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Maternal treatment with opioid analgesics and risk for birth defects

Published:February 24, 2011DOI:https://doi.org/10.1016/j.ajog.2010.12.039

      Objective

      We examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with birth defects.

      Study Design

      The National Birth Defects Prevention Study (1997 through 2005) is an ongoing population-based case-control study. We estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIS) for birth defects categories with at least 200 case infants or at least 4 exposed case infants.

      Results

      Therapeutic opioid use was reported by 2.6% of 17,449 case mothers and 2.0% of 6701 control mothers. Treatment was statistically significantly associated with conoventricular septal defects (OR, 2.7; 95% CI, 1.1–6.3), atrioventricular septal defects (OR, 2.0; 95% CI, 1.2–3.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.4–4.1), spina bifida (OR, 2.0; 95% CI, 1.3–3.2), or gastroschisis (OR, 1.8; 95% CI, 1.1–2.9) 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.

      Key words

      Major birth defects affect about 3% of the 4 million US live births each year
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      Congenital heart defects (CHD) are among the most common birth defects, affecting nearly 1% of US births,
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      See related editorial, page 281
      For Editors' Commentary, see Table of Contents
      Opioid medications are potent prescription analgesics that are the mainstay for treatment of severe pain.
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      Opioids are often used in combination with nonopioid analgesics, such as acetaminophen, and lower doses are also a component of some cough suppressants. Previous studies have shown that opioid analgesic use and abuse have been increasing in recent years,
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      • et al.
      Patterns of abuse among unintentional pharmaceutical overdose fatalities.
      but the effects of opioid use on the developing fetus during pregnancy are poorly understood.
      Associations between maternal first-trimester use of the opioid analgesic codeine and CHD in infants were found in 3 of 4 previous case-control studies,
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      Exogenous hormones and other drug exposures of children with congenital heart disease.
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      Congenital cardiac anomalies relative to selected maternal exposures and conditions during early pregnancy.
      with case counts ranging from 141–390 (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,
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      • Holford T.R.
      Exposure to prescribed drugs in pregnancy and association with congenital malformations.
      • Saxen I.
      Associations between oral clefts and drugs taken during pregnancy.
      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.
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      Exposure to prescribed drugs in pregnancy and association with congenital malformations.
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      First-trimester drug use and congenital disorders.
      Neural tube defects have not been associated with maternal opioid treatment in human pregnancy,
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      Birth defects and drugs in pregnancy.
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      Personal communication, 1993.
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      • Lammer E.J.
      Maternal illness, including fever and medication use as risk factors for neural tube defects.
      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.
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      • Schramm L.C.
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      • et al.
      Codeine: developmental toxicity in hamsters and mice.
      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.
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      • Spierings E.L.
      Migraine during pregnancy: options for therapy.
      Our study objective was to examine whether maternal therapeutic use of opioid analgesics in early pregnancy is associated with CHD or other birth defects.

