usually seen by primary care physicians in controlled environment. 7 These
benign outcomes apply only to cases of neonatal dehydration that is detected
before catastrophic events. If dehydration persists long enough, the adverse
effects are similar to those mediated by acidosis and hypovolemic shock.8
GLUCOSE ...............................................................................................
HYPOGLYCEMIA
Hypoglycemia should always be prevented and is probably the easiest
to prevent cause of NDD in neonates.9-11
HYPERGLYCEMIA
Whole blood sugar >125 or plasma sugar >140 mg/dl.9
Causes
Prematurity (especially ELBW babies), high glucose infusion rates, sick
neonates like sepsis (especially fungal sepsis), postoperative period, Drugs
(Steroids, aminophylline).
Each 18 mg/dl increase in blood sugar raises the osmolality by 1 mOsm/
dl and increases the risk of cellular dehydration. High osmolality may lead
to osmotic diuresis, dehydration and even cerebral hemorrhage, which
might have long-term implications.12
High blood glucose concentrations increase the risk of early death and
grade 3 or 4 intraventricular hemorrhage and the length of hospital stay
among survivors without intraventricular hemorrhage, which suggests that
prevention and treatment of hyperglycemia may improve the outcomes
of extremely low birth-weight infants.
Treatment
Down regulate glucose infusion rate by 1-2 mg/kg/min every 1-2 hr. If
the glucose concentration still remains dangerously high (>250 mg/dl),
insulin may have to be used.
Prevention
In ELBW, one may start with 5% dextrose. Start early feeds: promotes
insulin secretion, early aminoacid promotes insulin secretion.
PREVENTION AND MANAGEMENT OF DYSELECTROLYTEMIA ...

SODIUM DISTURBANCES
Normal serum sodium — 130-150 mEq/L
Usual daily requirements 2-3 mEq/kg/d (may be higher in ELBW)
Begin supplementation on Day 2-3 of life as indicated if weight
loss exceeds > 6% of body wt and serum sodium decreases to < 130
mEq/L.
Hyponatremia
Na < 130 mEq/L (concern if < 125 mEq/L).
Hyponatremia, when severe is associated with vomiting, lethargy, seizures,
respiratory irregularities and coma. It increases the risk of hearing impairment
in preterm babies and may be associated with other NDD.13
The correction of hyponatremia would depend on underlying pathology
(fluid excess or loss of sodium). One should not exceed 10-12 mEq/L
rise of sodium per day in chronic asymptomatic hyponatremia. Rapid and
complete correction of hyponatremia in adults has been associated with
central pontine myelinosis.14
Hypernatremia
Na >150 mEq/L.
More commonly pure water loss or water loss coupled with lesser degree
of sodium deficit, e.g. diarrhea, lactation failure, increased insensible losses
under warmer, osmotic dieresis, diabetes insipidus, renal imaturity. Rarely
net sodium gain, e.g. excess administration of normal saline boluses or
soda bicarbonate or improperly prepared formula.
Acute hypernatremia: Hypertonic ECF results in cell shrinkage, which
can lead to intracerebral bleed or cerebral venous thrombosis.
Chronic hypernatremia: Cells generate osmoprotective amino acids and
idiogenic osmoles to preserve neuronal cell volume.
Clinical features: Irritability, drowsiness alternating with irritability, excessive/
high pitched crying, hyperpnoea, doughy skin, fever, tremulousness, seizures,
focal deficit, coma.
• Signs of dehydration: weight loss, Urine Output >5 ml/kg/hr, Sp. Gr.
<1005, Urine osmolarity < 200 (e.g. renal tubular immaturity, diabetes
insipidus).
• Signs of over hydration, weight gain, UO normal or, Urine Na high,
e.g. excess NaHCO3/saline administration.
Treatment: Rate of decline in serum sodium should not be > 12 mEq/L
per day as abrupt fall in serum osmolality may lead to movement of water
into brain leading to brain edema with deleterious consequences.14
Hyper/hypokalemia
They are both associated with disturbances in systemic circulation and
indirect effects on neurodevelopment. Hyperkalemia can occur even when
urine output is normal and can result in sudden severe bradycardia and
circulatory collapse. Routine monitoring of serum potassium is indicated
in preterm and sick neonates. Management is extrapolated from adult

physiology and evidence to practices is not definite (Cochrane review).
NUTRITION .............................................................................................
GOALS
• Calorie intake 80-100 cal/kg/day for term infant, and 110-165 cal/kg/
day for preterm infant.
• Protein intake 3.5 gm/100 cal is appropriate, particularly in preterm
infant.
ENTERAL FEEDING
Start enteral feeds as early as possible and increase as per tolerance.
Breast Milk
Numerous beneficial effects of breast milk have been demonstrated for
term and near-term infants, including improved cognitive skills,15-24 improved
behavior ratings,25-27 Improved neurodevelopment has been related to the
presence of long-chain polyunsaturated fatty acids (LC-PUFA; arachidonic
and docosahexaenoic), which are found in human milk but not bovine
milk. . ELBW babies in the breast milk group were more likely to have
a Bayley Mental Development Index >85, higher mean Bayley Psychomotor
Development Index, and higher Bayley Behavior Rating Scale percentile
scores for orientation/engagement, motor regulation, and total score. For
every 10 ml/kg per day increase in breast milk ingestion, the Mental
Development Index increased by 0.53 points, the Psychomotor Development
Index increased by 0.63 points, the Behavior Rating Scale percentile score
increased by 0.82 points. In preterm babies breast milk should be
the feed of choice and all efforts should be made to encourage
mother and enhance milk production.28,29
If formula milk is used, several components have come under discussion:
• Polyunsaturated fatty acids (PUFA) are component of human milk and
many formulas and have been associated with body growth vision and
cognition.30,31
• Adding milk fortifier to human milk improves calcium and protein accretion
and greater weight gain and linear growth (short-term increase in OFC)
compared with unfortified human milk.32
Minimal Enteral Feeding and Necrotizing Enterocolitis (NEC)
Continuation of small non-nutritive amount (10 ml/kg/day) of enteral feed
during initial days might be trophic for gut mucosa and intestinal enzymes
and leads to better feed tolerance, once started and reduces total duration
of parenteral nutrition.33 Also, the risk of NEC is reduced. Among ELBW
infants, surgical NEC is associated with significant growth delay and adverse
neurodevelopmental outcomes at 18 to 22 months’ corrected age compared
with no NEC. Medical NEC does not seem to confer additional risk. Surgical
NEC is likely to be associated with greater severity of disease.34
PARENTERAL NUTRITION
Early use of parenteral nutrition may minimize protein loss and improve growth
and neurological outcome in NICU graduates. There is significant negative
protein balance (2% per day), if there is no amino acid supply in immediate
postnatal period. Amino acid intake of 1.1 to 2.3 gm/kg/day can change protein
balance to neutral to slightly positive side, even at low caloric intake.35 Higher
amino acid intake is required for optimal protein accretion. Early amino acid
(AA) were associated with significantly better growth outcomes at 36 weeks’
postmenstrual age, and fewer infants who received early AA were found to
have suboptimal head growth at 18 months’ CA.
SUMMARY ..............................................................................................
Maintenance of normal fluid and electrolyte status and good nutrition is
essential for normal functioning of all body systems and plays vital role
in improving survival and optimal neurodevelopmental outcome in sick
neonates. We should try our best to use evidence based practices in the
management, but unfortunately evidence may not be available for many
current standard practices. So it is of utmost importance to keep our mind
open and adopt evidence based changes in the management which is
bound to happen in times to come.
REFERENCES ........................................................................................
1. Friis-Hansen B. Body water compartments in children: Changes during growth
and related changes in body composition. Pediatrics 1961;28:169.
2. Bell EF, et al. Effect of fluid administration on the development of symptomatic
Patent Ductus Arteriosus and congestive heart failure in premature infants. N
Engl J Med 1980;302:598.
3. Bell EF et al: High volume fluid intake predisposes premature infants to necrotising
enterocolitis. Lancet 1979;2:90.
4. Bell EF, Acarregui MJ. Restricted versus liberal water intake for preventing morbidity
and mortality in preterm infants. Cochrane Database Syst Rev 2001;(3):CD000503.
5. Kecskes Z, Healy G, Jensen A. Fluid restriction for term infants with hypoxic-
ischaemic encephalopathy following perinatal asphyxia. Cochrane Database Syst
Rev 2005;20;(3):CD004337.
6. Kavvadia V, Greenough A, Dimitriou G, Hooper R. Randomised trial of fluid
restriction in ventilated very low birthweight infants. Arch Dis Child Fetal Neonatal
Ed. 2000;83(2):F91-6.
7. Escobar GJ, Liljestrand P, Hudes ES, et al. Five-Year Neurodevelopmental Outcome
of Neonatal Dehydration. J Pediatr 2007;151:127-33.
8. Finberg L, Kravath R, Hellerstein S. Hypernatremic dehydration. In: Water and
Electrolytes in Pediatrics: Physiology, Pathology and Treatment: Finberg L, Kravath
RE, Hellerstein S, editors. Philadelphia: Saunders 1993;124-34.
9. Miranda LE, Dweck HS: Perinatal glucose homeostasis: The unique character
of hyperglycemia and hypoglycemia in infants of very low birth weight. Clin
Perinatol 1977;4:351-65.
10. Charle A et al: Disorder of carbohydrate metabolism, In Taeusch HW, Ballard
RA and Gleason CA. Avery’s diseases of the Newborn, 8th ed. Elsevier 2005;1410-
22.
11. Lucas A, Morley R, Coler TJ. Adverse neurodevelopmental outcome of moderate
neonatal hypoglycemia. BMJ 1988;297:1304-8.
12. Hays SP, Smith EO, Sunehag AL. Hyperglycemia is a risk factor for early death
and morbidity in extremely low birth-weight infants. Pediatrics 2006;118(5):
1811-8.
13. Ertl T, Hadzsiev K, Vincze O, Pytel J, Szabo I, Sulyok E: Hyponatremia and
Sensorineural Hearing Loss in Preterm Infants. Biol Neonate 2001; 79:109-12.
14. Adrogue HJ, Madias NE. Hypernatremia. N Engl J Med 2000;342:1493-99.
15. Lucas A, Morley R, Cole TJ, Gore SM. A randomised multicentre study of human
milk versus formula and later development in preterm infants. Arch Dis Child
Fetal Neonatal Ed. 1994;70:F141-6.
16. Lucas A, Morley R, Cole TJ. Randomised trial of early diet in preterm babies
and later intelligence quotient. BMJ. 1998;317:1481-8.
17. Lucas A, Fewtrell MS, Morley R, et al. Randomized outcome trial of human
milk fortification and developmental outcome in preterm infants. Am J Clin Nutr
1996;64:142-51.
18. Lucas A, Gore SM, Cole TJ, et al. Multicentre trial on feeding low birthweight
infants: effects of diet on early growth. Arch Dis Child. 1984;59:722-30.
19. Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breast milk and subsequent
intelligence quotient in children born preterm. Lancet 1992;339:261-4.
20. Lucas A, Morley R, Cole T, Gore S. A randomized multicenter study of human
milk versus formula and later development in preterm infants. Arch Dis Child
1994;71:288-90.
21. Horwood LJ, Darlow BA, Mogridge N. Breast milk feeding and cognitive ability
at 7-8 years. Arch Dis Child Fetal Neonatal Ed 2001;84:F23-7.
22. Gale CR, Martyn CN. Breastfeeding, dummy use, and adult intelligence. Lancet
1996;347:1072-75.
23. Pollock JI. Mother’s choice to provide breast milk and developmental outcome.
Arch Dis Child. 1989;64:763-4.
24. Jacobson SW, Jacobson JL, Dobbing J, Beijers RJW. Breastfeeding and intelligence.
Lancet 1992;339:926.
25. Hart S, Boylan LM, Carroll S, Musick YA, Lampe RM. Brief report: breast-
fed one-week-olds demonstrate superior neurobehavioral organization. J Pediatr
Psychol 2003;28:529-34.
26. Horne RS, Parslow PM, Ferens D, Watts AM, Adamson TM. Comparison of
evoked arousability in breast and formula fed infants. Arch Dis Child 2004;89:22-
5.
27. Ooylan LM, Hart S, Porter KB, Driskell JA. Vitamin B-6 content of breast milk
and neonatal behavioral functioning. J Am Diet Assoc. 2002;102:1433-8.
28. American Academy of Pediatrics, Work Group on Breastfeeding. Breastfeeding
and the use of human milk. Pediatrics 1997;100:1035-9.
29. American Academy of Pediatrics, Section on Breastfeeding. Breastfeeding and
the use of human milk 2005;115:496-506.
30. Kashyap S, Forsynth M, Zucker C, et al. Effect of varying protein and energy
intake on growth and metabolic response in low birth weight infants. J Pediatr
1986;108:955-63.
31. Carlson SE, Werkman SH, Rhodes PG, et al. Visual acuity development in healthy
preterm infants: effect of marine oil supplementation. Am J Clin Nutr 1993;58:
35-42.
32. Greer FR, McCormick A. Improved bone mineralization and growth in preterm
infants fed fortified own mother’s milk. J Pediatr 1988;112:961-69.
33. Dunn L, Hulman S, Weiner J ET AL. Beneficial effects of early hypocaloric
enteral feeding on neonatal gastrointestinal function. J Pediatr 1988;112:622-
9.
34. Hintz SR, MD, Kendrick DE, Stoll BJ, et al. for the NICHD neonatal research
network. Neurodevelopmental and growth outcomes of extremely low birth weight
infants after necrotizing enterocolitis. Pediatrics 2005;115(3):696-703.
35. Rivera A, Bell EF, Bier DM. Effect of intravenous amino acids on protein metabolism
of preterm infants during first three days of life. diatr Res 33:10.
36. Poindexter BB, Langer JC, Dusick AM, Ehrenkranz RA. National Institute of
Child Health and Human Development Neonatal Research Network. Early provision
of parenteral amino acids in extremely low birth weight infants: relation to growth
and neurodevelopmental outcome. J Pediatr 2006;148(3):300-5.
Rhishikesh Thakre, MKC Nair
34
Follow-up Research—Some
Methodological Issues
The ‘disability process’ involves a postnatal impairment becoming a disability

