Jaundice is the most common morbidity in the first week of life.
It occurs in about 60% of term and 80% of preterm newborns.
In neonates, clinical jaundice appears when the total serum bilirubin (TSB) concentration exceeds 5 to 7 mg/dL.
It is globally ranked as the 7th leading cause of mortality in the early neonatal period.
Classification
Physiological Jaundice
This is attributable to the physiological immaturity of neonates.
It appears between 24 and 72 hours of life in term neonates.
TSB reaches a peak level of 12 to 15 mg/dL by 3 days and then starts falling.
In preterm neonates, the peak occurs between 3 and 7 days, and TSB can rise over 15 mg/dL.
Jaundice in most neonates is physiological and rarely requires treatment.
Pathological Jaundice
This is defined as bilirubin levels beyond the normal physiological range.
It generally requires further investigation and treatment.
Feature
Description
Time Of Onset
Visible jaundice in the first 24 hours of life.
Clinical Extent
Presence of jaundice on arms and legs on day 2 of life, or yellow palms and soles at any age.
Rate Of Rise
Rise of TSB more than 0.3 mg/dL/hour on day 1 and 0.2 mg/dL/hour beyond 24 hours.
Duration
Clinical jaundice persisting beyond 2 weeks in term and 3 weeks in preterm neonates.
Associated Signs
Any jaundice associated with features of bilirubin-induced neurological dysfunction.
Pathophysiology
Neonatal bilirubin production is two to three folds higher than that of adults.
This is due to
Increased red blood cell volume
A shortened red blood cell lifespan of 90 days.
The enzymes for bilirubin conjugation, specifically uridine diphosphogluconurate glucuronosyltransferase, have very little activity in neonates.
Defective uptake of bilirubin from plasma occurs due to decreased ligandin.
Enterohepatic circulation is enhanced due to deficient intestinal flora and high intestinal beta-glucuronidase activity. This causes increased reabsorption of conjugated bilirubin from the gut.
Risk Factors
Lower gestational age is a significant risk factor.
Hemolytic diseases, including immune-mediated causes or glucose-6-phosphate dehydrogenase deficiency, increase the risk.
A history of phototherapy in parents or a sibling is significant.
Extravasated blood, such as a scalp hematoma or significant bruising, increases bilirubin load.
Exclusively breastfed infants with suboptimal milk intake are at high risk.
Other factors include Down syndrome and macrosomic infants of diabetic mothers.
Clinical Assessment
All neonates should be visually inspected for jaundice at least every 12 hours during the initial 3 to 5 days.
Visual inspection should be done in bright natural light or bright white fluorescent light.
The skin should be blanched to note the extent of jaundice using Kramer's rule.
Kramer's Zone
Affected Area
Approximate TSB Level (Light Staining)
Approximate TSB Level (Deep Staining)
1
Face and neck
5 to 7 mg/dL
7 to 9 mg/dL
2
Chest and upper abdomen
7 to 9 mg/dL
9 to 11 mg/dL
3
Lower abdomen and thighs
9 to 11 mg/dL
11 to 13 mg/dL
4
Legs and arms/forearms
11 to 13 mg/dL
14 to 16 mg/dL
5
Palms and soles
13 to 15 mg/dL
17 mg/dL or more
BIND Scoring Matrix
Score
Mental Status
Muscle Tone
Cry Pattern
Oculomotor Signs (BIND-M)
0
Normal
Normal
Normal
Normal eye movements
1
Sleepy but arousable, decreased feeding
Persistent mild to moderate hypotonia
High-pitched when aroused
Divergent gaze or "sun-setting" sign
2
Lethargy, poor suck, persistent irritability, or jitteriness
Fluctuating tone (alternating hyper/hypotonia), early arching on stimulation
Shrill, difficult to console
Isolated paralysis of upward gaze
3
Semi-coma, seizures, apnea, or deep coma
Persistent retrocollis and opisthotonos, bicycling/twitching of extremities
Inconsolable crying, or cry weak/absent
Sustained nystagmus, fixed deviation, or anxious expression
Clinical Interpretation Reference
Total Score 1 – 3 (Mild): Early neurotoxicity. Generally reversible. Manage with immediate intensive phototherapy and close serial monitoring.
