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31(eg, surgery) and encouraged to reporttaking any medications not alreadymentioned.

We defined opioid exposure as maternalreport of using 1 products with any ofthe following components taken for thera-peutic reasons in any dose, duration, orfrequency: codeine, hydrocodone, meper-

the Centers for Disease Control and Prevention to the centers participating in the National Birthfects Prevention Study, listed as Acknowledgments in the online full-length article.

findings and conclusions in this report are those of the authors and do not necessarilyresent the official position of the Centers for Disease Control and Prevention.

2-9378/free Published by Mosby, Inc. doi: 10.1016/j.ajog.2010.12.039

For Editors Commentary, see Table of Contentsrs Broussard, Rasmussen, Reefhuis, Riehle-Colarusso, and Honein), Cenntrol and Prevention; the Department of Pharmacy Practice, Mercer Unianta, GA, and the Department of Medical Genetics, University of Britishild and Family Research Institute, Vancouver, British Columbia, Canada

sented at the 14th Annual Maternal and Child Health Epidemiology Confec. 10-12, 2008; the 56th Annual Epidemic Intelligence Service Conferenc24, 2009; the 49th Annual Meeting of the Teratology Society, Rio GrandeJuly 1, 2009; the 30th Annual David W. Smith Workshop on Malformationrphogenesis, Philadelphia, PA, Aug. 5-9, 2009; and the 25th Internationaarmacoepidemiology and Therapeutic Risk Management, Providence, RI

s work was supported through cooperative agreements under Program AnnSee related editorial, page 281

4 American Journal of Obstetrics& Gynecology APRIL 2011infants without birth defects (control in-fants) is selected from the same geo-graphic regions and time period as cases.Mothers are invited to participate in anhour-long computer-assisted telephoneinterview conducted in English or Span-ish 6 weeks to 2 years after the mothersestimated date of delivery. Mothers areasked about medications used for each

for Diseaseity (Dr Jann),

umbia, and theFriedman).

ce, Atlanta, GA,tlanta, GA, Apriluerto Rico, Junendnference ong. 17-19, 2009.

cement No. 02081In the NBDPS, an annual randomm the Epidemic Intelligence Service, Office of Workforce and Career Development (Drussard), Centers for Disease Control and Prevention; the Division of Birth Defects andaternal treatment wnd risk for birth defeeryl S. Broussard, PhD; Sonja A. RasmusM. Friedman, MD, PhD; Michael W. Ja

rgaret A. Honein, PhD, MPH; for the N

JECTIVE: We examined whether maternal opioonth before pregnancy and the first trimeste

th defects.UDY DESIGN: The National Birth Defects Preough 2005) is an ongoing population-based cimated adjusted odds ratios (ORs) and 95%s) for birth defects categories with at least 200xposed case infants.SULTS: Therapeutic opioid use was reportede mothers and 2.0% of 6701 control mothers

this article as: Broussard CS, Rasmussen SA, Reefhuis J

CKGROUND AND OBJECTIVEspite evidence of adverse fetal effectsth maternal codeine use and the pau-y of data on the effects of maternal useother opioids, such treatment is oftenumed to be safe during pregnancy.r objective was to examine whetherternal therapeutic use of opioid anal-ics in early pregnancy is associatedh opioid analgesicsts, MD, MS; Jennita Reefhuis, PhD;PharmD; Tiffany Riehle-Colarusso, MDnal Birth Defects Prevention Study

reatment betweens associated with

tion Study (1997-control study. Wenfidence intervalse infants or at least

2.6% of 17,449reatment was sta-

tistically significantly as(OR, 2.7; 95% CI, 1.195% CI, 1.23.6), hypo1.44.1), spina bifida(OR, 1.8; 95% CI, 1.12CONCLUSION: Consisteshows an association besic treatment and certainsidered by women and thsions during pregnancy.

l. Maternal treatment with opioid analgesics and risk for

th congenital heart defects (CHD) orer birth defects.

ATERIALS AND METHODSe analyzed data from the Nationalth Defects Prevention Study (NB-idiphSE;

iated with conoventricular septal defects), atrioventricular septal defects (OR, 2.0;stic left heart syndrome (OR, 2.4; 95% CI,, 2.0; 95% CI, 1.33.2), or gastroschisisin infants.ith some previous investigations, our studyen early pregnancymaternal opioid analge-th defects. This information should be con-physicians who are making treatment deci-

defects. Am J Obstet Gynecol 2011;204:314.e1-11.

