Maternal opioid use linked to several birth defects

Research
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OBSTETRICS
Maternal treatment with opioid analgesics

and risk for birth defects
Cheryl S. Broussard, PhD; Sonja A. Rasmussen, MD, MS; Jennita Reefhuis, PhD;
Jan M. Friedman, MD, PhD; Michael W. Jann, PharmD; Tiffany Riehle-Colarusso, MD, MSE;
Margaret A. Honein, PhD, MPH; for the National Birth Defects Prevention Study
OBJECTIVE: We examined whether maternal opioid treatment between
1 month before pregnancy and the first trimester was associated with
birth defects.
STUDY DESIGN: The National Birth Defects Prevention Study (1997
through 2005) is an ongoing population-based case-control study. We

estimated adjusted odds ratios (ORs) and 95% confidence intervals
(CIS) for birth defects categories with at least 200 case infants or at
least 4 exposed case infants.
(OR, 2.7; 95% CI, 1.1 6.3), atrioventricular septal defects (OR, 2.0;
95% CI, 1.23.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI,
1.4 4.1), spina bifida (OR, 2.0; 95% CI, 1.33.2), or gastroschisis
(OR, 1.8; 95% CI, 1.12.9) in infants.
CONCLUSION: Consistent with some previous investigations, our study
RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449
shows an association between early pregnancy maternal opioid analgesic treatment and certain birth defects. This information should be considered by women and their physicians who are making treatment decisions during pregnancy.
case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects
Key words: analgesic, birth defect, medication, opioid, pregnancy
Cite this article as: Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol
2011;204:314.e1-11.
ajor birth defects affect about 3% of

the 4 million US live births each
year1-3 and are a leading cause of infant
mortality.1,4 Congenitalheartdefects(CHD)
are among the most common birth defects, affecting nearly 1% of US births,5,6
and are the main contributor to infant

mortality attributable to birth defects.7,8
Opioid medications are potent prescription analgesics that are the mainstay for
treatment of severe pain.9 Opioids are often used in combination with nonopioid
analgesics, such as acetaminophen, and
lower doses are also a component of some
cough suppressants.10 Previous studies
have shown that opioid analgesic use and
From the Epidemic Intelligence Service, Office of Workforce and Career Development (Dr Broussard), Centers for Disease Control and
Prevention; the Division of Birth Defects and Developmental Disabilities, National Center on Birth Defects and Developmental Disabilities
(Drs Broussard, Rasmussen, Reefhuis, Riehle-Colarusso, and Honein), Centers for Disease Control and Prevention; the Department of
Pharmacy Practice, Mercer University (Dr Jann), Atlanta, GA, and the Department of Medical Genetics, University of British Columbia, and
the Child and Family Research Institute, Vancouver, British Columbia, Canada (Dr Friedman).
Presented at the 14th Annual Maternal and Child Health Epidemiology Conference, Atlanta, GA, Dec. 10-12, 2008; the 56th Annual Epidemic
Intelligence Service Conference, Atlanta, GA, April 20-24, 2009; the 49th Annual Meeting of the Teratology Society, Rio Grande, Puerto Rico, June
27-July 1, 2009; the 30th Annual David W. Smith Workshop on Malformations and Morphogenesis, Philadelphia, PA, Aug. 5-9, 2009; and the 25th
International Conference on Pharmacoepidemiology and Therapeutic Risk Management, Providence, RI, Aug. 17-19, 2009.
Received July 8, 2010; revised Sept. 29, 2010; accepted Dec. 20, 2010.
Reprints: Cheryl S. Broussard, PhD, Centers for Disease Control and Prevention, 1600 Clifton Rd. NE, MS E-86, Atlanta, GA 30333.
cbroussard@cdc.gov.
This work was supported through cooperative agreements under Program Announcement no. 02081 from the Centers for Disease Control and
Prevention to the centers participating in the National Birth Defects Prevention Study, listed as Acknowledgments in this article.
The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease
Control and Prevention.
0002-9378/free Published by Mosby, Inc. doi: 10.1016/j.ajog.2010.12.039
For Editors Commentary, see Table of Contents

See related editorial, page 281
314.e1
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abuse have been increasing in recent
years,11-13 but the effects of opioid use on
the developing fetus during pregnancy are
poorly understood.
Associations between maternal firsttrimester use of the opioid analgesic codeine and CHD in infants were found in
3 of 4 previous case-control studies,14-17
with case counts ranging from 141390
(and control counts of 176 3002). Most
previous studies considered CHD of any
type as a single group and had insufficient sample sizes to examine individual
heart defects.
Other studies have shown associations
between first-trimester codeine use and
other birth defects such as orofacial
clefts,18,19 but these findings have been
inconsistent across studies. Effects of
maternal use of opioids other than codeine have not been thoroughly studied,
but previous reports have shown no
increase in risks for birth defects following prenatal exposures to oxycodone,
propoxyphene, or meperidine.18,20 Neural tube defects have not been associated with maternal opioid treatment in
human pregnancy,21-23 but experimental studies showed increased frequencies of neural tube defects in the
offspring after treatment of pregnant
hamsters with high doses of morphine,
meperidine, pentazocine, hydromorphone, or propoxyphene.24,25
Despite evidence of adverse fetal effects
with maternal codeine use and the paucity
of data on the effects of maternal use of
other opioids, such treatment is often assumed to be safe during pregnancy.26 Our
study objective was to examine whether
maternal therapeutic use of opioid analgesics in early pregnancy is associated with
CHD or other birth defects.
M ATERIALS AND M ETHODS

