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1985;75;770-774 Pediatrics

Stubblefield and Kenneth J. Ryan

Shai Linn, Stephen C. Schoenbaum, Richard R. Monson, Bernard Rosner, Phillip G.
Epidemiology of Neonatal Hyperbilirubinemia
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770 PEDIATRICS Vol. 75 No. 4 April 1985
Epidemiology of Neonatal Hyperbilirubinemia
Shai Linn, MD, DrPH, Stephen C. Schoenbaum, MD, MPH,
Richard R. Monson, MD, DSc, Bernard Rosner, PhD,
Phillip G. Stubblefield, MD, and Kenneth J. Ryan, MD
From the Departments of Medicine Obstetrics and Gynecology, Brigham and W omens
Hospital, Harvard Medical School, Harvard Community Health Plan, and Department of
Epidemiology, Harvard School of Public Health, Boston
ABSTRACT. Interview and record review data from
12,023 singleton deliveries were analyzed to determine
the relationships between neonatal hyperbilirubinemia
(10 mg/dL or greater) and maternal characteristics. Con-
founding variables were controlled by multiple logistic
regression analysis. There was a statistically significant
positive relationship between hyperbilirubinemia and low
birth weight, Oriental race, premature rupture of mem-
branes, breast-feeding, neonatal infection, use of the
pill at time of conception, instrumental delivery, and
history of first trimester bleeding. M aternal smoking and
black race were negatively related to hyperbilirubinemia
and statistically significant. In this study, other previ-
ously suspected etiologic factors such as epidural anes-
thesia, parity, use of oxytocin in labor, and white race
were not associated with hyperbilirubinemia. Pediatrics
1985;75:770-774; neonatal hyperbilirubinem ia, low-birth-
weight infants, breast-feedings, sm oking in pregnancy.
Previous reports have indicated a relationship
between neonatal hyperbilirubinemia and diverse
factors including racial onigin,3 male gender, epi-
dural anesthesia,35 and instrumental delivery.56
Oxytocin usage during delivery has been implicated
by some,357#{176} but not confirmed by others.46114
Two studies56 have suggested a dose-response m e-
lationship with neonatal hyperbillirubinemia oc-
cunning only in association with very high doses of
oxytocin. Low birth weight and short gestation,3
neonatal infections,6 and breast-feeding617 have
also been reported to be associated with the occur-
rence of neonatal hypenbilirubinemia. Some189
have suggested that the effect of breast-feeding may
Received for publication April 18, 1984; accepted July 25, 1984.
Reprint requests to (S.C.S.) Harvard Community Health Plan,
M anagement Office, One Fenway Plaza, Boston, M A 02215.
PEDIATRIcS (ISSN 0031 4005). Copyright 1985 by the
American Academy of Pediatrics.
be enhanced by prior use of oral contraceptives, but
another study2 has not confirmed this.
In the present study, we have examined the oc-
currence of hyperbilirubinemia in the offspring of
more than 12,000 women who were interviewed
during their delivery hospitalization. Recognizing
that neonatal hyperbilirubinemia has multiple risk
factors that are likely to be interrelated, we have
focused the analysis on trying to determine the
independent contribution of each.
Study Population and Collection of Data
The data derive from the Delivery Interview Pro-
gram (DIP) at the Boston Hospital for W omen
Division of the Brigham and W omens Hospital.
The program was designed to examine the relation-
ship of late pregnancy outcomes and a variety of
exposures. During the study period (Aug 8, 1977 to
M arch 31, 1980), 14,458 women (84.4% of all
women delivering at the hospital) were approached
for an interview following delivery. Reasons for not
being approached were lack of sufficient personnel
to coven all deliveries (14.1% ), and treatment by
one physician who refused permission for his pa-
tients to participate in this study (1.5% ). On days
when there were not sufficient personnel to inter-
view all delivery patients, a random selection was
Of those who were approached and who had
singleton deliveries, 90.0% were interviewed. Rea-
sons for not being interviewed were early discharge
(5.4% ), refusal (2.9% ), language barrier (1.6% ),
and/or medical conditions that precluded an inter-
view (0.1% ). Information obtained from each
woman included previous medical and obstetric his-
tory and habit characteristics. W omen were also
asked about their last method of contraception.
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W e did not influence the ordering of bilinubin
determinations. Prior to the collection of data, we
defined hyperbilirubinemia as the presence of one
on more bilirubin determinations of 10 mg/dL or
greater. Information about the infants gestation
and delivery, the occurrence of hypenbilirubinemia,
and the highest bilirubin level (recorded only in the
last year of the study) were obtained by review of
the medical record.
