Neonatal Hyperbilirubinemia

Number: 0332

Policy

  1. Assessment of Neonatal Hyperbilirubinemia

    Aetna considers measurement of end-tidal carbon monoxide (CO) corrected for ambient CO (ETCOc), used either alone or in combination with the simultaneous measurement of total serum bilirubin (TSB) concentration experimental and investigational because measurement of ETCOc has not been proven to improve prediction of development of significant neonatal bilirubinemia over TSB alone.

    Aetna considers genotyping of SLCO1B1 and UGT1A1 experimental and investigational for assessing risk of neonatal hyperbilirubinemia because the clinical value of this approach has not been established.

    Aetna considers transcutaneous bilirubin devices for evaluating hyperbilirubinemia in term and near-term infants while undergoing phototherapy experimental and investigational becasue this approach is not reliable in infants in this setting.

  2. Treatment of Hyperbilirubinemia in Term and Near-Term Infants

    Aetna considers phototherapy medically necessary for term and near-term infants according to guidelines published by the American Academy of Pediatrics (AAP).  The following are general age-in-hours specific total serum bilirubin (TSB) threshold values for phototherapy based upon gestational age and the presence or absence of risk factors (isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase [G6PD] deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin of less than 3.0 g/dL [if measured]):

    Table: Age in Hours Specific TSB threshold values for phototherapy
    Age in hoursTotal Serum Bilirubin (TSB) Level in mg/dL
    RiskFootnotes*Low MediumHigh 
    24 >12 ≥10 ≥8
    48 >15 ≥13 ≥11
    72 >18 ≥15 ≥13.5

    Footnotes* Low Risk ≥38 weeks gestation and without risk factors; Medium Risk: ≥38 weeks gestation with risk factors or 35 to 37 6/7 weeks gestation without risk factors; High Risk: 35 to 37 6/7 weeks gestation with risk factors. 

    Notes: Prophylactic phototherapy is considered medically necessary for infants showing a rapid rise in bilirubin (greater than 1 mg/dL/hour) and as a temporary measure when one is contemplating exchange transfusion.  Clofibrate in combination with phototherapy for neonatal hyperbilirubinemia is considered experimental and investigational.

    Aetna considers exchange transfusion medically necessary for term and near-term infants according to guidelines published by the American Academy of Pediatrics (AAP).  The following are general age-in-hours specific TSB threshold values for exchange transfusion based upon gestational age and the presence or absence of risk factors (isoimmune hemolytic disease, glucose-6-phosphate dehydrogenase [G6PD] deficiency, asphyxia, significant lethargy, temperature instability, sepsis, acidosis, or albumin of less than 3.0 g/dL [if measured]):

    Table: Age in Hours Specific TSB threshold values for exchange transfusion
    Age in hoursTotal Serum Bilirubin (TSB) Level in mg/dL
    RiskFootnotes*Low MediumHigh 
    24 >19 >16.5 >15
    48 >22 >19 >17
    72 >24 >21 >18.5
    > 72 >25 >21 >18.5

    Footnotes* Low Risk ≥38 weeks gestation and without risk factors; Medium Risk: ≥38 weeks gestation with risk factors or 35 to 37 6/7 weeks gestation without risk factors; High Risk: 35 to 37 6/7 weeks gestation with risk factors. 

    According to available guidelines, inpatient treatment may be considered medically necessary for healthy full-term infants who present with a TSB greater than or equal to 20 mg/dL in the first post-natal week.  Inpatient treatment is generally not medically necessary for healthy full-term infants with a TSB less than 20 mg/dL, as these infants can usually be treated with expectant observation or home phototherapy.  Inpatient treatment may be medically necessary for pre-term infants who present with a TSB greater than or equal to 18 mg/dL.  Inpatient treatment is not generally medically necessary for preterm infants who present with a TSB less than 18 mg/dL, as these infants can usually be treated with expectant observation or home phototherapy.

  3. Criteria for discontinuation of phototherapy

    Consistent with available guidelines, continued phototherapy is not medically necessary for healthy term infants when the following criteria for discontinuation of phototherapy are met:

    Table: Criteria for discontinuation of phototherapy
    Age in daysTotal Serum Bilirubin (TSB) Level in mg/dL
    Full term infant > 1 day of age ≤14
    Preterm < 5 days old 10 or less
    Healthy preterms > 5 or more days of age 12 or less

    A delay in discharge from the hospital in order to observe the infant for rebound once the bilirubin has decreased is not considered medically necessary.  According to available guidelines, no further measurement of bilirubin is necessary in most cases.

  4. Preterm Infants

    Aetna considers management of physiologic hyperbilirubinemia medically necessary in preterm infants (defined as an infant born prior to 37 weeks gestation) according to guidelines published by the AAP.  In preterm infants, phototherapy should be initiated at 50 to 70 % of the maximum indirect levels below:

    Table: Phototherapy maximum indirect levels
    Birth weight in gramsMaximum Indirect Serum Bilirubin Concentration in mg/dL
      Uncomplicated Complicated Footnotes*
    < 1,000 ≥12 ≥10
    1,000 - 1,250 ≥12 ≥10
    1,251 - 1,499 ≥14 ≥12
    1,500 - 1,999 ≥16 ≥15
    2,000 - 2,500 ≥20 ≥18

    Footnotes* Complications include but are not limited to prenatal asphyxia, acidosis, hypoxia, hypoalbuminemia, meningitis, intraventricular hemorrhage, hemolysis, hypoglycemia, or signs of kernicterus.

  5. Home Phototherapy

    Aetna considers home phototherapy for physiologic jaundice in healthy infants with a gestational age of 35 weeks or more medically necessary if all of the following criteria are met:

    1. The infant is otherwise ready to be discharged from the hospital; and 
    2. The infant is feeding well, is active, appears well; and 
    3. TSB is less than 20 to 22 mg/dL in term infants, or less than 18 mg/dL in preterm infants; and 
    4. Arrangements have been made to evaluate the infant within 48 hours after discharge by an early office/clinic visit to the pediatrician, or by a home visit by a well-trained home health care nurse who should be able to:

      • Be available for follow-up clinical assessments and blood drawing as determined to be necessary by the responsible physician based on changes in bilirubin levels
      • Clinically assess the initial level of jaundice
      • Draw blood for bilirubin determinations
      • Encourage frequent feedings
      • Explain all aspects of the phototherapy system to the parents
      • Oversee set-up of the phototherapy system
      • Weigh the infant in the home

    Note: If levels do not respond by stabilizing (+/- 1 mg/dL) or declining, more intensive phototherapy may be warranted.