S) for infants born from Oct. 1, 1997,ough Dec. 31, 2005. NBDPS is an on-

ing multisite population-based casentrol study of 30 types of majoructural birth defects that focuses onosure immediately before and duringgnancy. Each of the study sites in 10tes ascertains deliveries with birth de-ts through birth defects surveillanceitc

sennn,atio

id tr wa

venaseco

cas

by. T

, et ane, oxycodone, propoxyphene, mor-ine, tramadol, methadone, hydromor-

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www.AJOG.org Obstetrics Researchone, fentanyl, and pentazocine. The ex-sure window of interest was the periodm 1 month before to 3 months afterception. Infants with 1 defect were

luded in multiple birth defectegories.Our primary analysis tested the hy-thesis that maternal therapeutic use ofioid analgesics in early pregnancy wasociated with the occurrence of CHD,ft lip and/or palate, or neural tube de-ts in infants. Secondarily, exploratoryalyses were performed in other birth

TABLEAssociations between maternal opioi

Birth defect

Hypothesis-testing analysis................................................................................................................

Controls................................................................................................................

Anencephaly/craniorachischisis................................................................................................................

Spina bifida................................................................................................................

Any of included heart defects.......................................................................................................

Laterality defects with CHD.......................................................................................................

Atrioventricular septal defect.......................................................................................................

Anomalous pulmonary venous return.......................................................................................................

Single ventricle/complex.......................................................................................................

Conotruncal defects.......................................................................................................

Tetralogy of Fallot.......................................................................................................

D-transposition of great arteries.......................................................................................................

Ventricular septal defect conoventricular.......................................................................................................

Left ventricular outflow tract obstruction.......................................................................................................

Hypoplastic left heart syndrome.......................................................................................................

Coarctation of aorta.......................................................................................................

Aortic stenosis.......................................................................................................

Right ventricular outflow tract obstruction.......................................................................................................

Pulmonary valve stenosis.......................................................................................................

Septal defects.......................................................................................................

Ventricular septal defect perimembranou.......................................................................................................

Atrial septal defect secundum.......................................................................................................

Atrial septal defect not otherwise specifie.......................................................................................................

CHD association: ventricular septal defec.......................................................................................................

CHD association: pulmonary valve stenos................................................................................................................

Cleft palate................................................................................................................

Cleft lip with cleft palate................................................................................................................

Cleft lip without cleft palate.........................................................................................................................

Broussard. Opioid analgesics and risk for birth defects. Am J Ofect groups. coSULTSthe 17,449 mothers of case infants

th various included birth defects, 4546%) reported opioid analgesic treat-nt. Among 6701 control mothers, 1340%) reported treatment in this timeriod. Opioids were most commonlyorted within the surgical procedures%), infections (34%), chronic dis-es (20%), and injuries (18%) sectionsthe questionnaire.Effect estimates were statistically sig-cantly elevated for all eligible CHD

nalgesic treatment and specific maj

Total no.a

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

6701.........................................................................................................................

340.........................................................................................................................

718.........................................................................................................................

7724.........................................................................................................................

198.........................................................................................................................

175.........................................................................................................................

206.........................................................................................................................

201.........................................................................................................................

1481.........................................................................................................................

672.........................................................................................................................

461.........................................................................................................................

110.........................................................................................................................

cts 1195.........................................................................................................................

357.........................................................................................................................

630.........................................................................................................................

253.........................................................................................................................

fects 1175.........................................................................................................................

867.........................................................................................................................

3482.........................................................................................................................

1402.........................................................................................................................

1507.........................................................................................................................

511.........................................................................................................................

atrial septal defect 528.........................................................................................................................

ventricular septal defect 131.........................................................................................................................

936.........................................................................................................................

1162.........................................................................................................................

614........................................................................................................................

et Gynecol 2011.mbined (odds ratio [OR], 1.4; 95% tub

APRIL 2011 Americnfidence interval [CI], 1.11.7). Statis-ally significant associations with ma-nal opioid use were found amongants with conoventricular, atrioven-cular, and atrial septal defect (not oth-

ise specified); hypoplastic left heartdrome; tetralogy of Fallot; or pulmo-

ry valve stenosis (Table). We found anificant association between maternalioid use between 1 month before and 3nths after conception and spina bi-

a (OR, 2.0; 95% CI, 1.33.2), as hy-thesized, but not with the other neural

birth defects

No. exposed aOR (95% CI)

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

134 Referent............................................................................................................

9 1.7 (0.843.4)............................................................................................................

