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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
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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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Code Code Description
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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Code Code Description
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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Code Code Description
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.
13. 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.
14. 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.
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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
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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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