  6. Metalloporphyrins

    Aetna considers the use of metalloporphyrins (e.g., stannsoporfin (tin mesoporphyrin), Stanate, WellSpring Pharmaceutical Corporation, Neptune, NJ) for the treatment of neonatal jaundice experimental and investigational because their safety and effectiveness for this indication has not been established. 

  7. Antenatal Phenobarbital

    Aetna considers the use of antenatal phenobarbital to reduce neonatal jaundice in red cell isoimmunized pregnant women experimental and investigational because its effectiveness has not been established.

  8. Zinc Supplementation

    Aetna considers zinc supplementation for the prevention of hyperbilirubinaemia experimental and investigational because its effectiveness has not been established.

  9. Massage Therapy:

    Aetna considers massage therapy experimental and investigational for the treatment of neonatal hyperbilirubinemia because its effectiveness has not been established.

  10. Probiotics:

    Aetna considers probiotics experimental and investigational for the treatment of neonatal hyperbilirubinemia because its effectiveness has not been established.

Background

Aetna's policy on treatment of hyperbilirubinemia in infants is adapted from guidelines from the American Academy of Pediatrics.

There is insufficient evidence to support the use of metalloporphyrins (e.g., stannsoporfin (tin mesoporphyrin), Stanate, WellSpring Pharmaceutical Corporation, Neptune, NJ) for the treatment of neonatal jaundice.  Guidelines from the AAP stated: “There is now evidence that hyperbilirubinemia can be effectively prevented or treated with tin-mesoporphyrin, a drug that inhibits the production of heme oxygenase.  Tin-mesoporphyrin is not approved by the U.S. Food and Drug Administration.  If approved, tin-mesoporphyrin could find immediate application in preventing the need for exchange transfusion in infants who are not responding to phototherapy."  A systematic evidence review prepared for the Cochrane Collaboration (Suresh et al, 2003) concluded that, based upon limitations of the evidence, "[r]outine treatment of neonatal unconjugated hyperbilirubinemia with a metalloporphyrin cannot be recommended at present."

In a Cochrane review, Thomas et al (2007) stated that neonates from isoimmunized pregnancies have increased morbidity from neonatal jaundice.  The increased bilirubin from hemolysis often needs phototherapy, exchange transfusion or both after birth.  Various trials in pregnant women who were not isoimmunized but had other risk factors for neonatal jaundice have shown a reduction in need for phototherapy and exchange transfusion by the use of antenatal phenobarbital.  A recent retrospective case-controlled study showed reduction in the need for exchange transfusion for the neonates from isoimmunized pregnancies.  These investigators evaluated the effects of antenatal phenobarbital in red cell isoimmunized pregnancies in reducing the incidence of phototherapy and exchange transfusion for the neonate.  Randomized and quasi-randomized controlled trials of pregnant women established to have red cell isoimmunization in the current pregnancy during their antenatal testing and given phenobarbital alone or in combination with other drugs before birth were selected for review.  All 3 review authors independently assessed study eligibility and quality.  No studies met the inclusion criteria for this review.  The authors concluded that the use of antenatal phenobarbital to reduce neonatal jaundice in red cell isoimmunized pregnant women has not been evaluated in randomized controlled trials.

Morris and colleagues (2008) compared aggressive versus conservative phototherapy for infants with extremely low birth weight.  These investigators randomly assigned 1,974 infants with extremely low birth weight at 12 to 36 hours of age to undergo either aggressive or conservative phototherapy.  The primary outcome was a composite of death or neurodevelopmental impairment determined for 91 % of the infants by investigators who were unaware of the treatment assignments.  Aggressive phototherapy, as compared with conservative phototherapy, significantly reduced the mean peak serum bilirubin level (7.0 versus 9.8 mg/dL [120 versus 168 micromol/L], p < 0.01) but not the rate of the primary outcome (52 % versus 55 %; relative risk, 0.94; 95 % confidence interval [CI]: 0.87 to 1.02; p = 0.15).  Aggressive phototherapy did reduce rates of neurodevelopmental impairment (26 %, versus 30 %for conservative phototherapy; relative risk, 0.86; 95 % CI: 0.74 to 0.99).  Rates of death in the aggressive-phototherapy and conservative-phototherapy groups were 24 % and 23 %, respectively (relative risk, 1.05; 95 % CI: 0.90 to 1.22).  In pre-planned subgroup analyses, the rates of death were 13 % with aggressive phototherapy and 14 % with conservative phototherapy for infants with a birth weight of 751 to 1,000 g and 39 % and 34 %, respectively (relative risk, 1.13; 95 % CI: 0.96 to 1.34), for infants with a birth weight of 501 to 750 g.  The authors concluded that aggressive phototherapy did not significantly reduce the rate of death or neurodevelopmental impairment.  The rate of neurodevelopmental impairment alone was significantly reduced with aggressive phototherapy.  This reduction may be offset by an increase in mortality among infants weighing 501 to 750 g at birth.

Guidelines from the Canadian Paediatric Society (2007) found that phenobarbitol, studied as a means of preventing severe hyperbilirubinemia in infants with G6PD deficiency, did not improve clinically important outcomes in a randomized controlled clinical study (Murki et al, 2005).

In a prospective double-blind study, De Luca et al (2008) compared the accuracy of a new transcutaneous bilirubinometer, BiliMed (Medick SA, Paris, France) with BiliCheck (Respironics, Marietta, GA), a widely available instrument, and with total serum bilirubin (TSB) measurement.  A total of 686 healthy newborns needing measurement of their bilirubin were enrolled over a 4-month period.  Serum and transcutaneous bilirubin (TcB) measurements were taken with both devices within 15 mins.  The order of use of the instruments was randomized.  The linear regression analysis showed a better correlation between BiliCheck and serum bilirubin (r = 0.75) than between BiliMed and serum bilirubin (r = 0.45).  BiliCheck variability (+/- 2 SD of the mean bias from serum bilirubin) was within -87.2 to 63.3 micromol/L, while BiliMed variability was within -97.5 to 121.4 micromol/L.  The receiver operating characteristic analysis (for serum bilirubin levels greater than 205.2 micromol/L or greater than 239.4 micromol/L) showed significantly higher areas under the curve for BiliCheck than those for BiliMed (p < 0.001).  The authors concluded that despite the potential practical advantages of BiliMed, its reduced diagnostic accuracy in comparison with BiliCheck does not justify its use in clinical practice.

