OBSTETRICS

OBSTETRICS

Maternal treatment with opioid analgesics

and risk for birth defects

Cheryl S. Broussard, PhD; Sonja A. Rasmussen, MD, MS; Jennita Reefhuis, PhD; Jan M. Friedman, MD, PhD; Michael W. Jann, PharmD; Tiffany Riehle-Colarusso, MD, MSE; Margaret A. Honein, PhD, MPH; for the National Birth Defects Prevention Study

OBJECTIVE: We examined whether maternal opioid treatment between 1 month before pregnancy and the first trimester was associated with

birth defects.

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

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, 1.23.6), hypoplastic left heart syndrome (OR, 2.4; 95% CI, 1.44.1), 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.

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

Cite this article as: Broussard CS, Rasmussen SA, Reefhuis J, et al. Maternal treatment with opioid analgesics and risk for birth defects. Am J Obstet Gynecol

2011;204:314.e1-11.

Major birth defects affect about3%of the 4 million US live births each year1-3 and are a leading cause of infant mortality.1,4 Congenitalheart defects(CHD) are among the most common birth defects, affecting nearly 1% of US births,5,6 and are the main contributor to infant mortality attributable to birth defects.7,8Opioid medications are potent prescription analgesics that are the mainstay for treatment of severe pain.9 Opioids are often used in combination with nonopioid analgesics, such as acetaminophen, and lower doses are also a component of some cough suppressants.10 Previous studies have shown that opioid analgesic use and abuse have been increasing in recentyears,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.

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.27 Classification of NBDPS cases has previously been described.6,28 Briefly, the process for NBDPS-eligible defects involves confirmation of the diagnosis from medical record abstracts and determining whether each case is an isolated defect, 1 of multiple unrelated major defects, or a component of a syndrome or other complex pattern.28 For CHD, classification is also performed on a second axis to describe the complexity

of cardiac involvement, by clinicians with expertise in pediatric cardiology. Simple heart defects are anatomically discrete or well-recognized single entities; associations are common, uncomplicated

combinations of heart defects; and heart defects that do not fall into either category are considered complex. Cardiac classification and subsequent grouping into larger categories are based on clinical and presumed developmental mechanisms that may have relevance in considering the teratogenic effect of exposures.6 An annual random sample of approximately 1200 liveborn infants without birth defects (control infants) is selected from the same geographic regions and time period as the cases, either from

birth certificates or birth hospitals. Mothers are invited to participate in an hour-long computer-assisted telephone interview, conducted by interviewers in English or Spanish, between 6 weeks and 2 years after the mothers estimated date of delivery (EDD) (average is 11 months post-EDD for cases and 9 months for controls). The interview assesses various maternal health factors, pregnancy history information, dietary

and other drug exposures, and sociodemographic characteristics. Exposures are assessed for the period from 3 months before conception through the end of the pregnancy. Pregnancy was defined as the time period from conception (ie, 2 weeks after the last menstrual period) to delivery, and pregnancy months for this analysis were consecutive 30-day periods. Mothers are asked about medications used for each specific illness (eg, influenza) or indication (eg, surgery) mentioned within the maternal health section of the questionnaire, and are also encouraged to report any other medications not already mentioned. Respondents are asked to report the start and stop dates, duration, and frequency of medication use using calendar dates or pregnancy months. All medications reported in each section of the interview are compiled and coded using the Slone Drug Dictionary, 29 which NBDPS licenses from Boston Universitys Slone Epidemiology Center. This dictionary links products to their active ingredients. We defined opioid exposure as maternal report of use of _1 products with any of the following components taken for therapeutic reasons in any dose, duration, or frequency: codeine, hydrocodone, meperidine, oxycodone,

propoxyphene, morphine, tramadol, methadone, hydromorphone, fentanyl, or pentazocine. We included

individual and combination products. The exposure window of interest was the period from 1 month before to 3 months after conception. We conducted multivariable logistic regression analyses to calculate adjusted odds ratios (ORs). We examined birth defect categories that had _200 cases or _4 exposed cases to limit analyses to defect categories that would likely have adequate statistical power and to enable us to identify potentially elevated risks among rarer defect groups. All models were adjusted for maternal age (continuous), race/ethnicity (non-Hispanic white, non-Hispanic black, Hispanic, other), education (_12 years, _12 years), prepregnancy obesity (body mass index _30, body mass index _30, using prepregnancy weight and height self-reported by the mother during the telephone interview), periconceptional smoking status (no smoking from 1 month before to 1 month after conception, smoking at least once in the same

period), and study center (10 sites previously listed). These variables were chosen based on the strength of their relation in univariate analyses with all NBDPS birth defects. There were maternal interviews from