      Materials and Methods

      We analyzed data from the National Birth Defects Prevention Study (NBDPS) for infants born Oct. 1, 1997, through Dec. 31, 2005. NBDPS is an ongoing multisite population-based case-control study of >30 types of major structural birth defects that focuses on exposures immediately before and during pregnancy. Each of the study sites (Arkansas, California, Georgia, Iowa, Massachusetts, New Jersey, New York, North Carolina, Texas, and Utah) ascertains deliveries with birth defects through birth defects surveillance systems using standard, detailed case definitions. The study was approved by institutional review boards of the Centers for Disease Control and Prevention and all other participating centers.
      NBDPS focuses on birth defects with unknown etiologies; therefore, infants with recognized chromosomal abnormalities or single-gene disorders are excluded. Some cardiac anomalies that are usually physiological rather than pathological were also excluded, eg, patent ductus arteriosus or patent foramen ovale in premature infants. In addition, some cardiovascular anomalies were excluded from NBDPS either because of their rarity, poor ascertainment in infancy, unclear significance (eg, insufficiency of the tricuspid, mitral, or pulmonary valves), or because they were vascular (noncardiac) defects or arrhythmias (nonstructural defects). All CHD cases were confirmed by echocardiography, cardiac catheterization, surgery, or autopsy.
      • Yoon P.W.
      • Rasmussen S.A.
      • Lynberg M.C.
      • et al.
      The National Birth Defects Prevention Study.
      Classification of NBDPS cases has previously been described.
      • Botto L.D.
      • Lin A.E.
      • Riehle-Colarusso T.
      • Malik S.
      • Correa A.
      Seeking causes: classifying and evaluating congenital heart defects in etiologic studies.
      • Rasmussen S.A.
      • Olney R.S.
      • Holmes L.B.
      • Lin A.E.
      • Keppler-Noreuil K.M.
      • Moore C.A.
      Guidelines for case classification for the National Birth Defects Prevention Study.
      Briefly, the process for NBDPS-eligible defects involves confirmation of the diagnosis from medical record abstracts and determining whether each case is an “isolated” defect, 1 of multiple unrelated major defects, or a component of a syndrome or other complex pattern.
      • Rasmussen S.A.
      • Olney R.S.
      • Holmes L.B.
      • Lin A.E.
      • Keppler-Noreuil K.M.
      • Moore C.A.
      Guidelines for case classification for the National Birth Defects Prevention Study.
      For CHD, classification is also performed on a second axis to describe the complexity of cardiac involvement, by clinicians with expertise in pediatric cardiology. “Simple” heart defects are anatomically discrete or well-recognized single entities; “associations” are common, uncomplicated combinations of heart defects; and heart defects that do not fall into either category are considered “complex.” Cardiac classification and subsequent grouping into larger categories are based on clinical and presumed developmental mechanisms that may have relevance in considering the teratogenic effect of exposures.
      • Botto L.D.
      • Lin A.E.
      • Riehle-Colarusso T.
      • Malik S.
      • Correa A.
      Seeking causes: classifying and evaluating congenital heart defects in etiologic studies.
      An annual random sample of approximately 1200 liveborn infants without birth defects (control infants) is selected from the same geographic regions and time period as the cases, either from birth certificates or birth hospitals.
      Mothers are invited to participate in an hour-long computer-assisted telephone interview, conducted by interviewers in English or Spanish, between 6 weeks and 2 years after the mother's estimated date of delivery (EDD) (average is 11 months post-EDD for cases and 9 months for controls). The interview assesses various maternal health factors, pregnancy history information, dietary and other drug exposures, and sociodemographic characteristics. Exposures are assessed for the period from 3 months before conception through the end of the pregnancy. Pregnancy was defined as the time period from conception (ie, 2 weeks after the last menstrual period) to delivery, and pregnancy “months” for this analysis were consecutive 30-day periods.
      Mothers are asked about medications used for each specific illness (eg, influenza) or indication (eg, surgery) mentioned within the maternal health section of the questionnaire, and are also encouraged to report any other medications not already mentioned. Respondents are asked to report the start and stop dates, duration, and frequency of medication use using calendar dates or pregnancy months.
