ORIGINAL ARTICLE

Clinical Characteristics of G6PD Deficiency in Infants With

Marked Hyperbilirubinemia
Yi-Hao Weng, MD* and Ya-Wen Chiu, PhDw

Summary: This study analyzes the clinical features of glucose6-phosphate dehydrogenase (G6PD) deciency in infants with
marked hyperbilirubinemia. We retrospectively assessed a cohort of
413 infants with peak total serum bilirubin (TSB) level Z20 mg/dL
from 1995 to 2007. The prevalence of G6PD deciency was
proportional to the level of peak TSB: 21.1% (81/383) in 20 mg/dL
to 29.9 mg/dL, 45.5% (10/22) in 30 mg/dL to 39.9 mg/dL, and
100% (8/8) in Z40 mg/dL. Male sex was more common in G6PD
deciency (75.8%). When compared with G6PD-normal infants,
those with G6PD deciency tended to have extreme hyperbilirubinemia (peak TSB level Z25 mg/dL) and hemoglobin value
<13 g/dL (P<0.001). Furthermore, mortality rate was signicantly higher in G6PD-decient infants (3.0%) than in the G6PDnormal counterparts (0.0%). Among 58 of the G6PD-decient
infants who were followed for more than 12 months, 4 developed
the classic neurologic manifestations of kernicterus (6.6%). These
ndings show that G6PD deciency is an important risk factor of
extreme hyperbilirubinemia, death, and kernicterus.
Key Words: glucose-6-phosphate dehydrogenase deciency, neonatal
hyperbilirubinemia, kernicterus

(J Pediatr Hematol Oncol 2010;32:1114)

lucose-6-phosphate dehydrogenase (G6PD) deciency

is a worldwide hereditary disorder with the potential
for causing neonatal hyperbilirubinemia (NH).14 Destruction of red blood cells by the contact with oxidative agents,
such as mothballs, has been labeled as a factor leading
to NH.5,6 In addition, there is increasing evidence that
G6PD-decient infants are at great risk for NH even in an
environment free from agents that can induce hemolysis.4,7
The pathogenesis may involve genetic interactions.8,9 NH
carries a substantial threat for deleterious complications,
including death and long-term neurologic impairments. The
total serum bilirubin (TSB) value has been used as a surrogate index to evaluate the risk of irreversible sequences.10
Although there is no distinguished threshold of a safe TSB
level to adopt, most physicians work with the assumption
that infants with a TSB level >20 mg/dL are vulnerable to
sequelae.11 With the advent of therapeutic intervention,
signicant complications have become rare in recent years.

Received for publication April 3, 2009; accepted July 26, 2009.

From the *Department of Pediatrics, Chang Gung Memorial Hospital,
Chang Gung University College of Medicine, Taoyuan; and
wDivision of Health Policy Research and Development, Institute of
Population Health Sciences, National Health Research Institutes,
Miaoli, Taiwan.
Supported in part by the National Health Research Institutes.
Reprints: Yi-Hao Weng, MD, Department of Pediatrics, Chang Gung
Childrens Hospital, 5 Fuxin Street, Guishan 333, Taoyuan,
Taiwan, ROC (e-mail: yihaoweng@adm.cgmh.org.tw).
Copyright r 2010 by Lippincott Williams & Wilkins

J Pediatr Hematol Oncol

In this cohort study, the spectrums of G6PD-decient

infants in relation to marked NH are evaluated. We illustrate G6PD deciency in severe NH by comparing its
prevalence within dierent levels of peak TSB. Although
NH with G6PD deciency has been widely investigated,
very little of the outcome has been studied.12 This survey
has identied the risk factors contributing to irreversible
sequelae in infants with G6PD deciency.

