Neonatal Jaundice

DR. AGELEBE. E

Bowen University Teach Hosp Ogbomoso

Introduction

• Most common medical problem in the newborn. Affects between 40 – 80% of newborn babies.

• Most cases are benign

• Potential for severe adverse consequences– Cerebral palsy– Mental retardation– Death

Source of Bilirubin

Haemoglobin 75-80%

Myoglobin

Haem-containing enzymes

-Cytochromes

-Catalase /Peroxidases

-Tryptophan pyrrolase

-In-effective erythropoiesis

20-25%

Bilirubin Metabolism

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• Breakdown product of haemoglobin– 1gm of Hb gives 35mg

Bilirubin• Enzyme action in the RES

– Heme oxygenase: Biliverdin, Fe & CO

– Biliverdin reductase: Bilirubin

– Bilirubin carried in blood bound to plasma albumin

• Uptake and Conjugation in the LIVER– Ligandin facilitates hepatic

uptake– Uridine

diphosphoglucuronyl transferase (UDPGT) catalyses conjugation with glucuronic acid

• Excretion in Bile and the GIT• Enterohepatic circulation

– Deconjugation by Beta-glucuronidase

Bilirubin Metabolism con’t

• Unconjugated bilirubin is carried in blood bound to plasma albumin

– Small fraction is “free”. This fraction increases when other molecules compete with bilirubin for albumin binding.

• Bilirubin conjugation is the biologically critical activity

– Converts water insoluble to water soluble bilirubin

• Activity of UDPGT is low at birth

– Rises to adult levels by 4 – 8 weeks of life

– Many variants of the encoding gene with varying levels of activity

– Links in the activity of UDPGT1 and pathogenesis of jaundice in G-6PD deficient neonates

Bilirubin Metabolism con’t

• Free Bilirubin in Plasma– Hydrophobic and lipophilic in character– Crosses biological membranes e.g blood-brain

barrier(BBB)

– Binding stable in molar concentration ratio of bilirubin:albumin of 0.5-1: 1 and normal plasma pH (solubility of bilirubin is very low at pH 7.4).

– Acidosis, Hypoalbuminaemia and Hyperbilirubinaemia destabilize the binding and lead to high levels of “free” unbound bilirubin.

Common Aetiology of NNJ

• Physiological Hyberbilirubinaemia

• Glucose-6-Phosphate Dehydrogenase Deficiency

• ABO Incompatibility

• Rhesus Iso-immunization

• Bacterial Infections /UTI

• Preterm/ Low Birthweight

• Breastfeeding/ Breast-milk Jaundice

Uncommon Causes of NNJ

• Crigler-Najjar Syndrome types I and II

• Gilbert’s disease

• Hypothyroidism

• Hypopituitarism

• Hereditary spherocytosis

Causes of Prolonged Indirect Hyperbilirubinaemia

• Breast milk jaundice

• Haemolytic disease

• Hypothyroidism

• Pyloric stenosis

• Crigler-Najjar sydrome

• Gilbert syndrome in breast-fed infants

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Causes of Prolonged direct Hyperbilirubinaemia

• Septicaemia

• Rotor syndrome

• Dubin–Johnson Syndrome

• Progressive Familial Intrahepatic Cholestasis Syndromes

• Alagille Syndrome

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Physiologic jaundice

• Diagnosis of exclusion after excluding infection, haemolysis, and metabolic diseases.

• Multifactorial: RBC mass, RBC life span, decreased UDP-glucuronyl transferase and ligandin, increased enterohepatic circulation

• Begins at >24 hrs

• Peaks at <= 12.0 mg/dL at day 3

• Preterms: at <=15.0 at day 5

Physiologic Hyperbilirubinaemia

• Diagnosis of exclusion after excluding infection, haemolysis, and metabolic diseases.

• Multifactorial: RBC mass, RBC life span, decreased UDP-glucuronyl transferase and ligandin, increased enterohepatic circulation

• Begins at >24 hrs

• Peaks at <= 12.0 mg/dL at day 3

• Preterms: at <=15.0 at day 5

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Breastfeeding jaundice

• Breastfeeding jaundice– Infant of mothers with difficulty in establishing

breastfeeding decreased PO intake

– Inadequate fluid and nutrient intake with significant weight loss

– Increased enterohepatic circulation with increased risks of hyperbilirubinaemia

– Onset 2-4dys’ peaks at 3-6dys

– Returns to normal after 3weeks

Breast milk jaundice

• Breastmilk jaundice– Increased enterohepatic circulation

• Increased beta-glucuronidase in BM &• Delay in establishment of intestinal microflora