19,059 cases and 6807 controls who met the inclusion dates. The participation rate was 70% for cases and 67% for controls. We excluded participants with missing data on whether they were treated with an opioid analgesic in early pregnancy, due either to an incomplete medication history from the interview or an unknown medication start or stop date. We excluded mothers with preexisting diabetes, which has been found to be a strong independent risk factor for birth defects.30,31 To focus our investigation on therapeutic opioid analgesic use, we also excluded mothers who reported opioid exposure in the form of illicit drugs such as heroin any time during pregnancy. Our final sample for analysis included 17,449 cases with the included defects and 6701 controls (Figure). Although the total number of cases included was greater than the total number of controls, controls substantially outnumbered cases in most analyses, each of which involved comparisons of infants with 1 particular category or subcategory of birth defects to all controls. Of note, infants with _1 defect were included in multiple birth defect categories. Our primary analysis tested the hypothesis that maternal therapeutic use of 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. Weconducted 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). The reasons for opioid use were based on the questionnaire topic under which the medication was reported. For the

66%of exposedwomenwhose 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 2CHDassociations (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], 1.11.7). 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 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, 1.06.6), and gastroschisis (OR, 1.8; 95% CI, 1.12.9). Limiting the exposure definition to the first 2 months after conception produced results very similar to the main estimates using exposure during the period from 1 month before to 3 months after conception (results not shown). Point estimates using the tighter exposure period definition were generally greater in magnitude; we saw the highest OR for hypoplastic left heart syndrome (OR, 3.7; 95% CI, 2.1 6.6). Codeine and/or hydrocodone accounted for the majority of statistically significant findings from the main analysis, and oxycodone was only significantly associated with pulmonary valve stenosis (Table 3). However, given that the CIs for the effect estimates for each specific birth defect overlap, we cannot conclude whether one medication would be preferable to another in terms of risk for birth defects. Most birth defects found to be statistically significantly associated with early pregnancy opioid treatment in the main analysis were also associated in the 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.

COMMENT

Using data from a large populationbased case-control study, we found associations between maternal therapeutic use of opioid medications in early pregnancy and several types of CHD, consistent with some previous findings for first-trimester use of the opioid codeine. 14-16 Previous reports considered associations with CHD as a single group; we also found a statistically significant association with an aggregate group that includes infants with any 1 of the 15 NBDPS-eligible diagnostic categories of heart defects (OR, 1.4; 95% CI, 1.11.7), but this risk is not directly comparable to those reported in previous studies because of differences in the CHD inclusion criteria. The ORs of greatest magnitude were observed for conoventricular septal defects, atrioventricular septal defects, atrial septal defects (not otherwise specified), and hypoplastic left heart syndrome, a defect that accounts for much of the infant mortality burden attributable to CHD.32 Even though our data set is the largest used to date to study opioid exposure andCHDand 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.24,25 Maternal opioid treatment has not been associated with an increased risk of neural tube defects in previous epidemiologic studies of human pregnancy,21-23 and additional evaluation of this observation is necessary. Similarly, the significant associations we observed in exploratory analyses with maternal opioid treatment among infants with hydrocephaly, glaucoma, or gastroschisis have not been previously reported. Given the probability that some findings may be due to chance, our results should be treated with caution and deserve further investigation. The prevalence of opioid treatment in early pregnancy among control and case mothers was observed to be 2-2.6%. 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 1994.11 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 decrease cellular proliferation, and blockade of opioid growth factor receptors with opioid antagonists increases DNA synthesis in multiple fetal tissues, including neural and cardiac tissues, consistent with our study results.34 Exogenous opioids might also act on opioid

growth factor receptors during embryogenesis, resulting in delayed cell growth and migration at critical times in development and consequent increased risk for certain birth defects. Our study has several strengths. We used data from the largest collaborative population-based study of birth defects in the United States. Whereas many previous studies of birth defects have not adequately characterized birth defects

phenotypes, our cases were reviewed by clinical geneticists with expertise in birth defects, and heart defects were also reviewed by clinicians with expertise in pediatric cardiology. Furthermore, grouping of CHD based on presumed developmental mechanisms may aid in understanding the potential effects of exposures.