26 2.0 (1.33.2)............................................................................................................

211 1.4 (1.11.7)............................................................................................................

4 1.2 (0.423.2)............................................................................................................

9 2.4 (1.24.8)............................................................................................................

4 0.71 (0.222.3)............................................................................................................

4 1.1 (0.423.2)............................................................................................................

41 1.5 (1.02.1)............................................................................................................

21 1.7 (1.12.8)............................................................................................................

10 1.1 (0.562.1)............................................................................................................

6 2.7 (1.16.3)............................................................................................................

36 1.5 (1.02.2)............................................................................................................

17 2.4 (1.44.1)............................................................................................................

11 0.88 (0.471.6)............................................................................................................

7 1.3 (0.612.9)............................................................................................................

40 1.6 (1.12.3)............................................................................................................

34 1.7 (1.22.6)............................................................................................................

87 1.2 (0.931.6)............................................................................................................

29 0.99 (0.651.5)............................................................................................................

43 1.3 (0.941.9)............................................................................................................

17 2.0 (1.23.6)............................................................................................................

17 1.7 (1.02.9)............................................................................................................

4 1.3 (0.463.7)............................................................................................................

25 1.3 (0.842.0)............................................................................................................

33 1.4 (0.962.1)............................................................................................................

9 0.68 (0.341.3)...........................................................................................................

(continued )REOfwi(2.me(2.perep(41easof

nifi

coticterinftrierwsynnasigopmofidpo

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bste defects studied.

an Journal of Obstetrics& Gynecology 315

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Research Obstetrics www.AJOG.org

31The exploratory analyses of maternalioid use for infants with 1 of 18er categories of birth defects found

tistically significant associations fordrocephaly (OR, 2.0; 95% CI, 1.0 ), glaucoma or anterior chamber eye

fects (OR, 2.6; 95% CI, 1.0 6.6), andtroschisis (OR, 1.8; 95% CI, 1.12.9).

Limiting the exposure definition to thest 2 months after conception pro-ced results very similar to the main es-ates using exposure during the pe-

d from 1 month before to 3 monthser conception.

MMENTing data from a large population-basedecontrol study, we found associationsween maternal therapeutic use of opi-

medications in early pregnancy anderal types of CHD, consistent with

TABLEAssociations between maternal opioi

Birth defect

xploratory analysis................................................................................................................

Controls................................................................................................................

Amniotic band syndrome/limb body wall com................................................................................................................

Hydrocephaly................................................................................................................

Cataracts................................................................................................................

Glaucoma/anterior chamber defects................................................................................................................

Anotia/microtia................................................................................................................

Esophageal atresia................................................................................................................

Intestinal atresia/stenosis................................................................................................................

Anorectal atresia/stenosis................................................................................................................

Hypospadias second/third degree................................................................................................................

Bilateral renal agenesis or hypoplasia................................................................................................................

Longitudinal limb deficiency.......................................................................................................

Longitudinal preaxial limb deficiency................................................................................................................

Transverse limb deficiency................................................................................................................

Craniosynostosis................................................................................................................

Diaphragmatic hernia................................................................................................................

Omphalocele................................................................................................................

Gastroschisis.........................................................................................................................

Odds ratios were adjusted for maternal age, race/ethnicity, educaaOR, adjusted odds ratio; CHD, congenital heart defect; CI, confida Some comparisons used fewer than total number of controls (egdiabetics (type 1 or 2) and mothers reporting exposure to opioid

Broussard. Opioid analgesics and risk for birth defects. Am J Oe previous findings for first-trimester tis

6 American Journal of Obstetrics& Gynecology APof codeine. We found statistically sig-cant associations of early pregnancy

ioid treatment among infants with spinada, as shown in hamster studies. The

nificant associations we observed in ex-ratory analyses with maternal opioidatment among infants with hydroceph-, glaucoma, or gastroschisis have notn previously reported and deserve fur-r investigation. The activity of opioids

d their receptors as growth regulatorsring embryologic development mayvide a mechanism that explains our

dings.We used data from the largest collab-tive population-based study of birth

fects in the United States. Whereasny previous studies of birth defects

ve not adequately characterized birthfect phenotypes, our cases were re-wed by clinical geneticists with exper-

nalgesic treatment and specific maj

Total no.a

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

6701.........................................................................................................................

x 203.........................................................................................................................

