Hyperbilirubinemia in Neonates: Types, Causes, Clinical Examinations, Preventive Measures and Treatments: A Narrative Review Article.

BACKGROUND: Hyperbilirubinemia, or jaundice, is a life threatening disorder in newborns. It is a multifactorial disorder with many symptoms. Generally, the physiological jaundice is the most prevalent type however in some regions pathological jaundice is also common. 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 remedial therapeutic measures for its treatment.
METHODS: The main databases including Scopus, Pubmed, MEDLINE, Google scholar and Science Direct were researched to obtain the original papers related to the newborns' hyperbilirubinemia. The main terms used to literature search were "newborns' hyperbilirubinemia", "newborns' jaundice", "Physiological Jaundice" and "Patholigical Jaundice". The timeframe included the obtained articles was from 1952 to 2015.
RESULTS: Neonatal jaundice due to breast milk feeding is also sometimes observed. Hemolytic jaundice occurs because of the incompatibility of blood groups with ABO and Rh factors, when the fetus and mother blood groups are not compatible and the fetus blood crosses the barrier of the umbilical cord before birth causing fetus blood hemolysis owing to severe immune response.
CONCLUSION: Jaundice is easily diagnosable however require quick and on the spot treatment. If not treated properly, it leads to many complications. Currently the treatment options for jaundice include photo therapy, chemotherapy, and vaccinations.

Introduction

One of the most prevalent clinical conditions in is hyperbilirubinemia (1). Neonatal hyperbilirubinemia is a common clinical problem encountered during the neonatal period, especially in the first week of life (2, 3). Nearly 8% to 11% of neonates develop hyperbilirubinemia. When the total serum bilirubin (TSB) rises above the 95th percentile for age (high-risk zone) during the first week of life, it will be considered as hyperbilirubinemia (4, 5).

Between 60%–80% of healthy infants are expected to present with idiopathic neonatal jaundice (6). Neonatal jaundice is the discoloration of skin and sclera color to yellowish in a newborn by bilirubin (7). Therefore it can create concern in the physician and anxiety in the parents. According to National Neonatal-Perinatal Database (NNPD) the incidence of neonatal hyperbilirubinemia in in-house live-births is 3.3%, while in extramural admissions morbidity due to hyperbilirubinemia accounted for 22.1% (8). In neonates, the dermal icterus is first noted in the face and when the bilirubin level rises, it proceeds to the body and then to the extremities. This condition is common in 50%–60% of newborns in the first week of life (8).

Bilirubin is not merely a nuisance molecule that has dire consequences, but bilirubin such as uric acid is an important antioxidant circulating in biologic system of neonate (9–11). However, high bilirubin levels can be toxic for central nervous system development and may cause behavioral and neurological impairment (Neurotoxicity or Kernicterus) even in term newborns (12–14). Five to ten percent of newborns developed jaundice required the management of hyperbilirubinemia (15). Neonatal jaundice may be on account of different parameters such as birth weight, gestational age, premature rupture of membranes, maternal infectious diseases or other illness during pregnancy, having different sources of origin, hence having different types (16).

The main causes of increased bilirubin mostly are: race, genetic polymorphisms; inherited and acquired defects e.g. spherocytosis, Gilbert’s syndrome, Najjar 1 and 2 Molecular genetics studies have shown the correlations between neonates hyperbilirubinemia and different genetic variations which can change in enzyme activity. For example variations in the uridine 5′-diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene may cause decreased enzyme activity in neonates and adults which leads to the unconjugated bilirubin accumulation. Also the variation in the organic anion transporter 2 (OATP2) gene may result in severe hyperbilirubinemia in neonates (17, 18). Variations of 388 G>A (Asp130Asn, rs2306283), 521 T>C (Val174Ala, rs4149056), 463 C>A(Pro155Thr, rs11045819) of the solute carrier organic anion transporter family member 1B1 (SLCO1B1) gene which encodes the hepatic solute carrier organic anion transporter 1B1, a putative bilirubin transporter, may dispose subjects to newborns hyperbilirubinemia by the limitation of hepatic bilirubin uptake (19–21). Furthermore, in a genome wide association study, two polymorphisms of SLCO1B3 gene (rs17680137 C>G and rs2117032 C>T) were observed to have a strong association with serum bilirubin levels and to contribute to idiopathic mild unconjugated hyperbilirubinemia in healthy adults (22, 23).

Search Method

The following databases were searched in this study: Scopus, Pubmed, MEDLINE, Google scholar and Science Direct. The main terms used to literature search were “newborns’ hyperbilirubinemia”, “newborns’ jaundice”, “Physiological Jaundice” and “Patholigical Jaundice”. The timeframe included the obtained articles was from 1952 to 2015.