We analyzed data from the National Birth
Defects Prevention Study (NBDPS) for infants born Oct. 1, 1997, through Dec. 31,
2005. NBDPS is an ongoing multisite
population-based case-control study of
30 types of major structural birth defects that focuses on exposures immediately before and during pregnancy. Each
of the study sites (Arkansas, California,
Georgia, Iowa, Massachusetts, New Jer-
sey, New York, North Carolina, Texas,

and Utah) ascertains deliveries with
birth defects through birth defects surveillance systems using standard, detailed case definitions. The study was approved by institutional review boards of
the Centers for Disease Control and
Prevention and all other participating
centers.
NBDPS focuses on birth defects with
unknown etiologies; therefore, infants
with recognized chromosomal abnormalities or single-gene disorders are excluded. Some cardiac anomalies that are
usually physiological rather than pathological were also excluded, eg, patent
ductus arteriosus or patent foramen
ovale in premature infants. In addition,
some cardiovascular anomalies were excluded from NBDPS either because of
their rarity, poor ascertainment in infancy, unclear significance (eg, insufficiency of the tricuspid, mitral, or pulmonary valves), or because they were
vascular (noncardiac) defects or arrhythmias (nonstructural defects). All
CHD cases were confirmed by echocardiography, cardiac catheterization, surgery, or autopsy.27
Classification of NBDPS cases has previously been described.6,28 Briefly, the
process for NBDPS-eligible defects involves confirmation of the diagnosis
from medical record abstracts and determining whether each case is an isolated defect, 1 of multiple unrelated
major defects, or a component of a syndrome or other complex pattern.28 For
CHD, classification is also performed on
a second axis to describe the complexity
of cardiac involvement, by clinicians
with expertise in pediatric cardiology.
Simple heart defects are anatomically
discrete or well-recognized single entities; associations are common, uncomplicated combinations of heart defects; and heart defects that do not fall
into either category are considered
complex. Cardiac classification and
subsequent grouping into larger categories are based on clinical and presumed
developmental mechanisms that may
have relevance in considering the teratogenic effect of exposures.6
An annual random sample of approximately 1200 liveborn infants without
Research
birth defects (control infants) is selected

from the same geographic regions and
time period as the cases, either from
birth certificates or birth hospitals.
Mothers are invited to participate in
an hour-long computer-assisted telephone interview, conducted by interviewers in English or Spanish, between 6
weeks and 2 years after the mothers estimated date of delivery (EDD) (average
is 11 months post-EDD for cases and 9
months for controls). The interview assesses various maternal health factors,
pregnancy history information, dietary
and other drug exposures, and sociodemographic characteristics. Exposures
are assessed for the period from 3
months before conception through the
end of the pregnancy. Pregnancy was defined as the time period from conception
(ie, 2 weeks after the last menstrual
period) to delivery, and pregnancy
months for this analysis were consecutive 30-day periods.
Mothers are asked about medications
used for each specific illness (eg, influenza) or indication (eg, surgery) mentioned within the maternal health section of the questionnaire, and are also
encouraged to report any other medications not already mentioned. Respondents are asked to report the start and
stop dates, duration, and frequency of
medication use using calendar dates or
pregnancy months.
All medications reported in each section of the interview are compiled and
coded using the Slone Drug Dictionary,29 which NBDPS licenses from Boston Universitys Slone Epidemiology
Center. This dictionary links products to
their active ingredients. We defined opioid exposure as maternal report of use of
1 products with any of the following
components taken for therapeutic reasons in any dose, duration, or frequency:
codeine, hydrocodone, meperidine, oxycodone, propoxyphene, morphine, tramadol, methadone, hydromorphone,
fentanyl, or pentazocine. We included
individual and combination products.
The exposure window of interest was the
period from 1 month before to 3 months
after conception.
We conducted multivariable logistic
regression analyses to calculate adjusted
APRIL 2011 American Journal of Obstetrics & Gynecology
314.e2
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odds ratios (ORs). We examined birth

defect categories that had 200 cases or
4 exposed cases to limit analyses to defect categories that would likely have adequate statistical power and to enable us
to identify potentially elevated risks
among rarer defect groups. All models
were adjusted for maternal age (continuous), race/ethnicity (non-Hispanic
white, non-Hispanic black, Hispanic,
other), education (12 years, 12
years), prepregnancy obesity (body mass
index 30, body mass index 30, using
prepregnancy weight and height self-reported by the mother during the telephone interview), periconceptional
smoking status (no smoking from 1
month before to 1 month after conception, smoking at least once in the same
period), and study center (10 sites previously listed). These variables were chosen based on the strength of their relation in univariate analyses with all
NBDPS birth defects.
There were maternal interviews from
19,059 cases and 6807 controls who met
the inclusion dates. The participation
rate was 70% for cases and 67% for controls. We excluded participants with
missing data on whether they were
treated with an opioid analgesic in early
pregnancy, due either to an incomplete
medication history from the interview or
an unknown medication start or stop
date. We excluded mothers with preexisting diabetes, which has been found to
be a strong independent risk factor for
birth defects.30,31 To focus our investigation on therapeutic opioid analgesic use,
we also excluded mothers who reported
opioid exposure in the form of illicit
drugs such as heroin any time during
pregnancy. Our final sample for analysis
included 17,449 cases with the included
defects and 6701 controls (Figure). Although the total number of cases included was greater than the total number
of controls, controls substantially outnumbered cases in most analyses, each of
which involved comparisons of infants
with 1 particular category or subcategory
of birth defects to all controls. Of note,
infants with 1 defect were included in
multiple birth defect categories.
Our primary analysis tested the hypothesis that maternal therapeutic use of
314.e3
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FIGURE
Included participants
National Birth Defects Prevention Study, 1997 through 2005. Flow diagram showing study participation rates and exclusion criteria for case and control participants, leading to final sample size
included in this analysis.
Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
opioid analgesics in early pregnancy was

