INTRODUCTION:

Neonatal jaundice is a disease occurs in a new born baby due to high bilirubin levels. It is characterized by yellowish discolouration of white part of eye and skin. If this condition is untreated, it may lead to seizures, cerebral palsy or kernicterus. Nearly 8% to 11% of neonates develop hyperbilirubinemia when total serum bilirubin level raises above the 95^th percentile.

Etiology:

Babies are at high risk for developing jaundice and most of them are premature babies who are born before 37 weeks gestation. The most common reason is babies who aren’t getting enough breast milk, either because they’re having a hard time feeding or their mother’s milk isn’t in yet and compatibility factors with the blood type of their mother.

Because, the compatibility factors lead to antibodies production which causes bilirubin levels to raise by destroying red blood cells.

METABOLISM OF BILIRUBIN:

Pathophysiology:

Bilirubin formation and metabolism:

The catabolism of heme leads to the formation of bilirubin as the final product. The heme is an essential component for several biological molecules and enzymes but, it is mainly incorporated in the haemoglobin which is the primary component of the red blood cells.²

· Bilirubin is formed mainly in the liver and spleen through two steps which include:

· Initially the porphyrin ring of the heme is degraded and catabolised by the enzyme known as hemeoxygenase.

· A green coloured compound called biliverdin

· It is formed as a result of the previous reaction. Carbon monoxide is released during this reaction.

· The formation of bilirubin from biliverdin is catalysed by the biliverdin reductase enzyme. Bilirubin is a toxic metabolite, so the body has physiological process to eliminate the bilirubin.³

· Bilirubin elimination process includes:

Hepatic uptake:

After the formation of the bilirubin, it is secreted into the blood circulation. Then, bilirubin will bind to the albumin to facilitate its transportation to the liver. The hepatocytes then reuptake the bilirubin and prepare it for excretion.⁴

Conjugation:

Bilirubin diglucuronide is produced by the conjugation of bilirubin with glucuronic acid, which is water soluble. Then the bilirubin product is eliminated by bile. The conjugation process occurs by the glucuronosyl transferase enzyme in the liver cells.⁵

Clearance and excretion:

After the bilirubin is conjugated in the liver, it is secreted into the bile which enters into the gastrointestinal tract. In the gastrointestinal tract the conjugated bilirubin is metabolized into urobilinogen by the gut enzyme which is oxidized into urobilin. In adults the conjugated bilirubin metabolism occurs in proper way.

However, the neonates have sterile gastrointestinal canal which delays the catalysation of the conjugated bilirubin. Due to this a small amount of excreted bile retains in the sterile tract. The leftover conjugated bilirubin undergoes unconjugation process by the enzymes present in the neonatal intestine which is beta-glucuronidase. Then the unconjugated bilirubin undergoes enterohepatic circulation. A small amount of bilirubin is cleared into the urine as urobilinogen.⁶

Pathogenesis:

There are different mechanisms for development of jaundice that may include either an increase in the bilirubin production, increase the enterohepatic circulation, or decrease bilirubin elimination.

Pathological jaundice:

Neonatal jaundice mainly occurs due to the pathological conditions. Pathological neonatal jaundice is either due to acquired or inherited conditions.

Pathological jaundice is the result of an increase in unconjugated bilirubin levels which is termed as "Indirect hyperbilirubinemia". It includes some characteristics like the appearance of jaundice within the first day of life, persistent jaundice manifestations for more than two weeks and dark coloured urine.

Acquired pathological neonatal jaundice develops mainly due to haemolysis of the red blood cells via three main diseases:

(A) Rhesus (Rh) haemolytic disease:

Haemolytic disease in neonates occurs when a Rh-negative mother has a baby with a Rh-positive father. If the Rh-negative mother has been sensitized to Rh positive blood, her immune system will make antibodies that attacks her baby. When these antibodies enter the baby's bloodstream, they will attack the red blood cells cause lysis of them.^7,8

(B) ABO blood group incompatibility:

ABO incompatibility is one of the contributing factors for jaundice. ABO incompatibility occurs when a mother's blood group is O and her baby's blood group is A or B, then the mother's immune system may react and make antibodies against her baby's red blood cells.^9,10

(C) Glucose 6 phosphate dehydrogenase deficiency:

It is a genetic condition which occurs due to deficiency of the enzyme glucose 6 phosphate dehydrogenase. This enzyme is crucial for the proper function of red blood cells: when this enzyme level is too low, premature breakdown of red blood cells occurs (haemolysis). When this accelerated loss is not compensated by the body mechanism, anaemia develops. However, deficiency of this enzyme alone is not sufficient to cause haemolysis; additional triggering factors are also required for the onset of symptoms.^11,12

Defective bilirubin conjugation to glucuronic acid and it include:

Breast milk jaundice:

Hyperbilirubinemia is also correlated with mother’s milk in neonates. Around 4% of the lactated babies have jaundice especially in third week of birth and also, they have increased bilirubin levels which is about 10mg/dl. A diagnosis should be done for breast milk jaundice if the serum bilirubin is predominantly unconjugated, other causes of prolonged jaundice have been eliminated and the infant is in healthy and along with proper weight. The baby should be breast fed continuously at more frequent intervals after that bilirubin levels will gradually diminish. Discontinuity of breastfeeding is recommended when bilirubin levels exceed 20 mg/dl.¹³

Gilbert syndrome:

It is genetic disorder which is caused due to decrease in uridine diphosphate- glucuronyltransferase activity which leads to decrease the ability to process bilirubin. Bilirubin is produced by the breakdown of red blood cells.^14-16

Crigler-Najjar syndrome:

Crigler-Najjar syndrome is a rare autosomal recessive inherited disorder characterized by the absence or decreased activity of UDP-glucuronosyltransferase, an enzyme required for glucuronidation of unconjugated bilirubin in the liver.^14-16

Lucey-Driscoll syndrome:

It is a condition which affects the enzymes which is needed for metabolism especially bilirubin. So it directly leads to increase in bilirubin levels in blood. It is also called as transient familial neonatal hyperbilirubinemia ^15.16

Dubin-Johnson syndrome:

Dubin Johnson syndrome (DJS). A genetic condition which is caused by a mutation process that makes bilirubin to collect in blood instead of going to digestive tract. In most cases, DJS presents in the second decade of life, and rarely may present in infant.^14-16

Rotor syndrome /Rotor type hyperbilirubinemia:

Rotors syndrome is a rare cause of conjugated and unconjugated hyperbilirubinemia. The disease is characterized by non-haemolytic jaundice due to chronic elevation of predominantly conjugated bilirubin (over 50%). This phenomenon is a result of impaired hepatocellular storage of conjugated bilirubin that leaks into plasma causing hyperbilirubinemia.^14-16

Clinical course:

The clinical course of Neonatal jaundice is characterized by the absence of jaundice at birth in the majority of infants, however with Total Serum Bilirubin (TSB) values that exceed the normal range for adults. This is followed by an increase in TSB which eventually manifests with detectable jaundice, typically on the 2nd–3rd day of life. However, infants with blood group isoimmunization may present with Neonatal jaundice on the very first day of life and then will require close follow-up and often therapeutic interventions. Historical data shows that to remove higher TSB levels only by advent therapies if they are absent the peak of Neonatal jaundice along with hyperbilirubinemia occurs in later stages. Thus, in Davidson’s study from 1941, the infants on the 10th centile reached a peak TSB of ~27 µmol/L (1.6 mg/dL) on the second day of life, while infants on the 90th centile peaked at TSB ~220 µmol/L (12.8 mg/dL) on the fourth day of life. The last longer of hyperbilirubinemia in Infants.

Higher as far exposure to bilirubin which causes greater in AUC. This may be predicted by early measurement of TSB and/or Transcutaneous Bilirubinometry (TcB) and charting the values on a nomogram relative to an infant’s age in hours. Similar findings were made by Fouzas and others, who constructed a nomogram based on TcB measurements taken twice daily during the first 5 days of life in late preterm infants.

TcB values peaked on the 3rd day of life in infants on the 5th and 25th centile, between the 3rd and 4th day of life in infants on the 50th centile, and on the 4th day of life in infants on the 75th and 95th centile. In a larger study that also included many term infants’ ≥37 weeks GA, TcB values for both the 50th, 75th, and 95th centiles peaked at 4.5 days of life.¹⁷

Guideline for neonatal jaundice:

A guideline was published in 2006 regarding the management principles for neonates along with jaundice by South African Medical School. Based on these guidelines, bilirubin levels and age of the neonates, observation, phototherapy and exchange transfusion are used for the management of neonatal jaundice.

The current guideline stipulated in the Standard Treatment Guidelines and Essential Medicines List (STG and EML) is to use weight and gestational age to decide the treatment, which may cause uncertainty because if the baby loses weight because of other illness. NICE (The National Institute for Health and Clinical Excellence) Clinical Guideline No 98 has given the management for this disease. They are

1. Provide information to all parents and caregivers of neonates regarding neonatal jaundice.

2. Examine all babies and identify risk factors for neonatal jaundice.

3. Inspect the skin, sclera and gums of the naked baby, in natural light, for the presence of jaundice.

4. Measure the bilirubin in all babies with clinical jaundice with a non-invasive, transcutaneous bilirubin meter.

The STG guideline is much harder when compared to NICE as it only takes into consideration the infant’s age and not their weight. According to the threshold table and the NICE guideline, the management is then divided into the following categories:

1. If value is lower than threshold, render normal neonatal care.

2. If value is in first bilirubin column, repeat the bilirubin measurement within 6–12 h.

3. If value is in second bilirubin column, consider phototherapy and repeat the bilirubin measurement in 6 h.

4. If value is in third bilirubin column, start phototherapy.

5. If value is in last bilirubin column, start phototherapy and arrange for exchange transfusion.

6. If the baby develops jaundice within 24 h of birth or any sign of sepsis is present, the baby must be managed or referred urgently for specialist care.