MATERIALS AND METHODS

Patients and Laboratory Analysis
Permission to collect the data was obtained from
the Institutional Review Board of Chang Gung Memorial
Hospital. Medical charts of infants admitted to the
neonatal intensive care units at Chang Gung Childrens
Hospital from 1995 to 2007 with marked hyperbilirubinemia (peak TSB value Z20 mg/dL) were reviewed. Infants
with a direct bilirubin value/TSB value r15% were
included. Those with the following conditions that could
confuse the neurologic outcomes were excluded: gestational
age less than 34 weeks, birth weight less than 2000 g,
perinatal asphyxia, and congenital disorders of the central
nervous system. TSB values were measured in a clinical
laboratory with a Unistat bilirubinometer (Cambridge
Instruments, Bualo, NY). As described in an earlier
study,4 the G6PD activity of red blood cells was determined
spectrophotometrically at 340 nm by the reduction of
NADP+ in the presence of glucose-6-phosphate. G6PD
deciency was conrmed with the enzyme activity below
12.5 U/gm Hb.
Clinical and laboratory data were collected by
examining the medical charts. Any other possible etiologies
causing NHsuch as infants of diabetic mothers, polycythemia, congenital hypothyroidism, spherocytosis, bacterial infection (sepsis, urinary tract infection, omphalitis),
gastrointestinal obstruction, breast feeding, cephalohematoma, bruise, ABO incompatibility (dened as any blood
group A or B newborn of group O mother), and Rh
incompatibility (dened as Rh-positive infants born to Rhnegative mothers)were recorded. G6PD enzymatic activity was examined in all infants with NH. Other routine
laboratory examinations included complete blood count,
reticulocytes, blood smear, total and direct bilirubin value,
blood and urine cultures, blood type, and direct Coombs
test. Phototherapy was applied when peak TSB Z12 mg/dL
at 24 to 47 hours old, Z14 mg/dL at 48 to 71 hours old,
Z15 mg/dL at 72 to 119 hours old, and Z17 mg/dL at
Z120 hours old. In addition, exchange transfusion (ET)
was carried out as indicated: peak TSB Z15 mg/dL at 24
to 47 hours old, Z20 mg/dL at 48 to 95 hours old, and
Z25 mg/dL at Z96 hours old. A routine examination for
TSB values was carried out at 1, 4, and 12 hours after ET.

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(1/1)

(7/7)

100
90
80

(8/14)

70
60
50

(18/48)

40
30
20

(2/8)

RESULTS
A total of 413 infants had peak TSB Z20 mg/dL
during the 13-year study period. G6PD deciency was
conrmed in 99 cases. The prevalence of G6PD deciency
in infants with peak TSB Z20 mg/dL was 24.0% (99/413).
Figure 1 illustrates the prevalence of G6PD deciency by
dierent levels of peak TSB. The prevalence of G6PD
deciency in the general population was adopted from a
published cohort of 42,110 neonates born in the same
hospital between 1994 and 2001.4 In general, the prevalence
of G6PD deciency increased proportionally with the
level of peak TSB: 21.1% in 20 to 29.9 mg/dL, 45.5% in
30 to 39.9 mg/dL, and 100% in Z40 mg/dL. Among male
infants, the prevalence of G6PD deciency was 3.5% in the
general population, 23.9% in infants with peak TSB level of
20 to 24.9 mg/dL, 37.5% in 25 to 29.9 mg/dL, 57.1% in 30
to 39.9 mg/dL, and 100% in Z40 mg/dL. Among female
infants, the prevalence was 1.2% in the general population,
12.7% in those with 20 to 24.9 mg/dL, 15.2% in 25 to
29.9 mg/dL, 25% in 30 to 39.9 mg/dL, and 100% in those
with Z40 mg/dL.
To identify the unique characteristics of G6PD deciency, we incorporated 10 variables (birth place, sex, birth
weight, gestational age, delivery mode, peak TSB level, age
at peak TSB, hemoglobin value, management, and acute
outcome) for the univariate analytic model (Table 1). The
analysis showed discrepancies between G6PD-decient
and G6PD-normal infants in 5 categories: sex, hemoglobin
value, peak TSB level, management, and acute outcome.
Males were more common among G6PD-decient infants
(P<0.001). In addition, infants with G6PD deciency were
more likely to have a hemoglobin value less than 13 g/dL
compared with infants without G6PD deciency (P<0.001).
Three among the G6PD-decient infants (3.0%) died. In
contrast, no fatalities were seen in G6PD-normal infants.
The mortality rate was signicantly higher in G6PDdecienct infants (P<0.05). Furthermore, G6PD-decient
infants tended to have a high peak TSB level (P<0.001)
and, therefore, required more ET (P<0.01) than G6PDnormal counterparts.
Among 99 G6PD-decient infants, 43 had combined
factors that may enhance hyperbilirubinemia. These factors
included breast feeding (n = 20), blood group incompatibility (n = 15), urinary tract infection (n = 3), omphalitis (n = 2), cephalohematoma (n = 5), gastrointestinal
obstruction (n = 2), congenital hypothyroidism (n = 1),