Trikalinos et al (2009) reviewed the effectiveness of specific screening modalities to prevent neonatal bilirubin encephalopathy.  These researchers identified studies through Medline searches, perusing reference lists and by consulting with United States Preventive Services Task Force (USPSTF) lead experts.  They included English-language publications evaluating the effects of screening for bilirubin encephalopathy using early TSB, TcB measurements, or risk scores.  Severe hyperbilirubinemia was used as a surrogate for possible chronic bilirubin encephalopathy (CBE), because no studies directly evaluated the latter as an outcome.  These investigators calculated the sensitivity and specificity of early TSB, TcB measurements, or risk scores in detecting hyperbilirubinemia.  A total of 10 publications (11 studies) were eligible.  Seven (2 prospective) studies evaluated the ability of risk factors (n = 3), early TSB (n = 3), TcB (n = 2), or combinations of risk factors and early TSB (n = 1) to predict hyperbilirubinemia (typically TSB greater than 95th hour-specific percentile 24 hours to 30 days post-partum).  Screening had good ability to detect hyperbilirubinemia: reported area-under-the-curve values ranged between 0.69 and 0.84, and reported sensitivities and specificities suggested similar diagnostic ability.  Indirect evidence from 3 descriptive uncontrolled studies suggested favorable associations between initiation of screening and decrease in hyperbilirubinemia rates, and rates of treatment or re-admissions for hyperbilirubinemia compared with the baseline of no screening.  No study assessed harms of screening.  The authors concluded that effects of screening on the rates of bilirubin encephalopathy are unknown.  Although screening can predict hyperbilirubinemia, there is no robust evidence to suggest that screening is associated with favorable clinical outcomes.

The USPSTF and the Agency for Healthcare Research and Quality (2009) reported on the effectiveness of various screening strategies for preventing the development of CBE.  The USPSTF reviewed experimental and observational studies that included comparison groups.  For harms associated with phototherapy, case reports or case series were also included.  The USPSTF concluded that the evidence is insufficient to assess the balance of benefits and harms of screening for hyperbilirubinemia to prevent CBE.

Hulzebos and associates (2011) examined the relationship between early postnatal dexamethasone (DXM) treatment and the severity of hyperbilirubinemia in extremely low birth weight (ELBW) preterm infants.  In 54 ELBW preterm infants, TSB and phototherapy (PT) data during the first 10 days were evaluated retrospectively.  These ELBW infants had participated in a randomized controlled trial of early DXM therapy that aimed to evaluate effects on chronic lung disease.  Infants had been treated with DXM (0.25 mg/kg twice-daily at postnatal day 1 and 2) or with placebo (normal saline).  Analysis was performed on an intention-to-treat basis.  A total of 25 infants had been randomized into the DXM group; 29 into the placebo group.  Mean TSB (120 +/-19 μmol/L versus 123 +/- 28 μmol/L, DXM versus placebo, respectively) and maximum TSB (178 +/- 23 μmol/L versus 176 +/- 48, DXM versus placebo, respectively) concentrations were similar.  Total serum bilirubin concentrations peaked 30 hours earlier in the DXM group (p ≤ 0.05).  The need for PT as well as the duration of PT were similar in both groups.  The authors concluded that early DXM treatment does not affect the severity of neonatal hyperbilirubinemia in ELBW preterm infants.  These findings seem compatible with the concept that factors other than bilirubin conjugation capacity are important for the pathophysiology of neonatal jaundice in ELBW preterm infants.

It is also important to note that there are serious health risks associated with corticosteroid therapy.  In a Cochrane review on early (less than 8 days) postnatal corticosteroid treatment for preventing chronic lung disease in preterm infants, Halliday et al (2010) concluded that the benefits of early postnatal corticosteroid treatment, especially DXM, may not out-weigh the known or potential adverse effects of this treatment.  Although early corticosteroid treatment facilitates extubation and reduces the risk of chronic lung disease and patent ductus arteriosus, it causes short-term adverse effects including gastro-intestinal bleeding, intestinal perforation, hyperglycaemia, hypertension, hypertrophic cardiomyopathy and growth failure.  Long-term follow-up studies reported an increased risk of abnormal neurological examination and cerebral palsy.  However, the methodological quality of the studies determining long-term outcomes is limited in some cases; the surviving children have been assessed predominantly before school age, and no study has been sufficiently powered to detect important adverse long-term neurosensory outcomes.  The authors concluded that there is a compelling need for the long-term follow-up and reporting of late outcomes, especially neurological and developmental outcomes, among surviving infants who participated in all randomized trials of early postnatal corticosteroid treatment.

In a Cochrane review, Gholitabar et al (2012) examined the safety and effectiveness of clofibrate in combination with phototherapy versus phototherapy alone in unconjugated neonatal hyperbilirubinemia.  Randomized controlled trials were identified by searching MEDLINE (1950 to April 2012) before being translated for use in The Cochrane Library, EMBASE 1980 to April 2012 and CINAHL databases.  All searches were re-run on April 2, 2012.  These investigators included trials where neonates with hyperbilirubinemia received either clofibrate in combination with phototherapy or phototherapy alone or placebo in combination with phototherapy.  Data were extracted and analyzed independently by 2 review authors (MG and HM).  Treatment effects on the following outcomes were determined: mean change in bilirubin levels, mean duration of treatment with phototherapy, number of exchange transfusions needed, adverse effects of clofibrate, bilirubin encephalopathy and neonatal mortality.  Study authors were contacted for additional information.  Studies were analyzed for methodological quality in a “Risk of bias” table.  A total of 15 studies (2 including preterm neonates and 13 including term neonates) were included in this review.  All but 1 of the included studies were conducted in Iran.  For preterm neonates, there was a significantly lower bilirubin level in the 100 mg/kg clofibrate group compared to the control group with a mean difference of -1.37 mg/dL (95 % CI: -2.19 mg/dL to -0.55 mg/dL) (-23 µmol/L; 95 % CI: -36 µmol/L to -9 µmol/L) after 48 hours.  For the term neonates, there were significantly lower bilirubin levels in the clofibrate group compared to the control group after both 24 and 48 hours of treatment with a weighted mean difference of -2.14 mg/dL (95 % CI: -2.53 mg/dL to -1.75 mg/dL) (-37 µmol/L; 95 % CI: -43 µmol/L to -30 µmol/L] and -1.82 mg/dL (95 % CI: -2.25 mg/dL to -1.38 mg/dL) (-31 µmol/L; 95 % CI: -38 µmol/L to -24 µmol/L), respectively.  There was a significantly lower duration of phototherapy in the clofibrate group compared to the control group for both preterm and term neonates with a weighted mean difference of -23.82 hours (95 % CI: -30.46 hours to -17.18 hours) and -25.40 hours (95 % CI: -28.94 hours to -21.86 hours), respectively.  None of the studies reported on bilirubin encephalopathy rates, neonatal mortality rates, or the levels of parental or staff satisfactions with the interventions.  The authors concluded that there are insufficient data from different countries on the use of clofibrate in combination with phototherapy for hyperbilirubinemia to make recommendations for practice.  They stated that there is a need for larger trials to determine how effective clofibrate is in reducing the need for, and duration of, phototherapy in term and preterm infants with hyperbilirubinemia.