      All medications reported in each section of the interview are compiled and coded using the Slone Drug Dictionary,
      • Kelley K.
      • Kelley T.
      • Kaufman D.
      • Mitchell A.
      The Slone drug dictionary: a research-driven pharmacoepidemiology tool.
      which NBDPS licenses from Boston University's Slone Epidemiology Center. This dictionary links products to their active ingredients. We defined opioid exposure as maternal report of use of ≥1 products with any of the following components taken for therapeutic reasons in any dose, duration, or frequency: codeine, hydrocodone, meperidine, oxycodone, propoxyphene, morphine, tramadol, methadone, hydromorphone, fentanyl, or pentazocine. We included individual and combination products. The exposure window of interest was the period from 1 month before to 3 months after conception.
      We conducted multivariable logistic regression analyses to calculate adjusted odds ratios (ORs). We examined birth defect categories that had ≥200 cases or ≥4 exposed cases to limit analyses to defect categories that would likely have adequate statistical power and to enable us to identify potentially elevated risks among rarer defect groups. All models were adjusted for maternal age (continuous), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, other), education (<12 years, ≥12 years), prepregnancy obesity (body mass index <30, body mass index ≥30, using prepregnancy weight and height self-reported by the mother during the telephone interview), periconceptional smoking status (no smoking from 1 month before to 1 month after conception, smoking at least once in the same period), and study center (10 sites previously listed). These variables were chosen based on the strength of their relation in univariate analyses with “all NBDPS birth defects.”
      There were maternal interviews from 19,059 cases and 6807 controls who met the inclusion dates. The participation rate was 70% for cases and 67% for controls. We excluded participants with missing data on whether they were treated with an opioid analgesic in early pregnancy, due either to an incomplete medication history from the interview or an unknown medication start or stop date. We excluded mothers with preexisting diabetes, which has been found to be a strong independent risk factor for birth defects.
      • Becerra J.E.
      • Khoury M.J.
      • Cordero J.F.
      • Erickson J.D.
      Diabetes mellitus during pregnancy and the risks for specific birth defects: a population-based case-control study.
      • Correa A.
      • Gilboa S.M.
      • Besser L.M.
      • et al.
      Diabetes mellitus and birth defects.
      To focus our investigation on therapeutic opioid analgesic use, we also excluded mothers who reported opioid exposure in the form of illicit drugs such as heroin any time during pregnancy. Our final sample for analysis included 17,449 cases with the included defects and 6701 controls (Figure). Although the total number of cases included was greater than the total number of controls, controls substantially outnumbered cases in most analyses, each of which involved comparisons of infants with 1 particular category or subcategory of birth defects to all controls. Of note, infants with >1 defect were included in multiple birth defect categories.
      Figure thumbnail gr1
      FIGUREIncluded 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.
      Our primary analysis tested the hypothesis that maternal therapeutic use of opioid analgesics in early pregnancy was associated with the occurrence of CHD, cleft lip and/or palate, or neural tube defects in infants. Secondary, exploratory analyses were also performed in other birth defect groups.
      We conducted subanalyses limiting either the exposure or birth defect groups. First, using the same case groups and exposure definition as the main analysis, we restricted the exposure time period to only the first 2 months after conception. Next, using the original case groups and the original exposure time period (1 month before to 3 months after conception), we estimated the effects of exposure to particular opioid analgesics. Because of the decreased sample size, we estimated crude ORs only for the most commonly reported components. Finally, using the same exposure definition as the main analysis, we examined cases with “isolated” birth defects or “simple, isolated” heart defects separately.

