Olusanya et al.

BMC Pediatrics (2015) 15:39

DOI 10.1186/s12887-015-0358-z

REVIEW Open Access

Management of late-preterm and term

infants with hyperbilirubinaemia in resource-
constrained settings
1* 2 3 4
Bolajoko O Olusanya , Tinuade A Ogunlesi , Praveen Kumar , Nem-Yun Boo , Iman F
5 6 7 8,9
Iskander , Maria Fernanda B de Almeida , Yvonne E Vaucher and Tina M Slusher

Abstract
Hyperbilirubinaemia is a ubiquitous transitional morbidity in the vast majority of newborns and a leading cause of
hospitalisation in the first week of life worldwide. While timely and effective phototherapy and exchange transfusion
are well proven treatments for severe neonatal hyperbilirubinaemia, inappropriate or ineffective treatment of
hyperbilirubinaemia, at secondary and tertiary hospitals, still prevails in many poorly-resourced countries accounting
for a disproportionately high burden of bilirubin-induced mortality and long-term morbidity. As part of the efforts to
curtail the widely reported risks of frequent but avoidable bilirubin-induced neurologic dysfunction (acute bilirubin
encephalopathy (ABE) and kernicterus) in low and middle-income countries (LMICs) with significant resource
constraints, this article presents a practical framework for the management of late-preterm and term infants (≥35
weeks of gestation) with clinically significant hyperbilirubinaemia in these countries particularly where local practice
guidelines are lacking. Standard and validated protocols were followed in adapting available evidence-based national
guidelines on the management of hyperbilirubinaemia through a collaboration among clinicians and experts on
newborn jaundice from different world regions. Tasks and resources required for the comprehensive management of
infants with or at risk of severe hyperbilirubinaemia at all levels of healthcare delivery are proposed, covering primary
prevention, early detection, diagnosis, monitoring, treatment, and follow-up. Additionally, actionable treatment or
referral levels for phototherapy and exchange transfusion are proposed within the context of several confounding
factors such as widespread exclusive breastfeeding, infections, blood group incompatibilities and G6PD deficiency,
which place infants at high risk of severe hyperbilirubinaemia and bilirubin-induced neurologic dysfunction in LMICs,
as well as the limited facilities for clinical investigations and inconsistent functionality of available phototherapy
devices. The need to adjust these levels as appropriate depending on the available facilities in each clinical setting
and the risk profile of the infant is emphasised with a view to avoiding over-treatment or under-treatment. These
recommendations should serve as a valuable reference material for health workers, guide the development of
contextually-relevant national guidelines in each LMIC, as well as facilitate effective advocacy and mobilisation of
requisite resources for the optimal care of infants with hyperbilirubinaemia at all levels.
Keywords: Clinical guidelines, Developing countries, Exchange transfusion, Hyperbilirubinaemia,
Kernicterus, Neonatal jaundice, Newborn care, Phototherapy

* Correspondence: [email protected]
1
Centre for Healthy Start Initiative, 286A, Corporation Drive, Dolphin Estate,
Ikoyi, Lagos, Nigeria
Full list of author information is available at the end of the article

© 2015 Olusanya et al.; licensee BioMed Central. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly credited. The Creative
Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data
made available in this article, unless otherwise stated.
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 2 of 12

Introduction literature from both high-income and LMICs to identify key

Neonatal hyperbilirubinaemia is a leading cause of hos- issues relevant to improved care at primary, secondary and
pital admission/re-hospitalisation in the first week of life tertiary levels in LMICs [28,29]. The existing guide-lines
globally [1-3]. Timely and appropriate treatment with were rated individually by the core working group (CWG)
phototherapy and/or exchange transfusion are effective in and one external content methodologist who had no prior
controlling excessive bilirubin levels in the affected in- involvement with generating these guidelines. The overall
fants [4,5]. Otherwise, severe hyperbilirubinaemia may average score for each guideline was com-puted based on the
progress to acute bilirubin encephalopathy (ABE) or ker- seven components of the AGREE-II instrument:
nicterus with a significant risk of mortality in newborns methodology, presentation, completeness, ap-propriateness,
[6-8]. Survivors may also acquire long-term neurodeve- overall quality, disposition for personal use and likelihood of
lopmental sequelae such as cerebral palsy, sensorineural recommending the guideline to others
hearing loss, intellectual difficulties or gross develop- [27]. We developed a practice framework for different
mental delays [9-13]. It is estimated that, worldwide, se- levels of newborn care based on essential tools and skills
vere hyperbilirubinaemia affects at least 481,000 term or considered appropriate for each level of care. The pro-
near-term newborn babies annually, of whom 114,000 die posals aimed at balancing the safe, effective, patient-
and more than 63,000 survive with moderate or se-vere centred, timely, efficient and equitable components of
disability [14,15]. At least, 75% of the affected in-fants quality care enunciated by the Institute of Medicine [30],
reside in sub-Saharan Africa and South Asia [14]. as well as minimising the risk of unintended harms such
In low- and middle-income countries (LMICs), delay in as costly, unnecessary overtreatment or increased parental
seeking care for infants with hyperbilirubinaemia as well anxiety. Where scientific evidence was lacking or limited,
as delay in providing appropriate treatment when affected proposed actions were based on consensus among the
infants present in health facilities is commonly reported CWG using the Delphi process [31]. The draft and final
[16,17]. Where phototherapy devices are avail-able, if at proposals were critically reviewed by an international
all, lack of relevant guidelines or inadequate knowledge panel of experts for scientific soundness and practicality.
of essential requirements for effective treat-ment results in The experts were identified and agreed by the CWG
frequent and potentially avoidable ex-change transfusions based on their independently verifiable work on the
[18-21]. We, therefore, set out to identify key subject-matter and with a view to achieving a fair rep-
considerations for the effective management of late- resentation from all world regions. While the expert panel
preterm and term infants (≥35 weeks of gesta-tion) with review was not intended as individual endorse-ment of the
significant hyperbilirubinaemia presenting at health entire framework, all comments and quer-ies were
facilities in LMICs. carefully addressed by the CWG in subsequent revisions.
Authors made reasoned judgment where contradictory
Review views were expressed by panel members on an issue [25-
Methodology 27]. For clarity and consistency the key terminologies and
Guidelines for the management of hyperbilirubinaemia in definitions used in this report are summarised in Table 1
high-income countries are unlikely to address the peculiar (also Additional file 2).
challenges in LMICs without appropriate modification
[17,22,23]. Adaptation of existing evidence-based guide- Levels of intervention and required facilities for severe
lines from one geographical, economic and socio-cultural jaundice
context to another is an internationally accepted alterna-tive The average AGREE II-GRS ratings of the 21 guidelines
to the more costly, time-consuming, de novo guideline reviewed ranged from 41% for Ghana and 99% for UK’s
development for improved health care delivery [24]. In this NICE (see Additional file 1: Table S1). Priority was given
report, we followed relevant protocols of the WHO to guidelines with high quality scores (≥70%) except for
Handbook for Guideline Development [25], ADAPTE issues pertinent to clinical practice in LMICs but not ex-
Guideline Adaptation Toolkit [26], and AGREE II-Global plicitly addressed by these guidelines such as factors ac-
Rating Scale [27], for the adaptation of clinical practice counting for delays in seeking and receiving appropriate
guidelines. Based on prior in-depth reviews of the litera-ture care [17]. Only four guidelines (Ghana, India, Kenya and
from 1970 to 2013 on the burden of neonatal hyper- WHO) were from eligible LMICs, and two (Ghana and
bilirubinaemia and current management practices in LMICs WHO) did not meet the 70% quality rating threshold. The
[17,22], we identified four major themes for im-proving the American Academy of Paediatrics (AAP) guideline was
care of affected infants namely: primary pre-vention, early the benchmark for the majority of high scoring na-tional
detection and monitoring, treatment and follow-up. We then guidelines including NICE [4,5]. The interventions and
undertook a review of existing guide-lines (see Additional tools proposed for each level of health care delivery are
file 1: Table S1) and relevant summarised in Table 2.
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 3 of 12