The use of a transcutaneous bilirubin meter is widely advocated because of its almost 100% accuracy to detect hyperbilirubinemia in term infants, safety owing to non-invasiveness, minimal operational costs and ability to be used in darker pigmented neonates. The cost-effectiveness of transcutaneous bilirubin meters also reported. It was calculated that the prevention of one or two cases of kernicterus per year justifies the cost of a transcutaneous bilirubin meter. It was reported by NICE.¹⁸

Investigations for all infants:

When jaundice appearing within 24hr it should be managed as haemolytic jaundice. We have to find out the baby’s blood group, Rh typing, DCT, PCV and then peripheral smear is checked for haemolytic and morphological character. When the bilirubin levels below the exchange transfusion level, this indicates the failure of therapy.

Treatment options:

There are many treatment options for jaundice but the foremost treatment option is Phototherapy.

Phototherapy:

Hyperbilirubinemia can be treated with phototherapy with or without adverse effect. The efficacy depends on surface area. The mechanism involved by converting the bilirubin to more water-soluble isomers. For the fastest photoisomerization reaction a monochromatic visible light range from 350-550 nm is used. Phototherapy will increase reactive oxygen species (ROS). These oxygen species oxidise some of the biomolecules which includes bilirubin.

Double surface phototherapy may be more effective. The light source which is Special blue tubes with the mark F20T12/BB should be used. By lowering the distance of the neonate to within 15–20 cm and by energy output may be increased in a phototherapy unit. Continuous phototherapy is better but during breast feeding it should be interrupted.^19-21

(a) Conventional Phototherapy:

Conventional phototherapy is used when the jaundice is non haemolytic or the progression is low and it is also called as fibric optic.

(b)Intensive phototherapy:

It is generally considered when the conventional phototherapy is not effective and used when the condition is haemolytic or increased bilirubin levels. It is followed by placing the baby on the Billi blanket and using additional phototherapy with increased blue lights and then followed by lowering are effective remedies.

Exchange Transfusion:

In developing countries, transfusion of blood is a rare event. But it is used frequently as an emergency rescue for severe neonatal jaundice. Exchange transfusion is performed by push pull method through umbilical venous catheter. The major adverse event is laboratory abnormalities. They are treatable & are asymptomatic.

Here the bilirubin and haemolytic antibodies are removed.

a) Rh Isoimmunization: For effective exchange transfusion blood should be Rh negative, for the best outcome the Rh-negative cells should suspend in AB plasma or in case of emergency Rh negative whole blood or baby’s cross match Rh negative blood group can be used. ⁽²²⁾

b) ABO Incompatibility: ABO incompatibility in new born can be transfused only with O blood group. For best outcome it must be packed in AB plasma whole blood.

c) Other situations: In case of the Cross-matche with baby’s blood group, blood volume used or double volume exchange should be kept in mind.

i. Blood Volume Used: Partial exchange is done at birth in Rh haemolytic disease: 50-ml/kg of packed cells.

ii. Double Volume Exchange: 2 × (80–100 ml/kg) and times birth weight (kg)

Pharmacological treatment:

Pharmacological treatment of neonatal jaundice can further be categorized by using phenobarbitone, Intravenous immunoglobulins and Metalloporphyrin etc.

(a) Phenobarbitone:

This agent helps in decreasing the level of bilirubin by interfering the bilirubin synthesis. The effect of phenobarbitone is not rapid and to provide its effect when it is used with a dose of 5mg/kg for 3-5 days prophylactically. It is effective in new-borns with haemolytic disease, extravasated blood pre term without any side effects.^23-24

(b) Intravenous Immunoglobulin (IVIG):

This is an alternative option for phototherapy. High dose IVIG (0.5–1 gr/kg) has shown to be effective in decreasing the needs of exchange transfusion and phototherapy in babies with Rh haemolytic disease.²⁵

(c) Metalloporphyrin:

These compounds are showing significant results in haemolytic and non-haemolytic settings without side effects but they are in experimental status.

(d) Follow-up:

Babies who are going for exchange transfusion should be under follow up for clinical risk for neurodevelopment outcome and hearing assessment (Brainstem Evoked Response Audiometry (BAER) should be done at 3 months of corrected age. For the risk of severe hyperbilirubinemia, systemic assessment should be performed before discharge. Based on the risk factors, early and focussed follow up should be given.

DISCUSSION:

From all these data we can conclude that the new born child should undergo screening for jaundice and nurses should be educated more about the neonatal jaundice. A study was conducted at Fayom University hospital, show the neonates with jaundice will prone to allergy than neonates without jaundice. So proper new born care is necessary.⁽²⁶⁾ Prolonged hospitalization and blood transfusions may be avoided if effective phototherapy is given as timely treatment. The core principles for management of neonatal jaundice are pre symptomatic detection, timely risk assessment, follow up monitoring and phototherapy treatment covering maximum body surface area.

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Received on 22.11.2022 Modified on 29.01.2023

Asian J. Pharm. Res. 2023; 13(3):200-205.

DOI: 10.52711/2231-5691.2023.00038