Total Score 4 – 6 (Moderate): Established neurotoxicity. Potentially reversible. Urgent preparation for emergency exchange transfusion alongside maximal intensive phototherapy.
Total Score 7 – 9+ (Severe): Advanced neurotoxicity. High risk of permanent structural injury (Kernicterus). Immediate rescue exchange transfusion required.
Unbound bilirubin can cross the intact blood-brain barrier and cause neuronal necrosis.
Acute bilirubin encephalopathy is the acute manifestation of bilirubin toxicity.
Early phase: Lethargy, hypotonia, poor suckle, or a high-pitched cry.
Intermediate phase: Hypertonia, irritability, fever, and seizures.
Advanced phase: Pronounced hypertonia with opisthotonos and retrocollis, shrill cry, apnea, coma, and death.
Kernicterus refers to the chronic and permanent clinical sequelae of bilirubin toxicity.
It presents as a tetrad of choreoathetoid cerebral palsy, sensorineural hearing loss, upward gaze palsy, and dental enamel dysplasia.
Management
Phototherapy
Phototherapy remains the mainstay of treating hyperbilirubinemia.
It uses light energy to change the shape and structure of bilirubin, converting it to molecules that can be excreted.
Effective phototherapy requires an irradiance of at least 30 μW/cm2/nm.
The wavelength must be between 460 and 490 nm, which matches the absorption spectrum of bilirubin.
High-intensity light-emitting diodes are preferred due to a narrow emission spectrum and low heat production.
The infant's eyes must be covered with a small patch to prevent retinal damage.
Breastfeeding should be continued with minimal interruptions.
Exchange Transfusion
Double volume exchange transfusion is the most effective method for rapidly removing bilirubin.
It replaces 85 percent of circulating red blood cells and causes a 50 percent fall in TSB immediately.
It is indicated for acute bilirubin encephalopathy or when TSB levels rise above the exchange cutoff.
It is performed by a pull-and-push technique using the umbilical venous route.
The total volume exchanged is 160 to 180 mL/kg.
Complications include infection, hypocalcemia, hypomagnesemia, portal vein thrombosis, and necrotizing enterocolitis.
Pharmacologic Therapy
Intravenous immunoglobulin may be considered in cases of isoimmune hemolytic disease.
It can be used when the bilirubin level reaches within 2 mg/dL of the exchange threshold.
However, routine use of intravenous immunoglobulin for hemolytic jaundice is not universally recommended in all units.
AAP 2022 Nomogram
These thresholds are based on expert opinion rather than strong evidence on when the potential benefits of phototherapy exceed its potential harms. Use total serum bilirubin concentrations; do not subtract the direct-reacting or conjugated bilirubin from the total serum bilirubin. In rare cases of severe hyperbilirubinemia in which the direct-reacting or conjugated bilirubin exceeds 50% of the TSB, consult an expert. Hyperbilirubinemia neurotoxicity risk factors include gestational age <38 weeks; albumin <3.0 g/dL; isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase (G6PD) deficiency, or other hemolytic conditions; sepsis; or any significant clinical instability in the previous 24 hours.
