Neonatal Hyperbilirubinemia

Jaundice attributable to immaturity of the newborn organ and systems

CRITERIA FOR PHYSIOLOGIC JAUNDICE

• Onset— Not before 24hours
• Daily rise— Does not exceed 5mg/dl
• Peak level— 12mg/dl in Term and 15mg/dl in Preterms
• Peak duration— 3rd – 5th day in Term; 5th – 7th in Preterms
• Duration— 7-10days in term babies and 2-3weeks in preterms
• Conjugated fraction— Does not exceed 10% of total

MECHANISM OF PHYSIOLOGIC JAUNDICE

• Increased Bilirubin load on liver cell
• Increase RBC volume, decrease RBC survival, increased E-H circulation
• Defective hepatic uptake of bilirubin
• Decrease Ligandin (Y-protein)
• Defective bilirubin conjugation
• Decrease activity of transferase enzyme (UDPGT – Uridyldiglucoronosyl Transferase)
• Defective bilirubin excretion.
• Excretion impaired but not rate-limiting

Major Reasons why a baby will have physiologic jaundice

1. Increased red cell mass
2. Reduced red cell survival
3. Reduction in activity of UDPGT

In addition

• Infants lack the bacterial flora necessary to convert bilirubin to urobilinogen, so unconjugated bilirubin persists throughout the entire GI tract.
• Also, meconium contains large amounts of unconjugated bilirubin
• Intensity and duration of physiologic jaundice varies widely

• Jaundice due to other aggravating factors
• Failure to meet at LEAST ONE of the CRITERIA for Physiological HB
• Note however that in majority of cases etiology is unknown

CAUSES OF UNCONJUGATED NON-PHYSIOLOGICAL HYPERBILIRUBINAEMIA

1. Over Production of Bilirubin

Haemolytic

• Antibody mediated haemolysis
• ABO Incompatibility, Rh Incompatibility
• Minor blood group incompatibility (anti-E & c, anti-Kell)
• Red Cell Enzyme defects
• G-6-P-D, Pyruvate kinase deficiency
• Red Cell Membrane defects
• Hereditary spherocytosis, Elliptocytosis

Extravascular Blood

• Bruises, IVH, Cephalohaematoma, Subgaleal hematoma

Drug Induced Hemolysis

• Vitamin K3 induced haemolysis

Polycythaemia

2. Conjugation Defects

Inherited reduction in glucoronosyl transferase

• Familial non-haemolytic jaundice (Crigler-Najjar type I)
• Autosomal recessive, Severe
• Familial non-haemolytic jaundice (Crigler-Najjar type II)
• Autosomal dominant, milder cause

Abnormal glucoronyl transferase

• Gilbert Syndrome

Acquired inhibition of glucorosyl tranferase

• Breast milk jaundice (5-b-pregnane-3a,20-b-diol or nonesterified long chain fatty acids) glucoronidase in some milk

CAUSES OF CONJUGATED NON-PHYSIOLOGICAL HYPERBILIRUBINAEMIA

1. Decreased Secretion

Impaired transport of the hepatocytes

• Congenital transport defect: Dubin-Johnson, Rotor syndrome
• Hepatocellular damage secondary to metabolic disorders (galactosaemia)

Obstruction of bile flow:

• Biliary atresia, extrinsic obstruction (intestinal obstruction) choledochal cyst
2. Mixed
• Prenatal infections
• Sepsis
• Multi-system disorders
• IDM, Perinatal asphyxia

ABO Haemolytic Disease

Description

• Action of maternal anti-A or anti-B antibodies on fetal erythrocytes of the corresponding blood group
• It is the commonest cause of Non-physiologic hyperbilirubinaemia

Pathogenesis

• Group O subjects have Anti-A or Anti-B antibodies of the IgG and IgM subclass in their plasma.
• In the event of a pregnancy with appropriate set up the IgG anti-A or anti-B antibodies cross the placenta to attack the fetal RBC
• These results in damage to erythrocytes and their destruction by the RES
• Attempts at repairing the partially damaged erythrocytes results in the formation of microspherocytes.

