UNIT-IV: NEONATOLOGY (Neonatology Nursing)

High-risk newborn and nursing responsibility in the care of newborn

NEONATAL HYPERBILIRUBINEMIA

Introduction

The term bilirubinemia refers to an excessive level of accumulated bilirubin in the blood and is
characterized by jaundice, or icterus, a yellowish discoloration of the skin, sclera, and nails.
Hyperbilirubinemia is a common finding in newborns and in most instances is relatively benign.
However, in extreme cases, it can indicate a pathologic state. Hyperbilirubinemia may result
from increased unconjugated or conjugated bilirubin. The unconjugated form or indirect
hyperbilirubinemia is the type most commonly seen in newborns.

Etiology

Causes of jaundice on the basis of age of onset

1. Within 24 hour of birth

1. Hemolytic disease of the newborn due to feto-maternal blood group incomapatibility (Rh,
ABO)

2. Intrauterine infections (TORCH, Syphilis, bacterial infections, etc)

3. Deficiency of red cell enzymes (Glucose-6-phosphate dehydrogenase, pyruvate kinase,

unstable hemoglobins, etc)

4. Administration of large amount of certain drugs ( Vit K, salicylates, oxytocin) to the

mother

5. Hereditary spherocytosis

6. Crigler-Najjar syndrome

7. Lucey-Driscoll syndrome

8. Homozygous alpha-thalassemia

2. Between 24 and 72 hours of age

1. Physiological jaundice appears during this period but can be aggravated and prolonged by

1. Immaturity
2. Birth asphyxia

3. Acidosis

4. Hypothermia

5. Hypoglycemia

6. Polycythemia

7. Cephalhematoma or concealed hemorrhage and bruising

8. Infections and mild hemolytic states due to fetomaternal blood group incompatibility,
spherocytosis and deficiency of red cell enzymes

9. Breastfeeding

3. After 72 hours of age

2. Septicemia

3. Neonatal hepatitis including other causes of intrauterine infections

4. Extrahepatic biliary atresia

5. Breast-milk jaundice

6. Metabolic diseases such as galactosemia, tyrosinemia, hereditary fructosemia, etc.

7. Cystic fibrosis

8. Intestinal obstruction

9. Hypothyroidism

10. Hypertrophic pyloric stenosis

11. Alpha-1 antitrypsin deficiency

Pathophysiology

Bilirubin physiology

Bilirubin is the end product of the catabolism of iron protoporphyrins or heme. The formation of
bilirubin from hemoglobin occurs in the reticuloendothelial system. Hemoglobin is made of
heme (an iron containing porphyrin derivative) and globin (made of 4 polypeptide chain). The
heme after destruction of RBC is converted to biliverdin and then to bilirubin and excreted in the
bile.

Transport, hepatic uptake and excretion

Once the bilirubin leaves the reticuloendothelial system, it is transported in the plasma to the
liver, bound reversely but tightly to albumin. Bilirubin, and not albumin, is transferred across the
cell membrane into the hepatocyte. Bilirubin is primarily bound to ligandin within the cell and
this binding prevents its backflow into circulation. This bound intracellular bilirubin is
transferred to the smooth endoplasmic reticulum for conjugation. Conjugation is aided by uridine
diphosphate glucuronyl transferase (UDPG-T) in the first 48 hours of life, only bilirubin
monoglucuronide is produced. After that bilirubin diglucuronide is the main product. Both this
product are water-soluble and are excreted into bile. This is an active energy dependent process
as the conjugated bilirubin is excreted against a large concentration gradient.

Enterohepatic circulation

The sterile intestine of the newborn is rich in a glucuronidase enzyme which splits bilirubin
glucuronide into bilirubin and glucuronic acid. This unconjugated bilirubin is now capable of
being reabsorbed and returned to the circulation.