Phototherapy Thresholds for Neonates without Risk Factors
Phototherapy Threshold for neonates with Risk Factors
Exchange Transfusion Thresholds for neonates without risk factors
Exchange Transfusion Thresholds for neonates with risk factors
Algorithm
Guidelines For Treatment of Jaundice in Neonates < 35 wks
(Adapted from NICE Guidelines, RCOG 2010)
Postnatal age:
Treatment
27 wk
28 wk
29 wk
30 wk
31 wk
32 wk
33 wk
34 wk
0 hr
Phototherapy
2.3
2.3
2.3
2.3
2.3
2.3
2.3
2.3
Exchange
4.7
4.7
4.7
4.7
4.7
4.7
4.7
4.7
6 hr
Phototherapy
2.9
2.9
2.9
2.9
3.2
3.2
3.2
3.2
Exchange
5.6
5.6
5.8
5.8
5.8
5.8
5.8
5.8
12 hr
Phototherapy
3.5
3.5
3.8
4.1
4.1
4.1
4.1
4.4
Exchange
6.7
6.7
6.7
6.7
7
7
7
7
18 hr
Phototherapy
4.1
4.1
4.4
4.7
4.7
5
5.3
5.6
Exchange
7.3
7.3
7.6
7.9
8.2
8.2
8.2
8.2
24 hr
Phototherapy
4.7
4.7
5
5.3
5.6
5.8
6.1
6.1
Exchange
8.2
8.5
8.5
8.8
9.4
9.4
9.4
9.6
30 hr
Phototherapy
5.6
5.6
5.8
6.1
6.1
6.7
7
7
Exchange
9.4
9.4
9.6
9.9
10.2
10.5
10.5
11.1
36 hr
Phototherapy
6.1
6.1
6.7
7
7.3
7.6
7.9
8.2
Exchange
10
10
10.8
11.1
11.4
12.3
11.7
12.3
42 hr
Phototherapy
6.7
6.7
7.6
7.9
8.2
8.5
8.8
8.8
Exchange
11
11
11.7
12.3
12.6
12.9
13.2
13.5
48 hr
Phototherapy
7.3
7.6
8.2
8.5
9.1
9.4
9.6
10.2
Exchange
12
12
12.9
13.2
13.5
14
14.3
14.6
54 hr
Phototherapy
7.9
8.2
8.5
9.1
9.4
9.9
10.5
11.1
Exchange
13
13
14
14.3
14.9
15.2
15.8
15.8
60 hr
Phototherapy
8.5
8.8
9.1
9.4
9.9
10.2
11.1
11.7
Exchange
14
14
15
15.5
15.8
16.4
17
17.5
66 hr
Phototherapy
9.1
9.4
9.6
10.2
10.8
11.1
11.7
12.3
Exchange
15
15
15.8
16.4
17
17.5
18.1
18.7
$\ge$72 hr
Phototherapy
9.4
9.9
11
11.1
11.7
12
12.6
13.2
Exchange
15
16
16
17
18.1
18.7
19.3
19.9
Guidelines For Treatment of Jaundice in Neonates $\ge$35 wks
(Adapted from AAP Guidelines, Pediatrics 2004)
Postnatal age
Treatment
Low risk
Medium risk
High Risk
0 hr
Phototherapy
6.5
5
3.6
Exchange
16
14
12
12 hr
Phototherapy
9.2
7.4
5.8
Exchange
17.5
15
13.5
24 hr
Phototherapy
11.5
9.5
7.8
Exchange
19
16.6
15
36 hr
Phototherapy
13.5
11.5
9.5
Exchange
20.5
18
16
48 hr
Phototherapy
15.2
13
11.2
Exchange
22
19
17
60 hr
Phototherapy
16.7
14.5
12.5
Exchange
23
20
18
72 hr
Phototherapy
17.7
15.5
13.5
Exchange
24
21
18.5
84 hr
Phototherapy
18.5
16.5
14
Exchange
24.5
21.6
18.8
96 hr
Phototherapy
20
17.5
14.5
Exchange
25
22
19
108 hr
Phototherapy
20.8
18
15
Exchange
25
22
19
120 hr
Phototherapy
21
18
15
Exchange
25
22
19
Risk Categories Definitions ( 35 wks)
Low Risk: 38 wks & well
Medium risk: 38 wks + risk factors OR 35-37 wks & well
High Risk: 35-37 wks + risk factors
Risk factors: Isoimmune hemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, S. Albumin <3 g/dl