Table 1 Terminologies and definitions adopted in this paper

Terminology Definitions
Clinically significant Significant hyperbilirubinaemia: any unconjugated bilirubin level requiring treatment with phototherapy which
hyperbilirubinaemia varies with post-natal age and aetiology (typically TSB ≥12 mg/dL (205 μmol/L) in many LMICs).
Severe hyperbilirubinaemia: Bilirubin levels at/near exchange transfusion levels based on post-natal age and aeti-
ology (typically TSB ≥20 mg/dL or 342 μmol/L in many LMICs) and/or any elevated TSB associated with signs of
acute bilirubin encephalopathy.
Bilirubin encephalopathy: abnormal neurological signs and symptoms caused by bilirubin toxicity to the basal
ganglia and various brainstem nuclei.
Acute bilirubin encephalopathy (ABE): acute manifestations of bilirubin toxicity seen within fourteen days after
birth. Classic early signs include poor feeding, lethargy and tone abnormalities progressing to high-pitched cry, in-
creasing hypertonia - especially of extensor muscles, with retrocollis, opisthotonus and obtundation in association
with the kernicteric facies.
Kernicterus: Permanent or chronic neurologic damage, including choreo-athetoid cerebral palsy, enamel dysplasia,
paralysis of upward gaze, hearing impairments including auditory neuropathy spectrum disorders.

Low- and middle-income coun- The target population for this review consists of the 91 countries with per capita Gross
National Income (GNI) of
tries (LMICs) ≤ US$6,000 using the Human Development Report 2013 by the United Nations Development Program (UNDP)
as there is no single definition of “resource-poor countries” in the literature and developmental status varies
greatly among the approximately 140 countries classified as LMICs by the World Bank [17]. (see Additional file 2:
Table S2)
Levels of health care delivery Three levels of healthcare delivery were considered: primary, secondary and tertiary. Typically, the primary level
consists of community health centres and outposts managed by community health workers. Secondary/first-
level referral centres include district or general hospitals while the tertiary level consists of specialist or teaching
hospitals.

Primary prevention provided during antenatal care, about hospitals in their

The contribution of maternal/family knowledge gaps re- communities that are able to provide requisite support for
garding the importance of neonatal jaundice commonly neonatal hyperbilirubinaemia [17].
manifesting in late presentation of infants with severe Mothers who deliver at home, especially those who do
hyperbilirubinaemia to health services in LMICs is well not attend antenatal clinics present a special challenge that
documented [17]. Mothers and families are able to de-tect must be appropriately addressed in various commu-nities.
jaundice from yellowish discolouration of the skin in their The inclusion of neonatal jaundice in the WHO
newborns accurately, if appropriately educated recommended training on essential newborn care for
[4]. Educating pregnant women, especially primigravidae traditional/home birth attendants, community and lay
during antenatal clinics, on the risks and adverse conse- health workers should be considered in such settings [34-
quences of severe hyperbilirubinaemia, avoidance of po- 36]. The training should also be geared towards avoidance
tentially harmful traditional/herbal therapies and the mis(use) of haemolytic agents or traditional therapies, early
of haemolytic agents should be a priority [17]. Routine recognition of the onset of jaundice by mothers and care
determination of mother’s blood type and timely provision of givers, and surveillance for timely presentation to the
anti-D globulin should be widely promoted to prevent Rh nearest health facility [17].
and neonatal jaundice due to other haemolytic diseases
[14,32]. Educational interactions with mothers and families Early detection, diagnosis and monitoring
must also recognise and seek to address com-mon barriers to Early identification of infants at risk of severe hyperbilir-
appropriate health-seeking behaviour for childhood illnesses ubinaemia is an essential component of newborn care. All
[17]. Although most infants are born outside hospitals in newborns at all levels should be examined within 24
many LMICs, pre-discharge counsel-ling of mothers who hours of birth and in the following two days. Mothers and
deliver in hospitals on the risks of hyperbilirubinaemia after other care-givers should be encouraged to look for
discharge should be considered. jaundice by blanching the skin (on the nose in particular),
Infants that are exclusively breastfed have an increased looking at the gums and examining the eyes [4]. The use
risk for severe hyperbilirubinaemia in the first 2 to 5 days of Kramer’s chart (see Additional file 3: Figure S1) espe-
of life compared to formula-fed infants [33]. It is there- cially in primary care settings remains valuable despite its
fore, essential to provide good lactation support to all limitation in correlating with the severity of jaundice
mothers at all levels of care to increase successful breast- [37,38]. So also is blanching of the gums possibly with an
feeding, at least 8–12 times a day, as breast-milk benefits icterometer, particularly in dark-skinned babies [39].
outweigh the risk [4,5,33]. Mothers, families and their Healthcare professionals and parents are capable of recog-
jaundiced infants will also be best served by information nizing jaundice, but not very good at assessing its severity
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 4 of 12

Table 2 Levels of intervention and suggested tools for managing neonatal hyperbilirubinaemia in low and
middle-income countries
Proposed tasks or tests [Applicable level of care]* Suggested tools and facilities
Primary prevention
• Education of existing and expectant mothers, families and health care providers on [P, S & T]: • Educational materials including posters and audio-
visual aids where available, pictures and/or video clips
o The transient physiologic course but with potential to increase to harmful levels of infant survivors of BIND and/or Kernicterus. This
and it's variability from baby to baby material should include signs of both early and late
o The avoidance of haemolytic substances (including camphor/naphthalene ABE/BIND and potential long-term consequences of
balls, menthol-containing powder, creams and balms, e.g. Wintergreen oil). ABE/BIND for both the community and the health care
providers. [P, S & T]

o The benefits of early detection accompanied by timely and appropriate treatment in Access to laboratory appropriately
health facilities adequately-equipped for newborn care. resourced for clinical investigations. [S & T]
o Discouraging traditional therapies as well as indiscriminate use of self-
prescribed medications e.g. ampicillin-cloxacillin.
o Recognition of acute bilirubin encephalopathy/Bilirubin-Induced Neurologic Dysfunction (BIND)