associated with the occurrence of CHD,
cleft lip and/or palate, or neural tube defects in infants. Secondary, exploratory
analyses were also performed in other
birth defect groups.
We conducted subanalyses limiting either the exposure or birth defect groups.
First, using the same case groups and exposure definition as the main analysis,
we restricted the exposure time period to
only the first 2 months after conception.
Next, using the original case groups and
the original exposure time period (1
month before to 3 months after conception), we estimated the effects of exposure to particular opioid analgesics. Because of the decreased sample size, we
estimated crude ORs only for the most
commonly reported components. Finally, using the same exposure definition
as the main analysis, we examined cases
with isolated birth defects or simple,
isolated heart defects separately.
R ESULTS
Of the 17,449 mothers of case infants
with various included birth defects, 454
(2.6%) reported opioid analgesic treat-
ment between 1 month before and 3

months after conception. Among 6701
control mothers, 134 (2.0%) reported
treatment in this time period. The most
commonly reported opioids were codeine (34.5%), hydrocodone (34.5%),
oxycodone (14.4%), and meperidine
(12.9%), with codeine and hydrocodone
exposure being slightly more common
among cases, and oxycodone and meperidine exposure slightly more common among controls. Lower maternal
education level, prepregnancy obesity,
and periconceptional smoking were all
slightly more frequent among cases than
controls (Table 1).
The reasons for opioid use were based
on the questionnaire topic under which
the medication was reported. For the
66% of exposed women whose treatment
could be linked to a specific reason, opioids were most commonly reported
within the surgical procedures (41%),
infections (34%), chronic diseases (20%),
and injuries (18%) sections of the
questionnaire.
The primary analysis included a total
of 7724 infants with 1 of 15 different
kinds of CHD. Some of these defects
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Research
TABLE 1
Characteristics of study population, National Birth Defects Prevention Study, 1997 through 2005
Variable
Cases n (%)
Controls n (%)
Study site
17,449
6701
OR (95% CI)
.......................................................................................................................................................................................................................................................................................................................................................................
Arkansas
2328 (13.3)
832 (12.4)
(referent)
California
2262 (13.0)
845 (12.6)
1.0 (0.91.1)
Georgia
2082 (11.9)
728 (10.9)
1.0 (0.91.1)
Iowa
1731 (9.9)
756 (11.3)
0.8 (0.70.9)
Massachusetts
2386 (13.7)
851 (12.7)
1.0 (0.91.1)
New Jersey
1513 (8.7)
573 (8.6)
0.9 (0.81.1)
New York
1258 (7.2)
592 (8.8)
0.8 (0.70.9)
667 (3.8)
395 (5.9)
0.6 (0.50.7)
Texas
2176 (12.5)
762 (11.4)
1.0 (0.91.1)
Utah
1046 (6.0)
367 (5.5)
1.0 (0.91.2)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
North Carolina
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Maternal age at delivery, y
17,449
6701
.......................................................................................................................................................................................................................................................................................................................................................................
20
1898 (10.9)
711 (10.6)
1.1 (1.01.2)
20-24
4111 (23.9)
1531 (22.9)
1.1 (1.01.2)
25-29
4478 (25.7)
1777 (26.5)
(referent)
30-34
4313 (24.7)
1743 (26.0)
1.0 (0.91.1)
35-39
2139 (12.3)
803 (12.0)
1.1 (1.01.2)
136 (2.0)
1.5 (1.21.8)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
40
509 (2.9)
................................................................................................................................................................................................................................................................................................................................................................................
Maternal race/ethnicity
17,397
6672
Non-Hispanic white
10,472 (60.2)
3993 (59.9)
Non-Hispanic black
1706 (9.8)
761 (11.4)
Hispanic
4033 (23.2)
1486 (22.3)
1.0 (1.01.1)
Other
1186 (6.8)
432 (6.5)
1.0 (0.91.2)
.......................................................................................................................................................................................................................................................................................................................................................................
(referent)
.......................................................................................................................................................................................................................................................................................................................................................................
0.9 (0.80.9)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Maternal education, y
17,326
6649
.......................................................................................................................................................................................................................................................................................................................................................................
12
3092 (17.9)
1121 (16.9)
1.1 (1.01.2)
12
14,234 (82.2)
5528 (83.1)
(referent)
16,722
6432
Body mass index 30
13,658 (81.7)
5399 (83.9)
(referent)
Body mass index 30
3064 (18.3)
1033 (16.1)
1.2 (1.11.3)
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Maternal prepregnancy obesity
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a
Folic acid supplement use
17,446
6701
.......................................................................................................................................................................................................................................................................................................................................................................
No use/use at another time
8608 (49.3)
3293 (49.1)
(referent)
Any use
8838 (50.7)
3408 (50.9)
1.0 (0.91.0)
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a
Smoking
17,358
6666
13,728 (79.1)
5407 (81.1)
(referent)
3630 (20.9)
1259 (18.9)
1.1 (1.11.2)
.......................................................................................................................................................................................................................................................................................................................................................................
None
.......................................................................................................................................................................................................................................................................................................................................................................
Any
................................................................................................................................................................................................................................................................................................................................................................................
Case group includes all infants with 1 eligible birth defects. Subjects with missing information for variable have been excluded from tallies for that variable only.
CI, confidence interval; OR, odds ratio.
a
Reported use from 1 month before to 1 month after pregnancy conception.
314.e4
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TABLE 2
Associations between maternal opioid analgesic treatment and specific major birth defects
Total no.a
Birth defect
No. exposed
aOR (95% CI)
Hypothesis-testing analysis
.......................................................................................................................................................................................................................................................................................................................................................................
Controls
6701
134
Anencephaly/craniorachischisis
340
Referent
1.7 (0.843.4)
Spina bifida
718
26
2.0 (1.33.2)
7724
211
1.4 (1.11.7)
Laterality defects with CHD
198
1.2 (0.423.2)
Atrioventricular septal defect
175
2.4 (1.24.8)
Anomalous pulmonary venous return
206
0.71 (0.222.3)
Single ventricle/complex
201
1.1 (0.423.2)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Any of included heart defects
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
Conotruncal defects
1481
41
1.5 (1.02.1)
Tetralogy of Fallot
672
21
1.7 (1.12.8)
D-transposition of great arteries
461
10
1.1 (0.562.1)
Ventricular septal defect conoventricular
110
2.7 (1.16.3)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
Left ventricular outflow tract obstruction defects
1195
36
1.5 (1.02.2)
Hypoplastic left heart syndrome
357
17
2.4 (1.44.1)
Coarctation of aorta
630
11
0.88 (0.471.6)
Aortic stenosis
253
1.3 (0.612.9)
1175
40
1.6 (1.12.3)
867
34
1.7 (1.22.6)
Septal defects
3482
87
1.2 (0.931.6)
Ventricular septal defect perimembranous
1402
29
0.99 (0.651.5)
Atrial septal defect secundum
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
Right ventricular outflow tract obstruction defects
..............................................................................................................................................................................................................................................................................................................................................................
Pulmonary valve stenosis
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
1507
43
1.3 (0.941.9)
Atrial septal defect not otherwise specified
511
17
2.0 (1.23.6)
CHD association: ventricular septal defect atrial septal defect
528
17
1.7 (1.02.9)
CHD association: pulmonary valve stenosis ventricular septal defect
131
1.3 (0.463.7)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Cleft palate
936
25
1.3 (0.842.0)
1162
33
1.4 (0.962.1)
614
0.68 (0.341.3)
.......................................................................................................................................................................................................................................................................................................................................................................
Cleft lip with cleft palate
.......................................................................................................................................................................................................................................................................................................................................................................
Cleft lip without cleft palate
................................................................................................................................................................................................................................................................................................................................................................................
were grouped into 1 of 4 larger phenotypic categories (conotruncal defects, left