in the early childhood, leading to a handicap later. Depending on the
age at which outcomes are measured, we need to make sure which out
of the three—impairment, disability or handicap—are we measuring.
Whereas in the first two years developmental delay and tone abnormalities
are important outcomes, neurodevelopmental disabilities (NDD) become
the outcome measure later on. Neurodevelopmental disabilities are a diverse
group of severe chronic conditions that begin at any point in development
up to 22 years of age, usually lasting throughout a person’s life time. 1
NDD include the following specific conditions or syndromes: mental
retardation, autistic spectrum disorders, attention deficit hyperactivity
disorder, learning disorders, epilepsy, hearing impairment, vision impairment,
CP and neuromuscular disorders.
Neurodevelopmental outcome studies continue to be reported from
most parts of the world, but there is very little consistency in the entry
criteria, measurement tools used as well as outcomes measured. These
studies have been criticized for the overall poor quality and hence standards
have been suggested for conducting developmental follow up studies. 2-5
Major criticisms include inadequate sample size, heterogeneity of populations,
short duration of follow-up, lack of control populations, lack of uniformity
in assessment of outcome and definitions of handicap, and questions with
regard to the representativeness of study samples and generalization of
results to other populations.
The majority of studies published since the 1970s have been descriptive
in nature attempting to monitor the outcomes associated with neonatal
intensive care and to examine specific risk factors. Most studies are
descriptions of longitudinal changes in outcome or cross-sectional in
nature.6-8 The planning of such studies has been problematic, partly because
FOLLOW-UP RESEARCH—SOME METHODOLOGICAL ISSUES 339
advances in technology and new therapies have, with few exceptions (for
example, surfactant), been introduced haphazardly and without controlled
trials. Thus, it is not surprising that follow-up studies have reported a
patchwork of outcomes.4 An additional problem inherent in determining
the long-term outcomes of very low birth weight infants is that, by the
time meaningful assessments of outcomes such as school-age performance
are obtained, neonatal treatment has also changed, and these changes
may have affected later outcomes.9 Changes in the definitions of normal
growth and cognitive outcomes over time also limit comparison between
studies, as exemplified by the recently revised Bayley Scales of Infant
Development-II, which is currently being used extensively in follow-up
studies.
EVALUATING LONG-TERM OUTCOME STUDIES ..........................

There are several factors to be considered in evaluating long-term outcome
studies.
SURVIVAL RATE
High mortality rates may indicate poor perinatal management, which may
have a detrimental effect on the long-term outcome of the survivors.
Increased mortality among high-risk infants may also be associated with
apparently improved outcomes in the surviving low birth weight children,
as those with the greatest potential for a poor outcome may have died.
REPRESENTATIVENESS OF THE STUDY SAMPLE

The majority of studies have been based on hospital samples that may
not be representative of all the survivors in a specific region. Furthermore,
hospital-based studies that include infants transported from community
hospitals are biased by the selective referral of the sickest infants.
SAMPLE CHARACTERISTICS
Outcomes are likely to vary in relation to differences in how the samples
are constituted. Sampling parameters to consider include;
• The range of birth weight and gestational age under study
• The rate of intrauterine growth failure
• Whether, children with congenital malformations or congenital infections
are included
• Perinatal and neonatal therapies used and rates of complications
• Socio-demographic indicators
• Behavioral characteristics of the parents, including smoking and drug

abuse
• Post-hospital-discharge medical care and complications
• Special interventions or stimulation programs.
THE NATURE OF CONTROL AND COMPARISON GROUPS

If studies are not composed of randomly assigned intervention and control
groups, then differences between the groups being compared must be
taken into consideration. At a minimum, study groups should be matched
for factors such as race, sex, and parental socioeconomic indices (marital
status, age, level of education, and occupation).10
DURATION OF FOLLOW-UP
Children must be followed to at least 18 to 24 months to assess severe
neurodevelopmental problems. Follow-up to early school age is required
to measure more subtle disturbances in areas such as fine motor ability,
visual-motor skills, behavior, and learning.
CORRECTION FOR PRETERM BIRTH

There is, in general, a consensus that the child’s age should be calculated
from the mother’s last menstrual period (postmenstrual age) rather than
from birth (postnatal age), at least until the child has a postnatal age
of three years.11
OUTCOMES MEASURED
Adverse effects of low birth weight vary in accordance with how outcomes
are assessed. Medical outcomes include abnormalities on physical and
neurological exams, growth attainment, illness, and re-hospitalizations.
Neurological outcomes, such as rates of CP or blindness, are not affected
by socio-demographic factors and, thus, are good markers of biological
risk. Neuropsychological measures that are sensitive to subtle degrees of
dysfunction include intelligence, memory, speech and language, psycho-
motor abilities, academic achievement, behavior, and attention. Social
competence, child temperament, and the impact of having a low birth
weight or very low birth weight child on the family system are additional
outcomes, but ones rarely considered in research studies.12-14 The
measurement of functional abilities include ratings by the physician or
caretakers15 of the child’s ability to perform age-appropriate activities of
daily living.
SAMPLE ATTRITION
Children lost to follow-up are more likely to come from lower socioeconomic
groups who generally have poorer outcomes. If the attrition of children
with poorer outcomes does not occur evenly from the study groups,
then the study outcomes will be heavily biased.
The study design to be used in follow-up depends on the research
question. For example;
• A randomized controlled trial for showing the effectiveness of an early
intervention program
• A case control design for measuring and quantifying the risk factors
• A diagnostic test evaluation for comparing a screening test against a
confirmatory test (gold standard)
• Descriptive (observational) studies to report neurodevelopmental
outcomes at different ages.
BIAS IN OUTCOME RESEARCH ........................................................