o The value of “clean birth” to prevent or minimize the risk of infection (sepsis)
• Referral to secondary or tertiary centers of all preterm babies (<35 weeks
gestation) and surveillance for full-term infants with history of medically-treated
jaundice in a sibling presenting at primary health centers. [P]
• Promotion and support for successful breastfeeding. [P, S & T]
• Screening of expectant mothers for the risk of blood group incompatibilities using
routine ABO & Rh with counseling on the importance of Rh immunoglobulin ensuring
availability when indicated. [P, S & T]
• Judicious use of oxytocin during labor. [S & T]
• Identification of babies with extensive bruises, cephalhaematomas and at risk for
concealed haematomas e.g. those from difficult deliveries. [P, S & T]
• Request blood test to rule out Glucose-6-phosphate dehydrogenase (G6PD)
deficiency in high-risk populations. [S & T]
• Early phototherapy for infants with hemolytic diseases. [S & T]
Early detection, diagnosis and monitoring
• Routine examination of all newborns within 24 hours of birth and the next 48 • Well-lit examination room or nursery with
hours for possible jaundice. [P, S & T] natural daylight (minimum). [P, S & T]
• If jaundice is suspected, examine infant naked in a well-lit room or, preferably in • Transcutaneous (TcB) Bilirubinometer e.g. JM103® or
natural daylight near a window guided by Kramer’s chart (Additional file 3: Figure S1). Bilicheck® (minimum) or Icterometer. [P, S & T]
Recognize that estimation of the degree of hyperbilirubinaemia based on visual signs
• Rapid micro device for total plasma/serum
of jaundice can lead to errors, particularly in darkly pigmented infants. Blanching of the
gum may be more reliable and helpful in dark skinned babies. [P, S & T] bilirubin (TSB) (minimum). [S & T]
• Bilirubinometer for total serum & direct
bilirubin measurement (minimum). [S & T]
• If jaundice is visible, measure the total serum bilirubin (TSB) or transcutaneous • Access to laboratory facilities for: [S & T]
bilirubin (TcB) level. TcB values above 12 mg/dl (205 μmol/L) should be cross-
checked where possible with TSB measurement. [P, S & T] o Blood group, Rh, G6PD tests (minimum)
o Components of sepsis screen such as Complete
Blood Count, Blood/Urine/CSF cultures, CRP
and/or other rapid screening tests

• Establish if infant has early signs of acute bilirubin encephalopathy (ABE) or qualifies
as high risk including possible hemolytic diseases, hypothermia, hypoglycemia, or
sepsis (see Algorithm in Figure 1). [P, S & T]
o Metabolic screening e.g. hypothyroidism,
• Follow the Algorithm and Table 3 for actionable levels. [P, S & T]
galactosaemia when indicated.
• Ensure follow-up of infants discharged before 48 hours after delivery especially those
with established risk factors within 1–2 days of discharge (take advantage of BCG visit
and any other times infants <2 weeks are seen). [P, S & T]
Treatment
• Follow the Algorithm and Table 3 for actionable levels after country specific adaptations. [S & T] • Effective Phototherapy Units [S & T]
• When indicated (particularly, in the presence of isoimmune haemolytic diseases), o Special Blue-light Phototherapy Unit (ideal)
ensure early treatment of newborns with intensive phototherapy to minimize the need
for exchange transfusion. [S & T]
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 5 of 12

Table 2 Levels of intervention and suggested tools for managing neonatal hyperbilirubinaemia in low and
middle-income countries (Continued)
• Ensure that the irradiance levels of phototherapy units are periodically monitored o Light emitting diodes (LED)
and the recommended specifications strictly followed. [S & T] Phototherapy Unit (ideal)
• Be familiar with simple and inexpensive adjustments that can significantly o Fluorescent white or blue bulbs (minimum)
improve the effectiveness of phototherapy devices. [S & T] • Irradiance Meters (spectro-radiometers) (ideal). [S & T]

• Access to blood bank with fresh (ideally less than 3 days old) whole blood for ET • Maximize irradiance by placing the units as close
appropriately compatible with mother and baby (O and Rh specific). [S & T] as possible without overheating the infants (usually
10–20 cm above the baby if using cool lights
• Intravenous immunoglobulins (IVIG) may be useful when nearing ET (unless specified otherwise by manufacturer), using
but existing evidence is not conclusive. [T] reflecting materials on all sides of cots, exposing as
much of the baby as possible (thereby maximizing
• Laboratory facilities for albumin [S & T] spectral power [irradiance x size of irradiated
area]); and change florescent tubes according to
manufacturer’s recommendations if available or
periodically (8–12 weeks) if unable to measure
irradiance levels [S & T]
• Ensure that the eyes are covered but keep the cover small to maximize surface o Consider bilirubin-albumin ratio in
available for PT. [P, S & T] addition to but not in lieu of total bilirubin
level as a factor in determining the need
• Ensure that male genitals are covered (controversial) unless for infants nearing
for an exchange transfusion.
exchange transfusion level. [P, S & T]
• Ensure that babies are placed in cots not incubators when under phototherapy unless
they are hypothermic. [S & T]
• Ensure that blood samples for relevant investigations are collected and refrigerated before initiating • If available, consider the use of duly approved
exchange transfusion and any blood samples are protected from light including the PT light. [S & T] filtered sunlight phototherapy (FS-PT) in tropical
settings with irregular electricity supply and lack of
• Ensure that an infant with clinical signs of moderate-severe ABE receives exchange
adequate or functional conventional phototherapy
transfusion promptly. Place the infant under the best phototherapy available while
(CPT) units with careful and frequent monitoring
preparing for the exchange transfusion.[S & T]
of infants for temperature fluctuations. [ P & S]
• Ensure that the infant remains adequately hydrated and is breastfeeding well/feeding well. [P, S & T]

• Avoid drugs that compete for albumin binding such as sulfonamides,

ceftriaxone, and acetylsalicylic acid. [S & T]
Follow-up evaluation
• Assessment of non-jaundiced infants on days 3 and 5. [P, S & T] • Tools for age-appropriate
developmental assessment. [S & T]
• Assessment of jaundiced infants regularly in the first 7–10 days or until jaundice
is clearly resolved. [P, S & T] • Automated Otoacoustic Emissions (AOAE). [S & T]

• Educate parents on the need for a follow-up neuro-developmental assessment of all infants • Automated Auditory Brainstem Response
treated for severe hyperbilirubinaemia with intensive phototherapy or exchange transfusion (AABR). [S & T]
or with a history of such treatment at age 3–6 months. [P, S & T]
• Access to diagnostic evaluation with Auditory
Brainstem Response (ABR) (ideal). [T]
• Ensure that, at the minimum, such developmental assessment includes auditory brainstem • Consider Magnetic Resonance Imaging (MRI)
response audiometry, language processing/language development and clinical evaluation of for early detection of potential neurotoxicity if
abnormalities of tone, posture and movements for infants with signs of ABE/BIND, who had readily available, can be done without sedation
exchange transfusion and those with a bilirubin level of >20 mg/dL. [S & T] and does not delay treatment. [T]
• Disseminate information on the local providers of age-appropriate developmental
evaluation of infants and young children to the affected parents on discharge or during
any subsequent clinical consultations. [S & T]
*Level of care where task/test should be available routinely: Primary/Community Health Center [P], Secondary/District Hospital [S], Tertiary/Children’s’ Hospital [T].
For a comprehensive list of essential infrastructural and human resources typically required for secondary/district hospitals see: UNICEF India. Toolkit for Setting up
of Special Care Units, Stabilization Units and Newborn Care Units. New Delhi: UNICEF India, 2009.
➢ → Conventional Phototherapy (CPT): Phototherapy in which intensity of blue light (400–520 nm) with a peak wavelength of 450 ± 20 nm not less than 8
μW/ cm2/nm is applied to the greatest possible surface area of the infant. The light sources are usually special blue fluorescent lamps, compact florescent
lamps (CFL) or halogen spotlights. If none of these are available, ordinary commercial white/daylight fluorescent lights should be considered, but brought
as close as possible (10-20 cm) to the baby without overheating.
➢ → Light-emitting diode Phototherapy (LED-PT): Phototherapy devices which emit most of their light in the 450–470 nm spectrum. This range corresponds to the
peak absorption wavelength (458 nm) at which bilirubin is broken down. Blue LEDs are power efficient, portable devices with low heat production so that they
can be placed very close to the skin of the infants without any apparent untoward effects.
➢ → Intensive Phototherapy (IPT): Phototherapy in which a high intensity of blue light (400–520 nm) ≥30 μW/cm2/nm is applied to the greatest possible
surface area of the infant. In usual clinical situations, this will require special high-intensity fluorescent tubes, or CPT lamps placed approximately 30 cm
(10 cm for cool blue light) above the infant, who can be nursed in a bassinet.
➢ → Filtered Sunlight Phototherapy (FS-PT): Treatment with specially filtered sunlight using custom pre-tested window-tinting films that protect against
potentially harmful ultra-violet and infra-red rays.
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 6 of 12