      Results

      Of the 17,449 mothers of case infants with various included birth defects, 454 (2.6%) reported opioid analgesic treatment between 1 month before and 3 months after conception. Among 6701 control mothers, 134 (2.0%) reported treatment in this time period. The most commonly reported opioids were codeine (34.5%), hydrocodone (34.5%), oxycodone (14.4%), and meperidine (12.9%), with codeine and hydrocodone exposure being slightly more common among cases, and oxycodone and meperidine exposure slightly more common among controls. Lower maternal education level, prepregnancy obesity, and periconceptional smoking were all slightly more frequent among cases than controls (Table 1).
      TABLE 1Characteristics of study population, National Birth Defects Prevention Study, 1997 through 2005
      VariableCases n (%)Controls n (%)OR (95% CI)
      Study site17,4496701
       Arkansas2328 (13.3)832 (12.4)(referent)
       California2262 (13.0)845 (12.6)1.0 (0.9–1.1)
       Georgia2082 (11.9)728 (10.9)1.0 (0.9–1.1)
       Iowa1731 (9.9)756 (11.3)0.8 (0.7–0.9)
       Massachusetts2386 (13.7)851 (12.7)1.0 (0.9–1.1)
       New Jersey1513 (8.7)573 (8.6)0.9 (0.8–1.1)
       New York1258 (7.2)592 (8.8)0.8 (0.7–0.9)
       North Carolina667 (3.8)395 (5.9)0.6 (0.5–0.7)
       Texas2176 (12.5)762 (11.4)1.0 (0.9–1.1)
       Utah1046 (6.0)367 (5.5)1.0 (0.9–1.2)
      Maternal age at delivery, y17,4496701
       <201898 (10.9)711 (10.6)1.1 (1.0–1.2)
       20-244111 (23.9)1531 (22.9)1.1 (1.0–1.2)
       25-294478 (25.7)1777 (26.5)(referent)
       30-344313 (24.7)1743 (26.0)1.0 (0.9–1.1)
       35-392139 (12.3)803 (12.0)1.1 (1.0–1.2)
       ≥40509 (2.9)136 (2.0)1.5 (1.2–1.8)
      Maternal race/ethnicity17,3976672
       Non-Hispanic white10,472 (60.2)3993 (59.9)(referent)
       Non-Hispanic black1706 (9.8)761 (11.4)0.9 (0.8–0.9)
       Hispanic4033 (23.2)1486 (22.3)1.0 (1.0–1.1)
       Other1186 (6.8)432 (6.5)1.0 (0.9–1.2)
      Maternal education, y17,3266649
       <123092 (17.9)1121 (16.9)1.1 (1.0–1.2)
       ≥1214,234 (82.2)5528 (83.1)(referent)
      Maternal prepregnancy obesity16,7226432
       Body mass index <3013,658 (81.7)5399 (83.9)(referent)
       Body mass index ≥303064 (18.3)1033 (16.1)1.2 (1.1–1.3)
      Folic acid supplement use
      Reported use from 1 month before to 1 month after pregnancy conception.
      17,4466701
       No use/use at another time8608 (49.3)3293 (49.1)(referent)
       Any use8838 (50.7)3408 (50.9)1.0 (0.9–1.0)
      Smoking
      Reported use from 1 month before to 1 month after pregnancy conception.
      17,3586666
       None13,728 (79.1)5407 (81.1)(referent)
       Any3630 (20.9)1259 (18.9)1.1 (1.1–1.2)
      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.
      Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
      a Reported use from 1 month before to 1 month after pregnancy conception.
      The reasons for opioid use were based on the questionnaire topic under which the medication was reported. For the 66% of exposed women whose treatment could be linked to a specific reason, opioids were most commonly reported within the surgical procedures (41%), infections (34%), chronic diseases (20%), and injuries (18%) sections of the questionnaire.
      The primary analysis included a total of 7724 infants with ≥1 of 15 different kinds of CHD. Some of these defects were grouped into 1 of 4 larger phenotypic categories (conotruncal defects, left ventricular outflow tract obstruction defects, right ventricular outflow tract obstruction defects, or septal defects) or into 1 of 2 CHD associations (ventricular septal defect + atrial septal defect, ventricular septal defect + pulmonary valve stenosis), and ORs were estimated for each case group and higher level classification in comparison to the same set of 6701 control infants.
      Effect estimates were statistically significantly elevated for all eligible CHD combined (OR, 1.4; 95% confidence interval [CI], 1.1–1.7). 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).
      TABLE 2Associations between maternal opioid analgesic treatment and specific major birth defects
      Birth defectTotal no.
      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.
      No. exposedaOR (95% CI)
      Hypothesis-testing analysis
       Controls6701134Referent
       Anencephaly/craniorachischisis34091.7 (0.84–3.4)
       Spina bifida718262.0 (1.3–3.2)
       Any of included heart defects77242111.4 (1.1–1.7)
        Laterality defects with CHD19841.2 (0.42–3.2)
        Atrioventricular septal defect17592.4 (1.2–4.8)
        Anomalous pulmonary venous return20640.71 (0.22–2.3)
        Single ventricle/complex20141.1 (0.42–3.2)
        Conotruncal defects1481411.5 (1.0–2.1)
        Tetralogy of Fallot672211.7 (1.1–2.8)
        D-transposition of great arteries461101.1 (0.56–2.1)
        Ventricular septal defect conoventricular11062.7 (1.1–6.3)