ventricular outflow tract obstruction defects, right ventricular outflow tract obstruction defects, or septal defects) or
into 1 of 2 CHD associations (ventricular
septal defect atrial septal defect, ventricular septal defect pulmonary valve
stenosis), and ORs were estimated for
each case group and higher level classification in comparison to the same set of
6701 control infants.
Effect estimates were statistically significantly elevated for all eligible CHD
314.e5
combined (OR, 1.4; 95% confidence interval [CI], 1.11.7). Statistically significant associations with maternal opioid
use were found among infants with
conoventricular septal defect, atrioventricular septal defect, atrial septal defect
(not otherwise specified), hypoplastic
left heart syndrome, tetralogy of Fallot,
or pulmonary valve stenosis (Table 2).
We also found a significant association
between maternal opioid use between 1
month before and 3 months after conception with spina bifida (OR, 2.0; 95% CI,
1.33.2), as hypothesized, but not with the
(continued )
other neural tube defects (anencephaly or

craniorachischisis) studied (Table 2).
The exploratory analyses of maternal
opioid use for infants with 1 of 18
other categories of birth defects found
statistically significant associations for
hydrocephaly (OR, 2.0; 95% CI, 1.0
3.7), glaucoma or anterior chamber eye
defects (OR, 2.6; 95% CI, 1.0 6.6), and
gastroschisis (OR, 1.8; 95% CI, 1.12.9).
Limiting the exposure definition to the
first 2 months after conception produced results very similar to the main estimates using exposure during the pe-
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TABLE 2
Associations between maternal opioid analgesic treatment and specific major birth defects (continued)
Total no.a
Birth defect
No. exposed
aOR (95% CI)
Exploratory analysis
.......................................................................................................................................................................................................................................................................................................................................................................
Controls
6701
134
Amniotic band syndrome/limb body wall complex
203
Referent
1.0 (0.372.9)
Hydrocephaly
301
11
2.0 (1.03.7)
Cataracts
217
1.6 (0.723.5)
Glaucoma/anterior chamber defects
103
2.6 (1.06.6)
Anotia/microtia
403
0.77 (0.282.1)
Esophageal atresia
434
12
1.4 (0.762.5)
Intestinal atresia/stenosis
266
0.88 (0.322.4)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Anorectal atresia/stenosis
623
18
1.5 (0.872.4)
1313
29
0.92 (0.591.4)
Bilateral renal agenesis or hypoplasia
112
1.3 (0.404.2)
Longitudinal limb deficiency
269
1.1 (0.492.6)
.......................................................................................................................................................................................................................................................................................................................................................................
Hypospadias second/third degree
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
157
1.3 (0.483.6)
Transverse limb deficiency
Longitudinal preaxial limb deficiency
415
1.0 (0.462.2)
Craniosynostosis
806
16
0.82 (0.481.4)
Diaphragmatic hernia
507
12
1.2 (0.662.2)
Omphalocele
267
1.3 (0.602.8)
Gastroschisis
726
26
1.8 (1.12.9)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Odds ratios were adjusted for maternal age, race/ethnicity, education, presence or absence of prepregnancy obesity, presence or absence of periconceptional smoking, and study center.
aOR, adjusted odds ratio; CHD, congenital heart defect; CI, confidence interval.
a
Some comparisons used fewer than total number of controls (eg, hypospadias only used male controls); number of cases includes those with nonmissing exposure data and excludes prepregnancy
diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
riod from 1 month before to 3 months

