JOURNAL OF TROPICAL PEDIATRICS, VOL. 59, NO.

4, 2013

Risk Factors Associated with Unconjugated Neonatal

Hyperbilirubinemia in Malaysian Neonates
by Feiliang Wong,1 NemYun Boo,2 and Ainoon Othman3
1
Unit NICU, Department of Pediatrics, UKMMC, 56000, Kuala Lumpur, Malaysia, Department of Pathology, UKMMC, 56000,
Kuala Lumpur, Malaysia
2
Faculty of Medicine and Health Sciences,Universiti Sains Islam Malaysia, 55100, Kuala Lumpur, Malaysia, Department of
Pathology, UKMMC, 56000, Kuala Lumpur, Malaysia
3
Pediatrics, Faculty of Medicine and Health Sciences, University of Tunku Abdul Rahman, Malaysia, 43000, Kuala Lumpur,
Malaysia

Corresponding author: Feiliang Wong, Department of Pediatrics, Universiti Kebangsaan Malaysia Medical Center, 56000, Bandar
Tun Razak, Cheras, Kuala Lumpur, Malaysia. Tel: þ603-9145-5459. Fax: þ603-9045-5459. E-mail <feiliang@gmail.com>.

Summary
Objective: To investigate the risk factors associated with neonatal hyperbilirubinemia in Malaysian
neonates.
Methods: A prospective study was conducted to investigate the effects of glucose-6-phosphate dehydro-
genase (G6PD) mutation, variant uridine diphosphate glucuronosyltransferase UGT1A1 gene and hep-
atic organic anion transporter protein (OATP2) gene on a group of neonates. Hyperbilirubinemia was
defined as a total serum bilirubin level of 250 mmol/l.
Results: Of 318 neonates, 52 (16.4%) had hyperbilirubinemia. The incidence of G6PD mutation was
5.4% (15/280) among these infants. The incidence of G6PD mutation was significantly higher in the
male neonates with hyperbilirubinemia (7.8%) when compared with the normal male neonates without
hyperbilirubinemia (1.8%; p ¼ 0.03). Logistic regression analysis showed that the significant risk
factors for neonatal hyperbilirubinemia were Malay ethnicity [adjusted odds ratio (OR), 2.77; 95%
confidence interval (CI): 1.31–5.86; p ¼ 0.007] and G6PD mutation (adjusted OR, 3.29; 95% CI:
1.06–10.1820; p ¼ 0.039). The gender, birth weight and gestation age of neonates, variant
c.211G > A and variant of OATP2 gene were not significant.
Conclusions: Neonates with Malay ethnicity and G6PD mutation were at risk for hyperbilirubinemia.

Key words: neonatal hyperbilirubinemia, G6PD mutation, OATP2, UGT1A1 c.211G > A.

Introduction life, and 25–30% of these patients developed severe

In Malaysia, national survey showed that 75% of
newborns contracted jaundice in the first week of
Acknowledgements
The authors wish to thank Chin TL, Ding CH,
Devarani P, Ng CWK, Mohd-Hafizuddin M,
Ravindran J and Vilmajit K for their effort in
blood sampling and entering of clinical data.
Funding
This project was funded by the Science Fund (no. 02-
01-02-SF0291) from the Ministry of Science,
Technology and Environment of Malaysia and
IMU research grant no. 145/2007 from the
International Medical University of Malaysia.
neonatal jaundice, defined as a serum bilirubin (SB)
concentration of 340 mmol/l [1]. Although generally
a benign transitional phenomenon with no overt clin-
ical impact, infants with severe jaundice risked
developing serious complications such as kernicterus.
Factors identified to be associated with non-physio-
logic neonatal jaundice include East Asian ancestry,
low birth weight, prematurity, breast milk feeding
and a sibling with neonatal jaundice [2]. However,
in nearly half of these neonatal jaundice cases, no
known factors were identified [3]. Risk factors such
as East Asian (Japanese, Korean or Chinese) ances-
try, an affected sibling and a family history of
the condition suggest that genetic factors are
involved [4, 5]. Gene variants of glucose-6-phosphate
dehydrogenase (G6PD), uridine diphosphate glucur-
onosyltransferase (UGT1A1, a hepatic bilirubin-