The analysis was limited to the 12,023 nondi-
abetic women who had singleton live deliveries. W e
excluded 70 cases of Rh on ABO incompatibility
and 71 cases in which infants received photothenapy
prophylactically before reaching a bilirubin level of
10 mg/dL (Table 1).
Analytic Techniques
W e compared maternal demographic character-
istics and habits, pregnancy and delivery events,
and neonatal outcomes for those infants who had
hypenbilirubinemia v those whose record did not
T A B L E 1 . Potential Subjects (17,136), Exclusions, and
Subjects Included in Final Analysis (12,023)*
Deliveries in study period 17,136
Subjects approached 14,458
Singleton deliveries 14,255
Nondiabetics 13,807
Interviewed 12,440
Live birth 12,364
No prophylactic phototherapy 12,293
No ABO or Rh incom patibility 12,023
* Fach category is a subset of the higher category.
show hyperbilirubinemia. For each characteristic,
the odds ratio (relative odds) of having hypembili-
rubinemia and the 95% confidence interval were
calculated. The odds ratio is the estimate of relative
risk which can be derived from case-control studies.
W e then perform ed an analysis by logistic negres-
sion to examine the odds ratio of having hyperbili-
nubinemia when all suspected confoundens were
controlled. For this analysis, all variables were di-
chotomized. W e chose cutoff points on the basis of
the distribution of the characteristics in the deliv-
ery population on according to a natural cutoff point
of interest (eg, one or more previous pregnancies v
no previous pregnancy). The final regression model
included the variables listed in Table 5. Because
various studies have reported an association be-
tween black, Oriental, and white race and neonatal
hypenbilirubinemia, we analyzed race in four cate-
gonies-black, Oriental, white, and other. Other
was then used as the reference category for the
remaining three groups.
Some of the characteristics of the study popula-
tion are presented in Table 2. In the crude data,
the characteristics older maternal age, being single,
having had a college education, receiving welfare,
higher gravidity, and higher parity were all statis-
tically significantly related to the occurrence of
neonatal hyperbilirubinemia. Neonatal hyperbili-
rubinemia was significantly more prevalent among
those who were Oriental. As has been previously
T A B L E 2 . Occurrence of Neonatal Hyper
Characteristics in 12,023 Patients
bilirubinemia in Re! ation to Selected M a temnal Demo graphic and M edical
No. with Neonatal Odds Ratio 95% Confidence
Characteristic Hyperbilirubinemia Interval
Age 35 yr 1,048 22.2 1.20 1.03, 1.40
Single 1,502 14.9 0.70 0.60, 0.81
W hite 1,836 20.0 0.83 0.70, 0.98
Oriental 183 49.2 5.19 3.83, 7.05
Black 1,819 12.1 0.46 0.47, 0.64
College education 782 20.9 1.29 1.17, 1.42
Receiving welfare 1,905 16.3 0.78 0.68, 0.89
Smoking 3+ cigarettes/d at delivery 2,625 15.5 0.71 0.63, 0.80
( v all others)
Alcohol in 1st trimester 2,732 19.7 1.02 0.91, 1.13
M arijuana use during pregnancy 1,217 18.9 0.96 0.83, 1.12
Previous history
Gravidity >1 4,915 20.5 1.12 1.03, 1.23
Parity >1 6,107 20.7 1.17 1.07, 1.28
Previous induced abortion(s) 2,178 19.2 0.98 0.87, 1.10
Using pill at time of conception 206 22.3 1.12 0.93, 1.35
M aternal ponderal index <18 kg/m2 113 27.4 1.57 1.04, 2.37
(light weight)
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reported, being black was related to a lower occur-
rence of hyperbilirubinemia. These relationships
were observed further within the group of babies
with hyperbilirubinemia. For example, 19% of the
Oriental infants with hypenbilirubinemia had a bil-
irubin 15 mg/dL whereas the percentages among
white and black infants were 6.9% and 2.2% , me-
Offspring of women who were smokers at the
time of delivery had a substantially lower occur-
rence of hyperbilirubinemia. Compared with
women who reported never smoking, women who
were smoking at least one pack of cigarettes a week
at the time of delivery had the lowest chance of
having a child with hyperbilirubinemia (odds ratio
0.69; 95% confidence interval 0.61, 0.78), whereas
women who smoked less had a slightly higher oc-
currence of hyperbilirubinemia in their offspring
(odds ratio 0.75; confidence interval of 0.57, 0.97).