after conception (results not shown).
Point estimates using the tighter exposure period definition were generally
greater in magnitude; we saw the highest
OR for hypoplastic left heart syndrome
(OR, 3.7; 95% CI, 2.1 6.6).
Codeine and/or hydrocodone accounted for the majority of statistically
significant findings from the main analysis, and oxycodone was only significantly associated with pulmonary valve
stenosis (Table 3). However, given that
the CIs for the effect estimates for each
specific birth defect overlap, we cannot
conclude whether one medication would
be preferable to another in terms of risk
for birth defects.
Most birth defects found to be statistically significantly associated with early
pregnancy opioid treatment in the main
analysis were also associated in the suba-
nalysis limited to isolated cases for

noncardiac defects or simple, isolated
cases for heart defects (Table 4). ORs
from the subanalysis were generally similar to those from the main analysis.
When reviewing the nonisolated cases,
we did not observe any pattern or common combinations of birth defects.
C OMMENT
Using data from a large populationbased case-control study, we found associations between maternal therapeutic
use of opioid medications in early pregnancy and several types of CHD, consistent with some previous findings for
first-trimester use of the opioid codeine.14-16 Previous reports considered
associations with CHD as a single group;
we also found a statistically significant
association with an aggregate group that
includes infants with any 1 of the 15
NBDPS-eligible diagnostic categories of

heart defects (OR, 1.4; 95% CI, 1.11.7),
but this risk is not directly comparable to
those reported in previous studies because of differences in the CHD inclusion criteria. The ORs of greatest magnitude were observed for conoventricular
septal defects, atrioventricular septal defects, atrial septal defects (not otherwise
specified), and hypoplastic left heart syndrome, a defect that accounts for much
of the infant mortality burden attributable to CHD.32
Even though our data set is the largest
used to date to study opioid exposure
and CHD and includes the most recently
available data from this ongoing study,
sample sizes for some individual CHD
categories are at the borderline for what
is required to observe these effects. Upon
subanalysis, codeine and hydrocodone
accounted for the majority of statistically
314.e6
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TABLE 3
Associations between common opioid components and specific major birth defects
Birth defect
Codeine
Hydrocodone
Oxycodone
Meperidine
No. exposed crOR

casesa
(95% CI)
No. exposed crOR

casesa
(95% CI)
No. exposed crOR

casesa
(95% CI)
No. exposed crOR

casesa
(95% CI)
.......................................................................................................................................................................................................................................................................................................................................................................
Anencephaly/
craniorachischisis
1.9 (0.675.3)
Spina bifida
1.5 (0.683.4)
11
2.5 (1.34.8)
Any of included heart defects 71
1.4 (0.982.1)
70
1.4 (0.992.1)
3.6 (1.310.2)
3.7 (1.310.4)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
28
1.0 (0.591.7)
30
1.2 (0.682.1)
..............................................................................................................................................................................................................................................................................................................................................................
Atrioventricular septal
defect
..............................................................................................................................................................................................................................................................................................................................................................
Conotruncal defects
14
1.5 (0.812.7)
16
1.7 (0.973.1)
0.75 (0.262.2)
1.4 (0.593.3)
10
2.4 (1.24.8)
1.7 (0.584.8)
15
2.0 (1.13.5)
14
1.9 (1.03.4)
1.0 (0.392.7)
..............................................................................................................................................................................................................................................................................................................................................................
Tetralogy of Fallot
..............................................................................................................................................................................................................................................................................................................................................................
Left ventricular outflow

tract obstruction defects
..............................................................................................................................................................................................................................................................................................................................................................
Hypoplastic left heart

syndrome
3.1 (1.46.9)
3.2 (1.47.1)
..............................................................................................................................................................................................................................................................................................................................................................
0.99 (0.352.8)
Aortic stenosis
2.5 (0.897.0)
10
1.3 (0.662.6)
13
1.0 (0.362.8)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
Right ventricular outflow

tract obstruction defects
1.8 (0.953.3)
2.1 (0.994.6)
1.3 (0.493.4)
..............................................................................................................................................................................................................................................................................................................................................................
1.3 (0.622.9)
12
2.2 (1.24.3)
Septal defects
24
1.1 (0.651.8)
26
1.2 (0.731.9)
11
Ventricular septal defect