        Left ventricular outflow tract obstruction defects1195361.5 (1.0–2.2)
        Hypoplastic left heart syndrome357172.4 (1.4–4.1)
        Coarctation of aorta630110.88 (0.47–1.6)
        Aortic stenosis25371.3 (0.61–2.9)
        Right ventricular outflow tract obstruction defects1175401.6 (1.1–2.3)
        Pulmonary valve stenosis867341.7 (1.2–2.6)
        Septal defects3482871.2 (0.93–1.6)
        Ventricular septal defect perimembranous1402290.99 (0.65–1.5)
        Atrial septal defect secundum1507431.3 (0.94–1.9)
        Atrial septal defect not otherwise specified511172.0 (1.2–3.6)
        CHD association: ventricular septal defect + atrial septal defect528171.7 (1.0–2.9)
        CHD association: pulmonary valve stenosis + ventricular septal defect13141.3 (0.46–3.7)
       Cleft palate936251.3 (0.84–2.0)
       Cleft lip with cleft palate1162331.4 (0.96–2.1)
       Cleft lip without cleft palate61490.68 (0.34–1.3)
      Exploratory analysis
       Controls6701134Referent
       Amniotic band syndrome/limb body wall complex20351.0 (0.37–2.9)
       Hydrocephaly301112.0 (1.0–3.7)
       Cataracts21771.6 (0.72–3.5)
       Glaucoma/anterior chamber defects10352.6 (1.0–6.6)
       Anotia/microtia40340.77 (0.28–2.1)
       Esophageal atresia434121.4 (0.76–2.5)
       Intestinal atresia/stenosis26640.88 (0.32–2.4)
       Anorectal atresia/stenosis623181.5 (0.87–2.4)
       Hypospadias second/third degree1313290.92 (0.59–1.4)
       Bilateral renal agenesis or hypoplasia11241.3 (0.40–4.2)
       Longitudinal limb deficiency26961.1 (0.49–2.6)
        Longitudinal preaxial limb deficiency15741.3 (0.48–3.6)
       Transverse limb deficiency41571.0 (0.46–2.2)
       Craniosynostosis806160.82 (0.48–1.4)
       Diaphragmatic hernia507121.2 (0.66–2.2)
       Omphalocele26771.3 (0.60–2.8)
       Gastroschisis726261.8 (1.1–2.9)
      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.
      Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
      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.
      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, 1.3–3.2), as hypothesized, but not with the other neural tube defects (anencephaly or craniorachischisis) studied (Table 2).
      The exploratory analyses of maternal opioid use for infants with ≥1 of 18 other categories of birth defects found statistically significant associations for hydrocephaly (OR, 2.0; 95% CI, 1.0–3.7), glaucoma or anterior chamber eye defects (OR, 2.6; 95% CI, 1.0–6.6), and gastroschisis (OR, 1.8; 95% CI, 1.1–2.9).
      Limiting the exposure definition to the first 2 months after conception produced results very similar to the main estimates using exposure during the period from 1 month before to 3 months after conception (results not shown). Point estimates using the tighter exposure period definition were generally greater in magnitude; we saw the highest OR for hypoplastic left heart syndrome (OR, 3.7; 95% CI, 2.1–6.6).
      Codeine and/or hydrocodone accounted for the majority of statistically significant findings from the main analysis, and oxycodone was only significantly associated with pulmonary valve stenosis (Table 3). However, given that the CIs for the effect estimates for each specific birth defect overlap, we cannot conclude whether one medication would be preferable to another in terms of risk for birth defects.
      TABLE 3Associations between common opioid components and specific major birth defects
      CodeineHydrocodoneOxycodoneMeperidine
      Birth defectNo. exposed cases
      Includes those with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
      crOR (95% CI)No. exposed cases
      Includes those with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
      crOR (95% CI)No. exposed cases
      Includes those with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
      crOR (95% CI)No. exposed cases
      Includes those with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
      crOR (95% CI)
      Hypothesis-testing analysis
       Anencephaly/craniorachischisis341.9 (0.67–5.3)
       Spina bifida71.5 (0.68–3.4)112.5 (1.3–4.8)
       Any of included heart defects711.4 (0.98–2.1)701.4 (0.99–2.1)281.0 (0.59–1.7)301.2 (0.68–2.1)
        Atrioventricular septal defect43.6 (1.3–10.2)43.7 (1.3–10.4)
        Conotruncal defects141.5 (0.81–2.7)161.7 (0.97–3.1)40.75 (0.26–2.2)51.0 (0.39–2.7)
        Tetralogy of Fallot61.4 (0.59–3.3)102.4 (1.2–4.8)41.7 (0.58–4.8)
        Left ventricular outflow tract obstruction defects152.0 (1.1–3.5)141.9 (1.0–3.4)
        Hypoplastic left heart syndrome73.1 (1.4–6.9)73.2 (1.4–7.1)
        Coarctation of aorta40.99 (0.35–2.8)41.0 (0.36–2.8)
        Aortic stenosis42.5 (0.89–7.0)2
        Right ventricular outflow tract obstruction defects101.3 (0.66–2.6)131.8 (0.95–3.3)92.1 (0.99–4.6)51.3 (0.49–3.4)
        Pulmonary valve stenosis81.3 (0.62–2.9)122.2 (1.2–4.3)82.4 (1.1–5.4)41.4 (0.47–4.0)