Physiological jaundice

Jaundice due to physiological immaturity of newborn babies is seen in nearly 60% of term and
80% of preterm neonates. It is due to elevation of unconjugated bilirubin concentration. It would
appear that physiological jaundice may provide useful protection to the baby against oxygen free
radical triggered neonatal disorders because bilirubin is potent antioxidant.

In term babies

4. It appears between 36 and 72 hours of age.

5. Maximum intensity of jaundice is seen on the 4th day.

6. Serum bilirubin does not exceed 15mg/dl and

7. Jaundice disappears by 10 days of life.

In preterm babies

1. It may manifest earlier but never before 24 hours of age.

2. The maximum intensity of jaundice is reached on the 5th or 6th day.

3. Serum bilirubin may go up to 15mg/dl and it may persist up to 14 days.

4. The designation of “physiological” jaundice in the preterm may appear as a misnomer
because jaundice due to physiologic handicaps of immaturity often requires phototherapy
and may even cause brain damage.

Possible mechanisms in physiological jaundice

The etiology of physiologic jaundice appears to be multifactorial.

1. Increase bilirubin load on liver cells

1. Over production of bilirubin due to polycythemia and reduced lifespan of fetal red blood
cells.

2. Increased production of blirubin from non-hemoglobin sources in the newborn.

2. Reduced uptake of bilirubin by the liver

1. Deficiency of ligandin or Y-acceptor protein in the hepatocytes.

3. Defective bilirubin conjugation

2. Deficiency of UDP glucose dehydrogenase during first few days of life.

4. Defective bilirubin excretion

Pathological jaundice (Unconjugated Hyperbilirubinema)

When jaundice in the newborn does not conform to the timetable described for physiological
jaundice or any if the following features characterizes pathological jaundice:

3. Clinical jaundice appearing in the first 24 hours.

4. Increase in level of total bilirubin by more than 0.5 mg/dl/hour or 5 mg/dl/24 hours.

5. Total bilirubin more than 15 mg/dl

6. Direct bilirubin more than 2.0 mg/dl

Causes

Increased production

1. Feto-maternal blood group incompatibility: Rh, ABO

2. Hereditary spherocytosis

3. Non-spherocytic hemolytic anemia: G6PD deficiency, pyruvate kinase deficiency, alpha

thalassemia, vitamin K induced hemolysis

4. Sepsis

5. Increased enterohepatic circulation: pyloric stenosis, or large bowel obstruction

Decreased clearance

1. Inborn errors of metabolism: Criggler-Najjar syndrome type I and II

2. Drugs and hormones: Hypothyroidism , Breastmilk jaundice

Breastmilk jaundice

Breastmilk jaundice is a misnomer since no factor in breastmilk has consistently been shown to
be causative of jaundice in neonates and this terminology should be better avoided. It is more
appropriate to term this condition as idiopathic jaundice. Labeling the condition as breastmilk
jaundice may undermine the efforts to promote breastfeeding.

The condition may manifest as persistence of physiological jaundice or it may appear for the first
time at the end of week. It is maximum in intensity between 10 and 14 days but
hyperbilirubinemia is never severe enough to need exchange blood transfusion. Multiple factors
operate to aggravate jaundice in breastfed babies.

Colonization of gut is delayed in breastfed infants resulting in greater deconjugation of bilirubin

and enhanced enterohepatic circulation. Hepatic conjugation of bilirubin is compromised due to
presence of 3-alpha, 20 beta pregnanediol is about 1 to 2% of women. High concentrations of
unsaturated fatty acids due to over activity of lipase may also inhibit hepatic glucuronyl
transferase enzyme and y-receptor protein. The inhibitory substance in the breast-milk is
excreted for a period of 2-8 weeks and breastfeeding should be continued unless critical levels of
bilirubin are achieved.