Watchko and Lin (2010) noted that the potential for genetic variation to modulate neonatal hyperbilirubinemia risk is increasingly being recognized.  In particular, polymorphisms across 3 genes involved in bilirubin production and metabolism:
  1. [glucose-6-phosphate dehydrogenase (G6PD),
  2. uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), and
  3. solute carrier organic anion transporter polypeptide 1B1 (SLCO1B1)] may interact with each other and/or environmental contributors to produce significant hyperbilirubinemia.
Variant gene co-expression including compound and synergistic heterozygosity enhances hyperbilirubinemia risk, contributing to the etiologic heterogeneity and complex nature of neonatal jaundice.

Liu et al (2013) examined if 3 variants (388 G>A, 521 T>C, and 463 C>A) of SLCO1B1 are associated with neonatal hyperbilirubinemia.  The China National Knowledge Infrastructure and MEDLINE databases were searched.  These researchers performed a systematic review with meta-analysis including genetic studies, which assessed the association between neonatal hyperbilirubinemia and 388 G>A, 521 T>C, and 463 C>A variants of SLCO1B1 between January of 1980 and December of 2012.  Data selection and extraction were performed independently by 2 reviewers.  A total of 10 articles were included in the study.  The results revealed that SLCO1B1 388 G>A is associated with an increased risk of neonatal hyperbilirubinemia (odds ratio [OR], 1.39; 95 % CI: 1.07 to 1.82) in Chinese neonates, but not in white, Thai, Latin American, or Malaysian neonates.  The SLCO1B1 521 T>C mutation showed a low risk of neonatal hyperbilirubinemia in Chinese neonates, while no significant associations were found in Brazilian, white, Asian, Thai, and Malaysian neonates.  There were no significant differences in SLCO1B1 463 C>A between the hyperbilirubinemia and the control group.  The authors concluded that the findings of this study demonstrated that the 388 G>A mutation of the SLCO1B1 gene is a risk factor for developing neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations; the SLCO1B1 521 T>C mutation provides protection for neonatal hyperbilirubinemia in Chinese neonates, but not in white, Thai, Brazilian, or Malaysian populations.

Petersen and colleagues (2014) stated that extreme hyperbilirubinemia (plasma bilirubin greater than or equal to 24.5 mg/dL) is an important risk factor for severe bilirubin encephalopathy.  Several risk factors for hyperbilirubinemia are known, but in a large number of patients, a causal factor is never established.  UGT1A1 is the rate-limiting enzyme in bilirubin's metabolism.  The genotype of Gilbert syndrome, the UGT1A1*28 allele, causes markedly reduced activity of this enzyme, but its association with neonatal hyperbilirubinemia is uncertain and its relationship with extreme hyperbilirubinemia has not been studied.  These researchers examined whether the UGT1A1*28 allele is associated with extreme hyperbilirubinemia.  The UGT1A1*28 allele was assessed in a case-control study of 231 white infants who had extreme hyperbilirubinemia in Denmark from 2000 to 2007 and 432 white controls.  Cases were identified in the Danish Extreme Hyperbilirubinemia Database that covers the entire population.  Genotypes were obtained through the Danish Neonatal Screening Biobank.  Subgroup analysis was done for AB0 incompatible cases.  No association was found between the UGT1A1*28 allele and extreme hyperbilirubinemia.  With the common genotype as reference, the odds ratio of extreme hyperbilirubinemia was 0.87 (range of 0.68 to 1.13) for UGT1A1*28 heterozygotes and 0.77 (range of 0.46 to 1.27) for homozygotes.  Also, no association was found for AB0 incompatible cases.  The authors concluded that the UGT1A1*28 allele was not associated with risk for extreme hyperbilirubinemia in this study.

Travan et al (2014) examined if UGT1A1 promoter polymorphisms associated with Gilbert Syndrome (GS) occur with a greater frequency in neonates with severe hyperbilirubinemia.  In a case-control study performed at a single hospital center in Italy, 70 subjects with severe hyperbilirubinemia (defined as bilirubin level greater than or equal to 20 mg/dL or 340 μmol/L) and 70 controls (bilirubin level less than 12 mg/dL or 210 μmol/L) were enrolled.  Both case and control subjects were full term newborns.  Polymerase chain reaction analysis on blood spot was performed to determine the frequency of UGTA1A1 promoter polymorphisms in cases and controls.  No statistical difference in the prevalence of UGTA1A1 gene variants was found between cases and controls (p = 1).  Thirteen infants homozygous for (TA)7 polymorphism associated with GS were in the case group (18.6 %) and 14 in the control group (20.0 %).  A heterozygous group was also equally distributed between cases (44.3 %) and controls (42.9 %).  No (TA)8 repeat was found in the 2 groups.  The authors concluded that in this study population, GS polymorphism alone did not appear to play a major role in severe neonatal hyperbilirubinemia in neonates without signs of hemolysis.

An UpToDate review on “Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants” (Wong and Bhutani, 2015) does not mention genotyping of SLCO1B1 and UGT1A1 as management tools.

Zinc Supplementation for the Prevention of Hyperbilirubinaemia:

In a Cochrane review, Mishra and colleagues (2015) examined the effect of oral zinc supplementation compared to placebo or no treatment on the incidence of hyperbilirubinaemia in neonates during the first week of life and to evaluate the safety of oral zinc in enrolled neonates.  These investigators searched CENTRAL (The Cochrane Library 2014, Issue 1), MEDLINE (1966 to November 30, 2014), and EMBASE (1990 to November 30, 2014).  Randomized controlled trials were eligible for inclusion if they enrolled neonates (term and pre-term) to whom oral zinc, in a dose of 10 to 20 mg/day, was initiated within the first 96 hours of life, for any duration until day 7, compared with no treatment or placebo.  These researchers used the standard methods of the Cochrane Collaboration and its Neonatal Review Group for data collection and analysis.  Only 1 study met the criteria of inclusion in the review.  This study compared oral zinc with placebo.  Oral zinc was administered in a dose of 5 ml twice-daily from day 2 to day 7 post-partum.  The drug was administered into the mouth of the infant by the plastic measure provided with the bottle or with a spoon.  Incidence of hyperbilirubinaemia, defined as serum total bilirubin (STB) greater than or equal to 15 mg/dL, was similar between groups (n = 286; risk ratio (RR) 0.94, 95 % CI: 0.58 to 1.52).  Mean STB levels, mg/dL, at 72 ± 12 hours were comparable in both the groups (n = 286; mean difference (MD) -0.20; 95 % CI: -1.03 to 0.63).  Although the duration of phototherapy in the zinc group was significantly shorter compared to the placebo group (n = 286; MD -12.80, 95 % CI: -16.93 to -8.67), the incidence of need for phototherapy was comparable across both the groups (n = 286; RR 1.20; 95 % CI: 0.66 to 2.18).  Incidences of side effects like vomiting (n = 286; RR 0.65, 95 % CI: 0.19 to 2.25), diarrhea (n = 286; RR 2.92, 95 % CI: 0.31 to 27.71), and rash (n = 286; RR 2.92, 95 % CI: 0.12 to 71.03) were found to be rare and statistically comparable between groups.  The authors concluded that the limited evidence available has not shown that oral zinc supplementation given to infants up to 1 week old reduces the incidence of hyperbilirubinaemia or need for phototherapy.

