Direct hyperbilirubinemia in infants with congenital heart disease
and Akira Oka
Pediatric Surgery, and
Pediatrics, Faculty of Medicine, The University of Tokyo, Tokyo, Japan
Abstract Background: The association between congenital heart disease (CHD) and infantile cholestasis, a key ﬁnding for
the diagnosis of biliary atresia (BA), has not been previously investigated. The aim of this study was therefore to
investigate the characteristics of direct hyperbilirubinemia (D-HB) in infants with CHD.
Methods: All neonates admitted to the present hospital and diagnosed with CHD in 2015 and 2016 were included.
D-HB (direct bilirubin ≥ 2.0 mg/dL) at ≤60 days of age and other clinical parameters were retrospectively reviewed.
Statistical analysis according to presence of D-HB was performed using chi-squared test or Wilcoxon rank sum test.
Results: Seventy-six patients (M:F, 36:40) were included in this study. CHD consisted of ventricular septal defect
in 17, patent ductus arteriosus in 10, and other in 49. Thirteen patients (17.1%) had D-HB at ≤60 days of age.
Resolution of D-HB (DB < 2.0 mg/dL) occurred in 10 of the 13 patients during the hospital stay, and this occurred
in ≤7 days in eight of the 10 patients. Sex, gestational age, birthweight, chromosomal anomalies, need for Fontan
operation for CHD repair, and/or cardiac operation were not associated with D-HB at ≤60 days of age.
Conclusion: While D-HB was frequently observed in infants with CHD, the majority of D-HB cases resolved spon-
taneously in ≤1 week. Neonatal clinical parameters or CHD status was not predictive of D-HB. D-HB lasting
>1 week in infants with CHD should be evaluated for the cause.
Key words biliary atresia, cholestasis, congenital heart disease, direct hyperbilirubinemia, infant.
Neonatal jaundice is a common symptom in the ﬁrst 2 weeks
after birth, and occurs in 2.4–15% of newborn infants.
infants with jaundice have unconjugated, indirect hyper-
bilirubinemia (HB) without any pathological implication. In
contrast, cholestatic jaundice with direct hyperbilirubinemia
(D-HB) in infants is regarded as abnormal, and recent guide-
lines recommend that neonates with jaundice lasting >2–
3 weeks of age should be evaluated for D-HB and, if present,
should undergo further evaluation for cholestasis.
reason for this early evaluation is early detection and prompt
Kasai operation for biliary atresia (BA).
Biliary atresia is a progressive obstructive disease of the bil-
iary tract, affecting 0.5–2.9 per 10 000 births.
structural anomalies are relatively common in infants with BA:
the incidence ranges from 13.4% to 20.3%.
Of the congeni-
tal anomalies coexisting with BA, congenital heart disease
(CHD) is one of the major ones, and is found in 6.3–15% of
infants with BA.
Therefore, neonates with CHD are thought
to be at high risk for BA. The characteristics of cholestatic jaun-
dice or D-HB, a ﬁrst clue for the suspicion and diagnosis of BA
in infants with CHD, has not been previously reported.
Thus, the aim of the study was to clarify the characteristics
(i.e. incidence, duration, etiology, and outcome) of D-HB in
infants with CHD.
All patients who met the following criteria were included in the
study: birth between January 2015 and November 2016;
echocardiography by pediatric cardiologists at the present hospi-
tal and diagnosis of CHD at ≤30 days of age; and admission to
the present hospital at ≤30 days of age irrespective of the reason
for admission. Patients who had no history of admission at
≤30 days of age were excluded from the study because blood
sampling is not routinely performed on an outpatient basis.
D-HB was deﬁned as serum direct bilirubin (DB) ≥2 mg/dL.
Patient characteristics such as sex, gestational age, birthweight,
diagnosis of CHD, chromosomal abnormalities, peak DB, total
bilirubin (TB) at peak DB and presence or absence of D-HB at
≤60 days of age were retrospectively obtained by chart review.
Given that this was a retrospective study, the timing and type of
blood sampling were selected by the attending doctors. Data on
the clinical course of the D-HB patients were also collected after
60 days of age by chart review.
Numerical data are expressed as mean Æ SD, unless otherwise
indicated. Statistical analysis according to the presence of
Correspondence: Jun Fujishiro, MD PhD, Department of Pediatric
Surgery, Faculty of Medicine, The University of Tokyo, Hongo
7-3-1, Bunkyo-ku, Tokyo 113-8655, Japan.
Received 16 July 2017; revised 29 October 2017; accepted 22
© 2017 Japan Pediatric Society
Pediatrics International (2018) 60, 179–182 doi: 10.1111/ped.13462