6 The study used multiple questions to ascertain medication use, and we were able to classify reported products into their component ingredients. Our findings are also subject to several limitations. Nonresponse is one of those limitations; however, the rates of nonresponse of 30% among case mothers and 33% among control mothers were similar. Exposure information was obtained through retrospective maternal self-report, which might result in recall bias and/or exposure misclassification, particularly given the variable time to interview. While the average time lag between delivery and interview was 9-11 months, some women who were interviewed 2 years after the EDD were asked to recall exposures up to 3 years in the past. Postpregnancy reporting of prescription medications has been shown to be relatively complete when very specific recall prompts are used, including questions on both medical conditions necessitating treatment and the treatment itself.35 This study included medication recall questions based on medical conditions, illnesses, or events but did not specifically ask about opioid medications by name, which could have negatively impacted recall. Whereas case mothers are generally more likely to have reflected on pregnancy exposures than control mothers in case-control studies, control infants in this study were not required to be healthy, but instead were live births without major birth defects. In addition, 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 ofCHD,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 at risk of an unintended pregnancy. TABEL 1 Karakteristik populasi penelitian, Lahir Cacat Nasional Pencegahan studi, 1997 sampai 2005 Variabel Kasus n (%) Kontrol n (%) OR (95% CI) Studi situs 17.449 6.701 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Arkansas 2328 (13.3) 832 (12.4) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... California 2262 (13.0) 845 (12,6) 1,0 (0,9-1,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Georgia 2.082 (11,9) 728 (10,9) 1,0 (0,9-1,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Iowa 1731 (9,9) 756 (11,3) 0,8 (0,7-0,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Massachusetts 2386 (13,7) 851 (12,7) 1,0 (0,9-1,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... New Jersey 1513 (8,7) 573 (8,6) 0,9 (0,8-1,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... New York 1258 (7,2) 592 (8,8) 0,8 (0,7-0,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... North Carolina 667 (3,8) 395 (5,9) 0,6 (0,5-0,7) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Texas 2176 (12,5) 762 (11,4) 1,0 (0,9-1,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Utah 1046 (6.0) 367 (5,5) 1,0 (0,9-1,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Usia ibu melahirkan, y 17449 6701 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 20 1898? (10.9) 711 (10,6) 1,1 (1,0-1,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 20-24 4111 (23,9) 1531 (22,9) 1,1 (1.0-1.2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 25-29 4478 (25,7) 1.777 (26,5) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 30-34 4313 (24,7) 1743 (26,0) 1,0 (0.9-1.1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 35-39 2139 (12,3) 803 (12,0) 1,1 (1.0-1.2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 40 509? (2,9) 136 (2,0) 1,5 (1,2-1,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Ibu ras / etnis 17397 6672 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Non-Hispanic putih 10.472 (60,2) 3.993 (59,9) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Non-Hispanik hitam 1706 (9,8) 761 (11,4) 0,9 (0,8-0,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hispanik 4033 (23,2) 1.486 (22,3) 1,0 (1,0-1,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Lainnya 1.186 (6,8) 432 (6,5) 1,0 (0,9-1,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Ibu pendidikan, y 17326 6649 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 12 3092? (17.9) 1.121 (16,9) 1,1 (1,0-1,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 12 14234? (82,2) 5.528 (83,1) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Ibu hamil obesitas 16722 6432 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Indeks massa tubuh? 30 13658 (81,7) 5.399 (83,9) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Indeks massa tubuh? 30 3064 (18,3) 1.033 (16,1) 1,2 (1,1-1,3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Asam folat suplemen usea 17446 6701 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Tidak menggunakan / digunakan di lain waktu 8.608 (49,3) 3.293 (49,1) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Setiap penggunaan 8838 (50,7) 3.408 (50,9) 1,0 (0,9-1,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Smokinga 17358 6666 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Tidak ada 13.728 (79,1) 5.407 (81,1) (rujukan) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Setiap 3.630 (20,9) 1.259 (18,9) 1,1 (1,1-1,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Kelompok kasus mencakup semua bayi dengan 1 cacat? berhak lahir. Subyek dengan informasi yang kurang untuk variabel telah dikecualikan dari tallies untuk itu variabel saja. CI, confidence interval; OR, odds ratio. penggunaan Dilaporkan dari 1 bulan sebelum sampai 1 bulan setelah pembuahan kehamilan. Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011. www.AJOG.org Obstetri Penelitian April

