0332 Neonatal Hyperbilirubinemia (2)...Kernicterus in full-term infants--United States, 1994 1998. MMWR Morb Mortal Wkly Rep. 2001;50(23):491 494. 13. Chawla D, Parmar V. Phenobarbitone

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Neonatal Hyperbilirubinemia

Policy History

Last Review

06/04/2020

Effective: 05/25/1999

Next

Review: 03/25/2021

Review History

Definitions

Additional Information

Clinical Policy Bulletin

Notes

Number: 0332

Policy *Please see amendment for Pennsylvania Medicaid at the end of this CPB.

I. Assessment of Neonatal Hyperbilirubinemia

Aetna considers measurement of glucose-6-phosphate

dehydrogenase (G6PD) levels medically necessary for

jaundiced infants who are receiving phototherapy,

where response to phototherapy is poor, or where the

infant is at an increased risk of G6PD deficiency due to

family history, ethnic or geographic origin.

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.

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Aetna considers genotyping of BLVRA, 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.

II. 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

hours

Total Serum Bilirubin (TSB) Level in

mg/dL

Risk* Low Medium High

24 >12 ≥10 ≥8

48 >15 ≥13 ≥11

72 >18 ≥15 ≥13.5

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* 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

hours

Total Serum Bilirubin (TSB) Level in

mg/dL

Risk* Low Medium High

24 >19 >16.5 >15

48 >22 >19 >17

72 >24 >21 >18.5

> 72 >25 >21 >18.5

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* 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.

III. 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 days Total 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

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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.

IV. 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 grams

Maximum Indirect Serum Bilirubin

Concentration in mg/dL

Uncomplicated Complicated *

< 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

* Complications include but are not limited to prenatal

asphyxia, acidosis, hypoxia, hypoalbuminemia,

meningitis, intraventricular hemorrhage, hemolysis,

hypoglycemia, or signs of kernicterus.

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V. 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:

A. The infant is otherwise ready to be discharged from

the hospital; and

B. The infant is feeding well, is active, appears well; and

C. TSB is less than 20 to 22 mg/dL in term infants, or

less than 18 mg/dL in preterm infants; and

D. 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.

VI. Metalloporphyrins

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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.

VII. 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.

VIII. Zinc Supplementation

Aetna considers zinc supplementation for the prevention of

hyperbilirubinaemia experimental and investigational because its

effectiveness has not been established.

IX. Massage Therapy

Aetna considers massage therapy experimental and

investigational for the treatment of neonatal hyperbilirubinemia

because its effectiveness has not been established.

X. Prebiotics / Probiotics

Aetna considers prebiotics / probiotics experimental and

investigational for the treatment of neonatal hyperbilirubinemia

because their effectiveness for this indication has not been

established.

Background

Aetna's policy on treatment of hyperbilirubinemia in infants is

adapted from guidelines from the American Academy of

Pediatrics.

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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

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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.

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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

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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

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(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 gr oup; 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

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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

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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: (i) [glucose-6-phosphate dehydrogenase

(G6PD), (ii) uridine diphosphate glucuronosyl transferase

1A1 (UGT1A1), and (iii) 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.

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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 popul ations.

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

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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

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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 Hyperbilirubinemia

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:

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-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

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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.

Yang and colleagues (2018) noted that zinc sulfate may be a

promising approach to treat neonatal jaundice. However, the

results remain controversial. These investigators conducted a

systematic review and meta-analysis to examine the safety

and efficacy of zinc sulfate on hyperbilirubinemia among

neonates. PubMed, Embase, Web of science, EBSCO,

Cochrane library databases, Ovid, BMJ database, and

CINAHL were systematically searched; RCTs evaluating the

effect of zinc sulfate versus placebo on the prevention of

jaundice in neonates were included. Two investigators

independently searched articles, extracted data, and assessed

the quality of included studies. The primary outcomes were

TSB on 3 days and 7 days, the incidence of

hyperbilirubinemia. Meta-analysis was performed using

random- or fixed-effect models. A total of 5 RCTs involving

645 patients were included in the meta-analysis. Overall,

compared with placebo, zinc sulfate supplementation failed to

significantly reduce TSB on 3 days (MD = 0.09 mg/dL; 95 % CI:

-0.49 to 0.67; p = 0.77), TSB on 7 days (MD = -0.37 mg/dL; 95

% CI: -98 to 0.25; p = 0.25) as well as the incidence of

hyperbilirubinemia (OR = 1.14; 95 % CI: 0.74 to 1.76; p = 0.56).