polycythemia (n = 1), spherocytosis (n = 1), and massive

bruise (n = 1). There were no signicantly dierent demographic characteristics between infants with and without
combined factors (data not shown).
Double-volume ET was carried out in 37 G6PDdecient infants, of which 6 required a second procedure.
The TSB values after ET were not available in 2 patients
because of their death, leaving 41 procedures to be analyzed. Before ET, the TSB level was 30.4 7.6 mg/dL. At
1 hour after ET, the TSB level signicantly reduced to
18.7 4.3 mg/dL. Thereafter, at 4 (n = 39) and 12 hours
(n = 36), there was no signicant decrease in the TSB level
(data not shown).
Table 2 displays the demographic and laboratory
data of G6PD-decient infants by dierent levels of peak
TSB. Death was more common in infants with a peak TSB
level Z40 mg/dL than in infants with a peak TSB level
<40 mg/dL (P<0.001). In addition, there was a signicant
correlation of peak TSB level with hemoglobin value
(P<0.05). Infants with a higher peak TSB level were more
likely to have hemoglobin value less than 13 g/dL than
infants with a lower peak TSB level. Other characteristics
including sex, birth place, birth weight, gestational age,
delivery mode, G6PD activity, presence of combined factors,
and age at peak TSBcarried no signicant dierences
between each level of peak TSB.

(5/33)

The statistical analyses were conducted using a

commercially available program (SPSS for Windows,
version 12.0). Categorical variables were analyzed using
the w2 test or Fisher exact test. Signicance was dened
as P<0.05. The TSB values related to ET were calculated
by the number of procedures rather than the number of
infants.

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Statistical Analyses

(6/126)1

Mortality associated with NH was dened as death

occurring within 7 days after the development of marked
hyperbilirubinemia without other known fatal causes.
Kernicterus was dened as having 2 or more of the
following symptoms after follow-up for more than 1 year:
(1) athetoid cerebral palsy, (2) gaze impairment, especially
of upward gaze, (3) delayed developmental milestones, and
(4) auditory disturbances.10

incidence of G6PD deficiency (%)

Weng and Chiu

10
0

Peak total serum bilirubin (mg/dL)

FIGURE 1. Prevalence of glucose-6-phosphate dehydrogenase

(G6PD) deficiency in different levels of peak total serum bilirubin
and general population. Solid bars indicate female population.
Empty bars indicate male population. n/n = number of G6PDdeficient infants/number of total infants.
r

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J Pediatr Hematol Oncol

Volume 32, Number 1, January 2010

Neonatal Hyperbilirubinemia With G6pd Deficiency

TABLE 1. Demographic and Clinical Data in 99 G6PD-deficient

and 314 G6PD-normal Infants With Peak TSB Value Z20 mg/dL

TABLE 2. Clinical Characteristics of 99 G6PD-deficient Infants by

Different Levels of Peak TSB

G6PD Status
Sex
Male
Female
Birth place
Inborn
Outborn
Delivery mode
Cesarean section
Vaginal delivery
Gestational age (wk)
<37
37-42
Birth weight (g)
<2500
Z2500
Peak TSB level (mg/dL)
20-24.9
25-29.9
30-39.9
40-50
Age at peak TSB (d)
<7
7-30
Hemoglobin (g/dL)
<13
13-22
Exchange transfusion
None
Once
More than once
Acute outcome
Death
Survival

Decient,
n (%)

Normal,
n (%)

Peak TSB Level (mg/dL)

P
<0.001

75 (75.8)
24 (24.2)

170 (54.1)
144 (45.9)
0.267

29 (29.3)
70 (70.7)

111 (35.4)
203 (64.6)

28 (28.3)
71 (71.7)

68 (21.7)
246 (78.3)

0.173
0.498
21 (21.2)
78 (78.8)

57 (18.2)
257 (81.8)
0.135

12 (12.1)
87 (87.9)

23 (7.3)
291 (92.7)
<0.001

58
23
10
8

(58.6)
(23.2)
(10.1)
(8.1)

244
58
12
0

(78.7)
(18.5)
(3.8)
(0)
0.128

52 (52.5)
47 (47.5)

192 (61.1)
112 (38.9)

43 (43.4)
56 (56.6)

78 (24.8)
236 (75.2)

62 (62.6)
31 (31.3)
6 (6.1)

249 (79.3)
57 (18.2)
8 (2.5)

<0.001
<0.01

<0.05
3 (3.0)
96 (97.0)

0 (0)
314 (100)

G6PD indicates glucose-6-phosphate dehydrogenase; TSB, total serum

bilirubin.