Furthermore, an UpToDate review on “Treatment of unconjugated hyperbilirubinemia in term and late preterm infants” (Wong and Bhutani, 2016) does not mention zinc supplementation as a management tool.

Sharma and colleagues (2017) examined the role of oral zinc supplementation for reduction of neonatal hyperbilirubinemia in term and preterm infants.  The literature search was done for various randomized control trial (RCT) by searching the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase, Web of Science, Scopus, Index Copernicus, African Index Medicus (AIM), Thomson Reuters (ESCI), Chemical Abstracts Service (CAS) and other data base.  This review included 6 RCTs that fulfilled inclusion criteria.  One study evaluated the role of zinc in very low birth-weight (VLBW) infants and remaining enrolled neonates  greater than or equal to 35 weeks of gestation.  The dose of zinc varied from 5 to 20 mg/day and duration from 5 to 7 days.  All the studies used zinc sulfate, only 1 study used zinc gluconate.  The total number of neonates enrolled in these different RCT were 749.  The authors concluded that the role of zinc in the prevention of neonatal hyperbilirubinemia is not supported by the current evidence.  Only 1 study was able to show reduction in the mean TSB level and requirement of phototherapy with zinc, and the remaining studies did not report any positive effect.  None of the studies showed any effect on the duration of phototherapy, incidence of phototherapy, age of starting of phototherapy and any serious adverse effect.

Transcutaneous Bilirubin Devices for Evaluation of Hyperbilirubinemia in Term and Near-Term Infants Exposed to or Undergoing Phototherapy:

In a prospective study, Casnocha and colleagues (2016) tested the accuracy of TcB measure in newborns undergoing phototherapy.  A total of 150 term Caucasian neonates, 255 measurements of TSB and TcB concentration were obtained 2 hours after discontinuing phototherapy.  TcB measurements obtained on the forehead, sternum, abdomen and covered lower abdomen were statistically compared with the corresponding TSB.   TcB consistently under-estimated TSB levels significantly.  The smallest but significant difference between TSB and TcB was found on the lower abdomen.  The correlation between TSB and TcB was found to be moderately close (r = 0.4 to 0.5).  TcB measurements were inaccurate, regardless of phototherapy technique (Bilibed, conventional phototherapy).   The authors concluded that phototherapy significantly interfered with the accuracy of transcutaneous bilirubinometry; TcB measurements performed 2 hours after stopping phototherapy were not reliable, even if they were performed on the unexposed body area.  They stated that TSB assessment remains necessary, if treatment of hyperbilirubinemia is being considered.

Nagar and associates (2016) noted that TcB devices are commonly used for screening of hyperbilirubinemia in term and near-term infants not exposed to phototherapy.  However, the accuracy of TcB devices in infants exposed to phototherapy is unclear.  These researchers conducted a systematic review of studies comparing TcB devices with TSB in infants receiving phototherapy or in the post-phototherapy phase.  Medline, Embase, Cochrane Library, CINAHL and Scopus databases (from inception to May 8, 2014) were searched.  Additional citations were identified from the bibliography of selected articles and from the abstracts of conference proceedings.  The studies were included if they compared TcB results with TSB in term and near-term infants during phototherapy or after discontinuation of phototherapy.  Two reviewers independently assessed studies for inclusion, and discrepancies were resolved with consensus.  Risk of bias was assessed using the QUADAS-2 tool.  A total of 14 studies were identified.  The pooled estimates of correlation coefficients (r) during phototherapy were: covered sites 0.71 (95 % CI: 0.64 to 0.77, 11 studies), uncovered sites 0.65 (95 % CI: 0.55 to 0.74), 8 studies), forehead 0.70 (95 % CI: 0.64 to 0.75, 12 studies) and sternum 0.64 (95 % CI: 0.43 to 0.77, 5 studies).  Two studies also provided results as Bland-Altman difference plots (mean TcB-TSB differences -29.2 and 30 µmol/L, respectively).  The correlation coefficient improved marginally in the post-phototherapy phase (r = 0.72, 95 % CI: 0.64 to 0.78, 4 studies).  The authors found a moderate correlation between TcB and TSB during phototherapy with a marginal improvement in the post-phototherapy phase.  They stated that further research is needed before the use of TcB devices can be recommended for these settings.

Furthermore, an UpToDate review on “Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants” (Wong and Bhutani, 2017) states that “TcB measurements are not reliable in infants undergoing phototherapy.  TcB should not be used in patients undergoing phototherapy’.

Massage Therapy:

Garg and colleagues (2017) stated that neonatal hyperbilirubinemia (NNH) is one of the leading causes of admissions in nursery throughout the world.  It affects approximately 2.4 to 15 % of neonates during the first 2 weeks of life.  These researchers evaluated the role of massage therapy for reduction of NNH in both term and preterm neonates.  The literature search was done for various RCTs by searching the Cochrane Library, PubMed, and Embase.  This review included total of 10 RCTs (2 in preterm neonates and 8in term neonates) that fulfilled inclusion criteria.  In most of the trials, Field massage was given; 6 out of 8 trials reported reduction in bilirubin levels in term neonates.  However, only 1 trial (out of 2) reported significant reduction in bilirubin levels in preterm neonates.  Both trials in preterm neonates and most of the trials in term neonates (5 trials) reported increased stool frequencies.  The authors concluded that the role of massage therapy in the management of NNH was supported by the current evidence.  However, they stated that due to limitations of the trials, current evidence is in sufficient regarding the use of massage therapy for the management of NNH in routine practice.

