INTRODUCTION:

Neonatal jaundice is one of the most common conditions, that requires medical emergency(1). Jaundice refers to the yellow colouration of the skin and the sclera, due to accumulation of bilirubin in the skin and mucous membrane(1). Jaundice is also referred as hyperbilirubinemia( raised levels of bilirubin in the body )(2). During the first week of life , all newborns have increased bilirubin levels by adult standards, with approximately 60% of term babies and 85% of preterm babies having visible jaundice(3). The level of bilirubin in the serum rises above 85umol/l (5mg/dl)(2).

Received on 29.04.2015 Modified on 22.06.2015

Research J. Pharm. and Tech. 8(6): June, 2015; Page 1087-1092

DOI: 10.5958/0974-360X.2015.00189.4

While in vitro, unconjugated bilirubin is cleared by the placenta, resulting in a cord serum bilirubin level usually of 35umol/L(2 mg/dl), or less. However, after birth, the level of jaundice, i.e physiological jaundice is a reflection of the bilirubin load to the liver , rate of hepatic excretion and ability of the serum binding protein to retain the bilirubin within the plasma (2). Hence there is increased serum bilirubin level after birth.

BILIRUBIN METABOLISM AND HYPERBILIRUBINEMIA:

Bilirubin is mainly produced by the breakdown of red blood cells.(4)As the red blood cells are lysed, they release hemoglobin. Heme molecules from hemoglobin are converted to bilirubin(4) .Red cells breakdown produces unconjugated bilirubin, which circulates mostly bound to albumin although some is free and hence is capable of entering the brain(4).Unconjugated bilirubin is metabolised to conjugated bilirubin in the liver, which then passes through the gut and is excreted via stool.(4). A fraction of bilirubin from the stool is reabsorbed into the blood via the portal circulation.(4) In short, bilirubin is formed by a two step process:

Heme-> (heme oxygenase in the spleen, liver and uncleared cells)-> carbon monoxide +biliverdin -> (biliverdin reductase ) -> bilirubin (5)

In young babies, u conjugated bilirubin can penetrate the membrane that lies btween the brain and the blood( the blood- brain barrier). U conjugated bilirubin is potentially toxic to the neural tissues (brain and spinal cord). Entry of unconjugated bilirubin into the brain can cause both short term and long term neurological dysfunction( bilirubin encephalopathy). The term kernicterus is used to denote the clinical features of acute or chronic bilirubin encephalopathy. The risk is increased with babies having increased bilirubin levels. (1)

Why are neonates susceptible to hyperbilirubinemia ?:

Neonates are susceptible to hyperbilirubinemia for many reasons. In term babies, bilirubin production is 2-3 times higher than the adult because newborns have more red blood cells, and these RBC's have a shorter life span. Newborns also have a relative deficiency of the enzyme UGT, and this enzyme does not reach adult levels until 14 weeks of age. Genetic variation in this enzyme also accounts for some predisposition to hyperbilirubinemia. As above, gut secretion of conjugated bilirubin is also decreased in newborn infants.(5). In most infants , peak TSB( total serum bilirubin) occurs from 48-96 hours of age and usually resolves within the first one to two weeks after birth(5).

TYPES OF NEONATAL JAUNDICE :(6)

PHYSIOLOGICAL JAUNDICE:

Jaundice attributable to physiological immaturity usually appears between 24-72 hours age, peaks by 4-5 days in term and 7th day in preterm neonates and disappears by 10-14 days of life. It is predominantly unconjugated and levels usually do not exceed 15 mg/dl. It's mostly observed in artificially fed babies. (6). The pattern of physiological jaundice also varies with factors like prematurity, ethnicity.(2)

PATHOLOGICAL JAUNDICE:

Bilirubin levels that deviate from the the normal range can be defined as pathological jaundice. Appearance of jaundice within 24 hours, increase in serum bilirubin beyond 5 mg/dl/day, peak levels above the expected normal range, presence of clinical jaundice beyond 2 weeks and conjugated bilirubin would be categorised under pathological jaundice.