Every study design has bias more in some and less in others. Bias refers
to any process, which tends to produce results or conclusions that are
systematically different from the truth. A process which affects results or
conclusion in a random way (i.e. not systematically) cannot be considered
as bias. Bias can cause a study to conclude, for example, that there is
no association between a risk factor and an outcome of interest, when
in truth, there is an association, or vice versa. Most biases which threaten
the validity of follow-up studies fall into one of three broad categories.
• Selection bias: Occurs when observations are made on a group of
babies that has been assembled incorrectly.
• Measurement bias: Occurs when the methods of measurement are
consistently dissimilar among groups of babies.
• Confounding bias: Occurs when two factors or processes are inter-
related or ‘travel together’, and it is incorrectly concluded that one
of the factors is the causal agent.
A clinical observation is valid if it corresponds to the true state of
affairs. For the observation to be valid, it must be neither biased nor
incorrect due to chance. It is useful to distinguish between two general
kinds of validity—internal validity or strength of study and external validity
or generalizability. Sampling bias occurs when observations and conclusions
about one group of babies are generalized to other group, who is not
similar. An impeccable study, with high internal validity, may be totally
misleading when the results are generalized to certain other populations.
CONTROLLING FOR SELECTION BIAS

• Randomization: The only way to equalize all perinatal factors, known
and unknown, is to assign the groups randomly, so that each baby
has an equal chance of falling into one or the other group.
• Restriction: The babies, who are enrolled in a study can be restricted
to only those possessing a narrow range or characteristics, forming
a homogeneous study group, but this reduces the generalisability of
the results.
• Matching: Babies can be matched as they enter the study so that
for each baby in one group there are one or more babies in the
comparison group with the same characteristics except for the factor
of interest. Apart from age and sex matching may be done for factors
like, stage or severity of HIE, rate of progression and prior treatments.
• Stratification: After data are collected, they can be analyzed and results
presented according to sub-groups of babies or strata decided apriori.
• Multivariate Analysis: Is a method for simultaneously considering the
effects of many variables. This is done by developing a mathematical
model based on some assumptions, relating independent variables to
the outcomes.
CONTROLLING FOR MEASUREMENT BIAS

• Blinding: In the assessment of outcome, in general, the more clear
cut are the end points used, lesser the opportunity there is for bias.
For example, we want to assess and compare the developmental
outcome between the group receiving early stimulation and the group
without early stimulation using Bayley Scale of Infant Development
(BSID). The developmental therapist doing BSID should not know,
which group the baby belongs to. She should not attempt to assign
a score on the same day, as there would be a tendency to adjust
the score based on clinical impressions.
• Confounding: “The term confounding refers to the effect of an
extraneous variable that wholly or partially accounts for the apparent
effect of an intervention (For example early stimulation) or masks an
underlying true association. Thus, an apparent association between
an intervention and outcome may actually be due to another variable.
Alternatively, the apparent lack of an association could result from
failure to control for the effect of some other factor. Methods by which
potential confounding variables can be handled in a study include
random allocation, stratified allocation, matching in analytic studies and
restriction in either selection or analysis.
POLICY PERSPECTIVES
We need to appreciate that parents do have a right to know about long-
term problems that might develop in their high-risk baby. Lack of consistency
in information provided by different healthcare teams creates uncertainty
and increases the stresses felt by parents.16
A country like India cannot yet afford to dedicate huge amount of
resources for perinatal and neonatal intensive care services. Hence, the
natural question that arises in the minds of planners and policy makers
would be the possibility of increasing numbers of children with disability
among those who survive after severe perinatal illnesses, extremely immature
birth and serious neonatal complications. This necessitates availability of
national data on outcome of NICU graduates and this means that:17
• Data should be collected for all infants <32 weeks’ gestation and all
those who get intensive care as well as recognized priority groups.
These same children should have their health and developmental status
ascertained at 1 and 2 years of age
• The data collection must become a core-funded aspect of clinical care
• Extra costs can be justified by the benefits that will follow in terms
of what works and what does not
• We need to have capacity building programs for the pediatricians and
the PHC doctors to equip them to provide follow-up services
• Mandatory national perinatal data collection should be extremely simple
and feasible.
REFERENCES
1. Accardo PJ, Whitman BY. Dictionary of developmental disabilities terminology.
Baltimore: Paul H. Brookes Publishing Co. 1996;87.
2. Bregman J, Kimberlin LVS. Developmental outcome in extremely premature infants:
Impact of surfactant. Pediatric Clinics of North America 1993;40,5:937-53.
3. Kiely JL, Paneth N. Follow up studies of low-birthweight infants: Suggestions
for design, analysis and reporting. Developmental Medicine and Child Neurology
1981;23:96-100.
4. Aylward GP, Pfeiffer ST, Wright A, Verhulst SJ. Outcome studies of low birth
weight infants published in the last decade: A metaanalysis. Journal of Pediatrics
1989;115:515-20.
5. Ornstein M, Ohlsson A, Edmonds J, Asztalos E. Neonatal follow-up of very low
birthweight/extremely low birthweight infants to school age: A critical overview.
Acta Paediatrica Scandinavica 1991;80:741-48.
6. HIFI Study Group. High-frequency oscillatory ventilation compared with
conventional intermittent mechanical ventilation in the treatment of respiratory
failure in preterm infants: Neurodevelopmental status at 16 to 24 months of
postterm age. Journal of Pediatrics 1990;117:939-46.
7. Horwood SP, Boyle MH, Torrance GW, Sinclair JC. Mortality and morbidity of
500- to 1,499-gram birth weight infants live-born to residents of a defined
geographic region before and after neonatal intensive care. Pediatrics 1982;69,5:
613-20.
8. Hack M, Caron B, Rivers A, Fanaroff AA. The very low birthweight infant: The
broader spectrum of morbidity during infancy and early childhood. Journal of
Developmental and Behavioral Pediatrics 1983;4:243-49.
9. Dunn HG, ed. Sequelae of low birthweight: The Vancouver Study. Clinics in
Developmental Medicine series. London: Mac Keith, 1986.
10. Sameroff AJ, Seifer R, Baldwin A, Baldwin C. Stability of intelligence from preschool
to adolescence: The influence of social and family risk factors. Child Development
1993;64:80-97.
11. DePietro JA, Allen MC. Estimation of gestational age: Implications for
developmental research. Child Development 1991;62:1184-99.
12. Landry SH, Chapieski ML, Richardson MA, et al. The social competence of children
born prematurely: Effects of medical complications and parent behaviors. Child
Development 1990;61:1605-16.
13. Crnic KA, Greenberg MT, Ragozin AS, et al. Effects of stress and social support
on mothers and premature and full-term infants. Child Development 1983;54,1:
209-17.
14. Ross G, Lipper EG, Auld PAM. Social competence and behavior problems in
premature children at school age. Pediatrics 1990;86:391-97.
15. Overpeck MD, Moss AJ, Hoffman HJ, Hendershot GE. A comparison of the
childhood health status of normal birth weight and low birth weight infants.
Public Health Reports 1989;104:58-70.
16. Marlow N, Green B. Editorial: The need to understand perinatal outcomes.
Seminars in Fetal and Neonatal Medicine 2007;12:329-31.
17. Andrew Lyon. How should we report neonatal outcomes? Seminars in fetal and
neonatal Medicine 2007;12:332-36.
Section 15
Counseling
35. Genetic Counseling—High Risk
Pregnancy
36. Parent Counseling
Sankar VH
35
Genetic Counseling—
High Risk Pregnancy
Genetic counseling is a communicative process, which deals with human

problems associated with the occurrence and or recurrence of a genetic
disorder in a family (American Society of Human Genetics). This should
include the possibility of prenatal diagnosis. Women, whose ethnic
background, race, age, personal or family history places them at increased
risk to have a fetus with genetic disease, should receive appropriate
counseling.
High risk pregnancies (genetic risk) that require genetic counseling are
as follows:
1. Advanced maternal age
2. Previous child Down syndrome/Positive triple test
3. Previous child with mental retardation
4. Previous child with single gene genetic disorder like thalassemia
5. Previous child with congenital abnormalities
6. Previous child with neural tube defect.
ADVANCED MATERNAL AGE ............................................................