Zinc sulfate showed no influence on phototherapy

requirement (OR = 0.90; 95 % CI: 0.41 to 1.98; p = 0.79), but

resulted in significantly decreased duration of phototherapy

(MD = -16.69 hours; 95 % CI: -25.09 to -8.3 hours; p < 0.0001).

The authors concluded that zinc sulfate could not reduce the

TSB on 3 days and 7 days, the incidence of hyperbilirubinemia

and phototherapy requirement, but resulted in significantly

decreased duration of phototherapy.

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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

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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

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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.

Prebiotics / 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:

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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,

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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.

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Armanian and colleagues (2019) stated that hyperbilirubinemia

occurs in approximately 2/3 of all newborns during the first

days of life and is frequently treated with phototherapy.

Although generally seen as safe, there is rising concern

regarding phototherapy and its potentially damaging effects on

DNA and increased side effects particularly for pre-term

infants. Other methods, such as enteral feeding

supplementation with prebiotics, may have an effective use in

the management of hyperbilirubinemia in neonates. In a

Cochrane review, these investigators examined if

administration of prebiotics reduces the incidence of

hyperbilirubinemia among term and pre-term infants compared

with enteral supplementation of milk with distilled

water/placebo or no supplementation. They used the standard

search strategy of Cochrane Neonatal to search the Cochrane

Central Register of Controlled Trials (CENTRAL 2018, Issue

5), Medline via PubMed (1966 to June 14, 2018), Embase

(1980 to June 14, 2018), and CINAHL (1982 to June 14,

2018). These investigators also searched clinical trials

databases, conference proceedings, and the reference lists of

retrieved articles for RCTs and quasi-randomized trials. They

considered all RCTs that studied neonates comparing enteral

feeding supplementation with prebiotics versus distilled

water/placebo or no supplementation. Two reviewers

screened papers and extracted data from selected papers.

They used a fixed-effect method in combining the effects of

studies that were sufficiently similar; and then used the

GRADE approach to assess the quality of the evidence. A

total of 3 small studies evaluating 154 infants were included in

this review. One study reported a significant reduction in the

risk of hyperbilirubinemia and rate of treatment with

phototherapy associated with enteral supplementation with

prebiotics (RR 0.75, 95 % CI: 0.58 to 0.97; 1 study, 50 infants;

low-quality evidence). Meta-analyses of 2 studies showed no

significant difference in maximum plasma unconjugated

bilirubin levels in infants with prebiotic supplementation (MD

0.14 mg/dL, 95 % CI: -0.91 to 1.20, I² = 81 %, p = 0.79; 2

studies, 78 infants; low-quality evidence). There was no


evidence of a significant difference in duration of phototherapy

between the prebiotic and control groups, which was only

reported by 1 study (MD 0.10 days, 95 % CI: -2.00 to 2.20; 1

study, 50 infants; low-quality evidence). The meta-analyses of

2 studies demonstrated a significant reduction in the length of

hospital stay (MD -10.57 days, 95 % CI: -17.81 to -3.33; 2

studies, 78 infants; I² = 0 %, p = 0.004; low-quality evidence).