Among 58 G6PD-decient infants who were followed

for more than 12 months, 4 were conrmed having the
clinical manifestations of kernicterus. To determine the risk
factors for the development of irreversible sequelae (death
or kernicterus), we analyzed 10 variablesbirth place, sex,
birth weight, gestational age, delivery mode, G6PD activity,
peak TSB level, age at peak TSB, hemoglobin value, and
presence of combined factors. The results showed that
infants with sequelae (n = 7; 3 death and 4 kernicterus) were
more likely to have a hemoglobin value less than 13 g/dL
(P<0.05) and peak TSB value Z25 mg/dL (P<0.01) than
those without sequelae (n = 54). In addition, all infants
with sequelae were born outside our hospital, which was
more common than those without sequelae (P<0.05).

DISCUSSION
This study depicts the clinical spectrum of G6PDdecient infants with peak TSB level Z20 mg/dL. By
comparing with G6PD-normal infants, we have disclosed
the unique properties of G6PD deciency with marked NH.
Our data showed that male sex was more common in G6PD
deciency. This is not surprising as the G6PD gene is
encoded in the X chromosome. In addition, we showed that
more G6PD-decient infants had a lower hemoglobin
value, an index of hemolysis. Although genetic interactions
r

2010 Lippincott Williams & Wilkins

Number (%)

20-24.9 25-29.9 30-39.9 40-50

n = 58 n = 23 n = 10 n = 8

Sex
Male
42
Female
16
Birth place
Inborn
21
Outborn
37
Delivery mode
Cesarean section 19
Vaginal delivery 39
Gestational age (wk)
<37
16
37-42
42
Birth weight (g)
<2500
8
Z2500
50
Combined factors
With
35
Without
23
G6PD activity
(U/g Hb)
<1.25
18
1.25-12.4
40
Age at peak TSB (d)
<7
36
7-30
22
Hemoglobin (g/dL)
<13
20
13-22
38
Acute outcome
Death
0
Survival
58

P
0.770

(72.4) 18 (78.3) 8 (80.0) 7 (87.5)

(27.6) 5 (21.7) 2 (20.0) 1 (12.5)
0.152
(36.2) 5 (21.7) 3 (30.0) 0 (0.00)
(63.8) 18 (78.3) 7 (70.0) 8 (100)
0.203
(32.8) 7 (30.4) 0 (0.00) 2 (25.0)
(67.2) 16 (69.6) 10 (100) 6 (75.0)
0.702
(27.6) 2 (8.7) 3 (30.0) 0 (0.00)
(72.4) 21 (91.3) 7 (70.0) 8 (100)
0.357
(13.8) 4 (17.4) 0 (0.00) 0 (0.00)
(86.2) 19 (82.6) 10 (100) 8 (100)
0.626
(60.3) 12 (52.2) 4 (40.0) 5 (62.5)
(39.7) 11 (47.8) 6 (60.0) 3 (37.5)
0.418
(31.0) 3 (13.0) 3 (30.0) 2 (25.0)
(69.0) 20 (87.0) 7 (70.0) 6 (75.0)
0.063
(62.1) 11 (47.8) 2 (20.0) 3 (37.5)
(37.9) 12 (52.2) 8 (80.0) 5 (62.5)
<0.05
(34.5) 11 (47.8) 5 (50.0) 7 (87.5)
(65.5) 12 (52.2) 5 (50.0) 1 (12.5)
<0.001
(0)
0 (0)
0 (0)
3 (37.5)
(100) 23 (100) 10 (100) 5 (62.5)

G6PD indicates glucose-6-phosphate dehydrogenase; TSB, total serum

bilirubin.