[4]. Notwithstanding, this visual assessment is generally TcB levels for phototherapy and exchange transfusion
more reliable and helpful in ruling out hyperbilirubinae- reflecting available evidence on current practices for the care
mia than estimating bilirubin levels [4]. of jaundiced infants in LMICs are presented in Table 3
The suggested pathways of care for all babies, adapted [17,22,52]. We adopted the tabular format in the Kenya 2013
from NICE guidelines, are described in Figure 1 [4]. At a guidelines (see Additional file 1: Table S1) for ease of
minimum, infants with gestational age <38 weeks, from reference at all levels of care. These conserva-tive bilirubin
high-risk racial groups, previous sibling(s) with a history levels may be warranted in settings where the incidence of
of treated jaundice, visible jaundice in the first 24 hours severe hyperbilirubinaemia is high, late presentation
of birth, family history of G6PD deficiency or blood common, determination of haemolytic risk (Blood
group incompatibilities, should be considered as high risk type/Rh/G6PD) is not possible routinely at birth, and quality
and should be monitored for hyperbilirubinaemia at all of phototherapy is sub-optimal. Higher levels for
levels of care [4,5]. Ongoing training of health workers on phototherapy and especially exchange transfusions at or near
the signs and symptoms of ABE including the use of a those recommended by the AAP or NICE guide-lines should
protocol for bilirubin-induced neurologic dysfunction be strongly considered in tertiary care settings with facilities
(BIND) is essential for facilitating timely re-ferral and for intensive phototherapy. A centre or hos-pital at any level
intervention (see Additional file 4: Table S3) [40,41]. that is not appropriately resourced to provide the required
Subtle, moderate and occasionally even ad-vanced BIND treatment should promptly refer the infant to the closest,
is likely reversible [42,43]. Timely detec-tion and appropriate health facility.
treatment of BIND as suggested by the AAP and others is There are various phototherapy devices using different
therefore, useful in forestalling the progres-sion of this light sources: fluorescent tubes, halogen lamps and light
potentially devastating condition. emitting diodes (LED). An effective phototherapy device
The objective tests for estimating and monitoring the should produce specific blue-light wavelengths (peak
degree of jaundice are transcutaneous bilirubin (TcB) emission: 450 ± 20 nm), preferably in a narrow band-
and/or TSB. TcB is a non-invasive, portable screening width to about 80% of an infant’s body surface area [18].
tool ideally used to determine the need for the more ac- Conventional phototherapy (CPT) should have an irradi-
2
curate TSB which requires a venous or capillary blood ance of at least 8-10 μW/cm /nm and intensive photo-
sample [44-47]. TcB values above 12 mg/dl (205 μmol/L) therapy should have an irradiance of ≥30 μW/cm /nm
2
should be checked where possible with TSB measure- (from either a single or multiple phototherapy units). LED
ment [47]. TcB becomes unreliable after commencement devices are as effective as other light sources in de-
of phototherapy unless measurements are taken from an creasing TSB but have special advantages in LMICs
area of skin that has been shielded from phototherapy [53,54]. They are more power efficient, portable, weigh
with a photo-opaque patch [47]. However, currently these less, have a longer life span and lower heat production,
devices, especially TSB, may not be readily afford-able in making them more suitable for intensive phototherapy
many resource-limited settings. Low-cost and minimally than fluorescent bulbs. Irradiance meters for monitoring
invasive point-of-care tools for plasma/serum bilirubin PT units should be readily available, as well as spare re-
measurements are currently being piloted and hold placement bulbs.
promise for LMICs [48]. The interpretation of TSB/TcB Costs of providing intensive or special care for jaun-diced
and the recommended actions are provided in Table 3 [47- newborns could be prohibitive, next only to that of caring for
51]. Besides TSB estimation, access to la-boratory preterm babies in LMICs [55]. However, the development of
facilities for real-time clinical investigations should at a affordable phototherapy devices and using simple
minimum include evaluation of blood group inexpensive enhancements such as hanging white reflecting
incompatibilities and G6PD status [4,5]. material around cots (being careful to avoid overheating
For infants delivered in hospitals and discharged before particularly from halogen lamps), chan-ging bulbs regularly
48 hours, follow up assessment within 1–2 days after dis- and reducing the distance between baby and lamps, improve
charge with a TcB, or at a minimum, physical the effectiveness of phototherapy [18,19,56,57]. WHO
examination should be considered. Table 3 may be used to maintains a valuable compendium of innovative and low-
assess the risk of subsequent hyperbilirubinaemia at the cost technologies including photother-apy devices
time of dis-charge. Infants who present in the first week recommended for LMICs [58]. Whatever the light-source,
of life should be routinely examined for possible jaundice. the effectiveness of phototherapy devices can be
compromised by erratic power supply, inadequate skin
Treatment exposure from overcrowding with multiple infants placed
Phototherapy and exchange transfusion are well- under a single device, sub-optimal irradiance levels, and poor
established as the most effective treatments for severe device maintenance [18,19]. Failure to address these issues is
hyperbilirubinaemia [4,5]. The proposed actionable TSB/ likely to increase the frequency of avoidable
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 7 of 12

Figure 1 Algorithm for the care of newborns with hyperbilirubinaemia in LMICs.

exchange transfusion. It is, therefore, essential that photo- receiving phototherapy. If enough effective phototherapy
therapy devices are properly monitored, regularly main- devices are not available in very busy resource-constrained
tained, and staff well trained on how to care for infants settings, clinical judgement as to which infants should
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 8 of 12