perimembranous
13
1.4 (0.782.7)
0.91 (0.431.9)
1.4 (0.474.0)
0.88 (0.431.8) 19
2.4 (1.15.4)
1.7 (0.903.1)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
0.79 (0.282.3)
..............................................................................................................................................................................................................................................................................................................................................................
Atrial septal defect

secundum
Atrial septal defect not

otherwise specified
CHD association:
ventricular septal defect
atrial septal defect
0.83 (0.391.8) 16
1.7 (0.953.0)
1.3 (0.563.0)
10
2.0 (0.964.3)
..............................................................................................................................................................................................................................................................................................................................................................
1.2 (0.443.4)
1.6 (0.624.0)
..............................................................................................................................................................................................................................................................................................................................................................
2.4 (1.15.2)
.......................................................................................................................................................................................................................................................................................................................................................................
Cleft palate
0.98 (0.412.3) 12
2.1 (1.13.9)
1.4 (0.752.8)
1.5 (0.783.0)
.......................................................................................................................................................................................................................................................................................................................................................................
11
11
1.7 (0.713.8)
................................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Hydrocephaly
Cataracts
2.6 (1.06.7)
2.1 (0.766.0)
2.4 (0.866.9)
Esophageal atresia
1.8 (0.714.6)
1.3 (0.503.2)
1.8 (0.814.0)
Hypospadias second/third
degree
11
0.89 (0.451.8)
0.47 (0.161.4)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
1.4 (0.523.8)
1.8 (0.764.2)
.......................................................................................................................................................................................................................................................................................................................................................................
Craniosynostosis
1.2 (0.492.7)
0.99 (0.392.5)
1.9 (0.794.4)
1.6 (0.624.0)
Gastroschisis
1.9 (0.944.0)
15
3.3 (1.86.1)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
1.9 (0.735.1)
................................................................................................................................................................................................................................................................................................................................................................................
crORs are presented for birth defect categories with at least 4 cases exposed to 1 of ingredients considered in this subanalysis.
CHD, congenital heart defect; CI, confidence interval; crOR, crude odds ratio.
a
Includes those with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
314.e7
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Research
TABLE 4
Associations between maternal opioid analgesic treatment and isolated and nonisolateda major birth defects
Birth defect
Isolated/simple isolated cases
Nonisolated/nonsimple
isolated cases
No. exposed
casesb
No. exposed
casesb
aORc (95% CI)
aORc (95% CI)
.......................................................................................................................................................................................................................................................................................................................................................................
Anencephaly/craniorachischisis
1.6 (0.783.4)
.......................................................................................................................................................................................................................................................................................................................................................................
Spina bifida
21
1.8 (1.13.0)
3.7 (1.49.6)
137
1.3 (1.01.7)
74
1.4 (1.11.9)
3.9 (1.69.2)
.......................................................................................................................................................................................................................................................................................................................................................................
Any of included heart defects
..............................................................................................................................................................................................................................................................................................................................................................
Atrioventricular septal defect
..............................................................................................................................................................................................................................................................................................................................................................
Conotruncal defects
24
1.2 (0.771.9)
17
2.1 (1.23.5)
Tetralogy of Fallot
2.2 (0.875.5)
..............................................................................................................................................................................................................................................................................................................................................................
16
1.6 (0.952.8)
D-transposition of great arteries
0.97 (0.452.1)
Ventricular septal defect conoventricular
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
5.1 (2.112.4)
1.6 (1.12.5)
1.3 (0.632.5)
..............................................................................................................................................................................................................................................................................................................................................................
Left ventricular outflow tract obstruction defects
27
Hypoplastic left heart syndrome
16
..............................................................................................................................................................................................................................................................................................................................................................
2.5 (1.54.3)
0.80 (0.322.0)
Aortic stenosis
1.3 (0.523.2)
Right ventricular outflow tract obstruction defects
33
1.9 (1.32.9)
27
2.0 (1.33.1)
1.1 (0.522.5)
Septal defects
48
1.1 (0.781.6)
39
1.4 (0.962.0)
Ventricular septal defect perimembranous
19
1.0 (0.621.7)
10
0.91 (0.461.8)
Atrial septal defect secundum
19
1.1 (0.701.9)
24
1.5 (0.972.4)
..............................................................................................................................................................................................................................................................................................................................................................
0.97 (0.422.2)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
0.89 (0.411.9)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
1.8 (0.814.1)
2.4 (1.24.8)
Cleft palate
Atrial septal defect not otherwise specified
19
1.2 (0.742.0)
1.7 (0.723.9)
26
1.3 (0.842.0)
2.8 (1.36.2)
0.72 (0.361.4)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Cleft lip without cleft palate
................................................................................................................................................................................................................................................................................................................................................................................
significant findings from our main analysis, but these drugs were also the most
frequently used, representing 69% of all
reported exposures.
Most estimated effect measures for
opioid-associated birth defects were
higher when using a tighter early pregnancy exposure period definition than
those seen with exposures at any time
during the first trimester or in the month
before conception. A stronger relationship with treatment confined to the critical window for embryologic development (3-8 weeks postfertilization) is
consistent with what would be expected
if the associations were causal.
We also found statistically significant
associations of early pregnancy opioid
treatment among infants with spina bi-
(continued )
fida, which concurs with experimental