Maternal age is an important and independent risk predictor of adverse
pregnancy outcomes. Advanced maternal age is associated with a higher
risk of stillbirth throughout gestation, and the peak risk period is 37-
41 weeks. Increasing maternal age is independently associated with
specific adverse outcomes.1 Advanced maternal age, after excluding
confounders, correlated with very preterm birth (gestational age <32 weeks)
[adjusted odds ratio (AOR) 1.51, 95% confidence intervals (CI) 1.04-
2.19], low birth weight (birth weight <2500 g) (AOR 1.69, 95% CI
1.47-1.94) and perinatal death (AOR 1.68, 95% CI 1.06-2.65).2
Advanced maternal age is also associated with increased risk of
cytogenetic abnormalities especially aneuploidies in the offspring
(Table 35.1). Recent reports based on large samples of oocytes or polar

bodies have provided evidence for correlation between increased aneuploidy
frequency and advanced maternal age.3
Table 35.1: Incidence of Down syndrome in relation to maternal age

Maternal age at the time of Incidence of
child birth (in years) Down’s syndrome
20 1 in 1500
25 1 in 1350
30 1 in 900
35 1 in 380
37 1 in 240
39 1 in 150
41 1 in 85
43 1 in 50
45 1 in 28
The high risk of aneuploidies with advancing maternal age is possibly

due to increased non disjunction of chromosomes. Different mechanisms
have been proposed.
• “Production line” hypothesis: This theory proposes that oocytes
mature in adult life in the same sequence as the oogonia entered
meiosis in fetal life. Oogonia that enter meiosis later in life are more
likely to be defective in the formation of chiasmata, and thus more
likely to undergo non disjunction.
• Defective microcirculation: This hypothesis proposes that aneuploidy
oocytes arise from a sequence of events. It begins with hormonal
imbalance that causes a less-than-optimal microvasculature to develop
around the maturing and mature follicles. The resulting decrease in
the size of the peri-follicular capillary bed leads to hypoxia and a
concomitant increase inside the follicle of carbon dioxide and anaerobic
products, such as lactic acid. This in turn causes a decrease in the
intracellular pH of the oocyte that diminishes the size of the spindle,
with consequent displacement and nondisjunction of a chromosome.
Recent molecular studies identified an abnormal mitochondrial function
and redox potentials in aged oocytes.
• Genetic Predisposition: The possibility of the presence of a genetic
predisposition to nondisjunction has also been proposed. There is some
evidence of an autosomal recessive gene that facilitates meiotic
nondysjunction.
The postulation hypothesized 1—95% of Down syndrome children inherit
their extra chromosome from the mother, and in 80% or more of these,
GENETIC COUNSELING—HIGH RISK PREGNANCY 349
the nondisjunction occurs in the first meiotic division, which is completed
in the ovary.2 The ovarian follicle containing the primary oocyte has no
internal circulation. The compromised microcirculation hypothesis explains
the occurrence of aneuploidy in primary and secondary oocytes, sperm
precursor cells, tumor and embryonic cells. It also explains why women
of all reproductive ages may have a Down syndrome child.5
The definitive method of excluding a cytogenetic abnormality in the
offspring is a diagnostic study—amniocentesis to study the karyotype of
the fetus. Invasive diagnostic tests are associated with a procedure related
fetal loss of 0.5 to 1%.
Among high-risk mothers (advanced maternal age, abnormal triple
screen, or both), many choose invasive testing as a first option, while
others use the information derived from genetic sonography to obtain
an adjusted risk for Down syndrome to guide their decision on genetic
amniocentesis.4 Genetic sonogram will help to modify the risk so that
an invasive test can be optimized.
Pre-implantation genetic aneuploidy screening (PGS) in the last decade
has allowed embryo selection in patients with an increased incidence of
embryonic numerical chromosome abnormalities (advanced maternal age,
recurrent miscarriage and recurrent implantation failure). PGS for aneuploidy
screening (PGD-AS), performed by polar body or blastomere analysis,
is used in infertile patients treated with assisted reproduction technologies,
especially in those with a poor prognosis, e.g. repeated IVF failure, advanced
maternal age, or recurrent spontaneous abortion.6,7 Rapid prenatal diagnostic
techniques like FISH and QF-PCR are newer developments that allow
quick decisions. These may totally replace conventional cytogenetics in
near future.8
PREVIOUS CHILD WITH DOWN SYNDROME .................................

Recurrence risk of Down’s syndrome will vary depending on the type
of Down syndrome (whether nondisjunction or translocation) and maternal
age.
THE CHANCE OF RECURRENCE OF TRISOMY 21 IN MOTHERS

WHO HAVE ONE AFFECTED CHILD9
For counseling purposes the chance of recurrences of Down syndrome
can be rounded of to 1% greater than the maternal age specific risk.
Trisomy 21 spontaneous or induced abortion has the same recurrence
risk consequences as the live birth of an affected infant.
PREVIOUS CHILD WITH ROBERTSONIAN TRANSLOCATION DOWN

SYNDROME (TRANSLOCATION BETWEEN 21 AND 13/14/15/22
CHROMOSOMES)
The distinction between de novo and familial forms of translocation Down

syndrome is crucial: this distinction is made by chromosomal studies of
the parents (Table 35.2). For the de novo translocation, a recurrence
risk figure of 1% is applicable (similar to nondisjunction Trisomy). In the
case of familial Robertsonian translocation Down syndrome, the genetic
risk for the female carrier is substantial. The risk to have a live born
child with translocation Down syndrome is 10-15%. For the male carrier,
the risk to have a child with translocation Down syndrome is small, about
1%. In case of 21/21 translocation carrier, the risk to have a Down syndrome
with translocation is 100%.
Table 35.2: Recurrence risk of Down’s syndrome

Chromosome constitution Risk to offspring
Affected child Father Mother
De novo inherited N N 1
13/21, 21/ 22 N C 10-15
13/21, 21/ 22 C N 5
21/21 C/N N/C 100
N—Normal, C—Affected Chromosome
Trisomy 21 and mosaicism—1 % risk of recurrence, parents karyotype not needed
PREVIOUS CHILD WITH MENTAL RETARDATION ........................

Mental retardation now more commonly referred to as global developmental
delay is characterized by intellectual functioning below normal, and
limitations in two or more of the adaptive skills.
Several clinical series suggest that a diagnosis or cause of the MC
can be identified in 40-60% of all patients undergoing evaluation.10
A careful clinical examination of mentally retarded child may provide some
clue for the diagnosis of chromosomal disorder or genetic syndromes.
Intracranial imaging offers valuable information in many patients with MR
and should be considered particularly in patients with microcephaly,
macrocephaly or neurological signs. In recent years fragile X syndrome
has been recognized as the commonest cause of inherited mental
retardation. All mentally retarded children should be investigated with
a cytogenetic analysis (karyotype) at 500 band level and fragile X analysis
should be done in all male MR children without any obvious cause. Fragile
X analysis requires chromosomal analysis under special conditions and
molecular studies. Targeted FISH and molecular cytogenetic studies should
be done when clinically indicated.11
It is worth while to do screening investigations for metabolic disorders
in all MC children. Specialized metabolic investigations may be done if
the clinical features suggest a metabolic disorder. Regression of milestones
is suggestive of a metabolic disorder. If mental retardation is associated
with neurological manifestations, organomegaly and/or seizures storage
disorders should be excluded.
Counseling of a couple with a MC child depends on the cause in
the proband.
• Chromosomal disorders: Aneuploidies like Trisomy 21/18/13 due
to non disjunction have a recurrence risk of 1% over and above the
maternal age related risk. In case of other chromosomal abnormalities,
the parents (both mother and father) should be evaluated for balanced
chromosomal rearrangements. If the parent’s karyotypes are normal
the recurrence risk is negligible—to the tune of 1%. However, fetal
karyotype by amniocentesis can be done to exclude chromosomal
abnormalities. If one of the parents has the chromosomal abnormality
(balanced rearrangements) the recurrence risk will depends on various
factors like length of translocated segment, involved chromosomes,
type of chromosomal rearrangements etc. Fragile X syndrome is a
X linked condition with recurrence risk of 50% in male siblings, half
of the heterozygote daughters may also be clinically affected.
• Metabolic Disorders: Since metabolic disorders are single gene
disorders, counseling similar to single gene disorders.
• Central nervous system malformations: see malformations
• Perinatal asphyxia: Recurrence risk in future pregnancies is negligible.
The couple should be advised optimal obstetric care and neonatal
management. A targeted anomaly scan is advised at 16-18 weeks.
• No definite etiology identified: If no definitive etiology is identified,
then the empiric recurrence risk of mental retardation in sibling is
approximately 5%.
PREVIOUS CHILD WITH SINGLE GENE DISORDERS ...................

Single gene disorders follow Mendelian laws of inheritance making it possible
to predict the risk of recurrence.
In autosomal dominant disorders the risk to an affected offspring is
50%. However, incomplete penetrance and variable expressivity will modify
the risk. New mutations are frequent causes of the appearance of a genetic
disease in an individual with no previous family history of disorder (example
Achondroplasia child to normal parents). Risk of recurrence in the sibling

depends on the genetic make up of the parents. If one of the parents
is affected, there is 50% chance of recurrence in siblings. If both parents
are normal, probably the disorder is due to a new mutation and recurrence
risk in sibling is negligibly low.
In autosomal recessive disease, both parents are carriers of mutant
gene and recurrence risk in sibling is 25% (1 in 4). Parents of children
with rare autosomal recessive disease are often consanguineous.
In case of X linked recessive disorders (e.g. Hemophilia), mother
may be a carrier for the disease. In such situations, risk of recurrence
in the male offspring is 50%. In case of a female offspring, 50% of them
will be carriers of the disease. In case with mother is not a carrier (sporadic
mutation in the affected child) recurrence risk is negligibly low. Only in
cases with gonadal mosaicism, there will be an increased recurrence risk.
PREVIOUS CHILD WITH MALFORMATIONS ...................................

In predicting risk of malformations, first step is trying to identify whether
the malformation is isolated or part of a syndrome. If a syndrome is
identified, recurrence risk will depends on the inheritance pattern of that
syndrome. If a definitive syndrome is not recognizable or the malformation
is isolated, recurrence risk is as for multifactorial disorders.
Causes of ventriculomegaly Recurrence risk
• Meningomyelocoele 5%
• Dandy Walker malformation 5%
• Lissencephaly 0 to 25%
• Holoprosencephaly 10%
• Hydrolethalus syndrome 25%
• Chromosomal 1 to 10%
NEURAL TUBE DEFECT (NTD) .........................................................