Clinical features

Early phase (First 1-2 days)

1. Poor sucking
2. Hypotonia
3. Lethargy
4. High pitched cry
5. Loss of moro reflex
Intermediate phase (3-7 days)
1. Hypertonia
2. Opisthotonus
3. Retrocollis
4. Fever
5. Seizures
6. Bulging of anterior fontanelle
Advanced phase (more than 1 week)
1. Pronounced opisthotonus
2. Apnea
3. Seizures
4. Coma and death
Chronic phase (1st year)
1. Hypotonia
2. Brisk tendon reflexes
3. Delayed development
Diagnosis
Assessment of severity of jaundice

Jaundice should be assessed in natural daylight by observing cephalocaudal progression of

jaundice. Jaundice appears in the newborn when serum bilirubin level exceeds 5 mg/dl. In
newborn infants, jaundice can be detected by blanching the skin with digital pressure, revealing
the underlying color of the skin and subcutaneous tissue. Kramer described the approximate
serum bilirubin level with the level of skin discoloration. Serum levels of total bilirubin are
approximately 4-6 mg/dl (zone 1), 6-8 mg/dl (zone 2), 8-12 mg/dl (zone 3), 12-14 mg/dl (zone 4)
and >15 mg/dl (zone 5).
Transcutaneous Bilirubinometry

This is the non-invasive method to assess serum bilirubin levels. The device measures the
intensity of yellow staining of skin and subcutaneous tissues. The value is displayed as either
transcutaneous bilirubin index or a bilirubin value.

Serum bilirubin measurements

The evaluation of the jaundice is not based solely on serum bilirubin levels but also on the timing
of the appearance of clinical jaundice, gestational age at birth, age in days since birth, family
history, including maternal Rh factor, evidence of hemolysis, feeding method, infant’s
physiologic status, and the progression of serial serum bilirubin levels.

Clinical approach to jaundice:

Is the newborn term or preterm?

Basic pathophysiology of jaundice is same in term and preterm neonates but lower gestation
babies are at higher risk of developing hyperbilirubinemia.

Is there evidence of hemolysis?

1. Setting of Rh or less frequently ABO incompatibility

2. Onset of jaundice within 24 hours

3. Presence of pallor and hydrops

4. Presence of hepato-splenomegaly

5. Presence of hemolysis on the peripheral blood

Raised reticulocyte count (>8%)

6. Rapid rise of bilirubin (>5mg/dl in 24 hours or >0.5mg/dl/hours)

Family history of significant jaundice:

Does the infant have an underlying serious disease? (sepsis, galactosemia)

7. Presence of lethargy

8. Poor feeding

9. Failure to thrive

10. Hepatosplenomegaly

11. Temperature instability

12. Apnea

Does the infant have cholestatic jaundice?

1. Presence of jaundice (>10 mg/dl) beyond 3 weeks

2. Presence of dark urine

3. Pale colored stools

Management

Aim of management

To ensure that serum bilirubin is kept at a safe level and brain damage is prevented.

Point to be remembered

NNH is a medical emergency and delay in its management can lead to irriversible brain damage
or death.

Prediction of severe hyperbilirubinemia

Pre-discharge serum bilirubin plotted on an hour-specific bilirubin nomogram is useful in

identifying newborns at high risk for developing significant hyperbilirubinemia. Risk factors for
development of severe NNH in infants of 35 or more weeks of gestation can be classified as
major or minor.
Major risk factors

1. Pre-discharge TSB in the high risk zone

2. Jaundice observed in the 1st 24 hour
3. ABO incompatibility and other known hemolytic disease
4. Elevated end tidal carbon-monoxide content in exhaled air (ETCO2)
5. Gestational age 35-36 wk
6. Previous sibling received phototherapy
7. Cephal-hematoma or significant bruising
8. Exclusive breastfeeding
Minor risk factors
1. Pre-discharge TSB level in the high intermediate risk zone.
2. Gestational age 37-38 wk
3. Jaundice observed before discharge
4. Previous sibling with jaundice
5. Macrosomic infant of a diabetic mother
6. Maternal age≥25 years
7. Male gender
Decreased risk (these factors are associated with decreased risk of significant jaundice)
1. TSB level in the low-risk zone
2. Gestational age≥41wk
3. Discharge from hospital after 72 hour
Advise for physiological jaundice:
1. The parents should be explained about the benign nature of jaundice

2. Frequent and exclusive breastfeed

3. Bring the baby to the hospital if the baby looks too yellow or yellow discoloration of the
skin beyond the legs.
4. Any newborn discharged prior to 72 hours of life should be evaluated again in the next 48
hours for adequacy of breastfeeding and progression of jaundice.