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 F. WONG ET AL.
conjugating enzyme) and hepatic organic anion
transporter protein (OATP2) have been reported
to be associated with increased risk of severe neo-
natal jaundice [6–11]. G6PD gene mutation may
cause neonatal jaundice through an acute hemolytic
event with or without an identifiable environmental
trigger, or when co-existing with UGT1A1 gene poly-
morphism. UGT1A1 promoter and coding region
may cause neonatal jaundice by decreasing the hep-
atic bilirubin conjugation. Polymorphism of OATP2
gene, which is a putative bilirubin transporter, may
cause neonatal jaundice by limiting hepatic bilirubin
uptake [26–28].
To identify risk factors of neonatal jaundice for
Malaysian populations, which consist of three
major ethnic groups (Malay, Chinese and Indian),
we developed molecular genotyping assays for a
panel of mutations and polymorphisms across the
G6PD, UGT1A1 and OATP2 genes. The selection
of genetic variants for this panel was based on infor-
mation published in the journals. Eight of the most
common G6PD mutations in local Chinese and
Malay neonates (c.1376G > T, c.1388G > A,
c.95A > G, c.1024C > T, c.871G > A, c.487G > A,
c.563C > T and c.392G > T) were included [12, 13].
Polymorphism c.211G > A of UGT1A1 gene, which
was reported to occur more frequently in Asia, was
examined rather than the promoter region (TA re-
peat) [14–17]. Variants c.388A > G and c.521T > C
of OATP2 gene were also included in this study.
Materials and Methods
Recruitment of patients
A prospective cohort study was carried out on 330
healthy term infants born in the Seremban Tuanku
Jaafar Hospital (HTJS), a state hospital in Malaysia.
Parental consent was obtained for all infants before
participation in the study. The study protocol was
approved by the institute’s research and ethics com-
mittees. At birth, a specimen of 20 ml of cord blood
was collected onto Whatman filter paper. This spe-
cimen was screened for G6PD mutations,
c.211G > A of UGT1A1 gene and mutations of the
OATP2 gene. All infants were subsequently moni-
tored by their nearest Maternal and Child Health
Clinic (MCHC). Infants who developed jaundice
had their SB level measured and monitored in the
MCHC. Those infants with SB level 250 mmol/l
were admitted to HTJS for therapy and further
investigation.
Extraction of genomic DNA from dried blood spot
Four punches of 1.5 mm spot from each dried blood
spot were subjected to DNA extraction using
QIAamp DNA Investigator Kit (Qiagen,
Germany). Five microliters of DNA from each sam-
ple was subjected to genotyping and sequencing.
Journal of Tropical Pediatrics Vol. 59, No. 4
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Genotyping of variants
Eight common G6PD mutations in the Malaysian
population were genotyped using Taqman minor
groove binder (MGB) probe assay (Applied
Biosystem, Foster City, CA) pre-spotted in two 96-
well plates [18]. Plate 1 consisted of c.1388G > A,
c.1376G > T, c.392G > T and c.95A > G. Plate 2 con-
sisted of c.563C > T, c.487G > A, c.871G > A and
c.1024C > T. Each plate screened 24 samples with
four different types of G6PD mutation simultan-
eously. Oligonucleotide primers and probes used
were designed based on the published G6PD se-
quence (X55448) from http://www.ncbi.nlm.nih.gov
using Primer Express Software version 2.0 (Applied
Biosystems, Foster City, CA). Each single well con-
sisted of one forward and one reverse primer to amp-
lify the region of interest, and two MGB probes, one
with VIC fluorescent dye (to detect the wild type) and
another one with FAM fluorescent dye (to detect the
mutant type), labeled at the 50 end of the probes; both
30 ends were labeled with non-fluorescent quencher.
Variants c.211G > A were screened using Taqman
MGB probe assay according to the previously pub-
lished method [19].
High-resolution melting (HRM) analysis was used
to genotype c.388A > G and c.521T > C [3].
Statistical analysis
The Statistical Package for Social Science version
12.1 (SPSS Inc, Chicago, IL) was used for analysis
of data. The Student’s t-test (unpaired) was used for
analysis of continuous variables with normal distri-
bution between groups. The 2 (or Fisher’s exact test
for expected values of <5) was used for analysis of
categorical variable. Forward logistic regression was
carried out to determine the significant risk factors
associated with severe hyperbilirubinemia.
Statistically significance was set at p < 0.05.
Results
Of the 318 newborn infants recruited in this study,
183 were Malay, 70 Chinese and 65 Indian.
Neonatal hyperbilirubinemia [peak total SB
(PTSB) level 250 mmol/l] developed in 16.4%
(n ¼ 52) of infants, with a median PTSB level of
291 mmol/l [interquartile range (IQR): 263, 308].
Among the 266 infants without neonatal hyperbilir-
ubinemia, 42.1% (n ¼ 112) did not develop jaundice
during the first month of life, and 57.9% (n ¼ 154)
had only mild jaundice, with a median PTSB level of
173 mmol/l (IQR: 100, 216). When compared with
neonates without hyperbilirubinemia, neonates with
hyperbilirubinemia had significantly higher propor-
tion of Malay ethnicity (p ¼ 0.01), significantly
lower mean birth weight (p ¼ 0.045) and mean gesta-
tion age (p ¼ 0.006; Table 1) and significantly higher
proportion of G6PD mutation (p ¼ 0.001). There was
no significant difference in the gender distribution,
281
 F. WONG ET AL.