TABEL 2 Asosiasi antara pengobatan analgesik opioid ibu dan spesifik cacat lahir utama Lahir cacat Jumlah no.a No terkena AOR (95% CI) Hipotesis-pengujian analisis .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Kontrol 6701 134 Referensi .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anencephaly / craniorachischisis 340 9 1.7 (0,84-3,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Spina bifida 718 26 2,0 (1,3-3,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Setiap cacat jantung termasuk 7724 211 1,4 (1,1-1,7) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Laterality cacat dengan CHD 198 4 1.2 (0,42-3,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrioventrikular cacat septum 175 9 2.4 (1,2-4,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Kembali anomali vena pulmonal 206 4 0,71 (0,22-2,3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Single ventrikel / kompleks 201 4 1.1 (0,42-3,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Conotruncal cacat 1481 41 1,5 (1.0-2.1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Tetralogi Fallot 672 21 1,7 (1,1-2,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ D-Transposisi arteri besar 461 10 1.1 (0,56-2,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Defek septum ventrikel conoventricular 110 6 2,7 (1,1-6,3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Waktu cacat saluran obstruksi outflow ventrikel 1195 36 1,5 (1.0-2.2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Sindrom hipoplasia jantung kiri 357 17 2,4 (1,4-4,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Coarctation dari aorta 630 11 0,88 (0,47-1,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Stenosis aorta 253 7 1.3 (0,61-2,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Hak cacat saluran obstruksi outflow ventrikel 1175 40 1,6 (1.1-2.3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Pulmonary stenosis katup 867 34 1,7 (1,2-2,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Cacat septum 3482 87 1.2 (0,93-1,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Defek septum ventrikel perimembranous 1402 29 0,99 (0.65-1.5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrial cacat septum secundum 1507 43 1,3 (0.94-1.9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ defek septum atrium tidak disebutkan secara spesifik 511 17 2,0 (1.2-3.6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ PJK asosiasi: defek septum ventrikel? cacat septum atrium 528 17 1,7 (1,0-2,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ PJK asosiasi: stenosis katup pulmonal? cacat septum ventrikel 131 4 1.3 (0,46-3,7) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah langit-langit 936 25 1,3 (0,84-2,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah bibir sumbing langit-langit dengan 1162 33 1,4 (0.96-2.1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah bibir sumbing tanpa langit-langit 614 9 0,68 (0,34-1,3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................TABEL 2 Asosiasi antara pengobatan analgesik opioid ibu dan spesifik cacat lahir utama (lanjutan) Lahir cacat Jumlah no.a No terkena AOR (95% CI) Analisa .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Kontrol 6701 134 Referensi .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Amniotic band syndrome / ekstremitas tubuh dinding kompleks 203 5 1.0 (0,37-2,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hidrosefali 301 11 2,0 (1,0-3,7) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Katarak 217 7 1.6 (0,72-3,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Glaukoma / cacat anterior chamber 103 5 2,6 (1,0-6,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anotia / microtia 403 4 0,77 (0,28-2,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Atresia esophagus 434 12 1.4 (0,76-2,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Usus atresia / stenosis 266 4 0,88 (0,32-2,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anorectal atresia / stenosis 623 18 1,5 (0,87-2,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hipospadia kedua derajat / ketiga 1.313 29 0,92 (0,59-1,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Bilateral ginjal agenesis atau hipoplasia 112 4 1.3 (0,40-4,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Longitudinal tungkai defisiensi 269 6 1.1 (0,49-2,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Longitudinal tungkai defisiensi preaxial 157 4 1.3 (0,48-3,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Transverse ekstremitas defisiensi 415 7 1.0 (0,46-2,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Craniosynostosis 806 16 0,82 (0,48-1,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hernia diafragma 507 12 1.2 (0,66-2,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Omphalocele 267 7 1.3 (0,60-2,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Gastroschisis 726 26 1,8 (1,1-2,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Odds rasio yang disesuaikan untuk ibu, usia ras / etnis, pendidikan, ada atau tidak adanya hamil, kehadiran obesitas atau tidak adanya periconceptional merokok, dan pusat studi. AOR, rasio odds yang disesuaikan; PJK, cacat jantung kongenital, CI, selang kepercayaan. sebuah Beberapa perbandingan yang digunakan kurang dari jumlah kontrol (misalnya, hipospadia hanya digunakan kontrol laki-laki); sejumlah kasus termasuk orang dengan data eksposur nonmissing dan tidak termasuk hamil penderita diabetes (tipe 1 atau 2) dan ibu pelaporan paparan opioid narkoba. Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011.