Characteristics of ABO disease

• May affect first child
• Degree of severity is similar among siblings
• Early non-physiological jaundice
• Anaemia may be mild or non-existent

Criteria for diagnosis

• Unconjugated hyperbilirubinaemia
• Jaundice during the first 24 hours
• An A or B baby of an O mother
• Increased number of microspherocytes
• Positive Coombs test
• Increased RBC production in the blood
• Reticulocytosis

Rhesus incompatibility

Description

• Due to action of maternal anti-D antibodies on the Rhesus antigen of fetal erythrocytes

Pathogenesis

• It is due to the entry of fetal cells into the maternal circulation
• As few as 0.05-0.1ml of cells is enough to produce immunization
• Following sensitization, Rh-negative subjects produce anti-D antibodies of the IgG class
• The antibodies crosses the placenta to attack fetal RBC
• The anti-body coated RBC is removed by the spleen in the fetus
• Before birth the main danger is anaemia
• After birth it is severe hyperbilirubinaemia
• In utero there is increase rate of erythrocyte production-
• Reticulocytosis and Nrbc
• Resulting in increased extramedullary erythropoiesis – liver, spleen and lungs
• Most severe infants manifest hydrops fetalis
• Massive edema, ascites and pleural effusion.
• Can lead to baby being stillborn

Characteristics of Rh disease

• Spares the first pregnancy
• Increasing degree of severity with subsequent pregnancies
• Early non-physiological jaundice
• Anaemia usually profound
• Hepatosplenomegally

Criteria for diagnosis

• Unconjugated hyperbilirubinaemia
• Jaundice during the first 24 hours
• Rh-Positive baby of Rh-negative mother
• Low Hb or PCV
• Strongly positive Coombs test
• Reticulocytosis
• Elevated levels of carboxyhaemoglobin

Prevention

• Focuses primarily on the administration of anti-D immunoglobulin to mothers after delivery or abortion of an Rh-positive fetus.
• This is in the form of human anti-D concentrate called RhoGAM (300ug)
• Acid elution test of Kleihauer and Betke can be used to detect cases of massive transplacental haemorrhage that will require larger doses of anti-D immunoglobulin

Pathogenesis

• RBC are liable to damage from oxidants
• Resulting in the formation of oxidized Hb which precipitates as Heinz bodies
• G6PD necessary for protecting the RBC from this oxidative stress
• Reduced GSH donates H- to reduce Oxidized Hb
• The Oxidized GSSH is reduced by NADPH
• The NADPH is derived from the HMP shunt at the G-6-PD step

Precipitants of acute haemolysis include

• Drugs
• Primaquine
• Nitrofurantoin
• Sulfonamides
• Nalidixic Acid
• Methylene blue
• Infections
• Naphthalene balls

• There is significant and prolonged elevation of un-conjugated Br
• Incidence is very low
• Usually a diagnosis of exclusion
• Thought to be due to
• The inhibition of the Glucoronosyl transferase by a steroid 3-a,20β pregnanediol
• Excess lipase librating FFA which interfere with protein binding and conjugation

Clinical course

• Usually noticed from the 5th day
• Continues to increase to the second week
• Essentially un-conjugated
• Has now been reported to be associated with Br Encephalopathy (previously, it was thought that it couldn’t result in encephalopathy)

Introduction

• Introduce Yourself: "Good day, I am Dr. [Your Name], and I will be taking care of your baby today. May I know your name and relationship to the baby?"
• Confirm Patient’s Identity: "Could you please tell me your baby’s name and date of birth?"
• Explain Purpose: "I’d like to ask some questions to understand why your baby has jaundice. Is that okay with you?"

Biodata

• Baby’s age: (in days or weeks) and sex.
• Place of delivery: Home, health center, or hospital.
• Gestational age: Term, preterm, or post-term.
• Birth weight and current weight.

History of Presenting Complaint

1. Time of Detection:
   • When was the yellow discoloration of the skin or eyes first noticed?
   • Was it within the first 24 hours, day 2–7, or after 7 days?
   • Where was it first observed (e.g., face, chest, limbs)?
2. Progression:
   • Has the jaundice spread or worsened?
   • Is it resolving or staying the same?
3. Associated Symptoms:
   • Feeding: Is the baby breastfeeding or formula-fed? Any difficulties with feeding (e.g., poor latching, low milk supply)?
   • Activity: Is the baby lethargic, excessively sleepy, or irritable?
   • Crying: Any high-pitched or excessive crying?
   • Urine: Is the urine dark or yellow-stained? How frequently does the baby urinate?
   • Stool: Is the stool pale, normal, or greenish? Frequency and consistency?
4. Features Suggestive of Bilirubin Encephalopathy:
   • Lethargy, poor feeding, high-pitched crying, arching of the back, or seizures.
5. Interventions:
   • Have any treatments been given (e.g., phototherapy, medications)?
   • Was the baby admitted to the hospital? For how long?
   • Any use of traditional remedies or substances?
6. Exposure to Substances:
   • Has the baby been exposed to hepatotoxic substances (e.g., camphor, menthol-containing substances)?