        Septal defects241.1 (0.65–1.8)261.2 (0.73–1.9)110.88 (0.43–1.8)191.7 (0.90–3.1)
        Ventricular septal defect perimembranous131.4 (0.78–2.7)80.91 (0.43–1.9)40.79 (0.28–2.3)
        Atrial septal defect secundum80.83 (0.39–1.8)161.7 (0.95–3.0)71.3 (0.56–3.0)102.0 (0.96–4.3)
        Atrial septal defect not otherwise specified41.2 (0.44–3.4)51.6 (0.62–4.0)
        CHD association: ventricular septal defect + atrial septal defect282.4 (1.1–5.2)
       Cleft palate60.98 (0.41–2.3)122.1 (1.1–3.9)
       Cleft lip with cleft palate111.4 (0.75–2.8)111.5 (0.78–3.0)71.7 (0.71–3.8)
      Exploratory analysis
       Hydrocephaly52.6 (1.0–6.7)42.1 (0.76–6.0)
       Cataracts342.4 (0.86–6.9)
       Esophageal atresia51.8 (0.71–4.6)3
       Anorectal atresia/stenosis51.3 (0.50–3.2)71.8 (0.81–4.0)
       Hypospadias second/third degree110.89 (0.45–1.8)40.47 (0.16–1.4)61.4 (0.52–3.8)91.8 (0.76–4.2)
       Craniosynostosis61.2 (0.49–2.7)50.99 (0.39–2.5)
       Diaphragmatic hernia61.9 (0.79–4.4)51.6 (0.62–4.0)
       Gastroschisis91.9 (0.94–4.0)153.3 (1.8–6.1)51.9 (0.73–5.1)
      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.
      Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
      a Includes those with nonmissing exposure data and excludes prepregnancy diabetics (type 1 or 2) and mothers reporting exposure to opioid street drugs.
      Most birth defects found to be statistically significantly associated with early pregnancy opioid treatment in the main analysis were also associated in the subanalysis limited to “isolated” cases for noncardiac defects or “simple, isolated” cases for heart defects (Table 4). ORs from the subanalysis were generally similar to those from the main analysis. When reviewing the nonisolated cases, we did not observe any pattern or common combinations of birth defects.
      TABLE 4Associations between maternal opioid analgesic treatment and “isolated” and nonisolated
      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);
      major birth defects
      Isolated/simple isolated casesNonisolated/nonsimple isolated cases
      Birth defectNo. exposed cases
      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;
      aOR
      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.
      (95% CI)
      No. exposed cases
      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;
      aOR
      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.
      (95% CI)
      Hypothesis-testing analysis
       Anencephaly/craniorachischisis81.6 (0.78–3.4)1
       Spina bifida211.8 (1.1–3.0)53.7 (1.4–9.6)
       Any of included heart defects1371.3 (1.0–1.7)741.4 (1.1–1.9)
        Atrioventricular septal defect363.9 (1.6–9.2)
        Conotruncal defects241.2 (0.77–1.9)172.1 (1.2–3.5)
        Tetralogy of Fallot161.6 (0.95–2.8)52.2 (0.87–5.5)
        D-transposition of great arteries70.97 (0.45–2.1)3
        Ventricular septal defect conoventricular065.1 (2.1–12.4)
        Left ventricular outflow tract obstruction defects271.6 (1.1–2.5)91.3 (0.63–2.5)
        Hypoplastic left heart syndrome162.5 (1.5–4.3)1
        Coarctation of aorta50.80 (0.32–2.0)60.97 (0.42–2.2)
        Aortic stenosis51.3 (0.52–3.2)2
        Right ventricular outflow tract obstruction defects331.9 (1.3–2.9)70.89 (0.41–1.9)
        Pulmonary valve stenosis272.0 (1.3–3.1)71.1 (0.52–2.5)
        Septal defects481.1 (0.78–1.6)391.4 (0.96–2.0)
        Ventricular septal defect perimembranous191.0 (0.62–1.7)100.91 (0.46–1.8)
        Atrial septal defect secundum191.1 (0.70–1.9)241.5 (0.97–2.4)
        Atrial septal defect not otherwise specified81.8 (0.81–4.1)92.4 (1.2–4.8)
       Cleft palate191.2 (0.74–2.0)61.7 (0.72–3.9)
       Cleft lip with cleft palate261.3 (0.84–2.0)72.8 (1.3–6.2)
       Cleft lip without cleft palate90.72 (0.36–1.4)0
      Exploratory analysis
       Hydrocephaly82.0 (0.96–4.2)3
       Cataracts72.0 (0.89–4.3)0
       Glaucoma/anterior chamber defects53.2 (1.2–8.2)0
       Esophageal atresia1112.2 (1.2–4.2)
       Intestinal atresia/stenosis41.0 (0.38–2.9)0
       Anorectal atresia/stenosis101.9 (0.96–3.6)81.1 (0.52–2.4)
       Hypospadias second/third degree260.91 (0.57–1.5)3
       Longitudinal limb deficiency242.0 (0.71–5.5)
        Longitudinal preaxial limb deficiency042.4 (0.84–6.6)
       Transverse limb deficiency50.84 (0.34–2.1)2
       Craniosynostosis160.92 (0.53–1.6)0
       Diaphragmatic hernia111.4 (0.73–2.6)1
       Omphalocele341.8 (0.64–5.0)
       Gastroschisis251.9 (1.2–3.1)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.
      Broussard. Opioid analgesics and risk for birth defects. Am J Obstet Gynecol 2011.
      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”).
      • Rasmussen S.A.
      • Olney R.S.
      • Holmes L.B.
      • Lin A.E.
      • Keppler-Noreuil K.M.
      • Moore C.A.
      Guidelines for case classification for the National Birth Defects Prevention Study.
      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.