BREAST FEEDING AND JAUNDICE:

Breast fed babies have a different pattern of physiological jaundice as compared to artificially fed babies. Jaundice in breast fed babies usually appears between 24-74 hours of age, peaks by 5-15 days of life and disappears by the third week of life. Authors have stated that this increased frequency is not related to characteristics of breast milk but rather to the pattern of breast feeding. Decreased frequency of breast feeding is associated with exaggeration of physiological jaundice.

BREAST MILK JAUNDICE:

It is associated with prolonged jaundice extending beyond the first two weeks of life. One or more substances like enzymes, 3 alpha and 20 beta pregnanediol in breast milk is thought to be responsible for breast milk jaundice(2).

HEMOLYTIC JAUNDICE:

In hemolytic jaundice , serum bilirubin levels exceed physiological levels and can be due to sepsis and inherited hemolytic diseases like glucose 6- phosphate dehydrogenase deficiency, ABO and Rh isoimmunisation.(2)

PROLONGED JAUNDICE:

Prolonged jaundice refers to jaundice persisting beyond the first two weeks of life in the term neonate, and causes include late onset Breast milk jaundice, congenital hypothyroidism and other rare inherited conditions(2).

CAUSES OF JAUNDICE:

CAUSES IN RELATION TO TIME FROM BIRTH: (3):

1.ONSET LESS THAN 24 HOURS:

· Always pathological

· Usually due to hemolysis

o Rhesus disease

o ABO incompatibility

· Exclude sepsis

· Rarer causes may include

o Blood group incompatibilities

o Red cell enzyme defect( G6PD deficiency )

o Red cell membrane defects

2. ONSET 24 HOURS TO 10 DAYS:

· Sepsis

· Hemolysis

· Polycythemia

· Breakdown of extravasated blood due to ,

o Cephalohaematoma

o Central nervous system haemorrhage

· Increased enterohepatic circulation which may be due to,

o Gut obstruction

· Physiological jaundice

· Breastfeeding jaundice

3. ONSET GREATER THAN 10 DAYS (AND ESPECIALLY GREATER THAN 2 WEEKS)

· Conjugated hyperbilirubinemia due to

o Idiopathic neonatal hepatitis

o Infections( hepatitis B, TORCH, sepsis )

o Congenital malformations

o Metabolic disorders

· Sepsis

· Hypothyroidism

· Haemolysis

· Breast milk jaundice

CAUSES OF UNCONJUGATED HYPERBILIRUBINEMIA: (2,4,5,7)

1. INCREASED LYSIS OF RBC

· Isoimmunisation

· RBC enzyme defect

· RBC structure abnormality

· Infections

· Sequestered blood

· Polycythemia

· Shortened life span of fetal RBC

2. DECREASED HEPATIC UPTAKE AND CONJUGATION OF BILIRUBIN:

· Immature glucuronyl transferase activity an all newborns

· Gilbert's syndrome

· Crier nijjar syndrome

· Pyloric stenosis

· Hypothyroidism

· Infants of diabetic mothers

· Breast milk jaundice

3. Increased Enterohepatic Reabsorption :

· Breast feeding jaundice

· Bowel obstruction

· No enteric feeding

CLINICAL EXAMINATION OF JAUNDICE:

Visual assessment remains the mainstay of jaundice surveillance in the new born. Assessment should be at least 8 to 12 hourly in the first 48 hours of life.(8) Originally described by Kramer, dermal staining of bilirubin may be used as a clinical guide to the level of jaundice.(6). According to Kramer, one can utilise the cephalocaudal progression of jaundice(8). The newborn should be examined in good daylight. The skin should be blanched with digital pressure and the underlying colour of the skin and subcutaneous tissue should be noted(6). Kramer drew attention to the observation that jaundice starts on the head and extends towards the feet as the level rises. He divided the infant into 5 zones, the SBR range associated with progression to the zones is as follows(8):