Neural tube defects are the most common congenital malformations. These
include anencephaly, iniencephaly, encephalocoele, meningomyelocele and
spina bifida. The reported prevalence varies geographically (6.3 to 10.92
per 1,000 births in Ireland and Wales to 1 per 1,000 in US). The prevalence
of NTD in various parts of India is reported from 0.5 to 11 per 1,000
births.
The risk of recurrence of an NTD after birth of one affected child
is 3-5%, which is 10 times higher than that of general population.
It increases to 10% after two affected children and 25% after three affected
children. Affected child should be examined, try to identify a syndromic
cause, if present. These syndromes carry a very different risk of recurrence
depending upon the mode of inheritance and may not be amenable
to prevention by folic acid. Some NTDs are associated with a polymorphism
in MTHFR gene (677 C-T).
The Medical Research Council on Vitamin Study Research Group (1991)
identified that if a woman, who previously delivered a baby with NTD,
took folic acid supplement before conception and through out first trimester,
the risk of recurrence is reduced by 72%. Efficacy of periconceptional
folate has been demonstrated in the Indian population (ICMR multicentric
trial). It is recommended that 4 mg of folic acid be given to the mothers
with previous child with NTD in periconceptional period. Unfortunately,
90-95% cases of NTD are sporadic, and occur without any family history,
and hence, not amenable to prevention.
As a primary prevention a lower 0.4 mg of folic acid is recommended
to all women in the reproductive age group. It has been proposed to
fortify breakfast cereals or bread to provide the recommended dietary
allowances. However, the efficacy and safety of this public health
intervention is yet to be validated.
AMNIOCENTESIS ..................................................................................
Advances in techniques in prenatal diagnosis have added new dimensions
to the genetic counseling. It is now possible to determine, in advance,
whether the fetus is affected or not with a specific genetic disorder.
Amniocentesis is the commonly used technique.
Amniocentesis is the aspiration of amniotic fluid for various biochemical
and genetic tests. The test is best performed at 16-17 weeks of gestation.
At this time, there is sufficient number of viable amniocytes. At this gestation
medical termination of pregnancy is considered safe for the woman, should
an abnormality be found.
• Amniocentesis is routinely performed in an outpatient facility under
aseptic precautions. An ultrasound examination is done before the
procedure to evaluate fetal number and viability, perform fetal biometric
measurements, establish placental location and estimate amniotic fluid
volume. It is preferable to screen the fetus for any congenital malfor-
mations.
• The needle insertion site is chosen in the abdomen so that an optimal
pocket of amniotic fluid is present. If possible, it is preferable to avoid
the placenta; if not possible select the thinnest portion of placenta
possible through which the needle can be inserted. The umbilical cord
insertion site should be identified and avoided. The maternal bowel

and bladder also should be located, as these should likewise to be
avoided.
• A local anesthetic may be used (2 to 3 ml of 1% xylocaine), but
not necessary always. The maternal skin should be cleaned with an
antiseptic solution (iodine based and spirit based) and sterile drapes
are placed around the insertion site. A 20 or 22 G spinal needle
is inserted under ultrasound guidance to the amniotic sac. Ultra
sonographic monitoring with continuous visualization of the needle
should be performed throughout the procedure.
• At this gestation 20 to 30 ml of amniotic fluid is usually aspirated.
The first several milliliters (2 ml) of amniotic fluid is aspirated to a
2-5 cc syringe. These first few milliliters are theoretically most likely
to contain maternal cells and should not be used for cytogenetic or
molecular studies. However, this can be used for biochemical estimations
like AFP.
• Amniotic fluid and urine are often indistinguishable in appearance.
The crystalline arborization pattern characteristic of amniotic fluid is
observed if the fluid is allowed to dry on an acid cleaned slide and
examined under low power (Ellias et al 1979). However, only rarely
are any test is necessary.
• Bloody amniotic fluid is aspirated in 1% to 2% cases. If the needle
is inserted transplacentally, there is more chance of bleeding. The blood,
which is almost maternal in origin, usually does not adversely affect
the amniotic cell growth. Bloody tap does not have an adverse
pregnancy outcome. By contrast, brown or dark red amniotic fluid,
which is suggestive of prior intra-amniotic bleeding, is associated with
poor fetal outcome. Pregnancy loss eventfully occurs in about one
third of cases (Milunsky 1986).
• The administration of Rh immunoglobulin (Rh Ig) to prevent Rh
isoimmunisation in unsensitized women with Rh positive fetuses remains
controversial, but almost all now advocate its routine use. The dose
to be administered remains controversial. The ACOG recommends
that 300 μg of RhIg should be administered for an exposure of 30
ml of fetal blood (ACOG 1999) whereas, in UK it is 50 μg before
20 weeks and 100 μg thereafter (Turnbull and Mackenzie 1983)
• After the amniocentesis the fetal heart rate is monitored. It is preferable
to show the fetal heart motion on ultrasound scan to the patient to
reduce the anxiety. Observation for 3-4 hours after the procedure
is required and is instructed to report if there is vaginal bleeding,
cramps or fever. Routine normal activities can be resumed following
the procedure; However, strenuous activities, long distance travel and
coitus are to be avoided for a couple of days.
• In case of multiple gestations, amniocentesis can usually be performed
on all fetuses separately, provided there is enough amniotic fluid. The
two sacs should be aspirated sequentially under ultrasonographic
visualization and the samples should be labeled properly to avoid wrong
result interpretation. Dye installation technique can be used for the
identification of different sacs, but not used nowadays in most of the
centers.
• The safety of the traditional amniocentesis has been addressed by
several large collaborative studies. In general there is a procedure related
fetal loss of 0.5%.
REFERENCES
1. Montan S. Increased risk in the elderly parturient. Curr Opin Obstet Gynecol
2007 Apr;19(2):110-2.
2. Delbaere I, Verstraelen H, Goetgeluk S, Martens G, De Backer G, Temmerman
M. Pregnancy outcome in primiparae of advanced maternal age. Eur J Obstet
Gynecol Reprod Biol 2007;135(1):41-6.
3. Pellestor F, Anahory T, Hamamah S. Effect of maternal age on the frequency
of cytogenetic abnormalities in human oocytes Cytogenet Genome Res.
2005;111(3-4):206-12.
4. Yeo L, Vintzileos AM. The use of genetic sonography to reduce the need for
amniocentesis in women at high-risk for Down syndrome. Semin Perinatol 2003
Apr;27(2):152-9.
5. Gaulden ME. Maternal age effect: the enigma of Down syndrome and other
trisomic conditions. Mutat Res 1992;296(1-2):69-88.
6. Donoso P, Staessen C, Fauser BC, Devroey P Current value of preimplantation
genetic aneuploidy screening in IVF. Hum Reprod Update 2007;13(1):15-25.
7. Caglar GS, Asimakopoulos B, Nikolettos N, Diedrich K, Al-Hasani S Preimplan-
tation genetic diagnosis for aneuploidy screening in repeated implantation failure.
Reprod Biomed Online 2005;10(3):381-8.
8. Leung WC, Lau ET, Lao TT, Tang MH. Rapid aneuploidy screening (FISH or
QF-PCR): the changing scene in prenatal diagnosis? Expert Rev Mol Diagn 2004;
4(3):333-7.
9. Hook EB. Chromosome abnormalities: prevalence, risk and recurrence. In Brock
DH, Rodeck DH, Ferguson-Smith MA (eds): Prenatal Diagnosis and screening,
Churchill Livingstone, Edinburgh 1992:p.351.
10. Evaluation of Mental Retardation: recommendations of a Consensus conference.
Am J Med Genet 1997;72:468-477.
11. Battaglia A, Carey JC. Diagnostic evaluation of developmental delay/mental
retardation: An overview. Am J Med Genet 2003;117C:3-14.
Meharban Singh
36
Parent Counseling
Birth of a baby fulfills one of the most fundamental needs of human

life and is a moment of great joy and celebration for the whole family.
Parents must have the necessary skills to provide a healthy start to their
babies who are a source of joy in the present and the greatest asset
and hope for the future.
HEALTH AND NUTRITION OF MOTHER .........................................

Women are the creators of progeny.
Health and well being of the
Health and well being of a baby is fetus depends upon the
intimately linked with the health and health and nutrition of the
nutrition of her mother. Healthy mothers mother (not the father!)
produce healthy babies and healthy and because she is both the seed
as well as the soil in which
well informed mothers are in a better baby is nurtured for 9 months.
position to look after the health and well —Meharban Singh
being of their babies. The growth of a
baby in the womb depends upon the quality of the seed (genetic
endowment) and adequacy of soil (maternal health and nutrition before
and during pregnancy). Adolescent children (especially girls) must receive
family life education and optimal nutrition (especially supplements of iron,
folic acid and calcium) so that they are nutritionally well prepared to
meet the challenge of parenthood. During peri-conceptional period (just
before conception and during first 8 weeks of pregnancy) mother should
have adequate intake of folic acid (500 microgram /day) to prevent
occurrence of neural tube defects and cleft lip.
After initial 3-4 months of pregnancy (especially after mid-pregnancy),
mother must take additional 250-500 calories and 30 g protein every
day to ensure her good health and provide nutrition to her growing
baby. She should consume a high fiber diet comprising of whole grain
PARENT COUNSELING 357
cereals, like wheat and brown rice, pulses, legumes, fresh green leafy
vegetables, seasonal fruits, milk and milk products. The non-vegetarian
women can take chicken, lean meat, fish and eggs. Adequate intake of
omega-3 fatty acids and docosohexaenoic acid (DHA) is also crucial to
enhance brain growth of the baby in the womb. Apart from wholesome
balanced diet, pregnant lady should also take nutritional supplements
including iron, folic acid, vitamin A, vitamin D, iodine, calcium, zinc and
DHA.
WHAT TO AVOID DURING PREGNANCY? .....................................

During first 3 months of pregnancy various organs of the baby are taking
shape and if anything goes wrong in Practical Tip
the environment of the baby at this During early pregnancy every drug
stage, there is a risk of development is potentially harmful to the growing
fetus unless proved otherwise. A drug
of congenital malformation (s). which is entirely safe for the pregnant
Mother should strictly avoid any self- woman, may be unsafe or even
medications at this stage and seek the dangerous for her baby in the womb.
help of her doctor for taking But during nursing, a drug that is safe
for the lactating mother is generally
medicines even for common problems safe for her suckling infant.
like fever, headache and vomiting.
She should not get herself exposed to any X-rays. Smoking, chewing
tobacco, consumption of alcohol or drugs of abuse must be avoided as
they can adversely affect the growth of the baby and may cause serious
developmental defects. Excessive intake of tea, coffee and cola drinks
should be avoided due to risk of adverse effects of caffeine. Whenever,
a woman visits any doctor for a health problem, she must inform her
doctor if she is pregnant so that the doctor prescribes those medicines
which are safe both for the mother as well as her growing baby.
THREE MANTRAS OF NEWBORN CARE ........................................