Types of Hyperbilirubinemia

Several types of Bilirubinemia have been reported in neonates including physiological jaundice, pathological jaundice, jaundice due to breastfeeding or breast milk and hemolytic jaundice including three subtypes due to Rh factor incompatibility, ABO blood group incompatibility and Jaundice associated with Glucose-6-phosphate dehydrogenase (G6PD) deficiency (24).

Physiological Jaundice

It is the most abundant type of newborn hyperbilirubinemia, having no serious consequences (25). Neurodevelopmental abnormalities including as athetosis, loss of hearing, and in rare cases intellectual deficits, may be related to high toxic level of bilirubin (26). Jaundice attributable to physiological immaturity which usually appears between 24–72 h of age and between 4th and -5th days can be considered as its peak in term neonates and in preterm at 7th day, it disappears by 10–14 days of life (27). Unconjugated bilirubin is the predominant form and usually its serum level is less than 15 mg/dl (28). Based on the recent recommendations of the AAP, bilirubin levels up to 17–18 mg/dl may be accepted as normal in term of healthy newborns (15).

Pathological Jaundice

Bilirubin levels with a deviation from the normal range and requiring intervention would be described as pathological jaundice (25). Appearance of jaundice within 24 h due to increase in serum bilirubin beyond 5 mg/dl/day, peak levels higher than the expected normal range, presence of clinical jaundice more than 2 weeks and conjugated bilirubin (dark urine staining the clothes) would be categorized under this type of jaundice.

Breast Feeding and Breast Milk Jaundice

Exclusively infants with breastfeeding have a different physiological pattern for jaundice compared with artificially feed babies (24). Jaundice in breast fed babies usually appears between 24–72 h of age, peaks by 5–15 days of life and disappears by the third week of life. Higher bilirubin levels have been reported in these infants (29). In case of breastfed newborns, mild jaundice may take 10–14 days after birth or may reoccur during the breast feeding period (30). Very large amounts of bilirubin rarely accumulate in the blood and cause cerebral lesions, a situation known as nuclear jaundice (31). These cuts may be followed by hearing loss, mental retardation, and behavioral disorders. A mild clinical jaundice has been observed in one third of all breastfed babies in the third week of life, which may persist for 2 to 3 months after birth in a few babies (32). Decreased frequency of breastfeeding is associated with exaggeration of physiological jaundice. One of the significant procedures to manage the jaundice in a term healthy baby is the mothers’ encouragement to breastfeed their babies at least 10–12 times per day (33).

Hyperbilirubinemia is also associated with breast milk of mother in neonates (34). About 2%–4% of exclusively breastfed babies have jaundice in excess of 10 mg/deal in the third week of life. These babies in the third week of life with bilirubin serum levels higher than 10mg/dl should be considered for prolonged jaundice (35). A diagnosis of breast milk jaundice should be investigated if the serum bilirubin is predominantly unconjugated, other causes of prolonged jaundice have been eliminated and the infant is in good health, vigorous and feeding well and gaining weight adequately (36). Mothers should be advised to continue breastfeeding at more frequent intervals and bilirubin levels usually diminish gradually. Discontinuity of breastfeeding is not recommended unless levels exceed 20 mg/dl (37).

Hemolytic Jaundice

The most common causes of hemolytic jaundice include (a) Rh hemolytic disease, (b) ABO incompatibility and (c) Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency and minor blood group incompatibility.

(A) Rh Factor Hemolytic Disease

Rhesus hemolytic disease of the newborns (RHDN) results from maternal red-cell alloimmunization (38). Maternal antibodies are produced against the fetal red blood cells, when fetal red blood cells are positive for a certain antigen, usually at what time a baby having Rh positive born to an Rh-negative mother (21) (and Rh-positive father), then maternal immunoglobulin (IgG) antibodies might cross the placenta into the fetal circulation and cause a wide variety of symptoms in the fetus, ranging from mild to severe hemolytic anaemia and fetal hydrops (39, 40). To facilitate early treatment in neonates who are dubitable to have Rh factor, a blood group and Rh typing, DCT, PCV (packed cell volume) and serum bilirubin on cord blood should be performed. A reticulocyte count should be sent before the first exchange transfusion (ET). Vigorous phototherapy is required immediately after the birth and it should be continued until a level, which is 5 mg/dl less than the level estimated for exchange blood transfusion (41). In preterm babies, lower values of intervention for treatment of Rh hemolytic disease have been demonstrated. Phototherapy and exchange blood transfusion are recommended when a level is greater than 0.5% and 1% birth weight (kg) respectively (29). Eight intravenous immunoglobulin (IVIG) can be used in a dose of 500 mg/kg 12 hourly × 2 doses after the first ET. After the first ET starting of Phenobarbitone 5 mg/kg/day × 5 may be recommended (24).

