Select Page

Article By

A Chapla

S. Nimbalkar


Hyperbilirubinemia or jaundice, is a life-threatening disorder in newborns. Jaundice is easily diagnosed but it requires quick and prompt treatment. If not treated properly it leads to many complications. Generally physiological jaundice is most prevalent, however pathological jaundice is also common and must be treated. Occurrence of bilirubin-associated encephalopathy, lends urgency to the diagnosis and management of neonatal jaundice. This review article focuses on a brief introduction to jaundice, its types and causes, measuring the bilirubin level, clinical approaches towards hyperbilirubinemia, different precautionary measures for the parents of babies suffering from hyperbilirubinemia and different therapeutic treatment options and ways to prevent complications like bilirubin encephalopathy which can cause severe neurodisability.


Jaundice, also known as hyperbilirubinemia, is the yellowish tinge/pigmentation of the sclera and skin caused by an increase in bilirubin production or a defect in bilirubin elimination. When the total serum bilirubin (TSB) rises above the 95th percentile for age (high risk) during the first week of life, it is considered as hyperbilirubinemia. Approximately 85% of all term newborns and most preterm infants develop clinical jaundice. However, only a small proportion of these need treatment. Most resolve on their own.

Newborns are often discharged from the hospital within 48 hours of birth. As a result, hyperbilirubinemia is not often detected before discharge. The practice of early newborn discharge has transformed neonatal hyperbilirubinemia from previously being an inpatient issue to an outpatient one. Currently, hyperbilirubinemia is one of the most common reasons for readmission of a newborn. As such, physicians should be comfortable with the diagnosis, evaluation, and management of the jaundiced newborn. The aim of early recognition and appropriate treatment is to prevent bilirubin encephalopathy (kernicterus) which can cause severe neurodisability.


Physiological jaundice:

This is caused by normal neonatal changes in bilirubin metabolism. Jaundice develops due to physiological immaturity. It usually appears between 24 to 72 hours of age and the bilirubin levels peak between day 4 and 5 of life in term neonates and around the 7th day in preterm neonates. This physiologic jaundice disappears by 10-14 days of life.[1]

Pathological jaundice:

Bilirubin levels with a deviation from the normal range and requiring intervention would be described as pathological jaundice. It is characterized by a rapidly rising serum bilirubin >5 milligram per decilitre (mg/dl) per day. The jaundice visibly appears up to palms and soles within the first 24 hours of life and there is an associated anaemia or hepatosplenomegaly. It is also pathological if the jaundice is prolonged (>7 to 10 days in a full-term infant) and/or there is an elevated conjugated bilirubin concentration (>2 mg/dl or conjugated is more than 20% of the total bilirubin).

Breastfeeding jaundice:

Exclusively breastfed infants have a different physiological pattern for jaundice compared with formula fed babies.[1] Jaundice in breastfed babies usually appears between 24 to 72 hours of age, peaks by 5 to 15 days of life and disappears by the third week of life. This increased frequency of jaundice in breastfed babies is not related to characteristics of breast milk but rather due to inadequate breastfeeding. Only treatment needed is mother’s encouragement to breastfeed her baby at least 10-12 times per day.

Breast milk jaundice:

Hyperbilirubinemia is also associated with breast milk of mother in neonates. About 2 – 4% of exclusively breastfed babies have jaundice with bilirubin levels more than 10 mg/dl in the third week of life. These babies in the third week of life with bilirubin serum levels higher than 10 mg/dl should be considered as a cause of prolonged jaundice. A diagnosis of breast milk jaundice should be investigated if the serum bilirubin is predominantly unconjugated and other causes of prolonged jaundice have been eliminated. Mothers should be advised to continue breastfeeding at more frequent intervals and bilirubin levels usually diminish gradually. Some babies may require phototherapy. Breastfeeding should not be stopped; neither for diagnosis nor treatment of breast milk jaundice.