5. Earlier or more frequent follow-up for those who have risk factors.

Management of pathological jaundice:

Laboratory confirmation of jaundice is indicated in:

1. Any term or near-term newborn with yellow staining of the skin beyond the
legs/estimated clinical.

2. Jaundice appearing within 24 hours should be managed as hemolytic jaundice.

3. All infants with bilirubin levels in the phototherapy range should have the following
investigations (as per availability of the facility)

1. Blood group

2. Coombs’test

3. Complete blood count

4. Smear for hemolysis and red blood cell morphology

5. Reticulocyte count

6. G6PD estimation

Management of neonatal hyperbilirubinemia in low birth weight babies based on bilirubin levels
(mg/dl) and relative health of the newborn

Serum Total Bilirubin (mg/dl)

Birth weight Healthy Sick

(gm)
Phototherapy Exchange Phototherapy Exchange
transfusion transfusion

Premature

<1000 5-7 11-13 4-6 10-12

 1001-1500 7-10 13-15 6-8 11-13

1501-2000 10-12 15-18 8-10 13-15

2001-2500 12-15 18-20 10-12 15-18

Term

>2500 15-18 20-25 12-15 Variable

Phototherapy
Phototherapy is widely accepted, relatively safe and effective method for treatment of NNH.
Mechanism of action
1. Photo-isomerization and photo-oxidation occurs during phototherapy.
2. Phototherapy converts toxic water insoluble unconjugated bilirubin to nontoxic water
soluble photoisomers which can be excreted in bile and urine without the need of hepatic
conjugation.
Phototherapy devices
1. Narrow spectral blue light
2. White day light flourescent lamps
3. Blue light emitting diodes (LEDs)
4. Blue compact flourescent tubes (CFT)
5. Double light system: the infant is placed on a fiber-optic cool biliblanket and
provided phototherapy from the top with halogen bulbs
Technique of giving phototherapy

1. Baby is placed under phototherapy naked except for eye patches to shield eyes from
intense light and cover the genitals in male infants.

2. The distance should be around 30 cm.

3. Position should be changed in every 2-3 hours.

4. Skin temperature should be monitored.

5. Should be continous except breaks for breastfeeding.

6. Maintain adequate hydration and good urine output.

Requirements for effective phototherapy

1. Minimum spectral irradiance or ‘flux’ of 15 µW/cm2/nm

2. The flux must be checked once a week with a radiometer and tubes should be replaced if
their flux falls below 15µW/cm2/nm.

3. The tubes should be changed after every 3 months or usage of 1000 hours or when their
ends blacken or tubes flicker.

4. To filter out ultraviolet rays, the tubelights should be shielded with plastic sheet or
plexiglass.

5. Using slings or curtains made of white cloth to reflect light on the baby.

6. Distance should not be more than 45 cm and can be reduced to 15-20 cm.

TSB levels:

1. Intensive phototherapy is likely to reduce the level of TSB by 30-40% in 24 hours OR 1-

2 mg/dl within 4-6 hours.