      Comment

      Using data from a large population-based case-control study, we found associations between maternal therapeutic use of opioid medications in early pregnancy and several types of CHD, consistent with some previous findings for first-trimester use of the opioid codeine.
      • Rothman K.J.
      • Fyler D.C.
      • Goldblatt A.
      • Kreidberg M.B.
      Exogenous hormones and other drug exposures of children with congenital heart disease.
      • Zierler S.
      • Rothman K.J.
      Congenital heart disease in relation to maternal use of Bendectin and other drugs in early pregnancy.
      • Bracken M.B.
      Drug use in pregnancy and congenital heart disease in offspring.
      Previous reports considered associations with CHD as a single group; we also found a statistically significant association with an aggregate group that includes infants with any 1 of the 15 NBDPS-eligible diagnostic categories of heart defects (OR, 1.4; 95% CI, 1.1–1.7), but this risk is not directly comparable to those reported in previous studies because of differences in the CHD inclusion criteria. The ORs of greatest magnitude were observed for conoventricular septal defects, atrioventricular septal defects, atrial septal defects (not otherwise specified), and hypoplastic left heart syndrome, a defect that accounts for much of the infant mortality burden attributable to CHD.
      • Boneva R.S.
      • Botto L.D.
      • Moore C.A.
      • Yang Q.
      • Correa A.
      • Erickson J.D.
      Mortality associated with congenital heart defects in the United States: trends and racial disparities, 1979-1997.
      Even though our data set is the largest used to date to study opioid exposure and CHD and includes the most recently available data from this ongoing study, sample sizes for some individual CHD categories are at the borderline for what is required to observe these effects. Upon subanalysis, codeine and hydrocodone accounted for the majority of statistically 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 bifida, which concurs with experimental studies performed in hamsters.
      • Geber W.F.
      • Schramm L.C.
      Congenital malformations of the central nervous system produced by narcotic analgesics in the hamster.
      • Williams J.
      • Price C.J.
      • Sleet R.B.
      • et al.
      Codeine: developmental toxicity in hamsters and mice.
      Maternal opioid treatment has not been associated with an increased risk of neural tube defects in previous epidemiologic studies of human pregnancy,
      • Heinonen O.P.
      • Slone D.
      • Shapiro S.
      Birth defects and drugs in pregnancy.
      • Rosa P.
      Personal communication, 1993.
      • Shaw G.M.
      • Todoroff K.
      • Velie E.M.
      • Lammer E.J.
      Maternal illness, including fever and medication use as risk factors for neural tube defects.
      and additional evaluation of this observation is necessary. Similarly, the significant associations we observed in exploratory analyses with maternal opioid treatment among infants with hydrocephaly, glaucoma, or gastroschisis have not been previously reported. Given the probability that some findings may be due to chance, our results should be treated with caution and deserve further investigation.
      The prevalence of opioid treatment in early pregnancy among control and case mothers was observed to be 2-2.6%. According 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.
      National Center for Health Statistics
      Health, United States, 2006.
      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.
      • Zagon I.S.
      • Verderame M.F.
      • McLaughlin P.J.
      The biology of the opioid growth factor receptor (OGFr).
      In addition, endogenous opioids can inhibit DNA synthesis and decrease cellular proliferation, and blockade of opioid growth factor receptors with opioid antagonists increases DNA synthesis in multiple fetal tissues, including neural and cardiac tissues, consistent with our study results.
      • Zagon I.S.
      • Wu Y.
      • McLaughlin P.J.
      Opioid growth factor and organ development in rat and human embryos.
      Exogenous opioids might also act on opioid growth factor receptors during embryogenesis, resulting in delayed cell growth and migration at critical times in development and consequent increased risk for certain birth defects.
      Our study has several strengths. We used data from the largest collaborative population-based study of birth defects in the United States. Whereas many previous studies of birth defects have not adequately characterized birth defects phenotypes, our cases were reviewed by clinical geneticists with expertise in birth defects, and heart defects were also reviewed by clinicians with expertise in pediatric cardiology. Furthermore, grouping of CHD based on presumed developmental mechanisms may aid in understanding the potential effects of exposures.
      • Botto L.D.
      • Lin A.E.
      • Riehle-Colarusso T.
      • Malik S.
      • Correa A.
      Seeking causes: classifying and evaluating congenital heart defects in etiologic studies.
      The study used multiple questions to ascertain medication use, and we were able to classify reported products into their component ingredients.
      Our findings are also subject to several limitations. Nonresponse is one of those limitations; however, the rates of nonresponse of 30% among case mothers and 33% among control mothers were similar. Exposure information was obtained through retrospective maternal self-report, which might result in recall bias and/or exposure misclassification, particularly given the variable time to interview. While the average time lag between delivery and interview was 9-11 months, some women who were interviewed 2 years after the EDD were asked to recall exposures up to 3 years in the past. Postpregnancy reporting of prescription medications has been shown to be relatively complete when very specific recall prompts are used, including questions on both medical conditions necessitating treatment and the treatment itself.
      • Mitchell A.A.
      • Cottler L.B.
      • Shapiro S.
      Effect of questionnaire design on recall of drug exposure in pregnancy.
      This study included medication recall questions based on medical conditions, illnesses, or events but did not specifically ask about opioid medications by name, which could have negatively impacted recall. Whereas case mothers are generally more likely to have reflected on pregnancy exposures than control mothers in case-control studies, control infants in this study were not required to be “healthy,” but instead were live births without major birth defects. In addition, 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.
      • Drews C.
      • Greenland S.
      • Flanders W.D.
      The use of restricted controls to prevent recall bias in case-control studies of reproductive outcomes.
      • Khoury M.J.
      • James L.M.
      • Erickson J.D.
      On the use of affected controls to address recall bias in case-control studies of birth defects.
      Misclassification of prepregnancy body mass index was also possible, with likely underestimation of the proportion of obese mothers among both case and control infants.
      • Brunner Huber L.R.
      Validity of self-reported height and weight in women of reproductive age.
      • Rowland M.L.
      Self-reported weight and height.
      • Gilboa S.M.
      • Correa A.
      • Botto L.D.
      • et al.
      Association between prepregnancy body mass index and congenital heart defects.
      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.
      Centers for Disease Control and Prevention
      Trends in infant mortality attributable to birth defects–United States, 1980-1995.
      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.
      • Canfield M.A.
      • Honein M.A.
      • Yuskiv N.
      • et al.
      National estimates and race/ethnic-specific variation of selected birth defects in the United States, 1999-2001.
      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 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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      Linked Article