301.........................................................................................................................

217.........................................................................................................................

103.........................................................................................................................

403.........................................................................................................................

434.........................................................................................................................

266.........................................................................................................................

623.........................................................................................................................

1313.........................................................................................................................

112.........................................................................................................................

269.........................................................................................................................

157.........................................................................................................................

415.........................................................................................................................

806.........................................................................................................................

507.........................................................................................................................

267.........................................................................................................................

726........................................................................................................................

presence or absence of prepregnancy obesity, presence or abseinterval.

ospadias only used male controls); number of cases includes thoet drugs.

et Gynecol 2011.e in birth defects. Heart defect cases the

RIL 2011re reviewed by clinicians with exper-e in pediatric cardiology.Exposure information was obtainedough retrospective maternal self-re-rt. This may have resulted in recall biasexposure misclassification, particularlyen the variable time to interview. Be-se the study does not collect informa-

n on medication dose, we were unableassess doseresponse relationships. Be-se the most commonly reported reasonopioid use was surgical procedures,

er medications, such as anesthesia,ld have been used concomitantly for

s or other indications.It is important to emphasize that an in-ased relative risk for any rare birth de-t with an exposure usually translateso only a modest absolute increase in riskove the baseline risk for birth defects. Itssential that health care providers weigh

birth defects (continued)

No. exposed aOR (95% CI)

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

134 Referent............................................................................................................

5 1.0 (0.372.9)............................................................................................................

11 2.0 (1.03.7)............................................................................................................

7 1.6 (0.723.5)............................................................................................................

5 2.6 (1.06.6)............................................................................................................

4 0.77 (0.282.1)............................................................................................................

12 1.4 (0.762.5)............................................................................................................

4 0.88 (0.322.4)............................................................................................................

18 1.5 (0.872.4)............................................................................................................

29 0.92 (0.591.4)............................................................................................................

4 1.3 (0.404.2)............................................................................................................

6 1.1 (0.492.6)............................................................................................................

4 1.3 (0.483.6)............................................................................................................

7 1.0 (0.462.2)............................................................................................................

16 0.82 (0.481.4)............................................................................................................

12 1.2 (0.662.2)............................................................................................................

7 1.3 (0.602.8)............................................................................................................

26 1.8 (1.12.9)...........................................................................................................

f periconceptional smoking, and study center.

ith nonmissing exposure data and excludes prepregnancyusenifiopbifisigplotrealybeetheanduprofin

orademahadevie

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wianwhingplafor

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any other publisher. The percentage of nominated publications in the final list was greatest for Elsevier as well: 24%.

the .

www.AJOG.org Obstetrics ResearchFor the full list, in search box at sla.org, type top journalsAPRIL 2011 Americth their potential risks when discussingalgesic treatment options with patientso are or may become pregnant, includ-reproductive-age women who are not

nning a pregnancy but might be at riskunintended pregnancy.

LINICAL IMPLICATIONS

Health care providers caring for preg-nant women should be aware of the

association between early-pregnancyopioid analgesic treatment and cer-tain birth defects in infants, includingsome types of congenital heart de-fects.

Health care providers must weigh thebenefits of opioid medications alongwith their potential risks when dis-cussing analgesic treatment optionswith patients who are or may becomepregnant, including reproductive-age

women who are not planning a preg-nancy but might be at risk for unin-tended pregnancy.

Better pathogenetic understanding isneeded to explain why opioid analge-sic treatment is associated with somebirth defects, but not others. f

Special recognition for AJOG and Elsevier

The Journal has won a place among the 100 Most Influential Journals of the Last 100 years in Biology and Medicinethe only obstetrics and gynecology journal to do so.

The Biomedical and Life Sciences Divi-sion of the Special Libraries Association identified the 100 journals through a member poll. The criterion: which journal in a given category was relied upon most by other journals in that category in making their own more specialized progress.

Elsevier had more nominations (82 of 403) and winning journals (20) than

High rank among the most influential journals of the past century

Named by theSpecial Libraries Association 2009

100 Most InfluentialMedicine and Biology

Journals of the Last 100 Years

THE ONLY OB/GYN JOURNAL SELECTEDan Journal of Obstetrics& Gynecology 317

Maternal treatment with opioid analgesics and risk for birth defectsBACKGROUND AND OBJECTIVEMATERIALS AND METHODSRESULTSCOMMENTCLINICAL IMPLICATIONS