Table 3 Suggested actionable treatment or referral TcB and/or TSB (mg/dL or μmol/L) levels in infants with
hyperbilirubinaemia
Age (in hours) Repeat TcB/TSB daily if Begin CPT or Refer Begin IPT or Refer Frequency of Monitoring Consider ET at
baby is not under PT at TcB/TSB at TcB/TSB TcB or TSB under PT TcB/TSB
0-12 any visible jaundice 2-3 (34–51) >3 (51)) 6 hrly 10-12 (171–205)
>12-24 ≥4 (68) 4-5 (68–86) >5 (86) 6 hrly 11-13 (188–222)
>24-36 ≥5 (86) 6-7 (103–120) >7 (120) 6 - 24 hrs 13-15 (222–257)
>36-48 ≥7 (120) 7-9 (120–154) >9 (154) 6 - 24 hrs 14-16 (239–274)
>48-60 ≥9 (154) 9-11 (154–188) >11 (188) 6 - 24 hrs 15-17 (257–291)
>60-72 ≥10 (171) 10-12 (171–205) >12 (205) 6 - 24 hrs 16-18 (274–308)
>72-84 ≥10.5 (180) 11-13 (188–222) >13 (222) 6 - 24 hrs 16-19 (274–325)
>84-96 ≥11 (188) 12-14 (205–239) >14 (239) 6 - 24 hrs 17-20 (291–342)
>96-108 ≥11.5 (197) 12-15 (205–257) >15 (257) 6 - 24 hrs 17-20 (291–351)
>108 ≥12 (205) 13-16 (222–274) >16 (274) 6 - 24 hrs 17-20 (291–351)
2
TcB (Transcutaneous bilirubinometry), TSB (Total serum bilirubin), PT (Phototherapy), CPT (Conventional PT) ≥10 μW/cm /nm, IPT (Intensive PT) ≥30
μW/cm2/nm, ET (Exchange transfusion).
AAP (American Academy of Pediatrics), LMICs (Low and middle-income countries), G6PD (Glucose-6-Phosphate Dehydrogenase).
Notes:
• → The above levels are primarily adapted from the high/medium risk categories of AAP guidelines. Generally, levels of 2 mg/dL (34 μmol/L) below AAP
recommendations are proposed due to multiple confounding factors such as the high risk status of many infants in LMICs, the limited facilities for clinical
investigations, quality variability of phototherapy devices and the high incidence of ABE/kernicterus in many LMICs [e.g. see Guidelines #15 & 17 in
Additional file 1: Table S1]. Phototherapy and especially exchange transfusion levels at or near those recommended by the AAP or NICE exchange
guidelines should be strongly considered in tertiary care settings with intensive phototherapy.
• → These proposals may be adjusted as appropriate depending on the available facilities in each clinical setting and the risk profile of the infant with a
view to avoiding overtreatment or under-treatment.
• → Factors that place infants at higher risk in many LMICs include but are not limited to widespread exclusive breastfeeding, G6PD deficiency,
unrecognised haemolysis such as blood group incompatibilities and sepsis/infection.[e.g. see Olusanya BO, Osibanjo FB, Slusher TM: Risk factors for
severe hyperbilirubinaemia in low and middle-income countries: a systematic review and meta-analysis. PLoS ONE 2015,10(2):e0117229.]
• → The distinction between when to begin CPT versus IPT is important in LMICs due to the sub-optimal quality of phototherapy and the limited number
of IPT units in many settings. No such clear distinction exists in the AAP guidelines.
• → If TcB level indicates PT, verify level using TSB measurement if available. It is acceptable to determine need for TSB with a TcB and it may be
acceptable to use TcB alone (under a photo-opaque patch) to follow infants under CPT. TcB values above 12 mg/dl (205 μmol/L) should be cross-
checked where possible with TSB measurement.
• → All blood specimens for TSB measurement must be shielded from light to prevent photo-degradation of the sample serum bilirubin.
A centre or hospital, at any level, not appropriately resourced to provide the required treatment should refer promptly to the closest suitable health facility.

receive priority based on the risk of ABE may be conventional treatment is not assured, the trade-off be-
required. Under such conditions, a BIND assessment can tween the risk of ABE/kernicterus and of exposure to
aid deci-sions for intervention [40,59]. sunlight remains a challenge that requires individual and
Guidelines for hyperbilirubinaemia in many high- informed judgment call in the patient’s best interest.
income countries prohibit exposure to sunlight as a form Immediate exchange transfusion is warranted when
of treatment [4,5,60]. This is primarily due to safety con- phototherapy has failed to effectively curtail the rate of
cerns regarding potentially harmful infrared and ultra- bilirubin rise and the TSB/TcB measurement is near ex-
violet rays and possible sunburn. In Ghana, exposure of change levels or the infant has any of the signs of mod-
jaundiced infants to sunlight is acknowledged as a treat- erate to advanced ABE regardless of the TSB/TcB levels
ment option [61], but WHO guidelines and some other (Figure 1, Table 3). This treatment is most likely to be
developing countries like Malaysia, India and Kenya dis- available at tertiary hospitals with trained personnel and
courage or have not made provisions for sunlight ther-apy facilities for special care, including monitoring and
(see Additional file 1: Table S1). However, mothers and resuscitation capabilities. As exchange transfusion is not
caregivers with or without the support of health workers without risks [69-71], its frequency should be mini-mised
continue to expose their jaundiced babies to direct as far as practicable. Exchange transfusion with G6PD
sunlight even in high-income countries [62-66]. Emerging deficient donor blood should be avoided where possible
evidence suggests that the potential risks can be mitigated as this may prolong time under phototherapy and result in
through specially filtered film canopies which have been repeat exchange transfusions [72]. Simi-larly, blood
successfully piloted in West Africa [67,68]. However, should be screened for HIV and hepatitis. Rh-negative
their use is still experimental and lim-ited to daytime care blood should be used for neonates with Rh-
at periods with favourable climatic conditions. In remote isoimmunisation while O group should be used for
tropical locations where access to neonates with ABO incompatibility.
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 9 of 12

The evidence in support of pharmacotherapies such as groups and community leaders. It may be helpful to
D-penicillamine, phenobarbital, metalloporphyrins, clofi- prepare separate documents for each level of care to avoid
brate, bile salts, laxatives and bilirubin oxidase are in- information overload especially at the primary care level.
conclusive and these interventions have not been While the scope of this framework is not ex-haustive, like
recommended [73]. Likewise traditional herbs or medi- any of the existing guidelines, we believe that most of the
cations used to treat newborn jaundice in many home recommendations will still be valuable to LMICs that did
settings are not recommended. not meet our selection criteria. Fi-nally, strong clinical
and public health leadership at all levels will be required
Follow-up evaluation to surmount the challenges that typically mitigate against
The manifestations of BIND such as cerebral palsy, initiatives for improved child and newborn care in LMICs
auditory impairments, epilepsy, gross motor deficits, [78,79].
behavioural problems and intellectual difficulties are not
uncommon in LMICs [9-13]. Follow-up evaluation of
Conclusions
survivors of severe hyperbilirubinaemia for potential
In sharp contrast to the practice in most high-income
neurodevelopmental sequelae is necessary to facilitate
nations, national guidelines for the effective manage-ment
early detection and intervention for the affected infants.
of severe hyperbilirubinaemia are rare in LMICs where
This must be considered as an integral part of any clin-
the disease burden is greatest. In this paper, the authors
ical protocol for the management of infants who have
have attempted to identify a number of key considerations
been treated for severe hyperbilirubinaemia. Because
for the effective management of hyper-bilirubinaemia in
hearing impairment, including auditory neuropathy
LMICs that can be considered truly resource-poor, based
spectrum disorders in the first year of life is often not
on their HDI status. Most of the recommendations have
clinically apparent, at-risk infants must be objectively
been adapted from existing evi-dence or consensus-based
evaluated within the first three months and monitored for
guidelines in the industria-lised world after extensive
language development in the first two years of life
consultations at different stages with experts from various
irrespective of the hearing test result. Referral to the
countries. Efforts were made to ensure that the proposed
audiology or otolaryngology unit of a tertiary hospital
framework is consist-ent with universally accepted
should therefore be considered. Several low-cost and
requirements for quality in healthcare. It is hoped that
simple-to-use validated tools for early developmental
these recommendations will assist in the development of
assessment as well as approaches to effective interven-
context-specific na-tional guidelines and mobilisation of
tion in resource-limited settings have also been docu-
requisite resources for the care of infants with or at risk of
mented [74,75].
severe hyperbi-lirubinaemia at all levels of healthcare
delivery in LMICs.
Limitations
While we set out to ensure that our recommendations are
realistic and consistent with the prevailing condi-tions in
most LMICs, the methodological approach used in this Additional files
document deserves clarification. We followed standard
protocols for guideline adaptation in-cluding a Additional file 1: Table S1. Current published guidelines/

comprehensive review of the priority issues to be recommendations for the management of hyperbilirubinaemia.