ZONE	1	2.	3.	4.	5
SBR(umol/L).	100.	150.	200.	250.	>250

A rough guide for level of dermal staining with level of bilirubin is included in the table given below (6)

AREA OF THE BODY. BILIRUBIN	LEVEL OF
Face	4-6 mg/dl
Chest, upper abdomen.	8-10 mg/dl
Lower abdomen, thighs.	12-14 mg/dl
Arms, lower legs.	15-18 mg/dl
Palms, soles	15-20 mg/dl

INVESTIGATION FOR NEONATAL JAUNDICE

· Total serum bilirubin

· Unconjugated and conjugated fractions in specific conditions

· Infants blood group, maternal blood group

· Direct Coomb's test

· Full blood count

· Reticulocyte count

· Peripheral blood film

· Blood culture, urine microscopy and culture

MEASUREMENTS OF BILIRUBIN LEVELS (6)

1. BIOCHEMICAL:

Laboratory estimation of total and conjugated bilirubin based on Vanden Bergh Reaction remains the gold standard for bilirubin estimation.

2. BILIMETER:

It is based on spectro- photometry and estimates total serum bilirubin. It is useful in neonates, as bilirubin is predominantly unconjugated.

3. TRANSCUTANEOUS BILIRUBINOMETER:

This method is non invasive and based on the principle of multi- wavelength spectral reflectance from the bilirubin staining in the skin. Variations due to skin thickness and pigmentation may interfere with the accuracy of the instrument.

FACTORS AFFECTING SEVERITY OF NEONATAL JAUNDICE (2):

The following factors are said to affect the severity of jaundice:

· Dehydration

· Large weight loss after birth

· Extravasation of blood, cephalohaematoma, contusion

· Swallowed maternal blood

· Infant of diabetic mother

· Acidosis

· Asphyxia

· GI tract obstruction: increase in enterohepatic circulation

G6 PD DEFICIENCY:(2):

G6PD deficiency is an inherited diseases disorder of the red blood cell, inherited in an x- linked recessive manner - males are affected while the females are carriers. G6PD is an enzyme essential in keeping glutathione in the reduced state that in turn is vital to maintain the integrity of the red cell me,brave . In G6PD deficiency the red blood cells are prone to haemolysis when exposed to oxidants or when certain foods or herbs are ingested. The incidence of G6PD deficiency varies among the various ethic groups as follows:

Chinese -3.1%

Malay - 1.4%

Indian -0.2%

These results were obtained by a fluorescent screening method, that had been found to be as sensitive and specific as other screening tests.

MANAGEMENT OF NEONATAL JAUNDICE:

· Perform a systemic assessment before discharge for the risk of severe hyperbilirubinemia.(7).

· Provide early and focussed follow up based on the risk assessment(7).

· Treat newborns with phototherapy or exchange transfusion to prevent the development of severe Hyperbilirubinemia and, possibly, bilirubin encephalopathy. (7).

· Use bilirubin level to determine the management of Hyperbilirubinemia in all babies.(1).

· Do not use the albumin/ bilirubin ration when making decisions about the management of Hyperbilirubinemia.(1).

Do not subtract conjugated bilirubin from total serum bilirubin when making decisions about the management of Hyperbilirubinemia. (1)

TREATMENT:

PHOTOTHERAPY:

Phototherapy is the first line treatment for neonatal jaundice and is effective in most babies in reducing TSB levels.(8).It converts bilirubin into water soluble monometer.(7). Its efficiency depends on,

· Surface area exposed to phototherapy(double surface phototherapy is more effective than single surface phototherapy)(6)

· The cause and severity of the hyperbilirubinemia(3)

· The light source, wavelength in the blue green spectrum are effective with special blue the most effective(3)

· Special blue tubes with the mark F20T12/BB should be used rather than F20T12/B lights.(6)

· The dose of phototherapy or irradiance administered(3)

· Irradiance or energy output can be increased in a phototherapy unit by decreasing the distance to within 15-20 cm of the infant (6)

· Lining the sides of the cot with white material that reflects the phototherapy light(3).