TABLE 1
The demographic characteristic of the hyperbilirubinemia and control group

Control subjects Hyperbilirubinemic p values

neonates
n ¼ 266 n ¼ 52

Ethnicity (%)
Malay 143 (53.8) 40 (76.9) 0.004*
Chinese 61 (22.9) 9 (17.3)
Indian 62 (23.3) 3 (5.8)
Gender (male/female) 139/126 26/25 0.8
Birth weight, g 3083  417 2958  356 0.03*
Gestation age, weeks 38.7  1.5 38.1  1.4 0.008*
Mother’s blood group n ¼ 262 n ¼ 52 0.8
O 107 (40.8) 24 (45.3)
A 64 (24.4) 11 (20.8)
B 75 (28.6) 15 (28.8)
AB 16 (6.1) 2 (3.8)
Mother’s rhesus blood group n ¼ 257 n ¼ 52 0.3
Positive 252 (98.1) 52 (100)
Negative 5 (1.9) 0
Mode of delivery (%) 0.9
Spontaneous vaginal delivery 228 (85.7) 46 (88.5)
Cesarean section 35 (12.6) 6 (11.3)
Vacuum 3 (1.1) 0
Type of feedings (%) n ¼ 265 n ¼ 52 0.7
Formula only 1 (0.38) 0
Mixed feeding 69 (26.0) 11 (21.2)
Exclusive breastfeeding 195 (73.6) 41 (78.8) 0.43

types of feedings, variant c.211G > A UGT1A1 gene
and variants OATP2 between the two groups.
Seventy-seven percent of hyperbilirubinemic neo-
nates were Malay, and this was significantly higher
than normal Malay neonates without hyperbilirubi-
nemia (54%; p ¼ 0.01). The proportion of hyperbilir-
ubinemic neonates of Chinese and Indian ethnicity
was lower than their distributions in this study
(Table 1).
G6PD mutation analysis was done in 280 neo-
nates, and the incidence of G6PD mutation was
5.3%. Of the 15 infants with G6PD mutation de-
tected, 11 were Malay (8 male and 3 female neo-
nates), 1 was Chinese and 3 were Indian. The most
common variants of G6PD mutation were
c.871G > A (n ¼ 6) and c.487G > A (n ¼ 6), which ac-
counted for 80% of the mutations. Other mutations
detected were c.563C > T (n ¼ 1), c.1024C > T (n ¼ 1)
and c.392G > T (n ¼ 1). No infant was found to have
the variants c.1388G > A, c.1376G > T or c.95A > G.
Of the 15 infants with G6PD variants detected, 8
were hemizygote. Three female neonates had homo-
zygote G6PD mutation, and four had heterozygote
G6PD mutation. Percentage of G6PD mutation was
significantly higher in the hyperbilirubinemic group
(7/52; 13.5%) when compared with the non-hyperbi-
lirubinemic group (8/228; 3.5%; p ¼ 0.01). Neonates
with G6PD mutation also had significantly higher
total SB (TSB) level when compared with neonates
without G6PD mutation (231 vs. 126 umol/l;
p ¼ 0.001).
The UGT1A1 gene (variation at c.211G > A) and
the variations of c.388G > A and c.521T > C of
OATP2 gene were identified in the hyperbilirubine-
mic and non-hyperbilirubinemic groups (Table 2).
The overall allele frequency for c.211G > A was
0.92. Heterozygote c.211G > A variant was detected
in 8.3%, and homozygote in 5.1% of the infants.
c.211G > A variant was most common among the
Chinese neonates (21/70; 30%) when compared
with the Malay (17/183; 9.3%) and Indian (4/62;
6.5%) neonates. The incidence of UGT1A1
c.211G > A was 9.6% in the hyperbilirubinemic and
14.1% in the non-hyperbilirubinemic groups, and no
significant difference was found between these two
groups of neonates (p ¼ 0.51; Table 2). The variations
(c.388G > A and c.521T > C) in the OATP2 gene
were not different between the two groups. The inci-
dence of OATP2 c.388G > A variant was 90.4% (47/
52) and 89.1% (237/266) in the hyperbilirubinemic
and non-hyperbilirubinemic groups (p ¼ 0.87), re-
spectively. Variation c.521T > C was found in
17.3% of hyperbilirubinemic neonates and 25.9%
of the non-hyperbilirubinemic neonates (p ¼ 0.22).
In our study, 5 of the 52 (9.6%) neonates in the
hyperbilirubinemic group co-expressed c.211G > A

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 F. WONG ET AL.