Though not statistically significant, the effect of
smoking was discernible even for women who
stopped smoking during their pregnancy. The odds
ratio for those who stopped smoking in the second
or third trimester was 0.70 (confidence interval
0.48, 1.03); for those who stopped smoking in the
first trimester, it was 0.94 (confidence interval 0.76,
1.16); for those who stopped smoking before preg-
nancy, it was 0.98 (confidence interval 0.87, 1.09).
Other habits, such as marijuana usage during
pregnancy, alcohol consumption in the first trimes-
ten, and previous induced abortions were not related
to hyperbilirubinemia. The use of oral contracep-
tion at the time of conception was not statistically
significantly related to the occurrence of neonatal
hypenbilirubinemia. Bleeding in the first and third
tnimestens, cervical incompetence, abruptio placen-
tae, placenta previa, premature rupture of mem-
branes, abnormal presentation, and instrumental
delivery were statistically significantly related to
neonatal hypembilirubinemia in the crude data (Ta-
ble 3). Toxemia, the occurrence of fetal distress,
use of oxytocin, and epidumal anesthesia were not
related. As shown in Table 4, low birth weight and
short gestation were strongly related to the occur-
TABLE 3. Occurrence of Neonatal Hyperbilirubinemia in Relation to Selected Preg-
nancy Events and Delivery Characteristics
No. with Neonatal Odds 95% Confi-
Characteristic Hyperbilirubi- Ratio dence
nemia Interval
Pregnancy events
Bleeding in:
1st trimester 1,142 24.9 1.45 1.26, 1.68
2nd trimester 445 20.2 1.11 0.88, 1.41
3rd trimester 575 24.0 1.39 1.14, 1.69
Toxemia or eclampsia 422 17.3 0.86 0.76, 1.11
Delivery characteristics
Abruptio placentae 127 29.1 1.71 1.17, 2.50
Placenta previa 65 36.9 2.43 1.49, 3.97
Premature rupture of membranes 241 22.2 1.22 1.08, 1.38
Instrumental delivery 4,303 22.0 1.28 1.18, 1.40
Oxytocin use 5,136 20.1 1.07 0.98, 1.17
Epidural anesthesia 5,207 20.0 1.07 0.97, 1.17
Fetal distress 381 18.1 0.91 0.70, 1.19
TABLE 4. Occurrence of Neonatal Hyperbilirubinemia in Relation to Selected Infant
No. with Neonatal Odds 95% Confi-
Characteristic Hyperbilirubi- Ratio dence
nemia Interval
Birth weight <2,500 g 834 42.7 3.45 3.01, 3.96
Gestation <37 wk 777 47.5 4.34 3.77, 4.98
M ajor malformations 310 28.4 1.66 1.30, 2.13
M inor malformations 745 16.5 0.82 0.67, 1.00
Neonatal infection or sepsis 121 40.5 2.85 2.01, 4.05
1-mm Apgar score <6 830 21.6 1.15 0.97, 1.36
S p e c i a l c a r e n u r s e r y 1 , 9 9 8 3 1 . 9 2 . 2 9 2 . 0 7 , 2 . 5 4
Breast-feeding 7,311 22.7 1.74 1.58, 1.92
M ale gender 6,210 21.1 1.25 1.14, 1.37
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TABLE 5. Odds Ratio and Confidence
Characteristics Potentially Associated
Interval Estimation by Logistic Regression for
with Neonatal Hyperbilirubinemia*
Characteristics Odds Ratio Confidence Interval of 95%
Low birth weight (<2,500 g) 3.60 3.10, 4.25
Being Oriental 3.56 2.53, 5.01
Premature rupture of membranes 1.91 1.55, 2.35
Breast-feeding 1.80 1.61, 2.01
Infants infection 1.55 1.04, 2.32
Use of the pill at time of conception 1.42 1.01, 2.01
M ale gender 1.28 1.17, 1.41
Instrumental delivery 1.25 1.12, 1.40
M ajor malformation 1.24 0.94, 1.63
Bleeding in 1st trimester 1.21 1.04, 1.41
W elfare 1.14 0.97, 1.34
Age >35 yr 1.09 0.97, 1.23
Epidural anesthesia 1.09 0.98, 1.22
Parity >1 1.03 0.93, 1.14
Oxytocin during labor 0.99 0.89, 1.10
No college education 0.98 0.87, 1.11
Being white 0.89 0.88, 1.06
Smoking 3+ cigarettes/d at delivery 0.77 0.68, 0.87
Being black 0.49 0.40, 0.60
* Listed are the odds ratios of having a baby with hyperbilirubinemia, controlling simul-
taneously for the other characteristics in the list.