Meta-analysis of the 3 studies showed a significant increase

in stool frequency in the prebiotic groups (MD 1.18, 95 % CI:

0.90 to 1.46, I² = 90 %; 3 studies, 154 infants; high-quality

evidence). No significant difference in mortality during hospital

stay after enteral supplementation with prebiotics was reported

(typical RR 0.94, 95 % CI: 0.14 to 6.19; I² = 6 %, p = 0.95; 2

studies; 78 infants; low-quality evidence). There were no

reports of the need for exchange transfusion and incidence of

acute bilirubin encephalopathy, chronic bilirubin

encephalopathy, and major neurodevelopmental disability in

the included studies. None of the included studies reported

any side effects. The authors concluded that current studies

are unable to provide reliable evidence regarding the

effectiveness of prebiotics on hyperbilirubinemia. These

researchers stated that additional large, well-designed RCTs

are needed in neonates that compare effects of enteral

supplementation with prebiotics on neonatal

hyperbilirubinemia with supplementation of milk with any other

placebo (particularly distilled water) or no supplementation.

Adjuvant Therapies (e.g., Clofibrate, and Metalloporphyrins) and Exchange Transfusion

In an evidence-based review on “Neonatal hyperbilirubinemia”,

Pace and colleagues (2019) stated that clofibrate,

metalloporphyrins, and ursodiol have been examined in the

management of unconjugated hyperbilirubinemia as

augmentation to phototherapy. Honar et al (2016) found that

ursodiol added at the time of phototherapy initiation showed a

significant reduction in peak bilirubin levels and duration of

phototherapy in term infants with unconjugated

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hyperbilirubinemia without any adverse effects. They stated

that a Cochrane review of clofibrate (2012) and

metalloporphyrins (2003) found that when added to

phototherapy, these medications significantly decreased

serum bilirubin levels and duration of phototherapy. However,

there was insufficient evidence to recommend their use

because of inadequate data on safety and long-term

outcomes. Moreover, these investigators stated that infants

with bilirubin levels greater than 25 mg/dL, those who are not

responding to phototherapy, and those with evidence of acute

bilirubin encephalopathy should be treated with exchange

transfusion, with initiation based on an infant’s age in hours

and neurotoxicity risk factors. Exchange transfusion involves

taking small aliquots of blood from the infant and replacing

them with donor red cells until the infant’s blood volume has

been replaced twice to remove bilirubin and antibodies that

may be causing hemolysis. Exchange transfusion should be

performed in a neonatal intensive care unit (NICU) due to

significant risks.

Genotyping of BLVRA

Li and colleagues (2019) examined the associations between

G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA rs699512

variants and the risk of neonatal hyperbilirubinemia in a

Chinese neonate population. A total of 447 Chinese neonates

with hyperbilirubinemia were selected as the study group and

544 healthy subjects were recruited as the control group

matched by baseline sex, age, feeding pattern and delivery

mode. Approximately 2 ml of peripheral venous blood was

taken from all subjects. The single nucleotide polymorphisms

(SNPs) of G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA

rs699512 loci were examined by the polymerase chain

reaction (PCR) and Sanger sequencing technique in the

peripheral blood of all subjects. For the G6PD 1388 G>A

SNP, individuals carrying the A-allele were associated with a

significantly increased risk of neonatal hyperbilirubinemia

(adjusted OR = 1.49, p < 0.001, 95 % CI: 1.31 to 1.67). This

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risk increased significantly in the CC genotype carriers at the

rs4149056 locus of the SLCO1B1 gene (OR = 2.17, 95 % CI:

1.87 to 2.33), whereas it decreased significantly in individuals

carrying the G-allele at the rs699512 locus of the BLVRA gene

(adjusted OR = 0.84, p = 0.01, 95 % CI: 0.75 to 0.95). The

G6PD 1388 G>A, SLCO1B1 rs4149056 and BLVRA rs699512

SNPs had a significant impact on STB levels. Moreover,

individuals carrying the A-allele of G6PD 1388 G>A and

BLVRA rs699512 had a significantly increased risk of

developing neonatal hyperbilirubinemia (OR = 5.01, p < 0.001,

95 % CI: 3.42 to 7.85). The authors concluded that genetic

variants of bilirubin metabolism genes, including G6PD 1388

G>A, SLCO1B1 rs4149056 and BLVRA rs699512, were

associated with the risk of neonatal hyperbilirubinemia, and

are potential markers for predicting the disorder.