TABLE 2
G6PD mutation, c.211G > A of UGT1A1 and c.388A > G and c.521T > C of OATP2 gene in
neonates with hyperbilirubinemia and control group

Control subjects Hyperbilirubinemic p

neonates
n ¼ 228 n ¼ 52

G6PD mutation
No mutation 220 45
Homozygous/heterozygous (female) 4 (1.8) 3 (5.9) 0.1
Hemizygous (male) 4 (1.8) 4 (7.8) 0.03*
n ¼ 263 n ¼ 52
Variant UGT1A1 gene (%)
Wild type 226 (86) 47 (90.4)
Nucleotide 211 G > A 37 (14.2) 5 (9.6) 0.5
211G > A/normal 22 4
211G > A/211G > A 15 1
Variant OATP2 gene
Wild type 25 (9.5) 4 (7.7)
Nucleotide 388A > G 172 (65.4) 37 (71.2) 0.4
Nucleotide 521T > C 2 (0.8) 0
Compound variations 64 (24.3) 11 (21.2) 0.7
Co-expression of UGT1A1 and OATP2 34 (13) 5 (9.6) 0.5
G6PD mutation with co-expression 2 (0.7%) 0 (0%) 1.0
of UGT1A1 and OATP2

TABLE 3
OR and 95% CI associated with suspected factors by multiple logistic regression analysis in
hyperbilirubinemic neonates

Factor Co-efficient SE Adjusted OR p

estimate

Malay neonate 1.02 0.381 2.77 (1.31–5.86) 0.007

G6PD mutation 1.191 0.586 3.29 (1.06–10.20) 0.039
c.211G > A UGT1A1 0.016 0.415 1.0 (0.49–2.48) 0.82
c.388G > A OATP2 0.09 0.274 1.1 (0.64–1.87) 0.74
c.521T > C OATP2 0.024 0.223 1.1 (0.63–1.51) 0.91
Gestation age, weeks 0.172 0.123 1.19 (0.93–1.51) 0.16
Birth weight, g 0 0 1 (1–1) 0.34

and OATP2 variants. The incidence of the co-ex-
pression of c.211G > A and OATP2 was not signifi-
cantly different between the hyperbilirubinemic
(9.6%) and non-hyperbilirubinemic groups (13%;
p ¼ 0.51).
Forward logistic regression analysis showed that
Malay ethnicity and G6PD mutation were independ-
ent risk factors for development of hyperbilirubine-
mia in neonates (Table 3). The gender, birth weight
and gestation age of neonates were not risk factors.
Discussions
Taqman MGB assay was first used to genotype vari-
ant c.211G > A of UGT1A1 gene in our previous
study [4]. We expanded this technique to genotype
the eight most common G6PD mutations in local
Malay and Chinese populations by using 96-well
plate. Each well represented a multiplexing of a
G6PD mutation. Two G6PD genotyping plates
were developed by using pre-spot technology from
Applied Biosystem (Foster City, CA). The primers
and probes for each G6PD mutation were pre-
loaded in the 96 wells and lyophilized to stabilize
the assay. Pre-spot G6PD plates were convenient to
use because it required only the addition of master
mix and template DNA. Another advantage of pre-
spot plates was that the risk of contamination was
greatly reduced owing to fewer times of pipetting
process. No post-polymerase chain reaction (PCR)
analysis was required because the PCR instruments
analyzed the result automatically. The whole process