  • Increased bilirubin production: Haemolytic disease due to Rh, ABO, or minor blood group incompatibility, G6PD deficiency, thalassemia, hereditary spherocytosis
  • Non haemolytic: prematurity, extravasated blood from cephalohematoma, subgaleal bleeds, cutaneous bruising, hematoma, polycythaemia
  • Others: Breast milk jaundice, exaggerated physiological jaundice, coagulation disorders, hypothyroidism
  • Disorder of bilirubin uptake and conjugation such as Crigler Najjar syndrome, Gilberts syndrome Types 1 and 2, Rotor syndrome


  • Cholestasis: either surgical or non-surgical (drugs)
  • Infections: congenital/acquired
  • Inborn errors of metabolism: galactosaemia, tyrosinemia, alpha1 antitrypsin deficiency, haemochromatosis, Dubin Johnson syndrome, mitochondrial cytopathies

Evaluation of a Patient with Hyperbilirubinemia:

To establish the diagnosis and plan the treatment modality a proper, systematic approach needs to be made, starting with the accurate history and examination followed by the necessary tests.


  1. Family history:

Any sibling with jaundice or anaemia may suggest blood group incompatibility, breast milk jaundice, haemolytic anaemia in family, liver disease, glucose-6-phosphate-dehydrogenase (G6PD) deficiency.

  1. Pregnancy history:

          a. Illness during pregnancy may suggest a congenital viral or toxoplasmosis infection.

          b. Infants of diabetic mothers are more likely to develop hyperbilirubinemia

          c. Maternal drugs.


  1. Labour and delivery history:

       Birth trauma may be associated with extravascular bleeding and haemolysis. Similarly, oxytocin use, birth asphyxia, delayed cord clamping, lower gestational age and small for gestational age (SGA) babies may be associated with polycythaemia and intrauterine infections.


  1. Infant history:

       Inadequate lactation and under feeding (predisposes to exaggeration of physiological jaundice), delayed or infrequent stooling, vomiting which can be due to sepsis, pyloric stenosis, or galactosemia.



Clinical assessment of jaundice in outpatient department can be done by Kramer’s rule. Dermal staining in newborns progresses in a cephalo-caudal direction. The newborn should be examined in good daylight. The physician should pale the skin by digital pressure and the underlying colour of skin and subcutaneous tissue should be noted. If the face alone is affected, then bilirubin is around 5 mg%, when up to chest level, it is around 8 mg%, up to abdomen, it is around 12 mg%, and when palms and soles are stained, it is around 20 mg%. Clinical assessment is unreliable if a new born has been receiving either phototherapy or has dark skin.


After assessing the skin, it is important to look for other signs indicative of pathological jaundice such as pallor, splenomegaly, petechiae, hydration , and weight status and hypothyroidism. Signs of blood loss or blood sequestration such as excessive bruising, hepatosplenomegaly, or cephalohematoma should be sought out as well.




Bilirubin level can be checked by the biochemical method, a Bilimeter, or a transcutaneous bilirubinometer.


  1. Biochemical: The gold standard method for bilirubin estimation is the total and conjugated bilirubin assessment based on the van den Bergh reaction.
  2. Bilimeter: Spectrophotometry is the base of Bilimeter and it assesses total bilirubin in the serum. Because of the predominant unconjugated form of bilirubin, this method has been found a useful method in neonates.
  3. Transcutaneous Bilirubinometer: This method is non-invasive and is based on the principle of multi wavelength spectral reflectance from the bilirubin staining in the skin. The accuracy of the instrument may be affected by variation of skin pigmentation and its thickness.



Complete blood count, haematocrit, peripheral smear, mother’s and baby’s blood group and Rh typing, direct antiglobulin or Coomb’s test, reticulocyte count, C-reactive protein (CRP), blood culture and sensitivity (C/S), liver function test, coagulation screen, urine routine analysis and C/S.


Only if required bearing in mind a specific diagnosis these investigations such as glucose 6-phosphate dehydrogenase (G6PD) screen, RBC enzyme assays, TORCH screen (Toxoplasmosis, Other virus, Rubella, Cytomegalovirus, Herpes simplex), urine for CMV, cerebrospinal fluid C/S, cranial ultrasound, abdominal ultrasound, computed tomography(CT) head, urine for reducing substances, urine organic acids, serum amino acids, thyroid function tests, and liver biopsy can be done as needed.



Kernicterus (bilirubin encephalopathy) is a rare but catastrophic bilirubin-induced brain injury that is one of the known causes of preventable cerebral palsy.[2,5] The signs are:

  • Lethargy, poor feeding, hypotonia, incomplete Moro’s reflex, unexplained irritability are danger signs of impending kernicterus (stage 1)
  • Seizures, opisthotonus, rigidity, and shrill cry indicate an advanced kernicterus (stage 2)


The classic tetrad of chronic, irreversible bilirubin encephalopathy is choreoathetoid cerebral palsy, deafness or hearing loss, impairment of upward gaze, and enamel dysplasia of the primary teeth.[2]


To prevent kernicterus an objective assessment of the presence or absence of jaundice should be done, the identification of risk factors of potentially severe disease should be identified, careful attention should be given to the parental concern regarding jaundice, poor feeding and lethargy identified early, and finally timely intervention for the infants with TSB greater than the 95th percentile.