After the initial expert care by the midwife or obstetrician to ensure safe
delivery and assist the baby to adapt from a dependent in utero abode
to an independent extrauterine existence, the care of a newborn baby
is guided by three principles. These principles include early and exclusive
breastfeeding, ensuring that the baby is kept warm and effectively clothed
and preventing development of any infection from visitors and environment.
BREASTFEEDING ..................................................................................
Breastfeeding is the birth right of every baby and like mother’s love there
is no substitute for mother’s milk. Breast milk is an ideal drink for all
babies whether big or small and Nectar of life

healthy or sick. The milk of a mother Nature is supreme. When a baby is
is best suited to serve the biological born, a readymade biologically unique
drink is available under the influence of
needs of her baby and no baby various hormones produced during
should be denied the milk of her pregnancy. Mother craves to put her
mother. baby on the breast while baby is keen
Breast milk has unique biological to suckle. Breastfeeding is complete
nourishment for them both, not only for
and chemical composition, is easily their body but as well for their soul.
digestible and is loaded with anti-
infective substances. Breastfed babies have reduced risk of infections
(diarrhea, cough and cold, pneumonia), non-infective disorders (allergy,
bronchial asthma, eczema) and certain adultonset diseases like obesity,
diabetes mellitus, high blood pressure, coronary artery disease and stroke.
And breast milk fed babies are smarter with higher IQ (compared to
formula-fed babies) because of high content of DHA and lactose in the
human milk. Breastfeeding is a boon for the suckling mother too because
it is convenient, provides partial contraception, reduces the risk of post-
delivery bleeding and provides protection against cancer of breast and
ovaries later in life. Breastfeeding also helps the mother to regain her
figure and pre-pregnancy body weight earlier because energy stores laid
down during pregnancy are consumed faster during nursing.
The baby should be placed on the
Practical Tip
tummy of the mother immediately During the period of exclusive breast-
after delivery to promote bonding and feeding, there is no need to give
breastfeeding. Baby should be put to any supplements of vitamins and
the breast within half to one hour of minerals to healthy full term babies.
The quality of breast milk can be
delivery or as soon as the mother has enhanced by taking a balanced
recovered from the stress and fatigue nutritious diet and supplements of
of labor. Even when baby has been micronutrients by the nursing mother
born by cesarean section, she should
be put to the breast as soon as the mother has recovered from the
effects of anesthesia. The practice of giving glucose water, honey, tea
or ghutti as first feed is condemned. The initial watery yellow milk which
is secreted during first 1-3 days (colostrum) must never be denied to
the baby. It is rich in proteins and protective antibodies and works like
a “vaccine shot” to protect the delicate baby. The baby should be fed
on a demand schedule (and not by clock) and most babies would like
to take feeds every 2-3 hours. Cry is the commonest signal of hunger
and if a baby is not crying due to a wet or soiled diaper, she should
be put to the breast. The baby should be given exclusive breastfeeding
during first 6 months (even water should not be offered in hot summer
months) of life. When your child is thirsty in summer, she is likely to
drink more milk and will have better weight gain.
When your baby is small or sick and cannot suck from the breast,
she can be given expressed breast milk (EBM) with a spoon or paladay.
Milk can be expressed manually or by a mechanical or electrical breast
pump. Before expressing the milk, baby should be encouraged to suckle
on the breast to promote lactation. Avoid bottle feeding due to risk of
infection and nipple confusion.
HOW TO KNOW THAT BABY IS GETTING ENOUGH MILK?

When baby is adequately fed, she is happy and playful for 2-3 hours
after the feed. The baby should pass dilute water-like urine at least 6-
8 times during the day and while breastfeeding the milk should drip
from the other breast. The best criterion that the baby is receiving adequate
milk is the satisfactory weight gain at a rate of 30 g, 20 g and 10 g
per day respectively during the three 4-monthly blocks during first year
of life. Excessive crying alone should not be taken as an evidence of
unsatisfactory lactation because babies cry due to a variety of causes like
discomfort of wet napkins, intestinal colic or wind, exposure to cold or
excessive clothing, insect or mosquito bites, boredom, etc.
HOW TO ENSURE ADEQUATE LACTATION?

A large number of traditional foods are credited to enhance lactation
but there is no scientific evidence for their efficacy. Mother should take
additional 550 calories/day to meet the energy cost of lactation and take
balanced nutritious diet with plenty of liquids. The diet of nursing mother
should be supplemented with commercially available micronutrients and
DHA to enhance the nutritional quality of her milk. The best strategies
to enhance milk yield include willingness or keenness on the part of the
mother to breastfeed, freedom from pain and anxiety, relaxed state of
mind and a vigorously sucking infant.
PROVISION OF WARMTH
The newborn babies lack the coping mechanisms to keep themselves
warm due to their poor capability to generate body heat. After birth
the baby should be promptly dried and effectively covered to prevent
fall in body temperature. Bath should be delayed to next day or till
the body temperature of the baby has stabilized. The cultural practice
of keeping the baby next to the mother in her bed is useful to provide
warmth to the baby and promote breastfeeding. During winter special
care should be taken to keep the room Practical Tip

warm with a radiator or hot air blower. The room temperature that feels
A basin full of water should be placed slightly uncomfortable or warm
to an adult is usually satisfactory
in front of the heater to increase humidity
to serve the biological needs of
in the room. The windows should be kept the baby.
closed so that there is no draughts of cold
air in the room. It is a good idea to keep the baby in a room wherein
sunlight peeps through a window or a door. The baby should be effectively
clothed with woolens from top to bottom with a cap, mittens and socks.
When effectively covered, her trunk should feel warm to touch and her
hands and feet should be reasonably warm and pink. The baby can
be kept warm by providing direct skin-to-skin contact by placing the naked
baby in direct contact with your bosom.
PREVENTION OF INFECTIONS ..........................................................

There is no need to apply any dressing or bandage over the navel. Skin
should be kept clean by daily bath or sponge depending upon the weather.
Natural orifices of the body like eyes, nostrils, mouth, nose, ears, bottom
etc should be cleaned with a wet cotton or damp cloth. Avoid instillation
of any surma or kajal in the eyes due to risk of irritation, cross infection
or even lead intoxication. Never instill any oil into the nostrils and ears
because of risk of aspiration pneumonia and fungal infection. In newborn
babies instillation of few drops of colostrum into the eyes has been shown
to reduce the risk of development of sticky eyes.
USEFUL TRADITIONAL HEALTH CARE PRACTICES ...................

A number of traditional practices for the care of newborn babies are
useful and should be promoted (Table 36.1).
Table 36.1: Useful traditional practices in the care of newborn babies

• Delivery at mother’s place
• Isolation of mother-baby dyad for 40 days
• Oil massage
• Universal and prolonged breastfeeding
• Instillation of colostrum in the eyes to prevent conjunctivitis
• Use of cup and spoon or paladay for top feeding
• Baby sleeping on mother’s bed
Body massage is popular and credited to improve circulation and muscle

tone, relieves fatigue and provide relaxation and sense of relief. Touch
is believed to send stimulatory messages to the brain to enhance neuro-
motor development of the baby. Any non-medicated non-irritating vegetable
oil like coconut oil or olive oil can be used for massage. Massage should
be done gently by the mother (not by an ayah) and she should interact
and talk with her baby while doing massage and performing other chores
like feeding, bathing, changing clothes, toilet care, etc.
IDENTIFICATION OF A SICK BABY .................................................

A large number of problems in newborn babies are either physiological
or minor developmental variations and are of no consequence and do
not need any treatment. Most babies born at term are healthy and do
not develop any health problems or difficulties when you protect them
against cold, promote exclusive breastfeeding, ensure asepsis and cleanliness
and provide your tender loving care. At times, the baby may develop
a serious health problem and vigilant parents should be able to identify
it, so that there is no delay in taking the child to a specialist or hospital
(Table 36.2).
Table 36.2: Common clues of sickness in a baby

• Inactive baby with refusal to take feeds or choking during feeds
• Excessive irritability or inconsolable crying
• Cold and pale extremities or fever
• Watery diarrhea
• Persistent or green-colored vomiting, abdominal distension and constipation
• Rapid breathing, chest indrawing, groaning and cough
• Jaundice extending up to palms and soles
• Bleeding from any site
• Seizures, up rolling of eyes or vacant stare
• Superficial infections like conjunctivitis, umbilical sepsis, boils, oral thrush,
etc.
PARENTAL ROLE IN THE NICU .......................................................

An increasing number of preterm, small and sick newborn babies are
being provided technology-based intensive care in the neonatal intensive
care unit (NICU). The prolonged stay of the baby in NICU is associated
with anxiety, uncertainty, emotional trauma, and lack of bonding between
the baby and her parents and elder siblings. The family dynamics are
greatly disturbed due to physical stress, emotional turmoil and financial
implications due to high cost of neonatal intensive care.
Most neonatologists tackle these issues by encouraging parents (especially
mother) to visit their babies in the NICU and by handling aforementioned
issues with equanimity, compassion and caring attitude. The frightening scene
of NICU is demystified by the health team by constantly informing and involving

the family in the care of their baby. The mother is encouraged to touch
and talk with her baby and provides routine care under the guidance of
nurses. She should provide intermittent skin-to-skin contact (Kangaroo-mother
care) which is credited to provide warmth and stability to the baby, enhance
mother–baby bonding and promote breastfeeding. Parents should provide
visual and auditory stimuli to their baby and try to establish eye-to-eye contact.
Family should remain in close contact with the health team to receive necessary
emotional support and professional guidance.
FATHER’S ROLE ..................................................................................