are alleged to induce NH in G6PD deciency,8,9 destruction

of red blood cells has still been observed in some circumstances.6,13,14 For instance, G6PD-decient infants who
were born outside medical centers were more susceptible to
hemolysis.15,16 Moreover, our study identied that infants
with G6PD deciency tended to have extreme NH, dened
as a peak TSB value Z25 mg/dL.1719 We also further
veried that lower hemoglobin value was closely related to
higher peak TSB level in G6PD-decient infants. These
ndings lead to the suggestion that extreme NH in G6PD
deciency is mediated, at least in part, by hemolysis.
To our knowledge, this study is the rst to illustrate
that the prevalence of G6PD deciency is proportional
to the level of peak TSB. In this study, more than one
half of infants with peak TSB level Z30 mg/dL were
G6PD-decient. In the past, isoimmune hemolytic disease
owing to blood group mismatch was the major cause of
extreme NH. With the introduction of immunoglobulin,
the incidence of severe NH by blood group incompatibility
has declined.20 In contrast, prevention of G6PD deciencyrelated NH by Taiwans newborn screen has been fruitless.21 Recent studies also reveal that G6PD deciency is
more common in infants with NH.4,7,12,22 Their data
and ours highlight the fact that G6PD deciency is an
important etiology of severe NH.
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Weng and Chiu

J Pediatr Hematol Oncol

Our study illustrated that infants with G6PD deciency were at increased risk of mortality. We identied
peak TSB value Z40 mg/dL as a risk factor for mortality,
which suggests that the leading cause of death was bilirubin
encephalopathy, not G6PD deciency itself. The results
were consistent with the known vulnerability of G6PDdecient infants to irreversible sequelae.12,2224 Moreover, we further extended such inquiries by showing that
extreme NH and low hemoglobin value were 2 relevant
risk factors for irreversible sequelae. Our recent study
showed similar ndings in blood group incompatibility.20
It is well recognized that high TSB level is a risk factor
for kernicterus.5,6 Nevertheless, how anemia causes brain
injury remains incompletely understood; probably because
products from the destruction of red blood cells potentiate
bilirubin encephalopathy.25
Our study has some limitations. One could question
that only 60% of infants were followed for more than
12 months. We believe they were representative, because
their demographic and laboratory data were similar with
those who were not followed regularly. Furthermore, we
did not exclude infants with any combined factors that
could aggravate anemia, NH, or kernicterus. But our
analysis has shown that infants with and without combined
factors had similar background features.
In conclusion, G6PD deciency is an important risk
factor for the development of severe NH and kernicterus.
High TSB level and low hemoglobin value are 2 crucial risk
factors for deleterious consequences. Management should
be prompt to avoid irreversible sequelae for infants with
G6PD deciency.

8. Weng YH, Chou YH, Cheng ML, et al. Increased heme

oxygenase-1 expression in glucose-6-phosphate dehydrogenase
decient human broblasts. Pediatr Res. 2002;51:328A.
9. Kaplan M. Genetic interactions in the pathogenesis of neonatal hyperbilirubinemia: Gilberts Syndrome and glucose6-phosphate dehydrogenase deciency. J Perinatol. 2001;21:
S30S34.
10. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the
newborn infant 35 or more weeks of gestation. Pediatrics.
2004;114:297316.
11. Watchko JF. Vigintiphobia revisited. Pediatrics. 2005;115:
17471753.
12. Katar S. Glucose-6-phosphate dehydrogenase deciency and
kernicterus of South-East anatolia. J Pediatr Hematol Oncol.
2007;29:284286.
13. Kaplan M, Hammerman C, Vreman HJ, et al. Acute hemolysis
and severe neonatal hyperbilirubinemia in glucose-6-phosphate
dehydrogenase-decient heterozygotes. J Pediatr. 2001;139:
137140.
14. Samanta S, Kumar P, Kishore SS, et al. Donor blood glucose 6phosphate dehydrogenase deciency reduces the ecacy of
exchange transfusion in neonatal hyperbilirubinemia. Pediatrics.
2009;123:e96e100.
15. Weng YH, Chou YH. Glucose-6-phosphate dehydrogenase
deciency with hyperbilirubinemia in neonates born inside and
outside a tertiary hospital. Clin Neonat. 2003;10:5053.
16. Chen SH, Lin KS, Lee TY, et al. Glucose-6-phosphate
dehydrogenase deciency and neonatal hyperbilirubinemia in
Chinese. Acta Paediatr Sinica. 1986;27:286293.
17. Salas AA, Mazzi E. Exchange transfusion in infants with
extreme hyperbilirubinemia: an experience from a developing
country. Acta Paediatr. 2008;97:754758.
18. Tiker F, Gulcan H, Kilicdag H, et al. Extreme hyperbilirubinemia in newborn infants. Clin Pediatr. 2006;45:257261.
19. Newman TB, Xiong B, Gonzales VM, et al. Prediction and
prevention of extreme neonatal hyperbilirubinemia in a mature
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