CONVENTIONAL PHOTOTHERAPY:

If jaundice is non-hemolytic or rate of rise of jaundice is slow then one can use either conventional or fibre optic phototherapy units.(6)

INTENSIVE PHOTOTHERAPY:

It implies the use of high levels of irradiance delivered to as much of the babies surface area as possible(3).

babies with any of the below given risk factors should start phototherapy according to their gestational age.(8).the risk factors include,

· Haemolysis

· G 6PD deficiency

· Asphyxia

· Proven sepsis

· Any baby who is unwell

· Albumin less than 30 gram/L

In babies with severe or rapidly increasing SBR, the efficiency of phototherapy can be optimized by removing all clothes and nappy and having more than one light above the baby and having the baby lie on a fibre optic or LED phototherapy mat.(8). phototherapy is effective yet there are a few side effects,(7)

· Dehydration

· Thermal instability

· Diarrhea

EXCHANGE TRANSFUSION:

It is the rapid removal of bilirubin. It is the removal of baby's blood with replacement of compatible blood.

RISKS:

Mortality, infection, hypocalcemia, metabolite disturbance. (7) During exchange transfusion do not :

· Stop continuous phototheraphy

· Perform a single volume exchange

· Use albumin priming

· Routinely administer intravenous calcium(1)

Following exchange transfusion:

· Maintain continuous multiple phototherapy

· Measure serum bilirubin level within 2 hours and manage according to the threshold table and treatment threshold graph.(1)

OTHER THERAPIES:

Do not use any of the following to treat hyperbilirubinemia.

· Agar

· Albumin

· Barbiturates

· Charcoal

· Cholestyramine

· Clofibrate

· D-penicillamine

· Glycerine

· Manna

· Metalloporphyrins

· Riboflavin

· Traditional chinese medicine

· Acupuncture

· Homeopathy(1)

DRUG THERAPHY:

Chelating agents like tin-mesophyrin can be used. its long term side effects are unknown.(7)

Phenobarbitone:

It improves hepatic uptake, conjugation, and excretion of bilirubin thus helping in lowering the bilirubin. however its effect takes time. when used porphylactically in a dose of 5 mg/kg for 3-5 days after birth, it has shown to be effective in babies with hemolytic jaundice, extravasated blood and in pre term babies without any significant side effect.(6)

METALLOPORPHYRINS:

These compounds are still experimental but showing promise in various hemolytic and non-hemolytic settings without significant side effects.(6)

KERNICTERUS:

Kernicterus is the yellow staining of specific area of brain tissue caused by an accumulation of unconjugated bilirubin in the brain. it results in bilirubin neurotoxicity and chronic bilirubin encephalopathy.(9)Kernicterus is the chronic and permanent neurologic sequelae of bilirubin induced neurologic dysfunction. acute bilirubin encephalopathy is the early manifestation of bilirubin toxicity to the brain.(5)

SYMPTOMS:(5)

Initially:

· Infants may be slightly lethargy

· Mild hypotonia

· Poor suck

· High pitched cry

Intermediate stage:

· Irritability

· Minimal feeding

· High pitched cry

Advanced stages:

· Deep coma

· Hypertonia

· No feeding ability

· Shrill cry

THE EXTENT OF NEURONAL INJURY DEPENDS ON:

The amount and duration of exposure to free bilirubin the susceptibility of the developing nervous system the relative amount of necrosis vs apoptosis produced whether surviving neurons will be functionally normal or more susceptible to other stressors either at the time of hyperbilirubinemia or afterwards(10) The american association of pediatrics have noted common clinical factors for severe hyperbilirubinemia. these include,