Birth and Perinatal History

1. Antenatal History:
   • Were there any complications during pregnancy (e.g., infections, diabetes, hypertension)?
   • Any maternal illness, especially during the first trimester (e.g., TORCH infections)?
   • Medications or herbal remedies taken during pregnancy?
   • Mother’s blood group and Rh status?
2. Birth History:
   • Place of delivery: Was the baby born at home, in a health center, or in a hospital?
   • Mode of delivery: Vaginal delivery, cesarean section, or instrumental delivery (e.g., vacuum extraction, forceps)?
   • Gestational age: Term, preterm, or post-term?
   • Birth weight: Baby’s weight at birth?
   • Immediate condition: Did the baby cry immediately after birth? Was there any need for resuscitation?
   • Delayed Cord Clamping: Was it practiced?
3. Neonatal Drugs:
   • Was the baby given any medications (e.g., chloral hydrate, pancuronium, vitamin K3, novobiocin)?
4. Hospital Stay:
   • Was the hospital stay short or prolonged?
   • Any concerns raised before discharge?

Family History

1. Jaundice in Siblings:
   • Did any previous children have jaundice? How severe was it? How was it treated?
2. Blood Group and Rh Compatibility:
   • Is there a known history of blood group or Rh incompatibility in the family?
3. Hereditary Conditions:
   • Any family history of hemolytic diseases, G6PD deficiency, or other enzyme deficiencies?
   • History of liver or metabolic diseases?

Nutritional History

1. Breastfeeding:
   • Is the baby breastfeeding exclusively, mixed feeding, or formula-fed?
   • Any difficulties with feeding, such as latching or inadequate milk supply?
2. Formula Feeding:
   • Type and preparation methods of formula used?

Social History

1. Maternal Health:
   • How is the mother’s health and well-being post-delivery?
2. Cultural Practices:
   • Any use of herbal remedies or traditional practices for jaundice?

Immunization History

• Has the baby received the BCG and Hepatitis B vaccines at birth?

Review of Systems

1. Hematologic:
   • Any signs of anemia (e.g., pallor) or bruising?
2. Hepatic:
   • Any concerns about liver swelling or masses?
3. General Well-being:
   • Any episodes of fever, irritability, or unusual behavior?

Summarize and Close

• Summarize: Recap key points from the history to confirm understanding.
• Ask: "Is there anything else you would like to add or ask about your baby?"
• Thank: "Thank you for sharing this information. It will help us understand your baby’s condition better."

Introduction

• Preparation:
  • Wash hands thoroughly and ensure a clean, warm, and well-lit examination area.
  • Gather necessary equipment: stethoscope, thermometer, measuring tape, gloves, and a flashlight or pen torch.
• Introduction and Consent:
  • Introduce yourself: "Good day, I am Dr. [Your Name], and I will be examining your baby today."
  • Explain the procedure: "This examination will involve assessing your baby's skin, eyes, abdomen, and general well-being to evaluate jaundice."
  • Obtain verbal consent.

General Observation

• Appearance:
  • Assess the baby’s overall condition, activity level, and posture.
  • Look for lethargy, irritability, or abnormal postures (e.g., opisthotonic posture indicating kernicterus).
• Color:
  • Examine the skin, sclerae, and mucous membranes for yellow discoloration under natural light or with a flashlight.
  • Use Kramer’s Rule to estimate bilirubin levels:
    • Face: 5-6 mg/dL
    • Chest/Nipple Line: 8 mg/dL
    • Abdomen: 10 mg/dL
    • Knees: 15 mg/dL
    • Feet: 20 mg/dL
• Hydration:
  • Assess mucous membranes, fontanelle (sunken in dehydration), skin turgor, and capillary refill time.
• Vital Signs:
  • Measure temperature (hypothermia or fever may indicate sepsis).
  • Assess heart and respiratory rates.

Systematic Examination

Head and Neck

• Fontanelles:
  • Palpate for bulging (raised intracranial pressure) or sunken fontanelles (dehydration).
• Eyes:
  • Inspect sclerae for icterus.
  • Note any sunset sign or abnormal eye movements.
• Oral Cavity:
  • Check mucous membranes for jaundice.
  • Look for hydration status and tongue moistness.
• Cephalohematoma or Bruising:
  • Palpate for birth trauma, as bruising increases bilirubin production.

Chest and Cardiovascular System

• Inspection:
  • Observe for pallor, cyanosis, and respiratory distress (e.g., nasal flaring, grunting, or retractions).
• Auscultation:
  • Listen for murmurs (e.g., congenital heart defects).
  • Assess breath sounds bilaterally.

Abdomen

• Inspection:
  • Note abdominal distension, visible veins, or abnormalities of the umbilical stump.
• Palpation:
  • Liver: Check for hepatomegaly.
  • Spleen: Assess for splenomegaly.
  • Masses: Palpate for any unusual lumps.
• Umbilical Cord:
  • Look for infection, delayed separation, or bleeding.