Genotyping of G6PD

Guidelines from the American Academy of Pediatrics (AAP,

2004) on management of hyperbilirubinemia in the newborn

infant state that "Measurement of the glucose-6-phosphate

dehydrogenase (G6PD) level is recommended for a jaundiced

infant who is receiving phototherapy and whose family history

or ethnic or geographic origin suggest the likelihood of G6PD

deficiency or for an infant in whom the response to

phototherapy is poor (evidence quality C: benefits exceed

harms)."

CPT Codes / HCPCS Codes / ICD-10 Codes

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

Code Code Description

CPT codes covered if selection criteria are met:

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36450 Exchange transfusion, blood; newborn

82247 Bilirubin; total

82248 direct

CPT codes not covered for indications listed in the CPB:

Genotyping of BLVRA - no specific code:

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

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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:

Prebiotics - no specific code

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]

Glucose-6-phosphate dehydrogenase (G6PD) levels:

CPT codes covered if selection criteria are met:

82955 Glucose-6-phosphate dehydrogenase (G6PD);

quantitative

82960 Glucose-6-phosphate dehydrogenase (G6PD);

screen

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

Z15.89 Genetic susceptibility to other disease [G6PD

deficiency]

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Z83.49 Family history of other endocrine, nutritional

and metabolic diseases [G6PD deficiency]

Z84.81 Family history of carrier of genetic disease

[G6PD deficiency]

The above policy is based on the following references:

1. 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.

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. 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.

4. 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).

5. Armanian AM, Jahanfar S, Feizi A, et al. Prebiotics for

the prevention of hyperbilirubinaemia in neonates.

Cochrane Database Syst Rev. 2019;8:CD012731.

6. Behrman RE, ed. Nelson Textbook of Pediatrics. 16th

ed. Philadelphia, PA: W.B. Saunders Co.; 2000:513

519.

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7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. 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.

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and treatment of unconjugated hyperbilirubinemia in

preterm neonates: A systematic review and meta-

analysis. Indian Pediatr. 2010;47(5):401-407.

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supplementation therapy for pathological neonatal

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15. 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.

16. 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.

17. Dennery PA. Metalloporphyrins for the treatment of

neonatal jaundice. Curr Opin Pediatr. 2005;17(2):167

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systematic review of randomized controlled trials. J

Matern Fetal Neonatal Med. 2017:1-10.

19. 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. 2019;32(1):154-163.

20. Evans D. Neonatal jaundice. In: BMJ Clinical Evidence.

London, UK: BMJ Publishing Group; November 2006.

21. French S. Phototherapy in the home for jaundiced

neonates. Evidence Centre Evidence Report.

Clayton, VIC: Centre for Clinical Effectiveness (CCE);

2003.

22. 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.

23. Gartner LM, Gartner LM,. Practice patterns in neonatal

hyperbilirubinemia. Pediatrics. 1998;101(1 Pt 1):25-31.

24. Gholitabar M, McGuire H, Rennie J, et al. Clofibrate in

combination with phototherapy for unconjugated

neonatal hyperbilirubinaemia. Cochrane Database

Syst Rev. 2012;12:CD009017.

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25. 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.

26. 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.

27. Hamelin K, Seshia M. Home phototherapy for

uncomplicated neonatal jaundice. Can Nurse. 1998;94

(1):39-40.

28. Hulzebos CV, Bos AF, Anttila E, et al. Early

corticosteroid treatment does not affect severity of

unconjugated hyperbilirubinemia in extreme low birth

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29. Ip S, Glicken S, Kulig J, et al. Management of neonatal

hyperbilirubinemia. Evidence Report/Technology

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AETNA BETTER HEALTH® OF PENNSYLVANIA

Amendment to Aetna Clinical Policy Bulletin Number: 0332 Neonatal

Hyperbilirubinemia

There are no amendments for Medicaid.

www.aetnabetterhealth.com/pennsylvania revised 06/04/2020

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Documents

0332 Neonatal Hyperbilirubinemia (2)...Kernicterus in full-term infants--United States, 1994 1998. MMWR Morb Mortal Wkly Rep. 2001;50(23):491 494. 13. Chawla D, Parmar V. Phenobarbitone