TABEL 3 Asosiasi antara komponen opioid umum dan spesifik cacat lahir utama Hydrocodone oxycodone codeine meperidin Lahir cacat No terkena casesa crOR (95% CI) No terkena casesa crOR (95% CI) No terkena casesa crOR (95% CI) No terkena casesa crOR (95% CI) Hipotesis-pengujian analisis .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anencephaly / craniorachischisis 3 4 1,9 (0.67-5.3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Spina bifida 7 1.5 (0,68-3,4) 11 2,5 (1,3-4,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Setiap cacat jantung termasuk 71 1.4 (0,98-2,1) 70 1.4 (0,99-2,1) 28 1.0 (0,59-1,7) 30 1,2 (0,68-2,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrioventrikular septal cacat 4 3,6 (1.3-10.2) 4 3,7 (1.3-10.4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Conotruncal cacat 14 1,5 (0,81-2,7) 16 1.7 (0,97-3,1) 4 0,75 (0,26-2,2) 5 1.0 (0,39-2,7) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Tetralogi Fallot 6 1.4 (0,59-3,3) 10 2,4 (1,2-4,8) 4 1.7 (0,58-4,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Waktu keluar ventrikel obstruksi saluran cacat 15 2,0 (1.1-3.5) 14 1,9 (1.0-3.4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Hipoplasia jantung kiri sindroma 7 3,1 (1.4-6.9) 7 3,2 (1.4-7.1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Coarctation dari aorta 4 0,99 (0,35-2,8) 4 1.0 (0,36-2,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Stenosis aorta 4 2.5 (0,89-7,0) 2 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Keluar ventrikel kanan obstruksi saluran cacat 10 1,3 (0.66-2.6) 13 1,8 (0.95-3.3) 9 2,1 (0.99-4.6) 5 1,3 (0.49-3.4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Pulmonary stenosis katup 8 1.3 (0,62-2,9) 12 2,2 (1,2-4,3) 8 2.4 (1,1-5,4) 4 1.4 (0,47-4,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Cacat septum 24 1.1 (0,65-1,8) 26 1,2 (0,73-1,9) 11 0,88 (0,43-1,8) 19 1.7 (0,90-3,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Ventricular septal defect perimembranous 13 1,4 (0.78-2.7) 8 0,91 (0.43-1.9) 4 0,79 (0.28-2.3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrial septal defect secundum 8 0,83 (0.39-1.8) 16 1,7 (0.95-3.0) 7 1,3 (0.56-3.0) 10 2,0 (0.96-4.3) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrial septal tidak cacat dinyatakan khusus 4 1,2 (0.44-3.4) 5 1,6 (0.62-4.0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ PJK asosiasi: ventrikel septal cacat ? atrial septal defect 2 8 2,4 (1.1-5.2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah langit-langit 6 0,98 (0,41-2,3) 12 2,1 (1,1-3,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah bibir sumbing langit-langit dengan 11 1.4 (0,75-2,8) 11 1,5 (0,78-3,0) 7 1.7 (0,71-3,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Analisa .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hidrosefali 5 2.6 (1,0-6,7) 4 2.1 (0,76-6,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Katarak 3 4 2.4 (0,86-6,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Esophageal atresia 5 1,8 (0,71-4,6) 3 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anorectal atresia / stenosis 5 1.3 (0,50-3,2) 7 1.8 (0,81-4,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hipospadia kedua / ketiga gelar 11 0,89 (0.45-1.8) 4 0,47 (0.16-1.4) 6 1,4 (0.52-3.8) 9 1,8 (0.76-4.2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Craniosynostosis 6 1.2 (0,49-2,7) 5 0,99 (0,39-2,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 6 hernia diafragma 1.9 (0,79-4,4) 5 1.6 (0,62-4,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Gastroschisis 9 1.9 (0,94-4,0) 15 3,3 (1,8-6,1) 5 1.9 (0,73-5,1) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ crORs disajikan untuk kategori cacat lahir dengan setidaknya 4 kasus terkena? 1 dari bahan-bahan dipertimbangkan dalam subanalysis ini. PJK, cacat jantung kongenital, CI, confidence interval; crOR, kasar odds ratio. sebuah Termasuk mereka dengan data eksposur nonmissing dan tidak termasuk hamil penderita diabetes (tipe 1 atau 2) dan ibu pelaporan paparan opioid narkoba. Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011. Penelitian Obstetri www.AJOG.orgTABEL 4 Asosiasi antara pengobatan analgesik opioid ibu dan "terisolasi" dan nonisolateda cacat lahir utama Terisolasi / terpencil kasus sederhana Nonisolated / nonsimple terisolasi kasus Lahir cacat No terkena casesb aORc (95% CI) No terkena casesb aORc (95% CI) Hipotesis-pengujian analisis .