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required only 1.5 h for each 96-well plate.
Furthermore, the assay was sensitive because it did
not require a highly purified DNA extraction and
clearly discriminated between the normal and
mutant allele [20]. HRM analysis distinguished geno-
types for c.388A > G and c.521 T > C. All samples
could be classified accordingly from melting curve
shape.
The incidence of hyperbilirubinemia was more
prevalent in the Malay than in the Chinese and
Indian neonates, and confirmed the widely recog-
nized ethnic variations in the incidence of neonatal
hyperbilirubinemia. Asian neonates were observed to
be more prone to develop hyperbilirubinemia and
with greater severity than Caucasian and Negro neo-
nates [21]. Reports from mainland China, Hong
Kong, Japan, Macau, Korea and Taiwan revealed
higher incidences of neonatal hyperbilirubinemia
than other populations, with an overall increased
risk for a TSB level of 20 mg/dl [342 mmol/l; odds
ratio (OR), 3.1; 95% confidence interval (CI):
1.5–6.3] [22]. The incidence of neonatal hyperbiliru-
binemia among the Chinese neonates in this
Malaysian cohort was similar to those reported in
Taiwan (11.5%) [16].
The association between hyperbilirubinemia and
the risk of kernicterus in G6PD-deficient Malaysian
neonates has been well established [23, 24]. The
present study showed that G6PD mutation was an
important factor associated with neonatal hyperbilir-
ubinemia. Studies have shown that the distribution of
G6PD mutations vary with geographical area and/or
ethnic group. c.871G > A is the most common muta-
tion in our populations (6/318; 1.9%) and is mainly
found in the Malays; this finding is in concordance
with a previous study in the Malays [13]. Our study
confirmed that the three most common G6PD muta-
tions among Malaysian Malays were c.871G > A
(n ¼ 5), c.487G > A (n ¼ 4) and c.563C > T (n ¼ 1).
Variation c.1376G > T or c.1388G > A is commonly
reported in the Chinese [12]. Both of these mutations
were not found in this study. One possible explan-
ation could be the relatively small samples size of
Chinese neonates with hyperbilirubinemia (n ¼ 9).
However, a larger series of clinical study is needed
to determine the relationship between the different
types of G6PD mutation and the severity of jaundice.
Results of our study also showed that the incidence
of G6PD mutation among the Malay neonates was
higher than among the other two ethnic groups.
Logistic regression analysis revealed that, after con-
trolling for various potential confounders, Malay
ethnicity (adjusted OR, 2.77; 95% CI: 1.31–5.86;
p ¼ 0.007) and G6PD mutation (adjusted OR, 3.29;
95% CI: 1.06–10.1820; p ¼ 0.039) were independent
risk factors for the occurrence of hyperbilirubinemia
in neonates.
Difference in the prevalence of mutation of the
G6PD, UGT1A1 and OATP2 genes could be an
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F. WONG ET AL.
important factor associated with the differing inci-
dences of neonatal hyperbilirubinemia among the dif-
ferent ethnic groups. Mutation c.211G > A was
reported to be a significant risk factor in the
Taiwanese and Japanese neonates. Huang et al [16,
25] found that c.211G > A was a risk factor asso-
ciated with severe neonatal jaundice in Taiwanese
neonates. Studies from Japan demonstrated that
c.211G > A was not only frequent but also played a
role in the development of neonatal jaundice in
Japanese neonates [16]. Our previous study on a
group of Chinese neonates showed that homozygous
c.211G > A was a significant risk factor of neonatal
jaundice [4]. In the present study, c.211G > A vari-
ants were not common among Malay neonates.
However, this does not preclude the co-existence of
other UGT1A1 mutations associated with unconju-
gated hyperbilirubinemia in Malays. Malay ethnic
preponderance toward severe neonatal jaundice in
this group of neonates may be due to other under-
lying genetic factors, and the co-existence of Malay-
specific UGT1A1 mutations needs to be explored
further. Furthermore, unlike the study by Huang
et al, which reported c.388A > G of OATP2 gene to
be a significant risk factor, our study showed that
c.388A > G was common among three ethnic
groups in Malaysia but not significantly associated
with neonatal hyperbilirubinemia. The high allele fre-
quency of the OATP2 c.388G > A in this study also
suggests that this polymorphism alone does not ac-
count for an increased hyperbilirubinemia risk. The
contribution of co-expression of OATP2 gene with
UGT1A1 variants in neonates with hyperbilirubine-
mia who also had G6PD mutation is not clear.
Previous study by Watchko et al showed that
co-expression of the G6PD mutation with UGT1A1
and OATP2 variant was higher in subjects with
hyperbilirubinemia [29]. Our small sample size
did not allow us to completely characterize the com-
plexity of the interactions of these potential
contributors.
In conclusion, this study has successfully de-
veloped genotyping methods for the rapid detection
of G6PD mutations, c.211G > A mutations and vari-
ations of OATP2. The G6PD genotyping plates de-
veloped were able to cover >90% of the variants
detected in the local population. This study showed
that the prevalence of G6PD mutation was common
in the Malaysian neonates, especially among those of
Malay ethnicity, and was significantly associated
with hyperbilirubinemia.
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