Probiotics:

Chen and co-workers (2017) stated that probiotics supplementation therapy could assist to improve the recovery of neonatal jaundice, through enhancing immunity mainly by regulating bacterial colonies.  However, there is limited evidence regarding the effect of probiotics on bilirubin level in neonates.  These researchers systematically evaluated the safety and efficacy of probiotics supplement therapy for pathological neonatal jaundice.  Databases including PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wan Fang Database (Wan Fang), Chinese Biomedical Literature Database (CBM), VIP Database for Chinese Technical Periodicals (VIP) were searched and the deadline was December 2016; RCTs of probiotics supplementation for pathological neonatal jaundice in publications were extracted by 2 reviewers.  The Cochrane tool was applied to assessing the risk of bias of the trials.  The extracted information of RCTs should include efficacy rate, serum total bilirubin level, time of jaundice fading, duration of phototherapy, duration of hospitalization, adverse reactions.  The main outcomes of the trials were analyzed by Review Manager 5.3 software.  The RR or MD with a 95 % CI was used to measure the effect.  A total of 13 RCTs involving 1,067 neonatal with jaundice were included in the meta-analysis.  Probiotics supplementation treatment showed efficacy [RR: 1.19, 95 % CI: 1.12 to 1.26), p < 0.00001] in neonatal jaundice.  It not only decreased the total serum bilirubin level after 3 days [MD: -18.05, 95 % CI: -25.51 to -10.58), p < 0.00001], 5 days [MD: -23.49, 95 % CI: -32.80 to -14.18), p < 0.00001], 7 days [MD: -33.01, 95 % CI: -37.31 to -28.70), p < 0.00001] treatment, but also decreased time of jaundice fading [MD: -1.91, 95 % CI: -2.06 to -1.75), p < 0.00001], as well as the duration of phototherapy [MD: -0.64, 95 % CI: -0.84 to -0.44), p < 0.00001] and hospitalization [MD: -2.68, 95 % CI: -3.18 to -2.17), p < 0.00001], when compared with the control group.  Additionally, no serious adverse reaction was reported.  The authors concluded that this meta-analysis showed that probiotics supplementation therapy was an effective and safe treatment for pathological neonatal jaundice.  Moreover, they stated that as the quality of included studies and the limitations of samples, the long-term safety and efficacy still need to be confirmed by long-term and high-quality research.

The authors stated that this study had several drawbacks.  First, because the value of jaundice fading in each guideline was different, the heterogeneity was high in time of jaundice fading.  It suggested that these researchers should use the same guideline to detect the time of jaundice fading in future study.  Second, according to Cochrane risk of bias estimation, randomized allocation of participants was mentioned in 9 trials.  Most of the included studies only mentioned the use of random allocation, but they did not describe the specific random allocation method.  So, it was hard for these investigators to determine whether the allocation scheme was appropriate and whether blinding of participants and personnel was implemented.  Some studies showed that unclear random allocation and allocation plan might exaggerate the hidden effect of up to 30 to 41 %.  Third, since RCTs of included studies centered in a short observation period and did not follow-up the patients in long-term, the methodological quality of clinical trials with probiotics supplementation therapy for neonatal jaundice needed further improvement.  Therefore, well-designed, large randomized, double blind, placebo-controlled trials would be needed to further confirm the efficacy of probiotics.  All of the outcome measures should be monitored by a standardized effective report system in clinical trials and rare serious adverse reaction could be observed through epidemiological studies.

Deshmukh and associates (2017) noted that neonatal jaundice requiring phototherapy is associated with significant socioeconomic burden including hospital re-admission, prolonged hospital stay, and separation of the baby from mother.  These investigators assessed the safety and efficacy of probiotics in reducing the need for phototherapy and its duration in NNH.  They performed a systematic review of RCTs of probiotic supplementation for prevention or treatment of jaundice in neonates (any gestation or weight) using the Cochrane methodology.  Primary outcome was the duration of phototherapy.  Secondary outcomes included incidence of jaundice, TSB level at 24, 48, 72, 96 hours, and day 7, duration of hospital stay, and adverse effects (e.g., probiotic sepsis).  Results were summarized as per GRADE guidelines.  A total of 9 RCTs (prophylactic: 6 trials, n = 1,761; therapeutic: 3 trials, n = 279) with low- to high-risk of bias were included.  Meta-analysis (random-effects model) showed probiotic supplementation reduced duration of phototherapy [n = 415, MD: -11.80 (-17.47 to -6.13); p < 0.0001; level of evidence (LOE): low]; TSB was significantly reduced at 96 hours [MD: -1.74 (-2.92 to -0.57); p = 0.004] and 7 days [MD: -1.71 (-2.25 to -1.17); p < 0.00001; LOE: low] after probiotic treatment.  Prophylactic probiotics did not reduce the incidence of jaundice significantly [n = 1,582, RR: 0.56 (0.25 to 1.27); p = 0.16; LOE: low].  There were no probiotic-related adverse effects.  The authors concluded that limited low-quality evidence indicated that probiotic supplementation may reduce the duration of phototherapy in neonates with jaundice.  Moreover, they stated that routine use of probiotics to prevent or treat neonatal jaundice cannot be recommended; large well-designed trials are needed to confirm these findings.

Table: CPT Codes / HCPCS Codes / ICD-10 Codes
Code Code Description

Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+":

CPT codes covered if selection criteria are met:

36450 Exchange transfusion, blood; newborn
82247 Bilirubin; total
82248     direct

CPT codes not covered for indications listed in the CPB:

81328 SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse drug reaction), gene analysis, common variant(s) (eg, *5)
81350 UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37)
81400 Molecular pathology procedure, Level 1(eg, identification of single germline variant [eg, SNP] by techniques such as restriction enzyme digestion or melt curve analysis) [for assessing risk of neonatal hyperbilirubinemia]
97124 Therapeutic procedure, 1 or more areas, each 15 minutes; massage, including effleurage, petrissage and/or tapotement (stroking, compression, percussion)

Other CPT codes related to the CPB:

81247 - 81249 G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis

HCPCS codes covered if selection criteria are met:

E0202 Phototherapy (bilirubin) light with photometer
S9098 Home visit, phototherapy services (e.g., Bili-lite), including equipment rental, nursing services, blood draw, supplies, and other services, per diem

HCPCS codes not covered for indications listed in the CPB:

J2560 Injection, phenobarbital sodium, up to 120 mg

ICD-10 codes covered if selection criteria are met:

P55.0 - P55.9 Hemolytic disease of newborn
P57.0 - P57.9 Kernicterus
P58.0 - P58.9 Neonatal jaundice due to other excessive hemolysis
P59.0 - P59.9 Neonatal jaundice from other and unspecified causes

ICD-10 codes not covered for indications listed in the CPB:

O36.111+ - O36.199+ Maternal care for other isoimmunization [not covered for the use of antenatal phenobarbital in red cell isoimmunized pregnant women]

The above policy is based on the following references:

  1. American Academy of Pediatrics, Provisional Committee for Quality Improvement and Subcommittee on Hyperbilirubinemia. Practice parameter: Management of hyperbilirubinemia in the healthy term newborn. Pediatrics. 1994;94(4 Pt 1):558-565 (reviewed 2000). 
  2. American Academy of Pediatrics and American College of Obstetricians and Gynecologist. Guidelines for Perinatal Care. 4th ed. Elk Grove Village, IL: AAP; 1997. 
  3. Behrman RE, ed. Nelson Textbook of Pediatrics. 16th ed. Philadelphia, PA: W.B. Saunders Co.; 2000:513-519. 
  4. Hamelin K, Seshia M. Home phototherapy for uncomplicated neonatal jaundice. Can Nurse. 1998;94(1):39-40. 
  5. Maisels MJ, Kring E. Length of stay, jaundice, and hospital readmission. Pediatrics. 1998;101(6):995-998. 
  6. Seidman DS, Stevenson DK, Ergaz Z, et al. Hospital readmission due to neonatal hyperbilirubinemia. Pediatrics. 1995;96(4 Pt 1):727-729. 
  7. Torres-Torres M, Tayaba R, Weintraub A, et al. New perspectives on neonatal hyperbilirubinemia. Mt Sinai J Med. 1994;61(5):424-428. 
  8. Lazar L, Litwin A, Nerlob P. Phototherapy for neonatal nonhemolytic hyperbilirubinemia. Analysis of rebound and indications for discontinuing phototherapy. Clin Pediatr. 1993;32:264-267. 
  9. Schuman AJ, Karush G. Fiberoptic vs conventional home phototherapy for neonatal hyperbilirubinemia. Clin Pediatr (Phila). 1992;31(6):345-352. 
  10. Newman TB, Maisels MJ. Evaluation and treatment of jaundice in the term infant: A kinder, gentler approach. Pediatrics. 1992;89:809-818. 
  11. Wennberg RP. Bilirubin recommendations present problems: New guidelines simplistic and untested. Pediatrics. 1992;89:821-822. 
  12. Merenstein GB. 'New' bilirubin recommendations questioned. Pediatrics. 1992;89:822-823. 
  13. Poland RL. In search of a 'gold standard' for bilirubin toxicity. Pediatrics. 1992;89:823-824. 
  14. Brown AK, Seidman DS, Stevenson DK. Jaundice in healthy term neonates: Do we need new action levels or new approaches? Pediatrics. 1992;89:827-828. 
  15. Johnson LH. Hyperbilirubinemia in the term infant: When to worry, when to treat. NY State J Med. 1991;91:483-489. 
  16. Savinetti-Rose B, Kempfer-Kline RE, Mabry CM. Home phototherapy with the fiberoptic blanket. The nurse’s role in caring for newborns and their caregivers. J Perinatol. 1990;10(4):435-438. 
  17. Ludwig MA. Phototherapy in the home setting. J Pediatr Health Care. 1990;4(6):304-308. 
  18. Grabert BE, Wardwell C, Harburg SK. Home phototherapy. An alternative to prolonged hospitalization of the full-term, well newborn. Clin Pediatr (Phila). 1986;25(6):291-294. 
  19. Gartner LM, Gartner LM,. Practice patterns in neonatal hyperbilirubinemia. Pediatrics. 1998;101(1 Pt 1):25-31. 
  20. Centers for Disease Control and Prevention (CDC). Kernicterus in full-term infants--United States, 1994-1998. MMWR Morb Mortal Wkly Rep. 2001;50(23):491-494. 
  21. Weisiger RA. Hyperbilirubinemia, conjugated. eMedicine J. 2002;3(1). Available at: http://www.emedicine.com/med/topic1065.htm. Accessed July 16, 2002. 
  22. Valaes T. Problems with prediction of neonatal hyperbilirubinemia. Pediatrics. 2001;108(1):175-177. 
  23. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants. Pediatrics. 2001;108:31-39. 
  24. Stevenson DK, Fanaroff AA, Maisels MJ, et al. Prediction of hyperbilirubinemia in near-term and term infants. J Perinatol. 2001;21 Suppl 1:S63-S87. 
  25. Natus Medical Inc. ETCOc - An indicator of elevated hemolysis in neonatal hyperbilirubinemia. Clinical Information. San Carlos, CA: Natus Medical Inc.; 2002. Available at: http://www.natus.com/information/breath_analysis/. Accessed July 16, 2002. 
  26. Conseil de Évaluation des Technologies de la Santé du Québec (CETS). Transcutaneous bilirubinometry in the context of early postnatal discharge. CETS 99-6 RE. Montreal, QC: CETS; October 2000. Available at: http://www.aetmis.gouv.qc.ca/fr/publications/scientifiques/maternite_naissance/1999_06_en.pdf. Accessed June 7, 2004.
  27. Porter ML, Dennis BL. Hyperbilirubinemia in the term newborn. Am Fam Physician. 2002;65(4):599-606.
  28. Maisels MJ, Watchko JF. Treatment of jaundice in low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 2003;88(6):F459-F463.
  29. Ip S, Glicken S, Kulig J, et al. Management of neonatal hyperbilirubinemia. Evidence Report/Technology Assessment No. 65. Rockville, MD: Agency for Healthcare Research and Quality (AHRQ); 2002.
  30. French S. Phototherapy in the home for jaundiced neonates. Evidence Centre Evidence Report. Clayton, VIC: Centre for Clinical Effectiveness (CCE); 2003.
  31. Evans D. Neonatal jaundice. In: BMJ Clinical Evidence. London, UK: BMJ Publishing Group; November 2006.
  32. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004;114(1):297-316.
  33. Dennery PA. Metalloporphyrins for the treatment of neonatal jaundice. Curr Opin Pediatr. 2005;17(2):167-169.
  34. Wennberg RP, Ahlfors CE, Bhutani VK, et al. Toward understanding kernicterus: A challenge to improve the management of jaundiced newborns. Pediatrics. 2006;117(2):474-485.
  35. Suresh GK, Martin CL, Soll RF. Metalloporphyrins for treatment of unconjugated hyperbilirubinemia in neonates. Cochrane Database Syst Rev. 2003;(1):CD004207.
  36. Thayyil S, Milligan DW. Single versus double volume exchange transfusion in jaundiced newborn infants. Cochrane Database Syst Rev. 2006;(4):CD004592.
  37. Makay B, Duman N, Ozer E, et al. Randomized, controlled trial of early intravenous nutrition for prevention of neonatal jaundice in term and near-term neonates. J Pediatr Gastroenterol Nutr. 2007;44(3):354-358.
  38. Canadian Paediatric Society, Fetus and Newborn Committee. Guidelines for detection, management and prevention of hyperbilirubinemia in term and late preterm newborn infants (35 or more weeks’ gestation). Reference No. FN07-02. Paediatrics Child Health. 2007;12(5):1B-12B.