Management of Hyperbilirubinemia:


(A) Physiological Jaundice


The nature of jaundice should be explained to the parents. The mother should be encouraged to breastfeed her baby frequently and exclusively, at least eight to twelve times per day in the initial several days, with no top feeds (formula) or glucose water. Adequate breastfeeding increases the enterohepatic circulation enabling the breakdown of bilirubin. Hence, its importance in maintaining the newborns hydration should be explained and understood by the mother.


If a newborn has been discharged prior to 72 hours of life, he/she should be evaluated again within 48 hours of discharge to assess the adequacy of breastfeeding and progression of jaundice. The mother should be instructed to return earlier to the hospital if the yellow colour/tinge of skin seems to be increasing and going from abdomen to the legs or any signs of poor feeding, lethargy or decreased urination are present.


(B) Pathological Jaundice


The treatment options for jaundice include phototherapy which may be either conventional orintensive, exchange transfusions, and pharmacological treatment which consists of phenobarbitone, intravenous immunoglobulins (IVIG), and metalloporphyrins.


(i) Phototherapy


Phototherapy remains the main treatment for neonatal jaundice. The main mechanism of action is by photo-oxidation of lipid soluble bilirubin to the more water soluble lumirubin. This is eliminated in urine and stool. Light of around 460 to 490 nanometer (nm), i.e. blue light is best suited for phototherapy. A mix of blue and white light is generally used. A spectral irradiance of 25-30 milli watt per square centimetre (mW/cm2 )/nm is required to provide adequate phototherapy.[4]


Conventional phototherapy uses overhead light sources using halogen lamps or compact florescent lamps (CFL), light emitting diodes (LEDs) and fibre-optic light sources. Fluorescent special blue light F20T12/BB and TL52 tubes lower bilirubin level most effectively because they deliver light in the blue-green spectrum, providing maximal absorption and good skin penetration.[4]


For administering phototherapy room temperature should be maintained between 25 to 28 degrees Celsius, all clothes should be removed except the diaper, the baby’s eyes should be covered with an eyepatch, and adequate distance should be maintained of around 30 to 45 cm between baby and the light source. Ensure optimum breastfeeding. Baby can be taken out for breastfeeding session. Hydration and temperature should be closely monitored when on phototherapy.


Adverse effects of phototherapy are rare but include diarrhoea, temperature instability, dehydration following excessive trans epidermal fluid losses, rashes, tanning, and bronze baby syndrome. Phototherapy is not recommended in conjugated hyperbilirubinemia due to the significant risk of bronze baby syndrome, possibly due to accumulation of porphyrin.


Phototherapy should be initiated and maintained as per the recommendations of American Academy of Pediatrics (AAP) guidelines for phototherapy.[3,4] Charts vary based on gestation and considers the bilirubin levels and the age of the baby (Table 1).

TC-Oct 2017 - Table1 - Gestational Age 35 +

Risk factors are defined as isoimmune haemolytic disease, G6PD deficiency, asphyxia, significant lethargy, temperature instability, sepsis, and metabolic acidosis.


The management of hyperbilirubinemia in the preterm infant (less than 35 weeks of gestation) follows a guideline for the initiation of phototherapy versus exchange transfusion,[5] and depends on gestational age as well as level of bilirubin. It is shown below (Table 2).

TC-Oct 2017 - Table2 - Approach to age 35 -

Intensive Phototherapy should have a spectral irradiance of more than 30 mW/cm2/nm. The intensity can be increased by bringing the light source closer to the baby (10 to 30 cm), increasing skin exposure, and increasing the spectral power.


Home Phototherapy can be done as an alternative to readmission to the hospital, phototherapy can be administered at home to healthy term infants >38 weeks gestation and without any risk factors.