(b) ABO Incompatibility

The incidence of the incompatibility of the ABO blood groups of the mother and fetus, when the mother has the blood group O and the newborn has the A or B blood group, is 15–20% of all pregnancies (42). Babies with O-blood group mothers should be closely checked for and discharged after 72 h. Routine cord blood screening is not recommended for newborns with O-group mothers (43). Jaundice owing to ABO incompatibility usually appears 24 h after the birth. In the presence of significant jaundice or jaundice appearing within 24 h, the work up for pathological jaundice should be done (44). Intensive phototherapy is advised at SB 12–17 mg/dl depending upon postnatal age of the baby. Exchange blood transfusion is indicated at TSB. The weight at birth as a criterion for phototherapy and ET may be used for preterm newborns (45).

(c) Jaundice Associated With G6PD Deficiency

Deficiency, hereditary spherocytosis, and minor group incompatibilities should be managed similar to ABO incompatibility. G6PD, most common enzymopathy, is the deficiency of an enzyme in RBCs (46). It is the most vital disease of the pathway of hexose monophosphate (47). Investigations for G6PD deficiency should be considered in infants with severe jaundice in a family with a history of significant jaundice or in a geographic origin associated with G-6-PD deficiency (48, 49). Decreased bilirubin conjugation resulted from variation in the UGT1A1 and OATP2 genes play an important role in the progression of hyperbilirubinemia in G6PD deficient newborns (17).

Clinical Examination of Jaundice

Originally described by Kramer (33), dermal staining of bilirubin may be used as a clinical guide to the level of jaundice. Dermal staining in newborns progresses in a cephalo-caudal direction (50). The newborn should be examined in good daylight. The physician should pale the skin by digital pressure and the underlying color of skin and subcutaneous tissue should be noted. Newborns who are detected the yellow skin beyond the thighs should have an urgent laboratory confirmation for bilirubin levels. Clinical assessment is unreliable if a newborn has been receiving phototherapy and has dark skin (51).

Measurement of Bilirubin Levels

Bilirubin level can be checked through biochemical method, Bilimeter or transcutaneous bilirubinometer (52–56).

Biochemical

The gold standard method for bilirubin estimation is the total and conjugated bilirubin assessment based on the van den Bergh reaction (57, 58).

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.

Transcutaneous Bilirubinometer

This method is noninvasive and is based on the principle of multi wavelength spectral reflectance from the bilirubin staining in the skin (59). The accuracy of the instrument may be affected by variation of skin pigmentation and its thickness (60).

Clinical Approach to Jaundice

The initial step in evaluation of any newborn for jaundice is to differentiate between physiological and pathological jaundice. A helpful algorithm as adapted by AAP (2004b) (61) is as follows.

Dependency on Newborn Period or Preterm

Preterm intervention values are different and depend on the degree of prematurity and birth weight (62–64).

Evidence of Hemolysis

Onset of jaundice within 24 h, presence of pallor and hydrops, presence of hepatosplenomegaly, presence of hemolysis on the smear of peripheral blood, increased count of reticulocyte (>8%), rapid rise of bilirubin (>5 mg/dl in 24 h or >0.5 mg/dl/hr) or a family history of considerable jaundice should create a suspicion of hemolytic jaundice (65).

Instructions and Precautionary Measure for Parents during Physiological Jaundice

The benign nature of jaundice should be explained and demonstrated to the parents. The mother should be encouraged to breast-feed her baby frequently and exclusively, at least eight to twelve times per day for initial several days, with no top feeds or glucose water whatsoever (66–68). Mother should be told to bring the baby to the hospital if the color on the legs looks as yellow as the face.

Any newborn discharged before 48 h of life should be evaluated again in the next 48 h for breastfeeding sufficiency and development of jaundice (3).

Management of pathological Jaundice

Confirmatory serum bilirubin level assessment is recommended for infants when they are noted to have yellow skin color outside of the thighs. The American Academy of Pediatrics (AAP) has laid down criteria for managing babies with bilirubin in the pathological range. Jaundice appearing within 24 h should be managed as hemolytic jaundice. The following investigations for all infants with bilirubin levels in the range of phototherapy including: baby’s blood group, Rh typing and DCT (if Rh factor is absent in mother or mother has O blood group); packed cell volume (PCV); peripheral blood smear (PBS) for checking hemolysis and morphology of red blood cell; reticulocyte count and G6PD estimation (if indicated) (61). Any hemolytic cause of jaundice is done by these assessments. An inability to see a decrease in bilirubin level to 1–2 mg/dL after 4–6 h and/or to keep the bilirubin below the exchange transfusion level has been defined as failure of phototherapy. However, irrespective of the bilirubin level, an exchange transfusion (ET) may be performed at the smallest doubt about bilirubin encephalopathy (69).