– Metabolite of progesterone (pregnane-3-alpha 20 β-diol)• Inhibits UDPGT activity

– Inflammatory cytokines in BM (IL-1 beta; IL-6)• Reduction in uptake, metabolism & excretion of

bilirubin

– High epidermal growth factor (EGF) in BM • Reduces GI motility• Onset 4-7days peaks at 5-15day • Returns to normal after 9weeks

Jaundice and the Brain

• Neonatal jaundice & Brain dysfunction– Unconjugated hyperbilirubinaemia the cause of bilirubin

encephalopathy

• Factors contributing to persistence (or resurgence)– Lack of adequate concern for the risks

– Early hospital discharges

– Limitations in our health care system to provide continuity of care

Management – Unconjugated Hyperbilirubinaemia

• Aim of management– Prevent bilirubin encephalopathy

• Important Facts to Note:– Only the “free” unconjugated bilirubin is toxic to the

newborn brain.– Lab. Measurement of free bilirubin is difficult. – TSB is used for decision making– No absolute safe level of bilirubin.

Management – Unconjugated Hyperbilirubinaemia

• Important Facts to Note:

– Risk of toxicity is increased by factors that destabilize the bilirubin-albumin binding and/or integrity of the BBB

– Jaundice in 1st 24hrs is almost always pathological (it should never be dismissed as physiological jaundice).• (note that bilirubin is an antioxidant and in low

levels play useful role in the overall wellbeing of the infant esp. in LBW, preterms)

Management: Important Steps

• Clinical evaluation

– History & Physical Exam.

– Lab. Investigations & Imaging Studies

Evaluation of Newborn with Jaundice.

• History should be thorough- (keeping in mind key epidemiological risk factors)

– Pregnancy and delivery, drugs.

– Asphyxia, trauma, cephalohaematoma

– Family hx., Hx of NNJ in older sibs, mother’s blood group

– Baby- feeding, general activity

Physical Examination of Baby should also be thorough-Assess jaundice (note cephalocaudal progression of jaundice), pallor, general activity, signs of encephalopathy etc (non-invasive methods of bilirubin estimation (transcutaneous bilirubinometry) if available should be used: Icterometer, Jaundice meter etc-physician estimates of severity may be misleading).

Cephalopedal Representation of Progression in

NNJ (Kremer et al).

Zone SBR mg/dl

• 1 = 5 mg/dl

• 2 = 10 mg/dl

• 3 = 15 mg/dl

• 4 = 20 mg/dl

• 5 > 25 mg/dl

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Clinical Features of KernicterusACUTE FORM

Phase 1 (1st 1–2 days): poor sucking, stupor, hypotonia, seizures

Phase 2 (middle of 1st wk): hypertonia of extensor muscles, opisthotonos, retrocollis, fever

Phase 3 (after the 1st wk): hypertoniaCHRONIC FORM

First year: hypotonia, active deep tendon reflexes, obligatory tonic neck reflexes, delayed motor skills

After 1st yr: movement disorders (choreoathetosis, ballismus, tremor), upward gaze, sensorineural hearing loss

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Evaluation contd.• Lab. Investigations:

– Total serum bilirubin (TSB), Conjugated bilirubin (CB).

• Wide variations - inter- &intra- Lab.

• TSB values used in decision making except when conjugated levels are high

– Haemoglobin, Haematocrit

– Blood groups (baby & mother) Rh. Factor

– Coomb’s test,G6PD Assay, Serum albumin

– Urinalysis for reducing substances.

– End-tidal carbon monoxide (ETCO) in breath. An index of bilirubin production. (an apparatus for this exists)

Management Option-1

• Re-assurance and Observation on Outpatient basis:

– Otherwise healthy term newborn

– Presenting after 72hrs.

– Mild jaundice (TSB< 10mg/dl or 170umol/l)

– Available for review within 24-48hrs – very important.

Management Option-2 • Pharmacotherapy.

Phenobarbital increases bilirubin conjugation and excretion

– Limited by slow action (takes 72hrs to become effective). No use in acute jaundice

– May be useful for prophylaxis in at risk neonates

– Can be combined with option 1 to accelerate excretion.

Tin-mesoporphyrin (SnMP) and Tin-protoporphyrin (SnPP) which inhibit the action of the microsomal enzyme-heme oxygenaseand therefore prevent production of bilirubin have shown promise in clinical trials (has been used in Crigglar-Najjar and G-6PD). They may replace phototherapy in future.