      • Maternal treatment with opioid analgesics and risk for birth defects: additional considerations
        American Journal of Obstetrics & GynecologyVol. 205Issue 3
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          Broussard et al1 utilize a case-control study to conclude there is a relationship between early pregnancy opioid analgesic use and certain birth defects. However, 3 concerns severely limit its future research and clinical usefulness. First, drug use data are collected retrospectively “between 6 weeks and 2 years” postdelivery. This method risks selective recall or confirmation bias, and this extended recall window (with unknown duration between cases and controls) compromises the study's internal validity.
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      • Opioid exposure and birth defects
        American Journal of Obstetrics & GynecologyVol. 205Issue 3
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          It was with great interest that I read the report of Broussard and colleagues1 from the National Birth Defects Prevention Study, “Maternal treatment with opioid analgesics and risk for birth defects.” This well-done large study truly has the power to answer many questions about drug exposure and risks to the developing fetus. Obstetric providers are ever in need of up-to-date, accurate data to populate counseling discussions on medication use in pregnancy. The authors do a very nice job of reporting the results and the limitations of these types of studies.
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      • Maternal treatment with opioid analgesics and risk for birth defects
        American Journal of Obstetrics & GynecologyVol. 205Issue 3
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          We found the study by Broussard et al1 entitled “Maternal treatment with opioid analgesics and risk for birth defects” very interesting; however, we believe there is a serious flaw in the authors' interpretation of recall bias. Although the authors acknowledge potential recall bias among women who delivered a baby with malformations when compared with control women with healthy children, they state that “even in studies of reproductive outcomes, exposure misclassification is likely to be non-differential and results in estimates biased towards the null.”2,3
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      • Reply
        American Journal of Obstetrics & GynecologyVol. 205Issue 3
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          We appreciate the continued interest in our study and the opportunity to respond to letters from Haas and from ‘t Jong and Koren. We acknowledge that the increased relative risk for certain birth defects that we observed in our study to be associated with early pregnancy opioid analgesic treatment translates to only a modest increase in absolute risk for any of the specific birth defects. This and other previously noted study limitations are always important to keep in mind when interpreting our work; however, taken with previous literature, our findings raise legitimate concerns regarding opioid treatment during early pregnancy and indicate the need for further investigation into the observed associations.
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