Baby care is a full time job and quite a tiring task if left to mother alone.
It is important that both parents should share the joys and jolts of bringing
up the children. Father can help in many ways by doing certain tasks
for the baby or by helping the spouse in various household chores. Most
mothers provide low key stimulation to the baby like gentle rocking,
cuddling, caressing, singing and soothing activities. On the other hand
fathers tend to handle the baby more roughly, making lot of noise while
rocking and bouncing the baby. When father actively participates in baby
care, it leads to better inter-parental harmony and peace at home. It
is important that both parents should accompany the baby when they
visit the doctor for vaccinations and health check-up.
The chapter is based on excerpts from a popular parenting manual
by the author, The Art and Science of Baby and Child Care, Sagar
Publications, New Delhi, 3rd edition 2007.
PARENTING THE HIGH-RISK NEWBORN

1. Parenting is an art with a strong scientific basis.
2. In the community there are many positive along with few negative harmful
practices.
3. Ultimately parents and not the doctors/nurses is the custodian of the newborn.
4. Teach them the science behind the art of parenting in a non-technical way.
5. High risk baby is perceived as different, taking away the natural parenting
instincts.
6. Doctors/Nurses as parents of high risk newborns are no different from lay
parents.
7. Participation and partnership in baby care takes away the undue emotional
burden.
8. Breast feeding, bedding in and early stimulation help to sustain parental
bonding.
9. Try to involve the father in all baby care activities and mother in decision
making.
10. The family, especially the grand parents forms the best support system for
mother.
Index
A efficacy vs safety 320

genomic imprinting 323
Adverse effects of postnatal corticosteroids 195 malformations in different organ systems
Apnea 101 321
doxapram 111 childhood cancer 32
management 105 evaluation of published studies 321
monitoring and evaluation 104 growth 323
neurodevelopment 102 neurological problems 322
pathophysiology 101 retinopathy of prematurity 323
prevention and treatment 105 use of medical services 323
antenatal steroids 106
blood transfusion 106
carnitine supplementation 108 B
CO2 inhalation 107
Benefits of postnatal corticosteroids 195
immunization 108
Brain injury 33
kangaroo mother care 106
Brai n-ori ented management of perinatal
kinesthetic stimulation 108
asphyxia 52
methylxanthines 109
antioxidants (Allopurinol) 54
noxious stimuli 106
calcium channel blockers 54
oxygen supplementation 107
hyperbaric oxygen treatment 54
pharmacological treatment 109
magnesium sulphate 54
position 108
predictors of outcome 55
prevention of prematurity 105
acidosis 56
sensory stimulation 107
APGAR score 56
temperature 107
cerebral edema and increased ICP
role of home monitoring 105
(>10 mm Hg) 57
tocolysis 106
fetal distress 55
ventilation 111
intra-uterine passage of meconium 56
continuous positive airway pressure
MRI findings 57
111
neonatal seizures 56
high-flow nasal cannulae 112
outcome in relation to severity of HIE
intubation and assisted ventilation 112
56
nasal intermittent positive pressure
prolonged depression (lower extended
ventilation 112
APGAR score) 56
Asphyxia causes neurological brain deficits 45
resuscitation in room air versus 100%
neuropathology 47
oxygen 53
basal ganglia and brainstem 48
selective head cooling 53
cerebral edema 47
systemic hypothermia 53
focal cerebral infarction 48
parasagittal injury 48
selective neuronal necrosis 47 C
white matter injury 48
primary neuronal injury 46 Cardio-respiratory and neurological depression
secondary neuronal injury 46 41
apoptosis 47 Cerebral autoregulation 13
excitotoxic amino acid injury 46 Clinical examination protocol 209
free radical injury 46 neurobehavior 211
nitric oxide 47 neurobehavioral assessment 211
Assisted reproductive technique 319 neuroimaging 214
complications due to multiple pregnancies CT scan 214
320 EEG 215
magnetic resonance imaging (MRI) making faces 265

214 moving objects 266
neurosonogram 214 vision 265
Physiological brain imaging 215 touch 267
neurological examination 213
baby massage 267
physical examination 209
rocking, walking and swinging 268
Cornblath’s ‘operational threshold’ 76
setting 267
technique 267
D touch therapy 268
touch-effect on infants 269
Developmental evaluation 243 understand her ‘cues’ 264
assessment of vision in early infancy 251 waiting guest 264
assessment of hearing loss in early Early stimulation in NICU 259
infancy 253 aims 259
assessment of reti nopathy of
early intervention and parents 261
prematurity (ROP) 252
importance 260
audiometry and BERA 255
brai nstem evoked response newborn stimulation in NICU 263
audiometry (BERA) 256 over stimulation 262
visual development 251 precautions 262
developmental assessment — below 2 years Early stimulation protocol 270
244 8-10 months period
ten commandments in assessment 244 activities 274
tools and techniques in developmental 12-15 months period 275
assessment 245 4-6 months period 272
CDC gradi ng for major motor auditory stimulation 272
milestones 249 general activities 272
developmental assessment scale for 6-8 months period 273
Indian infants (DASII) 246 general activities 273
Trivandrum developmental screening
10-12 months period 274
chart (TDSC) 245
activities 274
Discharge protocol 225
assessment of the child’s home environment 0-2 months period 270
228 activities 271
home environment 228 auditory 270
tools 229 tactile 271
discharge planning 225 vestibulo/kinesthetic 271
checklist before discharging a high risk visual 270
neonate 225 2-4 months period 271
checklist of NDD with definitive auditory 271
therapy 227 general stimulation 272
role of developmental therapist 225 tactile stimulation 271
role of primary care physician 225
visual 271
role of treating pediatrician/
Etiology and risk factors for perinatal
neonatologist 225
asphyxia 48
E
F
Early stimulation after discharge 264
Follow-up protocol 230
babies need ‘walls’ around them 264
behavoral problems/learning disorders 234
babies need peace and quiet 264
developmental assessment 234
hearing 266 recommended schedule 234
playing music 266 function assessment 235
talking and imitation 266 general care/medical issues 231
newborn stimulation at home 265 growth, nutrition and medical assessment
bold patterns with strong contrast 265 230
INDEX 365
neurological examination 232 best screening tools 77
abnormal neurological signs on clinical diagnosis 77
newborn 233 epidemiology 75
active tone 233 impact on neurodevelopment 74
assessment of passive tone 232 pathophysiology 73
cranial nerve examination 233 prevention 78
postural reflexes at 9 months 233
primitive reflexes at 3 months 233
red flags 233 I
nutrition 231 Impact of perinatal asphyxia on
Follow-up research—some methodological neurodevelopmental outcome 42
issues 338 attention deficit hyperactivity disorder and
bias in outcome research 341 behavioral probems 45
controlling for measurement bias 342 autism and pervasive devel opment
controlling for selection bias 342 disorders 45
policy perspectives 343 cerebral palsy 42
evaluating long-term outcome studies 339 ataxic CP 43
correction for preterm birth 340 athetoid (dyskinetic) CP 42
duration of follow-up 340 hemiplegic CP 43
nature of control and comparison spastic tetraplegic CP 43
groups 340 epilepsy 44
outcomes measured 340 hearing impairment 44
representativeness of the study sample learning disability 44
339 visual impairment 44
sample attrition 341 Impairment of placenta or pulmonary gas
sample characteristics 339 exchange 41
survival rate 339 Inborn errors of metabolism (IEM) 88
common neurological presentations
associated with IEM 89
G acute encephalopathy 90
ataxia 90
Genetic counselling high risk pregnancy 347
chronic encephalopathy with non-
advanced maternal age 347
neural involvement 90
amniocentesis 353
chronic encephalopathy without non-
neural tube defect (NTD) 352
neuronal involvement 90
previous child with Down syndrome 349
movement disorders 90
previous child with malformations 352 myopathy 90
previous child with mental retardation 350 seizures 90
previous child with single gene disorders stroke 90
351 current understanding of pathophysiology
Granulocyte transfusions 167 88
accumulation of a normally minor
metabolite 89
H accumulation of a substrate 88
Hearing stimulation in early pregnancy 291 deficiency of a product 89
early stimulation for hearing impairment secondary metabolic phenomena 89
291 impact on neurodevelopment 89
general activities 292 investigations 91
techniques 292 management and prevention 91
treatment 92
High risk newborn 3
immediate therapy 92
at-risk concept 3
long-term treatment 92
environmental factors 7
follow-up and early intervention 4
intrauterine infections 6 L
low birth weight 5
newborn encephalopathy 5 Late neurological disability associated with
policy implication 7 hypoxia-ischemia 57
Hypoglycemia 73 Lesch-Nyhan disease 90
M monochorionic twin pregnancy 313