High dose intravenous immunoglobulin (IVIG) 500-1000 mg/kg. Has been used with limited success in Rh- and ABO incomp. May reduce need for EBT. (mode of action unknown)

Management Option-3• Phototherapy.

– Currently, primary mode of treatment.– Photoenergy accelerates excretion of bilirubin thru’

• Photooxidation: slow process• Configurational isomerization: rapid process. Changes

lipid soluble isomers (4Z, 15Z) to water-soluble isomers (E,Z; Z,E; E,E)

• Structural isomerization: Intramolecular cyclization with formation of lumirubin.

(Photoproducts are excreted in bile and to some extent in urine. Lumirubin is the primary pigment in bile during phototherapy. Note that phototherapy immediately protects against encephalopathy because the photoproducts are water-soluble and therefore no longer neurotoxic)

Phototherapy:Important basic principles.

• Wavelength– Bilirubin absorbs light in 450-460 nm. Longer wavelengths

penetrate skin better.• Irradiance

– Irradiation level of 30-40 uW/cm2/nm most effective• Distance b/w infant and light source.

– Should not be >50 cm. Maybe <10 cm, but note concern about thermal burn. 10 – 20 cm distance ideal.

• Surface area– The larger the surface area the better. Reflective materials

maybe used to increase area of irradiation.• Nature & Character of light source

– May affect energy delivery. Narrow spectrum light sources are more efficient but more expensive.

Phototherapy.

• Indications:– Moderate to severe hyperbilirubinaema– Prophylaxis in preterm babies– Prevention of post-EBT rebound hyperbilirubinaemiaNote: Intensive phototherapy can be delivered with use of high

energy light sources and reflective material. Also, 2 or 3 units may be used for same baby to deliver “double” or “triple” phototherapy.

Undesirable &Toxic effects (minimal) include:Increased fluid loss (IWL, loose stools)Retinal damage –Eyes should be covered.Damage to gonads in males.Erythema of the skin (transient)Bronze-baby syndrome- high conjugated bili levels

Management Option-4

• Exchange Blood Transfusion

– Indicated where there is risk or potential risk of BIND

• Severe hyperbilirubinaemia (TSB> 20mg/dl or 340umol/l)

• High rate of rise of bilirubin (>1mg/dl/hr or >5mg/dl/24hrs)

• Low albumin levels

• Concomitant anaemia (Hb. <12gm/dl)

• Presence of other danger signs-indicate potential for compromise of BBB.

Management Option –4 EBT.• DANGER SIGNS:

– Family Hx. of significant haemolytic disease

– Onset in the first 24hr of life

– Signs of severe illness:

• Vomiting, lethargy, poor feeding, high pitched cry, fever

(under these conditions, EBT may be done at lower levels of TSB. For preterm babies, EBT are done at lower levels of TSB)

(Note that agents that compete with bilirubin for albumin binding, acidosis will lead to high levels of “free’ bilirubinwhile hyperosmolality, hypercarbia, hypertension will impair the blood-brain barrier).

Management Option-4 EBT.

• Procedure for EBT:

– All precautions regarding blood transfusion should be observed.

– Fresh whole blood X-matched against baby and mother’s blood (not more than 4 days for ACD or CPD blood)

– Double-volume exchange (160ml/kg) is usual

– Blood aliquots of 5, 10, or 20ml may be exchanged at each cycle depending on size and clinical state of baby

Management Option-4, EBT.• COMPLICATIONS:

– Complications of blood tx.- infections, transfusion reactions, etc.

– Complications of catheter placement- perforation, wrong placement, vasospasm, necrotizing enterocolitis, etc

– Complications of EBT per se- haemodynamic changes that follow the push-pull process, electrolyte changes-hypocalcaemia, hyperkalaemia etc.

– Others- hypothermia, hypoglycaemia– Morbidity, Mortality risks may be significant esp in

sick preterm infants (apnea, bradycardia, cyanosis, respiratory arrest, pulmonary oedema, cardiac arrest)

Unconjugated Hyperbilirubinaemia: Summary

• Still contributes significantly to neonatal mortality and long-term handicap in our sub-region

• Education is very important both to health workers and the public (esp. at ANC)

• No case of clinical jaundice should dismissed without investigation

• Early discharges should be well advised about jaundice

• Glucose water is no treatment for NNJ

• Breastfeeding rarely causes severe NNJ

Bilirubin encephalopathy is a tragic condition which can be prevented with simple technology. No baby should

be afflicted with this condition in this present age.