Natural sunlight exposure, also called heliotherapy, provides sufficient irradiance in 425 to 475 nm band.[6] However, filtered sunlight can be used as alternative in low resource settings when phototherapy devices are not available. The use of direct sunlight is not recommended as a therapeutic option to prevent jaundice because of the risk of sunburn and the exposure to potentially harmful ultraviolet radiation (UV), which increases the risk for developing skin malignancies.[6] There is also the possibility of hypothermia and hyperthermia which may develop inadvertently. In addition, there is the possibility of delayed treatment if undue faith is put in sunlight phototherapy. Hence sunlight exposure for phototherapy is not recommended.


(ii) Exchange Transfusion:


Exchange transfusion is a potentially life-saving emergency procedure that acutely reduces the level of bilirubin. During the time interval needed to set up an exchange transfusion, infants should receive intensive phototherapy. This method is used to remove bilirubin from the circulation when intensive phototherapy fails or in certain infants with any clinical signs of bilirubin-induced neurologic dysfunction (BIND).[7] It should only be performed by trained personnel in a neonatal intensive care unit (NICU).


Immediately after a double volume exchange transfusion (about 160 to 180 mL/kg), bilirubin values decrease to half the value prior to the procedure. Fresh type O Rh-negative irradiated packed RBCs that are suspended in AB plasma and cross-matched against maternal plasma and cells are used.[7] The unit is reconstituted to a haematocrit of 50% to 55%. Exchange transfusion is usually performed through an umbilical venous catheter using a push-pull technique in which aliquots of the patient’s blood are removed and replaced with the donor blood.


(iii) Intravenous Immunoglobulin (IVIG):


National Institute for Health and Clinical Excellence (NICE) guidelines on neonatal jaundice recommend the use of IVIG in babies whose bilirubin levels remain above the threshold for exchange transfusion, have signs of kernicterus, or have rapidly rising bilirubin levels despite phototherapy.[8] The recommended dose is 0.5 to 1 gram per kilogram body weight (g/kg) given over 2 hours and then repeat the dose in 12 hours if needed. It is given while preparing for exchange transfusion. Agents such as metalloporphyrins or phenobarbitone are not recommended as effective treatments.


Babies having roughly 20 mg/dl serum bilirubin and that requiring exchange transfusion should be kept under follow-up in the high-risk clinic for neurodevelopmental outcome.[9] Hearing assessment (Brainstem Evoked Response Audiometry (BERA) should be done at 3 months of corrected age.



Hyperbilirubinemia is more severe in newborns. Therefore, precautionary measures should be adopted by both parents, and clinicians to diagnose and treat the disease properly.




Management of hyperbilirubinemia should follow:


  1. At Risk approach: Greater caution for infants with higher risk for encephalopathy.
  2. Low threshold for initiating phototherapy in these patients.
  3. A regular hospital policy for evaluation of bilirubin levels in all infants and management of hyperbilirubinemia.
  4. Exchange transfusion when indicated.
  5. Specific recommendations for follow-up bilirubin assessment in infants discharged before 72 hours of age.


TC-Oct 2017 - Art1 - Writers



  1. American Academy of Pediatrics, Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics 2004; 114:297-316.
  2. National Institute of Health and Care Excellence Guideline C G98. 2010.
  3. Bhutani VK. American Academy of Pediatrics Committee on Fetus and Newborn. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 weeks or more of gestation. Pediatrics. 2011; 128(4): e 1046-52.
  4. Maisels MJ, Bhutani VK, Bogen D, et al. Hyperbilirubinemia in the newborn infant ≥35 weeks’ gestation: an update with clarifications. Pediatrics.2009;124:1193-1198.
  5. Maisels MJ, Watchko JF, Bhutani VK, et al. An approach to the management of hyperbilirubinemia in the preterm infant less than 35 weeks of gest at ion. J Perinatol.2012;32:660-664.
  6. Cloherty and Stark’s Manual of Neonatal Care. 8th Eichenwald EC, Hansen AR, Stark AR, Martin CR (Editors). Philadelphia: Wolters Kluwer, Lippincott Williams Wilkins. 2016
  7. Cremer RJ, Richards DH. Influence of sunlight on hyperbilirubinemia of infants. Lancet 1958;1:1094
  8. Ramachandran A. Neonatal hyperbilirubinemia. Paediatrics and Child Health; April 2016;26(4): 162-168.
  9. Johnson L, Bhutani VK. The clinical syndrome of bilirubin-induced neurologic dysfunction. SeminPerinatol. 2011;35:101-113.