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OBSTETRICS
1 month before pregnancy and the first trimester was associated with
birth defects.
STUDY DESIGN: The National Birth Defects Prevention Study (1997
(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.
case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects
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.
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
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.
Research
314.e2
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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.
R ESULTS
Of the 17,449 mothers of case infants
with various included birth defects, 454
(2.6%) reported opioid analgesic treat-
Obstetrics
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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
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
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
13,658 (81.7)
5399 (83.9)
(referent)
3064 (18.3)
1033 (16.1)
1.2 (1.11.3)
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
a
17,446
6701
.......................................................................................................................................................................................................................................................................................................................................................................
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
Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
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
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)
198
1.2 (0.423.2)
175
2.4 (1.24.8)
206
0.71 (0.222.3)
Single ventricle/complex
201
1.1 (0.423.2)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
Conotruncal defects
1481
41
1.5 (1.02.1)
Tetralogy of Fallot
672
21
1.7 (1.12.8)
461
10
1.1 (0.562.1)
110
2.7 (1.16.3)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
1195
36
1.5 (1.02.2)
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)
1402
29
0.99 (0.651.5)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
1507
43
1.3 (0.941.9)
511
17
2.0 (1.23.6)
528
17
1.7 (1.02.9)
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)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
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 )
Obstetrics
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Research
TABLE 2
Associations between maternal opioid analgesic treatment and specific major birth defects (continued)
Total no.a
Birth defect
No. exposed
Exploratory analysis
.......................................................................................................................................................................................................................................................................................................................................................................
Controls
6701
134
203
Referent
1.0 (0.372.9)
Hydrocephaly
301
11
2.0 (1.03.7)
Cataracts
217
1.6 (0.723.5)
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)
112
1.3 (0.404.2)
269
1.1 (0.492.6)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
157
1.3 (0.483.6)
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.
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
314.e6
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TABLE 3
Associations between common opioid components and specific major birth defects
Birth defect
Codeine
Hydrocodone
Oxycodone
Meperidine
Hypothesis-testing analysis
.......................................................................................................................................................................................................................................................................................................................................................................
Anencephaly/
craniorachischisis
1.9 (0.675.3)
Spina bifida
1.5 (0.683.4)
11
2.5 (1.34.8)
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
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
3.1 (1.46.9)
3.2 (1.47.1)
..............................................................................................................................................................................................................................................................................................................................................................
Coarctation of aorta
0.99 (0.352.8)
Aortic stenosis
2.5 (0.897.0)
10
1.3 (0.662.6)
13
1.0 (0.362.8)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
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
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)
..............................................................................................................................................................................................................................................................................................................................................................
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)
................................................................................................................................................................................................................................................................................................................................................................................
Exploratory analysis
.......................................................................................................................................................................................................................................................................................................................................................................
Hydrocephaly
Cataracts
2.6 (1.06.7)
2.1 (0.766.0)
2.4 (0.866.9)
Esophageal atresia
1.8 (0.714.6)
Anorectal atresia/stenosis
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)
Diaphragmatic hernia
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.
Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
314.e7
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Research
TABLE 4
Associations between maternal opioid analgesic treatment and isolated and nonisolateda major birth defects
Birth defect
Nonisolated/nonsimple
isolated cases
No. exposed
casesb
No. exposed
casesb
Hypothesis-testing analysis
.......................................................................................................................................................................................................................................................................................................................................................................
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)
.......................................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
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)
0.97 (0.452.1)
..............................................................................................................................................................................................................................................................................................................................................................
..............................................................................................................................................................................................................................................................................................................................................................
5.1 (2.112.4)
1.6 (1.12.5)
1.3 (0.632.5)
..............................................................................................................................................................................................................................................................................................................................................................
27
16
..............................................................................................................................................................................................................................................................................................................................................................
2.5 (1.54.3)
Coarctation of aorta
0.80 (0.322.0)
Aortic stenosis
1.3 (0.523.2)
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)
19
1.0 (0.621.7)
10
0.91 (0.461.8)
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
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)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
................................................................................................................................................................................................................................................................................................................................................................................
Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
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 )
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
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TABLE 4
Associations between maternal opioid analgesic treatment and isolated and nonisolateda major birth defects
(continued)
Birth defect
Nonisolated/nonsimple
isolated cases
No. exposed
casesb
No. exposed
casesb
Exploratory analysis
.......................................................................................................................................................................................................................................................................................................................................................................
Hydrocephaly
2.0 (0.964.2)
Cataracts
2.0 (0.894.3)
3.2 (1.28.2)
Esophageal atresia
Intestinal atresia/stenosis
1.0 (0.382.9)
Anorectal atresia/stenosis
10
1.9 (0.963.6)
26
0.91 (0.571.5)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
11
2.2 (1.24.2)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
1.1 (0.522.4)
.......................................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
2.0 (0.715.5)
2.4 (0.846.6)
..............................................................................................................................................................................................................................................................................................................................................................
.......................................................................................................................................................................................................................................................................................................................................................................
0.84 (0.342.1)
Craniosynostosis
16
0.92 (0.531.6)
Diaphragmatic hernia
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.
Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
Obstetrics
www.AJOG.org
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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