twin to twin transfusion syndrome
Meconium aspiration syndrome (MAS) 117 (TTTS) 314
epidemiology 118
guidelines for management 120
antibiotics 122 N
extracorporeal membrane
oxygenation (ECMO) 122 Neonatal jaundice 82
nitric oxide 122 bilirubin causes brain damage 82
sildenafil 122 expected long-term sequelae of severe
steroids 121 jaundice 83
surfactant therapy 121 BERA 83
ventilation 120 MRI 83
Neonatal seizures 62
guidelines for the prevention 119
duration of seizure 64
amnioinfusion 119
EEG 65
intrapartum monitoring 119
etiology 63
intrapartum suctioning 119
gestational age 65
post delivery intubation and management of neonatal seizures 66
endotracheal suctioning 120 management of seizure 66
prevention of post term pregnancy 119 neuroimaging 65
pathophysiology and impact on neurological examination 66
neurodevelopment 117 origin of seizure 64
Monitoring tools for perinatal asphyxia and their prevention 66
clinical value 49 risk of seizures and clinical circumstances
clinical assessment after birth 50 62
multi-organ dysfunction 50 screening and diagnosis 66
severity of encephalopathy 50 serious risk factor 62
intra-partum fetal monitoring 49 timing of insult 65
electronic fetal monitoring (EFM) and type of seizure 63
fetal scalp pH monitoring 49 clonic 64
fetal ECG analysis 49 myoclonic 64
postnatal investigations 50 subtle 63
cerebral blood flow velocities 51 Neonatal sepsis 157
cranial ultrasound 50 diagnosis 159
CT scan 51 epidemiology 158
EEG and amplitude integrated EEG investigations 159
(aEEG) cerebral function management practices in a neonate with
monitoring 52 suspected sepsis 163
magnetic resonance imaging (MRI) 51 prevention of neonatal sepsis 163
magnetic resonance spectroscopy 52 pathophysiology and impact on
Motor stimulation in early infancy 279 neurodevelopment 157
creeping 281 treatment 161
intervention for head control 279 Neonatal shock 143
intervention to promote crawling 281 cerebral blood flow (CBF) 145
intervention to promote rolling 280 etiology 145
intervention to promote sitting 282 hypotension and CNS morbidity/
intervention to promote standing 283 neurodevelopmental outcome 147
interventions for development of hand low CBF and long term outcome 149
function 284 low cerebral blood flow and CNS
Multiple fetal pregnancies 312 morbidity/neurodevelopmental
impact on neurodevelopment 312 outcome 148
assisted reproductive technology (ART) phases of neonatal shock 144
313 physiology 144
factors in pregnancy and labour 313 reliability of clinical parameters in
fetal reduction and vanishing twin assessment of cerebral blood
syndrome 316 flow in preterm babies 145
growth discordance 314 treatment of low SVC flow and
intra-uterine death of one twin 314 neurodevelopment outcome 152
INDEX 367
treatment of shock and O
neurodevelopmental outcome 150
corticosteroids 152 Organization of neurodevelopmental follow-up
inotropes (dopamine versus 236
dobutamine) 151 for babies at high risk of NDD 237
volume expansion 150 for babies at low risk of NDD 236
volume expansion versus inotropes for babies at moderate risk of NDD 236
150
Neonatal transport 186
acute complications—peumothorax 202 P
CLD/BPD 202
adjuncts—surfactant 202 Pain and analgesia 175
asynchronous breathing 201 assessment of pain in neonates 177
duration of ventilation 201 common painful procedures in neonatal
factors in mechanical ventilation 198 period 176
PaCO2 198 diagnostic 176
PaO2 200 surgical 176
pH 199 therapeutic 176
impact of neonatal transport on outcomes pathophysiology 175
186 prevention and management 177
in-utero transport 186 treatment modalities for pain 178
mean airway pressure and optimal lung Parent counseling 356
volume 200 breastfeeding 357
communication 189 father’s role 362
documentation 189 health and nutrition of mother 356
early recognition 187 identification of a sick baby 361
ethics 189
parental role in the NICU 361
logistic issues in transfer of neonates-
prevention of infections 360
duration of transport 188
provision of warmth 359
monitoring during transfer 188
three mantras of newborn care 357
networking 188
patient selection 187 useful traditional health care practices 360
responsibilities of referring center 188 Perinatal asphyxia 41
reverse transfer 189 Perinatal steroids 194
stabilization before transfer 188 Persistent pulmonary hypertension of newborn
standard protocols for neonatal (PPHN) 126
transport 189 diagnosis 130
nursing issues 201 epidemiology 128
organization of a neonatal transport service pathophysiology 126
189 PPHN and neurodevelopmental outcome
drugs 190 127
equipment 189 prevention of risk factor 130
neonatal transport team 189 treatment 131
transport ambulance 189 correction of acidosis 131
ventilation strategies 202 correction of hypovolemia/hypotension
Neurodevelopmental outcomes of preterm/LBW 132
30 mechanical ventilation 132
cerebral palsy (CP) 31
minimal handling 131
growth 33
sedation and paralysis 132
health outcomes 34
treatment of associated conditions 132
hearing impairment 31
intelligence quotient (IQ) 32 surfactant therapy 133
learning difficulties 32 inhaled nitric oxide (iNO) 133
quality of life 34 extracorporeal membrane
social development, behavior and oxygenation (ECMO) 134
psychological problems 33 alternative vasodilator therapy 135
visual impairment 31 Prenatal risk factors 295
Nutrition, fluid and electrolytes 329 risk factors 295
growth restriction 296 R

intrauterine infections 299
maternal diseases 305 Recent advances in measuring blood glucose
maternal factors 307 77
maternal nutrition and brain Risk stratification for neurodevelopmental
development 298 disability 207
prematurity 295 need for risk stratification 207
teratogens 307 anticipatory guidance to parents 207
Preterm brain injury 13 assigning level of follow-up 207
cerebral palsy 16 Role of IVIg in neonatal sepsis 166
interventions to prevent preterm brain Role of pentoxyfylline in neonatal sepsis 166
injury 16
clinical presentation of PVH-IVH 15
impact on neurodevelopment 16 S
management of preterm baby 21
Screening protocol 216
administrative strategies in NICU 23
retinopathy of prematurity (ROP) screening
cerebral perfusion 21
correct coagulopathy 23 216
optimize respiratory management 22 screening for congenital hypothyroidism
unproven therapies 23 220
optimize peri-partum management 20 screening for hearing impairment 219
delay cord clamping 20 screening for metabolic disorders 222
resuscitation 20 Surveillance sonography 15
pathophysiology 13
prenatal 17
T
antenatal steroids (ANS) 18
antibiotics in prelabour rupture of Tandem mass spectrometry (TMS) 96
membranes (pROM) 19
mode of delivery of preterm 20
prevention of prematurity 17 V
screening and diagnosis of preterm brain
Vision stimulation in early pregnancy 287
injury 24 body image 291
clinical examination 24 early detection of visual abnormalities in
neurosonographic screening for IVH- young children 288
PVH and WMD 24 encouraging exploration 291
treatment of IVH 25 object permanence 291
treatment of acute IVH supportive stimulation techniques for visually impaired
measures 25 children 289
treatment of posthemorrha gic intervention to promote eye focus and
hydrocephalus 25 following 289
withdrawal of care decision in severe senses as leaning tool 290
IVH 27 techniques 289
Preterm/low birth weight 29 visual stimulation 288

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The High Risk

Amitava Sen, Kolkata Nitin K Shah, Mumbai

Malik GK, Lucknow Tanmaya R Amladi, Mumbai

Mathur NB, New Delhi Uma S Nayak, Vadodara

JAYPEE BROTHERS MEDICAL PUBLISHERS (P) LTD

First Edition: 2008

Abbas Hyderi MD Dinesh Kumar Chirla

Lakshmi MA Naveen Jain DM (Neo)

Narayanan Potti Ranjan Kumar Pejaver

The accreditation process of Level-II care introduced by National Neonatology

This book attempts to organize currently available knowledge

Altaf Jameel Khan, Resident, KIMS, Thiruvananthapuram

SECTION 2: PREMATURITY AND LOW BIRTH WEIGHT

SECTION 3: NEONATAL ENCEPHALOPATHY

SECTION 4: METABOLIC PROBLEMS

SECTION 5: RESPIRATORY PROBLEMS

SECTION 6: PERFUSION PROBLEMS

SECTION 8: NEURODEVELOPMENTAL ASSESSMENT

SECTION 9: NEURODEVELOPMENTAL FOLLOW-UP

SECTION 10: DEVELOPMENTAL EVALUATION

SECTION 11: EARLY DEVELOPMENTAL STIMULATION

SECTION 12: DEVELOPMENTAL THERAPY

SECTION 13: PRENATAL STRATEGIES

SECTION 14: UNEXPLORED TERRITORIES

SECTION 15: COUNSELING

NICU Neonatal Intensive Care Unit

Sustained global initiatives and efforts of local governments have improved

AT-RISK CONCEPT ..............................................................................

risk” newborns may be replaced by the concept of “optimality”. Newborns

FOLLOW-UP AND EARLY INTERVENTION .....................................

LOW BIRTH WEIGHT ..........................................................................

NEWBORN ENCEPHALOPATHY .........................................................

encephalopathy there was evidence of intra-uterine hypoxia in 90% and

INTRAUTERINE INFECTIONS ..............................................................

POLICY IMPLICATION .........................................................................

Very preterm babies (gestation < 32 weeks) are at increased risk of

Adverse neurodevelopmental outcome in very preterm babies depends

CURRENT UNDERSTANDING OF PATHOPHYSIOLOGY1,2 .................

passive situation. When a pressure-passive circulatory pattern is challenged

The major sequel of PVH-IVH relate to the destruction of cerebral

CLINICAL PRESENTATION OF PVH-IVH .........................................

Classification of hemorrhagic and/or ischemic abnormalities

• Isolated GM and/or IVH

GM/IVH—Germinal matrix / intraventricular hemorrhage

IMPACT ON NEURODEVELOPMENT3-5 ................................................................

BEST PRACTICES - INTERVENTIONS TO PREVENT

• Timing of delivery: Risk of continuing pregnancy with an

Antenatal Steroids (ANS)8-12

Antibiotics in Prelabour Rupture of Membranes (pROM)13

Mode of Delivery of Preterm15

OPTIMIZE PERI-PARTUM MANAGEMENT

Delay Cord Clamping18

MANAGEMENT OF PRETERM BABY

• Provide developmental care, decrease noise, and minimize handling

Optimize Respiratory Management

Administrative Strategies in NICU24

SCREENING AND DIAGNOSIS OF PRETERM BRAIN INJURY

Neurosonographic Screening for IVH – PVH and WMD

TREATMENT OF IVH ...........................................................................

KEY POINTS – reducing NDD due to preterm brain injury (WMD)