rence of neonatal hyperbilirubinemia. M ale gender,
major malformations, neonatal infection or sepsis,
being treated in the special care nursery, and
breast-feeding also were related to hypenbilirubi-
Several of these factors, which showed relation-
ships to neonatal hyperbilinubinemia in the crude
data, are obviously interrelated. The remainder of
the analysis was directed toward determining the
independent contribution of various factors. The
results of the logistic regression analysis are pre-
sented in Table 5. Low birth weight, being Oriental,
having premature rupture of membranes, breast-
feeding, neonatal infection, using the pill at time of
conception, having a male baby, instrumental deliv-
eny, bleeding in the first trimester were all positively
and independently statistically significantly related
to neonatal hyperbilirubinemia. Negatively related
variables were smoking three on more cigarettes pen
day at delivery and being black. Other variables,
including oxytocin usage and epidural anesthesia
were not found to be statistically significantly me-
This study characterizes the occurrence of neo-
natal hyperbilirubinemia in an American popula-
tion. W e recognize that hyperbilirubinemia of 10
mg/dL might be of little clinical importance and
that the major clinical concern is associated with
higher levels of bilinubin. Nevertheless, we chose
for this study to define hypembilirubinemia at the
level of 10 mg/dL to have a sufficient number of
patients so that we could analyze the independent
contributions of each of the several associated van-
ables. Using this cutoff level may also give a clearer
picture of each of the variables. Infants who are
most likely to develop the highest bilirubin levels,
ie, very low-birth-weight infants, routinely undergo
interventions to prevent the development of hyper-
bilinubinemia before having reached the highest
levels, and this precludes full assessment of the
contribution of other factors. From our more lim-
ited analysis of the subset of data on infants with
bilirubin levels 10 mg/dL, it does appear that the
epidemiology of clinically significant hyperbiliru-
binemia ( 15 mg/dL) follows the epidemiology of
hypenbilirubinemia in general.
The positive relationship between Oriental eth-
nicity and the negative relationship of black origin
to the occurrence of neonatal hyperbilirubinemia
could be superficially explained by failure to detect
the condition among blacks or an increased tend-
ency to draw blood for bilirubin tests among infants
of Oriental mothers simply on the basis of their
colon. Our data, however, do not support this, be-
cause the relationship held even in the subset of
the study population in which all had bilinubin
levels 10 mg/dL. This high occurrence of hyper-
bilirubinemia among neonates of Oriental origin
supports previous findings of higher bilirubin levels
among Asiatic neonates in Singapore2 and in Eng-
land.3 To date, no pathophysiologic basis for this
finding has been established. Also ofspecial interest
was the negative relationship between maternal
smoking and neonatal hyperbilirubinemia. Consist-
ent underreporting or overreporting of previous
events by women who had an adverse pregnancy
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outcome woul d consti tute a recal l bi as. A l though
recal l bi as coul d be an expl anati on of our f i ndi ngs,
we do not bel i eve that thi s real l y occurred. The
i ntervi ews were conducted accordi ng to a standard
questi onnai re, and nei ther the women nor the i n-
tervi ewers were f ul l y aware of the study f ocus.
M oreover, most of the data were obtai ned f rom the
record i n addi ti on to the i ntervi ew, whi ch wi l l mm-
i mi ze any tendency to such a recal l bi as. Fi nal l y,
recal l bi as shoul d be consi stent. I t coul d not expl ai n
the f act that i n thi s study maternal hi story of pi l l
use at concepti on i s posi ti vel y associ ated wi th
hypenbi l i nubi nemi a, whereas maternal hi story of
smoki ng i s negati vel y associ ated.
A l though neonatal hyperbi l i rubi nemi a i s a com-
mon event, i t i s of i nterest because at i ts extreme
i t has cl i ni cal si gni f i cance and i t al so can be the
source of consi derabl e parental concern. Cl i ni ci ans
need to be aware of the mul ti pl e i ndependent ri sk
f actors f or hypembi l i rubi nemi a and shoul d f ol l ow
cl osel y neonates wi th one or more ri sk f actors.
Thi s work was supported by a grant f rom the Nati onal
Bi rth Def ects Foundati on.
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1985;75;770-774 Pediatrics
Stubblefield and Kenneth J. Ryan
Shai Linn, Stephen C. Schoenbaum, Richard R. Monson, Bernard Rosner, Phillip G.
Epidemiology of Neonatal Hyperbilirubinemia
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