2. In a term baby, PT is stopped when TSB level falls to 13-14mg/dl.

3. When PT is stopped there is likely to be a rebound in TSB level by 1-2 mg/dl during next
6-12 hours.

Side effects

1. Increased insensible water loss can cause dehydration.

2. Loose green stools.
3. Skin rashes
4. Hypo or hyperthermia
5. Retinal damage: effect of high intensity light on the growing retina is uncertain. It is
essential therefore, that the eyes of all newborns exposed to phototherapy be covered with
sufficient layers of opaque material.
6. Bronze baby syndrome: in this condition the skin, urine and serum become brownish
black after several days of phototherapy. It is seen more often in neonates with
conjugated hyperbilirubinemia. Babies recover fully after several days once the
phototherapy is discontinued.
Exchange blood transfusion

It is the most effective and reliable method to reduce bilirubin levels.

Choice of blood

1. For ABO incompatibility: O Rh compatible blood cross matched against mother and
infant

2. For Rh isoimmunization: O negative cross matched blood

Indications

At birth

1. Hydrops fetalis due to Rh hemolytic disease

2. Cord blood bilirubin more than 4.5mg/dl

3. Cord blood Hb less than 11 g/dl

After birth

1. Rise in bilirubin levels more than 1mg/dl/hour despite phototherapy

2. Serum bilirubin levels more than 20mg/dl in hemolytic jaundice

3. Serum bilirubin levels more than 25-30mg/dl in non-hemolytic jaundice

4. Clinical suspicion of acute bilirubin encephalopathy

5. Infants complicated by perinatal hypoxia, hypothermia, acidosis, hypoglycemia, sepsis

and drugs should be exchanged at a relatively lower serum bilirubin level.
When facilities are available, brainstem evoked response audiometry (BERA) can be done to
assess the need for exchange blood transfusion.

Mechanism

1. It removes bilirubin, antibodies, sensitized RBCs and corrects anemia.

2. Normally, double volume exchange transfusion is carried out which replaces 87% of
infant’s blood volume and serum bilirubin levels decline by 50%.
Exchange transfusion routes

1. Umbilical vein

2. Femoral vein

3. Radial vein

Complications

1. Hazards of blood transfusion (risk of malaria, syphilis, CMV, HIV and Hep B & C)

2. Overloading of circulation with cardiac failure or shock following excessive deficit.

3. Hypocalcemia, hyperkalemia, acidosis and sudden cardiac arrest or arrhythma may occur
during exchange tranfusion.

Complications of NNH

Transient encephalopathy

Early bilirubin induced neurologic dysfunction is transient and reversible. This is suspected by
increasing lethargy with rising bilirubin levels but recovery following or prompt exchange
transfusion.

Kernicterus

Kernicterus describes the yellow staining of the brain cells. There is evidence that a fraction of
unconjugated bilirubin crosses the blood-brain barrier in neonates with physiologic
hyperbilirubinemia. This includes staining and necrosis of neurons in the basal ganglia,
hippocampal cortex, subthalamic nucei and cerebellum. Multiple factors contribute to bilirubin
neurotoxicity; therefore, serum bilirubin levels alone do not predict the risk of brain injury.
Clinically, kernicterus is described in phases, which may progress over 24 hours to 7 days.

Phase I: poor suck, lethargy, hypotonia, depressed sensorium

Phase II: fever, hypertonia progressing to opisthotonus

Phase III: high pitched cry, convulsions, death.

References:

1. Singh, Meherban, Care of the Newborn, Revised 8th edition, 2017, CBS Publishers and
Distributors Pvt. Ltd, 324-344
2. Ghai, O.P., Ghai Essential Pediatrics, 6 th edition, CBS Publishers and distributors; 2006,
169-174

3. Gupta, Piyush, Textbook of Pediatrics, 1st edition, CBS publishers, New Delhi, 2013

4. Hockenberry Marilyn J., Wilson David, Wong’s Essentials of Pediatric Nursing, First
South Asian Edition, Reed Elsevier India Pvt. Ltd., 220-224

5. Comprehensive Newborn Care In-Service Training Level II for Nurses, Reference

Manual, Government of Nepal, Ministry of Health, National Health Training Centre,
January 2017.