Research

Obstetrics

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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.
RESULTS: Therapeutic opioid use was reported by 2.6% of 17,449
case mothers and 2.0% of 6701 control mothers. Treatment was sta-

tistically significantly associated with conoventricular septal defects

(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
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.

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.

B ACKGROUND AND O BJECTIVE

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.
Our objective was to examine whether
maternal therapeutic use of opioid analgesics in early pregnancy is associated

with congenital heart defects (CHD) or

other birth defects.

M ATERIALS AND M ETHODS

We analyzed data from the National
Birth Defects Prevention Study (NB-

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.
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 the online full-length 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

American Journal of Obstetrics & Gynecology APRIL 2011

DPS) for infants born from 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
exposure immediately before and during
pregnancy. Each of the study sites in 10
states ascertains deliveries with birth defects through birth defects surveillance
systems using standard, detailed case
definitions.
In the NBDPS, an annual random
sample of approximately 1200 liveborn
infants without birth defects (control infants) is selected from the same geographic regions and time period as cases.
Mothers are invited to participate in an
hour-long computer-assisted telephone
interview conducted in English or Spanish 6 weeks to 2 years after the mothers
estimated date of delivery. Mothers are
asked about medications used for each
illness (eg, influenza) or indication
(eg, surgery) and encouraged to report
taking any medications not already
mentioned.
We defined opioid exposure as maternal
report of using 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, hydromor-

Obstetrics

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Research

TABLE

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

................................................................................................................................................................................................................................................................................................................................................................................

Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.

phone, fentanyl, and pentazocine. The exposure window of interest was the period
from 1 month before to 3 months after
conception. Infants with 1 defect were
included in multiple birth defect
categories.
Our primary analysis tested the hypothesis that maternal therapeutic use of
opioid analgesics in early pregnancy was
associated with the occurrence of CHD,
cleft lip and/or palate, or neural tube defects in infants. Secondarily, exploratory
analyses were performed in other birth
defect groups.

(continued )

R ESULTS
Of the 17,449 mothers of case infants
with various included birth defects, 454
(2.6%) reported opioid analgesic treatment. Among 6701 control mothers, 134
(2.0%) reported treatment in this time
period. Opioids were most commonly
reported within the surgical procedures
(41%), infections (34%), chronic diseases (20%), and injuries (18%) sections
of the questionnaire.
Effect estimates were statistically significantly elevated for all eligible CHD
combined (odds ratio [OR], 1.4; 95%

confidence interval [CI], 1.11.7). Statistically significant associations with maternal opioid use were found among
infants with conoventricular, atrioventricular, and atrial septal defect (not otherwise specified); hypoplastic left heart
syndrome; tetralogy of Fallot; or pulmonary valve stenosis (Table). We found a
significant association between maternal
opioid use between 1 month before and 3
months after conception and spina bifida (OR, 2.0; 95% CI, 1.33.2), as hypothesized, but not with the other neural
tube defects studied.

APRIL 2011 American Journal of Obstetrics & Gynecology

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Research

Obstetrics

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TABLE

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.

Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.

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 period from 1 month before to 3 months
after conception.

C OMMENT
Using data from a large population-based
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
316

use of codeine. We found statistically significant associations of early pregnancy

opioid treatment among infants with spina
bifida, as shown in hamster studies. The
significant associations we observed in exploratory analyses with maternal opioid
treatment among infants with hydrocephaly, glaucoma, or gastroschisis have not
been previously reported and deserve further investigation. The activity of opioids
and their receptors as growth regulators
during embryologic development may
provide a mechanism that explains our
findings.
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
defect phenotypes, our cases were reviewed by clinical geneticists with expertise in birth defects. Heart defect cases

American Journal of Obstetrics & Gynecology APRIL 2011

were reviewed by clinicians with expertise in pediatric cardiology.

Exposure information was obtained
through retrospective maternal self-report. This may have resulted in recall bias
or exposure misclassification, particularly
given the variable time to interview. Because the study does not collect information on medication dose, we were unable
to assess doseresponse relationships. Because the most commonly reported reason
for opioid use was surgical procedures,
other medications, such as anesthesia,
could have been used concomitantly for
this or other indications.
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 risk for birth defects. It
is essential that health care providers weigh
the benefits of these medications along

Obstetrics

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with their potential risks when discussing
analgesic treatment options with patients
who are or may become pregnant, including reproductive-age women who are not
planning a pregnancy but might be at risk
for unintended pregnancy.
CLINICAL IMPLICATIONS

Health care providers caring for pregnant women should be aware of the

association between early-pregnancy

opioid analgesic treatment and certain birth defects in infants, including
some types of congenital heart defects.
Health care providers must weigh the
benefits of opioid medications along
with their potential risks when discussing analgesic treatment options
with patients who are or may become
pregnant, including reproductive-age

Research

women who are not planning a pregnancy but might be at risk for unintended pregnancy.
Better pathogenetic understanding is
needed to explain why opioid analgesic treatment is associated with some
birth defects, but not others.
f

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