studies performed in hamsters.24,25 Maternal opioid treatment has not been associated with an increased risk of neural
tube defects in previous epidemiologic
studies of human pregnancy,21-23 and
additional evaluation of this observation
is necessary. Similarly, the significant associations we observed in exploratory
analyses with maternal opioid treatment
among infants with hydrocephaly, glaucoma, or gastroschisis have not been previously reported. Given the probability
that some findings may be due to chance,
our results should be treated with caution and deserve further investigation.
The prevalence of opioid treatment in
early pregnancy among control and case
mothers was observed to be 2-2.6%. Ac-
cording to the National Health and Nutrition Examination Survey, the percentage of women aged 18-44 years who
reported prescription narcotic drug
use in the month prior to interview
from 1999 through 2002 was approximately 5%. In this same time period,
women of all ages reported more use
than men, and use among women increased by nearly one-half from that reported in 1988 through 1994.11
The activity of opioids and their receptors as growth regulators during embryologic development may provide a
mechanism that explains our findings.
One native opioid peptide, opioid
growth factor, acts as a negative growth
regulator.33 In addition, endogenous
opioids can inhibit DNA synthesis and
314.e8
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TABLE 4
Associations between maternal opioid analgesic treatment and isolated and nonisolateda major birth defects
(continued)
Birth defect
Isolated/simple isolated cases
Nonisolated/nonsimple
isolated cases
No. exposed
casesb
No. exposed
casesb
aORc (95% CI)
aORc (95% CI)
.......................................................................................................................................................................................................................................................................................................................................................................
Hydrocephaly
2.0 (0.964.2)
Cataracts
2.0 (0.894.3)
Glaucoma/anterior chamber defects
3.2 (1.28.2)
Esophageal atresia
Intestinal atresia/stenosis
1.0 (0.382.9)
10
1.9 (0.963.6)
Hypospadias second/third degree
26
0.91 (0.571.5)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
11
2.2 (1.24.2)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
1.1 (0.522.4)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Longitudinal limb deficiency
2.0 (0.715.5)
2.4 (0.846.6)
..............................................................................................................................................................................................................................................................................................................................................................
Longitudinal preaxial limb deficiency
.......................................................................................................................................................................................................................................................................................................................................................................
Transverse limb deficiency
0.84 (0.342.1)
Craniosynostosis
16
0.92 (0.531.6)
11
1.4 (0.732.6)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
Omphalocele
Gastroschisis
25
1.8 (0.645.0)
.......................................................................................................................................................................................................................................................................................................................................................................
1.9 (1.23.1)
................................................................................................................................................................................................................................................................................................................................................................................
aORs are presented for birth defect categories with at least 4 exposed cases considered in this subanalysis.
aOR, adjusted odds ratio; CI, confidence interval.
a
Defects that never occur isolated (eg, amniotic band sequence) were not included in this analysis. Both congenital heart defects and noncardiac defects could occur as isolated defect, as one of
multiple unrelated major defects, or as component of syndrome or other complex pattern (either of latter being nonisolated).28 For congenital heart defects, classification also occurs on second axis
focused on heart to describe complexity of cardiac involvement. Simple heart defects are anatomically discrete or well-recognized single entity; associations are defined as common, uncomplicated
combinations of heart defects; and heart defects that do not fall into either category are considered complex (latter 2 were considered nonsimple for this analysis); b Number of cases includes those
with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs; c Odds ratios were adjusted for maternal age, race/ethnicity,
education, presence or absence of prepregnancy obesity, presence or absence of periconceptional smoking, and study center.
decrease cellular proliferation, and

blockade of opioid growth factor receptors with opioid antagonists increases
DNA synthesis in multiple fetal tissues,
including neural and cardiac tissues,
consistent with our study results.34 Exogenous opioids might also act on opioid
growth factor receptors during embryogenesis, resulting in delayed cell growth
and migration at critical times in development and consequent increased risk
for certain birth defects.
Our study has several strengths. We
used data from the largest collaborative
population-based study of birth defects
in the United States. Whereas many previous studies of birth defects have not
adequately characterized birth defects
phenotypes, our cases were reviewed by
clinical geneticists with expertise in birth
defects, and heart defects were also
314.e9
reviewed by clinicians with expertise

in pediatric cardiology. Furthermore,
grouping of CHD based on presumed
developmental mechanisms may aid in
understanding the potential effects of exposures.6 The study used multiple questions to ascertain medication use, and we
were able to classify reported products
into their component ingredients.
Our findings are also subject to several
limitations. Nonresponse is one of those
limitations; however, the rates of nonresponse of 30% among case mothers and
33% among control mothers were similar. Exposure information was obtained
through retrospective maternal self-report, which might result in recall bias
and/or exposure misclassification, particularly given the variable time to interview. While the average time lag between
delivery and interview was 9-11 months,
some women who were interviewed 2