considered, the formation of a working group, qual-ity Additional file 2: Table S2. Eligible low and middle-income
countries (GNI per capita ≤$6,000).
rating of existing guidelines and independent review by a
Additional file 3: Figure S1. Guide to dermal staining with
panel of leading clinicians and experts on newborn care approximate serum bilirubin levels (Modified Kramer’s Scale).
from different world regions [25-27]. However, we did Additional file 4: Table S3. Bilirubin-Induced Neurological
not grade specific studies in support of various pro-posals Dysfunction (BIND) II Scoring.
in this paper, more so because the body of evi-dence was
predominantly adapted from existing guidelines or
Abbreviations
supported by the best available data from LMICs AAP: American Academy of Pediatrics; ABE: Acute Bilirubin Encephalopathy;
[17,22,76]. Neonatal hyperbilirubinaemia is fre-quently BIND: Bilirubin induced neurologic dysfunction; CPT: Conventional
underpinned by complex interactions of diverse biological phototherapy; CWG: Core Working Group; ET: Exchange transfusion;
FS-PT: Filtered-Sunlight Phototherapy; G6PD: Glucose-6-Phosphate
and environmental risk factors across popu-lations. It is Dehydrogenase; GNI: Gross National Income; HDI: Human Development
our view therefore, that each LMIC still needs to develop Index; LED: Light emitting diodes; LMIC: Low- or middle-income country;
context-specific guidelines for their own population [77]. LMICs: Low and middle-income countries; NICE: National Institute for Health
and Clinical Experience; NNJ: Neonatal Jaundice; PT: Phototherapy; TSB: Total
Such an initiative should be broadened to involve key Serum/Plasma Bilirubin; TcB: Transcutaneous Bilirubin; UNDP: United Nations
stakeholders including parent Development Program; WHO: World Health Organization.
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 10 of 12

Competing interests References

The authors declare that they have no competing interests. 1. The Young Infants Clinical Signs Study Group. Clinical signs
that predict severe illness in children under age 2 months: a
multicentre study. Lancet. 2008;371:135–42.
Authors’ contributions 2. Burke BL, Robbins JM, Bird TM, Hobbs CA, Nesmith C, Tilford JM.
BOO conceptualised and designed the study, coordinated the literature Trends in hospitalizations for neonatal jaundice and kernicterus in
search, review and evaluation of available guidelines on neonatal jaundice the United States, 1988–2005. Pediatrics. 2009;123:524–32.
and drafted the initial manuscript. She provided overall leadership for the 3. Tomashek KM, Crouse CJ, Iyasu S, Johnson CH, Flowers LM. A
development of the practice framework, ensuring that the comments from comparison of morbidity rates attributable to conditions originating in the
the expert panel were diligently addressed and reflected in the revised perinatal period among newborns discharged from United States hospitals,
manuscript. TAO contributed to the review and evaluation of available 1989–90 and 1999–2000. Paediatr Perinat Epidemiol. 2006;20:24–34.
guidelines on neonatal jaundice, the development of Figure 1 and Tables 2
and 3, and drafting of the manuscript. PK, NYB, IFI, MFBA critically 4. National Institute for Health and Clinical Excellence (NICE). Neonatal
reviewed the first draft for intellectual content and relevance to practice in jaundice. (Clinical guideline 98.), 2010. www.nice.org.uk/CG98.
LMICs and contributed significantly to further development of Figure 1 and 5. American Academy of Pediatrics (AAP). Management of
Tables 2 and 3. YEV & TMS contributed significantly to the development of hyperbilirubinaemia in the newborn infant 35 or more weeks of
the supporting data for the first draft including the review and evaluation of gestation. Pediatrics. 2004;114:297–316.
the existing guidelines and subsequent revision of the manuscript to reflect 6. Slusher TM, Vreman HJ, McLaren DW, Lewison LJ, Brown AK,
contributions from the expert review panel. All authors reviewed and Stevenson DK. Glucose-6-phosphate dehydrogenase deficiency and
approved the final manuscript as submitted and take full responsibility for carboxy-hemoglobin concentrations associated with bilirubin-related
the views expressed in the paper. Core Working Group (CWG): BOO, morbidity and death in Nigerian infants. J Pediatr. 1995;126:102–8.
TAO, YEV and TMS. 7. English M, Ngama M, Musumba C, Wamola B, Bwika J, Mohammed
S, et al. Causes and outcome of young infant admissions to a
Kenyan district hospital. Arch Dis Child. 2003;88:438–43.
Acknowledgements
8. Hameed NN, Na' Ma AM, Vilms R, Bhutani VK. Severe neonatal
We thank Henry Akinbi (USA/Nigeria), Peter Dijk (Netherlands), Finn Ebbesen
hyperbilirubinemia and adverse short-term consequences in
(Denmark), Mike English (UK/Kenya), Thor Hansen (Norway), Priscilla Joe
Baghdad, Iraq. Neonatology. 2011;100:57–63.
(USA), Michael Kaplan (Israel), Jeffrey Maisels (USA), Elizabeth Molyneux
(Malawi), Margaret Nakakeeto (Uganda), Janet Rennie (UK), Michael Sgro
9. Mwaniki MK, Atieno M, Lawn JE, Newton CR. Long-term
(Canada), David Stevenson (USA), Jon Watchko (USA), Richard Wennberg
neurodevelopmental outcomes after intrauterine and neonatal
insults: a systematic review. Lancet. 2012;379:445–52.
(USA) and Alvin Zipursky (Canada) for their invaluable comments made
anonymously on earlier drafts of this paper. One of our expert reviewers, a 10. Gladstone M. A review of the incidence and prevalence, types
retired paediatrician from the UK, who made significant contributions to this work and aetiology of childhood cerebral palsy in resource-poor
opted to remain anonymous. Another internal reviewer from the USA declined
settings. Ann Trop Paediatr. 2010;30:181–96.
11. Amin SB, Smith T, Wang H. Is neonatal jaundice associated with autism spectrum
acknowledgement for his inputs. Two internal reviewers invited from India and
disorders: a systematic review. J Autism Dev Disord. 2011;41:1455–63.
Australia/Papua New Guinea did not provide their comments before the
manuscript was submitted for publication. We are especially indebted to Peter 12. Olusanya BO, Somefun AO. Sensorineural hearing loss in
Dijk, Thor Hansen, Michael Kaplan, Elizabeth Molyneux and David Stevenson infants with neonatal jaundice in Lagos: a community-based
for further review of the final version before submission. The named authors study. Ann Trop Paediatr. 2009;29:119–28.
alone are responsible for the views expressed in this paper. 13. Maulik PK, Darmstadt GL. Childhood disability in low- and middle-
income countries: overview of screening, prevention, services,
legislation, and epidemiology. Pediatrics. 2007;120 Suppl 1:S1–55.
14. Bhutani VK, Zipursky A, Blencowe H, Khanna R, Sgro M, Ebbesen F,
Funding source et al. Neonatal hyperbilirubinemia and Rhesus disease of the
No external funding was received by any of the authors for this work. newborn: incidence and impairment estimates for 2010 at regional
and global levels. Pediatr Res. 2013;74 Suppl 1:86–100.
15. Lawn JE, Blencowe H, Oza S, You D, Lee AC, Waiswa P, et al. Lancet
Financial/academic disclosure Every Newborn Study Group. Every Newborn: progress, priorities, and
The authors have no financial relationships relevant to this article to disclose.
potential beyond survival. Lancet. 2014;384:189–205.
Some authors had conducted research projects or done systematic reviews on
16. Iskander I, Gamaleldin R, Kabbani M. Root causes for late
neonatal jaundice relevant to this paper. However, these engagements did not
presentation of severe neonatal hyperbilirubinaemia in Egypt.
pose any material risk of bias in the development of this document. An earlier
East Mediterr Health J. 2012;8:882–7.
version of this work was presented at the Global Prevention of Kernicterus
17. Olusanya BO, Ogunlesi TA, Slusher TM. Why is kernicterus still a
Network plenary track of the Pediatric Academic Societies and Asian Society for
major cause of death and disability in low and middle-income
Pediatric Research joint annual scientific meeting held in Vancouver, Canada,
countries? Arch Dis Child. 2014;99:1117–21.
May 3 – 6, 2014.
18. Bhutani VK, Cline BK, Donaldson KM, Vreman HJ. The need
to implement effective phototherapy in resource-constrained
Author details
1 settings. Semin Perinatol. 2011;35:192–7.
Centre for Healthy Start Initiative, 286A, Corporation Drive, Dolphin Estate,
2
19. Cline BK, Vreman HJ, Faber K, Lou H, Donaldson KM, Amuabunosi E, et al.
Ikoyi, Lagos, Nigeria. Department of Paediatrics, Olabisi Onabanjo University Phototherapy device effectiveness in Nigeria: irradiance assessment and
3
Teaching Hospital, Sagamu, Nigeria. Department of Paediatrics, Neonatal Unit, potential for improvement. J Trop Pediatr. 2013;59:321–5.
Postgraduate Institute of Medical Education and Research, Chandigarh, India.
4 20. Pejaver RK, Vishwanath J. An audit of phototherapy units.
Department of Population Medicine, Faculty of Medicine and Health Sciences,
Indian J Pediatr. 2000;67:883–4.
Universiti Tunku Abdul Rahman, Bandar Sungai Long, Selangor, Malaysia.
5 6 21. Owa JA, Ogunlesi TA. Why we are still doing so many exchange blood
Department of Paediatrics, Cairo University, Cairo, Egypt. Division of
transfusion for neonatal jaundice in Nigeria. World J Pediatr. 2009;5:51–5.
Neonatology, Federal University of São Paulo-UNIFESP, São Paulo, SP, Brazil.
7 22. Olusanya BO, Emokpae AA, Zamora TG, Slusher TM. Addressing the burden of
Division of Neonatal/Perinatal Medicine, School of Medicine, University of
8 severe neonatal hyperbilirubinaemia in low and middle-income countries with
California at San Diego, San Diego, USA. Division of Global Paediatrics,
9 significant G6PD-deficiency. Acta Paediatr. 2014;103:1102–9.
University of Minnesota, Minneapolis, Minnesota, USA. Hennepin County
23. Khassawneh M, Rubaie Z, Khashashneh I, Makhlouf F, Alkafajei A.
Medical Centre, Minneapolis, Minnesota, USA.
Adherence with American Academy of Pediatrics guidelines when
managing neonatal jaundice in Jordan. Res Rep Neonatol. 2013;3:27–31.
Received: 12 December 2014 Accepted: 30 March 2015
24. Fervers B, Burgers JS, Voellinger R, Brouwers M, Browman GP, Graham ID, et
al. ADAPTE Collaboration. Guideline adaptation: an approach to enhance
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 11 of 12