· Jaundice in the first 24 hours of life

· Visible jaundice before discharge

· Previous jaundice in the sibling

· Gestation 35-38 weeks

· Exclusive breastfeeding

· East asian race

· Bruising, cephalohematoma

· Maternal age >25 years

· Male sex(5,11)

PREVENTION OF KERNICTERUS:

In order to prevent kernicterus, the clinician should follow the following guidelines (12):

· Promote and support successful breastfeeding

· Establish nursery protocol for the identification and evaluation of hyperbilirubinemia

· Measure the total serum bilirubin or transcutaneous bilirubin levels of infants jaundiced in first 24 hours.

· Recognise that visual estimation of the degree of jaundice can lead to errors, particularly in dark pigmented infants.

· Interpret all bilirubin levels according to the infant's age in hours

· Recognise that infant's, 38 weeks gestation, particularly those who are breast fed, are at a higher risk of developing hyperbilirubinemia and require closer surveillance and monitoring.

· Perform a systemic assessment for the risk of sever hyperbilirubinemia on all infants prior to discharge

· Provide parents with written and oral information about new born jaundice

· Provide appropriate follow up based on time of discharge and the risk assessment

· Treat newborns, when indicated, with phototherapy or exchange transfusion

CONCLUSION:

Timely recognition of hyperbilirubinemia followed by effective phototherapy makes exchange transfusion and prolonged hospitalization unnecessary. the core principles of management of hyperbilirubinemia for neonates with idiopathic hyperbilirubinemia include, pre symptomatic detection, timely risk assessment, scheduled follow up monitoring, phototherapy guided by measurement of light power, treatment of maximum body surface, use of emergency protocol that emphasizes bilirubin biodistribution.(13).

The potential risk of kernicterus in the newborn is a biologic certainty, if the natural postnatal progression of hyperbilirubinemia is inadequately monitored or treated or when there is unpredictable predilection of the infant. public-private health care partnerships have the potentials to prevent kernicterus in local communities by adopting national standards that not only prevent adverse encounters but allow for non adversarial solutions. kernicterus preventable in most cases but with untreatable and tragic sequelae, is a matter of public health concern that requires implementation of safer community healthcare standards to prevent its occurrence(14).

REFERENCES:

1. National Institute for Health and Care Excellence, Neonatal Jaundice, May 2010.

2. Clinical Practice Guidelines, Management of Jaundice in Healthy Term Newborns, Feb 2003 .

3. Neonatal Jaundice-Prevention, Assessment, and Management. Queensland Maternity and Neonatal Clinical Guideline Program, Dec. 2012.

4. Intensive Care Nursery House Staff Manual, Neonatal Jaundice, University of California 2004.

5. Alison Chu, Poj Lysouvakson, feb 2008.

6. Ramesh Agarwal, Rajiv Aggarwal, Ashok Deorari, Vinod K Paul, Division of Neonatology, Department of Paediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi.(2009).

7. Recent Advances in Management of Neonatal Jaundice, Dr Lee Le Ye, National University of Healthcare System, 1997.

8. Phill Beebey and Nick Evans, RPA Newborn Care Guidelines, Nov 2011.

9. Managing Newborn Hyperbilirubinemia and Preventing Kernicterus, Penny Smith, Neonatal Nurse Specialist Vol 29, No 1, June 2013.

10. Vinod K Bhutani, Lois Johnson, The Jaundiced Newborn in the Emergency Department: Prevention of Kernicterus , June 2008.

11. Prevention of Acute Bilirubin Encephalopathy and Kernicterus in Newborns, Position Statement #3049, Nann Board of Directors, March 2010.

12. Revised Guidelines to help Prevent Kernicterus, The Joint Commission, August 31st 2004.

13. Eur J Pediatr (2006) 165: 306-319.

14. Vinod K Bhutani, Kernicterus as a Never- Event: a Newborn Safety Standard. Vol 72, Jan 2005.