  39. Murki S, Dutta S, Narang A, et al. A randomized, triple-blind, placebo-controlled trial of prophylactic oral phenobarbital to reduce the need for phototherapy in G6PD-deficient neonates. J Perinatol. 2005;25(5):325-330.
  40. Thomas JT, Muller P, Wilkinson C. Antenatal phenobarbital for reducing neonatal jaundice after red cell isoimmunization. Cochrane Database Syst Rev. 2007;(2):CD005541.
  41. Maisels MJ, McDonagh AF. Phototherapy for neonatal jaundice. N Engl J Med. 2008;358(9):920-928.
  42. Morris BH, Oh W, Tyson JE, et al; NICHD Neonatal Research Network. Aggressive vs. conservative phototherapy for infants with extremely low birth weight. N Engl J Med. 2008;359(18):1885-1896.
  43. De Luca D, Zecca E, Corsello M, et al. Attempt to improve transcutaneous bilirubinometry: A double-blind study of Medick BiliMed versus Respironics BiliCheck. Arch Dis Child Fetal Neonatal Ed. 2008;93(2):F135-F139.
  44. Trikalinos TA, Chung M, Lau J, Ip S. Systematic review of screening for bilirubin encephalopathy in neonates. Pediatrics. 2009;124(4):1162-1171.
  45. US Preventive Services Task Force; Agency for Healthcare Research and Quality. Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy: US Preventive Services Task Force recommendation statement. Pediatrics. 2009;124(4):1172-1177.
  46. Stevenson DK, Wong RJ. Metalloporphyrins in the management of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med. 2010;15(3):164-168.
  47. Chawla D, Parmar V. Phenobarbitone for prevention and treatment of unconjugated hyperbilirubinemia in preterm neonates: A systematic review and meta-analysis. Indian Pediatr. 2010;47(5):401-407.
  48. Halliday HL, Ehrenkranz RA, Doyle LW. Early (< 8 days) postnatal corticosteroids for preventing chronic lung disease in preterm infants. Cochrane Database Syst Rev. 2010;(1):CD001146.
  49. Hulzebos CV, Bos AF, Anttila E, et al. Early corticosteroid treatment does not affect severity of unconjugated hyperbilirubinemia in extreme low birth weight preterm infants. Acta Paediatr. 2011;100(2):170-174.
  50. Ambalavanan N, Carlo WA. Kernicterus. Digestive System Disorders. Ch. 96.4. In: Nelson Textbook of Pediatrics. RM Kliegman, BF Stanton, JW St. Geme, et al., eds. 19th ed. Santa Barbara, CA: Elsevier Saunders; 2011.
  51. Bhutani VK; Committee on Fetus and Newborn; American Academy of Pediatrics. Phototherapy to prevent severe neonatal hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2011;128(4):e1046-e1052.
  52. Kumar P, Chawla D, Deorari A. Light-emitting diode phototherapy for unconjugated hyperbilirubinaemia in neonates. Cochrane Database Syst Rev. 2011;12:CD007969.
  53. Okwundu CI, Okoromah CA, Shah PS. Prophylactic phototherapy for preventing jaundice in preterm or low birth weight infants. Cochrane Database Syst Rev. 2012;1:CD007966.
  54. Gholitabar M, McGuire H, Rennie J, et al. Clofibrate in combination with phototherapy for unconjugated neonatal hyperbilirubinaemia. Cochrane Database Syst Rev. 2012;12:CD009017.
  55. Bhutani VK, Stark AR, Lazzeroni LC, et al; Initial Clinical Testing Evaluation and Risk Assessment for Universal Screening for Hyperbilirubinemia Study Group. Predischarge screening for severe neonatal hyperbilirubinemia identifies infants who need phototherapy. J Pediatr. 2013;162(3):477-482.
  56. Watchko JF, Lin Z. Exploring the genetic architecture of neonatal hyperbilirubinemia. Semin Fetal Neonatal Med. 2010;15(3):169-175.
  57. Liu J, Long J, Zhang S, et al. The impact of SLCO1B1 genetic polymorphisms on neonatal hyperbilirubinemia: A systematic review with meta-analysis. J Pediatr (Rio J). 2013;89(5):434-443.
  58. Petersen JP, Henriksen TB, Hollegaard MV, et al. Extreme neonatal hyperbilirubinemia and a specific genotype: A population-based case-control study. Pediatrics. 2014;134(3):510-515.
  59. Travan L, Lega S, Crovella S, et al. Severe neonatal hyperbilirubinemia and UGT1A1 promoter polymorphism. J Pediatr. 2014;165(1):42-45.
  60. Wong RJ, Bhutani VK. Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants. UpToDate [online serial]. Waltham, MA: UpToDate; reviewed January 2015.
  61. Mishra S, Cheema A, Agarwal R, et al. Oral zinc for the prevention of hyperbilirubinaemia in neonates. Cochrane Database Syst Rev. 2015;7:CD008432.
  62. Wong RJ, Bhutani VK. Treatment of unconjugated hyperbilirubinemia in term and late preterm infants. UpToDate Inc., Waltham, MA. Last reviewed January 2016.
  63. Casnocha Lucanova L, Matasova K, Zibolen M, Krcho P. Accuracy of transcutaneous bilirubin measurement in newborns after phototherapy. J Perinatol. 2016;36(10):858-861.
  64. Nagar G, Vandermeer B, Campbell S, Kumar M. Effect of phototherapy on the reliability of transcutaneous bilirubin devices in term and near-term infants: A systematic review and meta-analysis. Neonatology. 2016;109(3):203-212.
  65. Sharma D, Farahbakhsh N, Sharma P, Shastri S. Role of oral zinc supplementation for reduction of neonatal hyperbilirubinemia: A systematic review of current evidence. J Matern Fetal Neonatal Med. 2017;30(16):1953-1962.
  66. Wong RJ, Bhutani VK. Evaluation of unconjugated hyperbilirubinemia in term and late preterm infants. UpToDate Inc., Waltham, MA. Last reviewed January 2017.
  67. Garg BD, Kabra NS, Balasubramanian H. Role of massage therapy on reduction of neonatal hyperbilirubinemia in term and preterm neonates: A review of clinical trials. J Matern Fetal Neonatal Med. 2017:1-9.
  68. Chen Z, Zhang L, Zeng L, et al. Probiotics supplementation therapy for pathological neonatal jaundice: A systematic review and meta-analysis. Front Pharmacol. 2017;8:432.
  69. Deshmukh J, Deshmukh M, Patole S. Probiotics for the management of neonatal hyperbilirubinemia: A systematic review of randomized controlled trials. J Matern Fetal Neonatal Med. 2017:1-10.
  70. Mehrad-Majd H, Haerian MS, Akhtari J, et al. Effects of Gly71Arg mutation in UGT1A1 gene on neonatal hyperbilirubinemia: A systematic review and meta-analysis. J Matern Fetal Neonatal Med. 2017 Dec 10:1-11 [Epub ahead of print].