efficiency in guideline development and improve utilisation. BMJ Qual Saf. 49. Maisels MJ, Kring E. Transcutaneous bilirubin levels in the first
2011;20:228–36. 96 hours in a normal newborn population of > or = 35 weeks'
25. World Health Organisation. WHO Handbook for guideline gestation. Pediatrics. 2006;117:1169–73.
development. Geneva: WHO; 2012. 50. De Luca D, Jackson GL, Tridente A, Carnielli VP, Engle WD. Transcutaneous
26. The ADAPTE Collaboration. The ADAPTE Process: Resource bilirubin nomograms: a systematic review of population differences and analysis
Toolkit for Guideline Adaptation. Version 2.0; 2009. Retrieved < of bilirubin kinetics. Arch Pediatr Adolesc Med. 2009;163:1054–9.
October 20, 2014>, from http://www.g-i-n.net. 51. Mishra S, Chawla D, Agarwal R, Deorari AK, Paul VK.
27. AGREE Next Steps Consortium. The AGREE II Instrument Transcutaneous bilirubin levels in healthy term and late preterm
[Electronic version], 2009. Retrieved <October 20, 2014>, Indian neonates. Indian J Pediatr. 2010;77:45–50.
from http:// www.agreetrust.org 52. Dijk PH, Hulzebos CV. An evidence-based view on
28. World Health Organisation. Pocket Book of Hospital Care for hyperbilirubinaemia. Acta Paediatr Suppl. 2012;101:3–10.
Children: Guidelines for the Management of Common Childhood 53. Tridente A, De Luca D. Efficacy of light-emitting diode versus other light
Illnesses. 2nd ed. Geneva: World Health Organisation; 2013. sources for treatment of neonatal hyperbilirubinemia: a systematic
29. The Partnership for Maternal, Newborn & Child Health. A Global Review review and meta-analysis. Acta Paediatr. 2012;101:458–65.
of the Key Interventions Related to Reproductive, Maternal, Newborn and 54. Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy
Child Health (RMNCH). Geneva, Switzerland: PMNCH; 2011. for unconjugated hyperbilirubinaemia in neonates. Cochrane
30. Institute of Medicine. Crossing the Quality Chasm: A New Health System for Database Syst Rev. 2011;12, CD007969.
st 55. Anwar Z, Butt TK. Cost of patient care in neonatal unit. Pak
the 21 Century. Washington, DC: The National Academies Press; 2001.
Paediatr J. 2009;33:14–8.
31. Jones J, Hunter D. Consensus methods for medical and
health services research. BMJ. 1995;311:376–80. 56. Djokomuljanto S, Quah BS, Surini Y, Noraida R, Ismail NZ,
Hansen TW, et al. Efficacy of phototherapy for neonatal
32. World Health Organisation Working Group. Glucose-6-phosphate
jaundice is increased by the use of low-cost white reflecting
dehydrogenase deficiency. Bull World Health Organ. 1989;67:601–11.
curtains. Arch Dis Child Fetal Neonatal Ed. 2006;91:439–42.
33. Academy of Breastfeeding Medicine Protocol Committee. ABM 57. De Carvalho M, De Carvalho D, Trzmielina S, Lopes JM,
clinical protocol #22: guidelines for management of jaundice in Hansen TW. Intensified phototherapy using daylight
the breastfeeding infant equal to or greater than 35 weeks' fluorescent lamps. Acta Paediatr. 1999;88:768–71.
gestation. Breastfeed Med. 2010;5:87–93. 58. World Health Organisation. Medical devices and eHealth solutions:
34. Gill CJ, Phiri-Mazala G, Guerina NG, Kasimba J, Mulenga C, compendium of innovative health technologies for low-resource settings 2011–
MacLeod WB, et al. Effect of training traditional birth attendants 2012. Geneva: WHO; 2013 [http://apps.who.int/iris/bitstream/10665/
on neonatal mortality (Lufwanyama Neonatal Survival Project): 88229/1/9789241505918_eng.pdf].
randomised controlled study. BMJ. 2011;342:d346. 59. Postgraduate Institute of Medical Education and Research (PGIMER).
35. Bhutta ZA, Soofi S, Cousens S, Mohammad S, Memon ZA, Ali I, Jaundice. In: Dutta S, Kumar P, editors. The PGI NICU Handbook of
et al. Improvement of perinatal and newborn care in rural Protocols Fourth Edition. Chandigarh, India: The New Heart Trust; 2010.
Pakistan through community-based strategies: a cluster- 60. Queensland Maternity and Neonatal Clinical Guidelines.
randomised effectiveness trial. Lancet. 2011;377:403–12. Neonatal jaundice. Australia: Queensland Government; 2012
36. Gogia S, Ramji S, Gupta P, Gera T, Shah D, Mathew JL, et al. Community [http://www.health.qld.gov.au/qcg/ documents/g_jaundice.pdf].
based newborn care: a systematic review and meta-analysis of evidence: 61. Republic of Ghana, Ministry of Health. Neonatal Jaundice: problems of the
UNICEF-PHFI series on newborn and child health. India Indian Pediatr. newborn in Standard Treatment Guidelines, Sixth edition. Accra:
2011;48:537–46. Ghana National Drugs Programme (GNDP); 2010 [http://apps.who.int/
37. Tikmani SS, Warraich HJ, Abbasi F, Rizvi A, Darmstadt GL, Zaidi AK. medicinedocs/documents/s18015en/s18015en.pdf].
Incidence of neonatal hyperbilirubinemia: a population-based 62. Boo NY, Gan CY, Gian YW, Lim KS, Lim MW, Krishna-Kumar
prospective study in Pakistan. Trop Med Int Health. 2010;15:502–7. H. Malaysian mothers' knowledge & practices on care of
38. Hatzenbuehler L, Zaidi AK, Sundar S, Sultana S, Abbasi F, Rizvi A, et al. neonatal jaundice. Med J Malaysia. 2011;66:239–43.
Validity of neonatal jaundice evaluation by primary health-care workers and 63. Okperi BO. Neonatal jaundice and birth asphyxia as major causes of
physicians in Karachi. Pakistan J Perinatol. 2010;30:616–21. cerebral palsy in Nigeria: are doctors’ wrong beliefs and practices part
39. Valman HB. The first year of life: Jaundice in the of the problem? Int J Med Biomed Res. 2013;2:226–30.
newborn. BMJ. 1989;299:1272–4. 64. Rasul CH, Hasan MA, Yasmin F. Outcome of neonatal hyperbilirubinemia
40. Gamaleldin R, Iskander I, Seoud I, Aboraya H, Aravkin A, Sampson in a tertiary care hospital in Bangladesh. Malays J Med Sci. 2010;17:40–4.
PD, et al. Risk factors for neurotoxicity in newborns with severe 65. Petrova A, Mehta R, Birchwood G, Ostfeld B, Hegyi T.
neonatal hyperbilirubinemia. Pediatrics. 2011;128:e925–31. Management of neonatal hyperbilirubinemia: pediatricians'
41. Radmacher PG, Groves FD, Owa JA, Ofovwe GE, Amuabunos EA, practices and educational needs. BMC Pediatr. 2006;6:6.
Olusanya BO, et al. A modified bilirubin-induced neurologic 66. Harrison SL, Buettner PG, MacLennan R. Why do mothers still
dysfunction (BIND-M) algorithm is useful in evaluating severity of sun their infants? J Paediatr Child Health. 1999;35:296–9.
jaundice in a resource-limited setting. BMC Pediatrics. 2015;15:28. 67. Slusher TM, Vreman HJ, Olusanya BO, Wong RJ, Brearley AM,
42. Hansen TW. Prevention of neurodevelopmental sequelae of jaundice Vaucher YE, et al. Safety and efficacy of filtered sunlight in treatment of
in the newborn. Dev Med Child Neurol. 2011;53 Suppl 4:24–8. jaundice in African neonates. Pediatrics. 2014;133:e1568–74.
43. Johnson L, Bhutani VK, Karp K, Sivieri EM, Shapiro SM. Clinical report from the pilot 68. Slusher TM, Olusanya BO, Vreman HJ, Wong RJ, Brearley
USA Kernicterus Registry (1992 to 2004). J Perinatol. 2009;29 Suppl 1:S25–45.
AM, Vaucher YE, et al. Treatment of neonatal jaundice with
filtered sunlight in Nigerian neonates: study protocol of a non-
44. Rylance S, Yan J, Molyneux E. Can transcutaneous
inferiority, randomized controlled trial. Trials. 2013;14:446.
bilirubinometry safely guide phototherapy treatment of neonatal
69. Salas AA, Mazzi E. Exchange transfusion in infants with extreme
jaundice in Malawi? Paediatr Int Child Health. 2014;34:101–7.
hyperbilirubinemia: an experience from a developing country.
45. Akahira-Azuma M, Yonemoto N, Ganzorig B, Mori R, Hosokawa S, Matsushita T, Acta Paediatr. 2008;97:754–8.
et al. Validation of a transcutaneous bilirubin meter in Mongolian neonates:
70. Dikshit SK, Gupta PK. Exchange transfusion in neonatal
comparison with total serum bilirubin. BMC Pediatr. 2013;13:151.
hyperbilirubinemia. Indian Pediatr. 1989;26:1139–45.
46. Slusher TM, Angyo IA, Bode-Thomas F, Akor F, Pam SD, Adetunji AA, et 71. Ibekwe RC, Ibekwe MU, Muoneke VU. Outcome of exchange
al. Transcutaneous bilirubin measurements and serum total bilirubin blood transfusions done for neonatal jaundice in Abakaliki, South
levels in indigenous African infants. Pediatrics. 2004;113:1636–41. eastern Nigeria. J Clin Neonatol. 2012;1:34–7.
47. O'Connor MC, Lease MA, Whalen BL. How to use: transcutaneous 72. Samanta S, Kumar P, Kishore SS, Garewal G, Narang A. Donor blood glucose 6-
bilirubinometry. Arch Dis Child Educ Pract Ed. 2013;98:154–9. phosphate dehydrogenase deficiency reduces the efficacy of exchange
48. Coda Zabetta CD, Iskander IF, Greco C, Bellarosa C, Demarini S, transfusion in neonatal hyperbilirubinemia. Pediatrics. 2009;123:e96–100.
Tiribelli C, et al. Bilistick: a low-cost point-of-care system to
measure total plasma bilirubin. Neonatology. 2013;103:177–81.
Olusanya et al. BMC Pediatrics (2015) 15:39 Page 12 of 12