Treatment Options for Jaundice

The treatment options for jaundice include phototherapy further subdivided to conventional, intensive and exchange transfusion, and pharmacological treatment subdivided to phenobarbitone, intravenous immunoglobulins (IVIG), metalloporphyrins and follow up remedies (70).

Phototherapy

Hyperbilirubinemia can be treated easily without or with a minimal adverse effect with phototherapy (71, 72). The efficacy of phototherapy depends on surface area exposed to phototherapy: Double surface phototherapy may be more effective than single surface phototherapy (73). Spectrum of light source: Special blue tubes with the mark F20T12/BB should be used rather than F20T12/B lights and Irradiance or energy output may be increased in a phototherapy unit by lowering the distance of the neonate to within 15–20 cm (74, 75). Continuous phototherapy is better than intermittent phototherapy. Phototherapy should not be interrupted except during breast-feeding or nappy change (40, 76–80).

(a) Conventional Phototherapy

One can use conventional or fiber-optic phototherapy units provided jaundice is non-hemolytic or its progression is slow.

(b) Intensive Phototherapy

In the circumstances including hemolytic jaundice, rapidly increasing bilirubin, or ineffectiveness of a conventional unit, using of intensive phototherapy is warranted. Placing the baby on the bili-blanket and using additional overhead phototherapy units contain blue lights and then lowering the phototherapy units to within a distance of 15–20 cm are two significant remedies (81).

(c) Exchange Transfusion

Through exchange transfusion bilirubin and hemolytic antibodies are removed (82).

: Always, Blood using for exchange transfusion should be negative Rh isoimmunization, negative for Rh factor. O (Rh) negative packed cells suspended in AB plasma will be the best choice. O (Rh) negative whole blood or cross-matched baby’s blood group (Rh negative) may also be used in an emergency (83, 84).

Only O-blood group should be used for exchange transfusion in newborns with ABO incompatibility. The best choice would be O group (Rh compatible) packed cells which are suspended in O group/AB plasma whole blood (Rh compatible with baby).

: In case of the Cross-matched with baby’s blood group blood volume used or double volume exchange should be kept in mind.

: Partial exchange is done at birth in Rh hemolytic disease: 50-ml/kg of packed cells.

: 2 × (80–100 ml/kg) × birth weight (kg)

Pharmacological Treatment

Pharmacological treatment of neonatal jaundice can further be categorized into different subheadings such as phenobarbitone, Intravenous immunoglobulins and Metalloporphyrins etc. (35, 85–87).

Bilirubin processing including hepatic uptake, conjugation and its excretion are ameliorated by this agent thus helps in decreasing level of bilirubin. However the effect of phenobarbitone is not rapid and takes time to show. When used for 3–5 days in a dose of 5 mg/kg after birth prophylactically, it has shown to be effective in babies with hemolytic disease, extravasated blood and in pre-term without any significant side effects. There is a huge literature documenting efficacy and mechanism of action and complications of treatment for Phenobarbital (88–94).

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 hemolytic disease (95–102).

These compounds are still experimental but showing promising results in various hemolytic and non-hemolytic settings without significant side effects (88, 103–107).

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 (61, 108). Hearing assessment (Brainstem Evoked Response Audiometry (BAER)) should be done at 3 months of corrected age (109).

Recent Advances

Hour-specific bilirubin nomograms have been constructed based on routine pre-discharge bilirubin assessment (81, 110, 111). These charts are useful in predicting hyperbilirubinemia based on a bilirubin level done after 24 h of age. However the mentioned charts are prepared based on infants born in the West and probable need to be assessed and validated on Asian infants or on regional basis before they can be used for routine newborn care.

Conclusion

Hyperbilirubinemia is more severe in newborns. Therefore precautionary measure should be adopted by both parents, and clinicians to diagnose and treat the disease properly. Government and public health organizations should arrange seminars, workshops and trainings for mothers regarding neonatal jaundice. Medical scientists should search for new treatments and preventive measures having no side effects and capable of recovering babies more speedily. Partners should screen their ABO blood groups as well as Rh factor before marriage. Consanguineous marriages should be avoided.

Ethical considerations

Ethical issues (Including plagiarism, informed consent, misconduct, data fabrication and/or falsification, double publication and/or submission, redundancy, etc.) have been completely observed by the authors.