Skin

• Extent of Jaundice:
  • Perform blanching by applying light pressure to reveal the underlying skin color.
  • Confirm severity with Kramer’s zones or use instruments like an icterometer/bilirubinometer.
• Signs of Bleeding or Hemolysis:
  • Look for petechiae, bruising, or pallor.
• Rashes:
  • Check for erythema toxicum or septic skin lesions.

Limbs and Extremities

• Tone and Reflexes:
  • Assess muscle tone (e.g., hypo- or hypertonia).
  • Elicit primitive reflexes (e.g., Moro, rooting, sucking).
• Peripheral Jaundice:
  • Examine palms and soles for jaundice (may indicate severe hyperbilirubinemia).

Neurological Examination

• Alertness:
  • Observe for lethargy or hyperalertness.
• Tone:
  • Note hypo- or hypertonia, opisthotonic postures, or diminished Moro reflex.
• Crying:
  • Assess for a high-pitched cry, which can suggest bilirubin encephalopathy.
• Seizures:
  • Look for abnormal movements or jerking.

Summary

• Document Findings:
  • Record signs of jaundice, dehydration, or neurological abnormalities.
  • Note associated findings such as hepatosplenomegaly or cephalohematoma.
• Plan:
  • Correlate findings with history and initiate further investigations:
    • Total and direct bilirubin levels.
    • Blood group typing and Coombs test.
    • Complete blood count (CBC).
• Communicate:
  • Explain findings and management plan to the caregiver.
  • Offer reassurance and outline next steps.
• Thank the Caregiver:
  • Conclude: "Thank you for your cooperation. We will take the necessary steps to ensure your baby receives the best care."

Investigations for Neonatal Jaundice/Hyperbilirubinemia

1. Serum Bilirubin Levels
   • Total Serum Bilirubin (TSB): Determines the severity of jaundice.
   • Direct (Conjugated) and Indirect (Unconjugated) Bilirubin: Differentiates between conjugated and unconjugated hyperbilirubinemia.
   • Transcutaneous Bilirubinometry (TcB): Non-invasive screening tool; requires confirmation with TSB if levels are elevated.
2. Blood Group and Rh Typing
   • Maternal and Neonatal ABO and Rh Typing: Detects ABO or Rh incompatibility.
3. Hematological Tests
   • Full Blood Count (FBC):
     • Assesses hemoglobin levels for anemia or polycythemia.
     • White blood cell and platelet counts can indicate infection or sepsis.
   • Peripheral Blood Smear: Detects abnormal red cell morphology, such as spherocytes (hereditary spherocytosis) or fragmented cells (hemolysis).
   • Reticulocyte Count: Elevated levels indicate active hemolysis.
   • Direct Antiglobulin Test (DAT/Coombs Test): Confirms immune-mediated hemolysis.
   • G6PD Activity: Screens for G6PD deficiency, a common cause of hemolysis in susceptible populations.
4. Infection Screening
   • Blood Culture: Detects bacteremia or sepsis.
   • C-Reactive Protein (CRP) and Procalcitonin Levels: Elevated in sepsis or significant infection.
   • Urine Culture: Screens for urinary tract infections, especially in prolonged jaundice.
5. Liver Function Tests (LFTs)
   • ALT, AST, and GGT: Evaluate liver function and potential hepatocellular injury.
   • Albumin and Total Protein: Assess liver synthetic function.
6. Thyroid and Metabolic Screening
   • Thyroid Function Tests (TFTs): Rule out congenital hypothyroidism.
   • Galactosemia Testing: Identify metabolic disorders that may present with jaundice.
7. Imaging Studies (if indicated)
   • Abdominal Ultrasound: Examines liver, gallbladder, and biliary tree for structural anomalies like biliary atresia.
   • Hepatobiliary Scintigraphy (HIDA Scan): Evaluates bile flow to confirm biliary obstruction or atresia.
   • Chest X-ray: Rules out associated congenital anomalies.
8. Genetic and Specialized Tests
   • Genetic Testing: Investigates hereditary conditions like Gilbert syndrome or Crigler-Najjar syndrome.
   • Pyruvate Kinase Activity: Rules out rare enzymatic causes of hemolysis.
9. Stool and Urine Analysis
   • Urinalysis: Detects bile pigments or reducing substances (e.g., in galactosemia).
   • Stool Color: Pale stools suggest conjugated hyperbilirubinemia, indicating biliary obstruction.

• Anticipatory care
• Phototherapy
• EBT

The Goal of Therapy

The goal of therapy is to prevent severe hyperbilirubinemia and its complications, such as kernicterus and bilirubin encephalopathy, without causing undue harm. Management strategies are tailored to the severity of jaundice and the underlying cause.