73. Schulz S, Wong RJ, Vreman HJ, Stevenson DK.

Metalloporphyrins - an update. Front Pharmacol.
2012;3:68. doi:10.3389/fphar.2012.00068. eCollection.
74. Ertem IO, Dogan DG, Gok CG, Kizilates SU, Caliskan A, Atay G,
et al. A guide for monitoring child development in low- and
middle-income countries. Pediatrics. 2008;121:e581–9.
75. Yousafzai AK, Lynch P, Gladstone M. Moving beyond prevalence studies:
screening and interventions for children with disabilities in low-income and
middle-income countries. Arch Dis Child. 2014;99:840–8.
76. Guyatt GH, Oxman AD, Kunz R, Falck-Ytter Y, Vist GE, Liberati A, et al.
Going from evidence to recommendations. BMJ. 2008;336:1049–51.
77. Haroon M, Ranmal R, McElroy H, Dudley J. On behalf of the
Royal College of Paediatrics and Child Health Clinical Standards
Committee. Developing clinical guidelines: how much rigour is
required? Arch Dis Child Educ Pract Ed. 2015;100:89–96.
78. English M, Wamae A, Nyamai R, Bevins B, Irimu G. Implementing
locally appropriate guidelines and training to improve care of serious
illness in Kenyan hospitals: a story of scaling-up (and down and left
and right). Arch Dis Child. 2011;96:285–90.
79. Basnet S, Adhikari N, Koirala J. Challenges in setting up
pediatric and neonatal intensive care units in a resource-
limited country. Pediatrics. 2011;128:e986–92.

Submit your next manuscript to BioMed Central

and take full advantage of:

• Convenient online submission

• Thorough peer review
• No space constraints or color figure charges
• Immediate publication on acceptance
• Inclusion in PubMed, CAS, Scopus and Google Scholar
• Research which is freely available for redistribution

Submit your manuscript at

www.biomedcentral.com/submit