years after the EDD were asked to recall exposures up to 3 years in the past.
Postpregnancy reporting of prescription
medications has been shown to be relatively complete when very specific recall
prompts are used, including questions
on both medical conditions necessitating treatment and the treatment itself.35
This study included medication recall
questions based on medical conditions,
illnesses, or events but did not specifically ask about opioid medications by
name, which could have negatively impacted recall. Whereas case mothers are
generally more likely to have reflected
on pregnancy exposures than control
mothers in case-control studies, control
infants in this study were not required to
be healthy, but instead were live births
without major birth defects. In addition,
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previous analyses of the issue of recall bias
have found that even in studies of reproductive outcomes, exposure misclassification is likely to be nondifferential and
result in estimates biased toward the
null.36,37 Misclassification of prepregnancy body mass index was also possible,
with likely underestimation of the proportion of obese mothers among both case
and control infants.38-40
The study does not collect information on medication dose, so we were unable to assess dose-response relationships. Because many of the medication
products included in our analysis were
multiple-component products, one
must consider the influence of other ingredients. Also, because the most commonly reported reason for opioid use
was surgical procedures, other medications (eg, anesthesia) could have been
used concomitantly for this or other indications. Confounding by indication is
unlikely for opioid medications because
of the wide range of conditions they are
used to treat.
In conclusion, we found that maternal
opioid analgesic treatment early in pregnancy was associated with certain types
of birth defects in infants, including
some types of CHD, which are important
contributors to infant morbidity and
mortality.8 Identification of a biologically plausible mechanism supports this
finding, although better pathogenetic
understanding is needed to explain why
opioid analgesic treatment is associated
with some defects but not others.
It is important to emphasize that an
increased relative risk for any rare birth
defect with an exposure usually translates into only a modest absolute increase
in risk above the baseline birth defects
risk. For example, the estimated birth
prevalence of hypoplastic left heart syndrome in the United States is 2.4/10,000
live births.2 Our findings suggest a potentially 2.4-fold increased risk for a hypoplastic left heart syndrome-affected
pregnancy in a woman taking opioid analgesics periconceptionally; this would
suggest up to a 5.8 in 10,000 (0.06%)
chance of that woman having an infant
with hypoplastic left heart syndrome. It
is critical that health care providers
weigh the benefits of these medications
along with their potential risks when discussing analgesic treatment options with
patients who are or may become pregnant,
including reproductive-aged women who
are not planning a pregnancy but might be
f
at risk of an unintended pregnancy.
ACKNOWLEDGMENTS
Coding of drug information in NBDPS used the
Slone Drug Dictionary, under license from the
Slone Epidemiology Center at Boston University, Boston, MA. Centers participating in the
NBDPS: University of Arkansas for Medical Sciences, Little Rock, AR (Charlotte Hobbs, MD;
U50/CCU613236); California March of Dimes,
Oakland, CA (Gary Shaw, DrPH; U50/
CCU913241); University of Iowa, Iowa City, IA
(Paul Romitti, PhD; U50/CCU713238); Massachusetts Department of Public Health,
Boston, MA (Marlene Anderka, PhD; U50/
CCU113247); New York State Department of
Health, Albany, NY (Charlotte Druschel, MD;
U50/CCU223184); University of North Carolina
School of Public Health, Chapel Hill, NC (Andrew Olshan, PhD, Robert Meyer, PhD; U50/
CCU422096); Texas Department of State
Health Services, Austin, TX (Mark Canfield,
PhD; Peter Langlois, PhD; U50/CCU613232);
Utah Department of Health, Salt Lake City, UT
(Marcia Feldkamp, PhD, PA, MSPH; U50/
CCU822097).
We wish to thank the study participants, interviewers, and collaborators at all of the Centers
for Birth Defects Research and Prevention.
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Maternal opioid use linked to several birth defects

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Maternal opioid use linked to several birth defects

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Research

Maternal treatment with opioid analgesics

through 2005) is an ongoing population-based case-control study. We

RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449

Key words: analgesic, birth defect, medication, opioid, pregnancy

ajor birth defects affect about 3% of

and are the main contributor to infant

For Editors Commentary, see Table of Contents

American Journal of Obstetrics & Gynecology APRIL 2011

M ATERIALS AND M ETHODS

sey, New York, North Carolina, Texas,

birth defects (control infants) is selected

APRIL 2011 American Journal of Obstetrics & Gynecology

odds ratios (ORs). We examined birth

opioid analgesics in early pregnancy was

American Journal of Obstetrics & Gynecology APRIL 2011

ment between 1 month before and 3

Maternal age at delivery, y

Body mass index 30

Body mass index 30

Maternal prepregnancy obesity

Folic acid supplement use

No use/use at another time

Reported use from 1 month before to 1 month after pregnancy conception.

APRIL 2011 American Journal of Obstetrics & Gynecology

aOR (95% CI)

Laterality defects with CHD

Atrioventricular septal defect

Anomalous pulmonary venous return

Any of included heart defects

D-transposition of great arteries

Ventricular septal defect conoventricular

Left ventricular outflow tract obstruction defects

Hypoplastic left heart syndrome

Ventricular septal defect perimembranous

Atrial septal defect secundum

Right ventricular outflow tract obstruction defects

Pulmonary valve stenosis

Atrial septal defect not otherwise specified

CHD association: ventricular septal defect atrial septal defect

CHD association: pulmonary valve stenosis ventricular septal defect

Cleft lip with cleft palate

Cleft lip without cleft palate

were grouped into 1 of 4 larger phenotypic categories (conotruncal defects, left

American Journal of Obstetrics & Gynecology APRIL 2011

other neural tube defects (anencephaly or

aOR (95% CI)

Amniotic band syndrome/limb body wall complex

Glaucoma/anterior chamber defects

Bilateral renal agenesis or hypoplasia

Longitudinal limb deficiency

Hypospadias second/third degree

Transverse limb deficiency

Longitudinal preaxial limb deficiency

riod from 1 month before to 3 months

nalysis limited to isolated cases for

NBDPS-eligible diagnostic categories of

APRIL 2011 American Journal of Obstetrics & Gynecology

No. exposed crOR

No. exposed crOR

No. exposed crOR

No. exposed crOR