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anencephaly / craniorachischisis 8 1.6 (0,78-3,4) 1 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Spina bifida 21 1,8 (1,1-3,0) 5 3,7 (1,4-9,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Setiap cacat jantung termasuk 137 1,3 (1,0-1,7) 74 1,4 (1,1-1,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrioventrikular cacat septum 3 6 3.9 (1,6-9,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Conotruncal cacat 24 1.2 (0,77-1,9) 17 2,1 (1,2-3,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Tetralogi Fallot 16 1.6 (0,95-2,8) 5 2.2 (0,87-5,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ D-Transposisi arteri besar 7 0,97 (0,45-2,1) 3 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Defek septum ventrikel conoventricular 0 6 5.1 (2,1-12,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Waktu ventrikel keluar cacat obstruksi saluran 27 1.6 (1,1-2,5) 9 1.3 (0,63-2,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Sindrom hipoplasia jantung kiri 16 2,5 (1,5-4,3) 1 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Coarctation dari aorta 5 0,80 (0,32-2,0) 6 0,97 (0,42-2,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Stenosis aorta 5 1.3 (0,52-3,2) 2 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Keluar ventrikel kanan cacat obstruksi saluran 33 1,9 (1,3-2,9) 7 0,89 (0,41-1,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Pulmonary stenosis katup 27 2.0 (1,3-3,1) 7 1.1 (0,52-2,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ 48 cacat septum 1.1 (0,78-1,6) 39 1.4 (0,96-2,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ cacat septum ventrikel perimembranous 19 1.0 (0,62-1,7) 10 0,91 (0,46-1,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Atrial cacat septum secundum 19 1.1 (0,70-1,9) 24 1,5 (0,97-2,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ defek septum atrium tidak dinyatakan khusus 8 1.8 (0,81-4,1) 9 2,4 (1,2-4,8) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah langit-langit 19 1.2 (0,74-2,0) 6 1.7 (0,72-3,9) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah bibir sumbing langit-langit dengan 26 1.3 (0,84-2,0) 7 2,8 (1,3-6,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Celah bibir sumbing tanpa langit-langit 9 0,72 (0,36-1,4) 0 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011. (Lanjutan)TABEL 4 Asosiasi antara pengobatan analgesik opioid ibu dan "terisolasi" dan nonisolateda cacat lahir utama (Lanjutan) Terisolasi / terpencil kasus sederhana Nonisolated / nonsimple terisolasi kasus Lahir cacat No terkena casesb aORc (95% CI) No terkena casesb aORc (95% CI) Analisa .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hidrosefali 8 2.0 (0,96-4,2) 3 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Katarak 7 2.0 (0,89-4,3) 0 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Glaukoma / cacat bilik anterior 5 3.2 (1,2-8,2) 0 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Atresia esofagus 1 11 2.2 (1,2-4,2) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Usus atresia / stenosis 4 1.0 (0,38-2,9) 0 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Anorectal atresia / stenosis 10 1.9 (0,96-3,6) 8 1.1 (0,52-2,4) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Hipospadia kedua derajat / ketiga 26 0,91 (0,57-1,5) 3 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Longitudinal tungkai defisiensi 2 4 2.0 (0,71-5,5) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................................................ Longitudinal defisiensi preaxial ekstremitas 0 4 2.4 (0,84-6,6) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Transverse ekstremitas defisiensi 5 0,84 (0,34-2,1) 2 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Craniosynostosis 16 0,92 (0,53-1,6) 0 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... 11 hernia diafragma 1.4 (0,73-2,6) 1 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Omphalocele 3 4 1.8 (0,64-5,0) .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ....... Gastroschisis 25 1,9 (1,2-3,1) 1 .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. .................................................. ................ aORs disajikan untuk kategori cacat lahir dengan setidaknya 4 kasus terpapar dipertimbangkan dalam subanalysis ini. AOR, rasio odds yang disesuaikan; CI, selang kepercayaan. sebuah Cacat yang tidak pernah terjadi "terisolasi" (misalnya, urutan band ketuban) tidak dimasukkan dalam analisis ini. Kedua cacat jantung bawaan dan cacat noncardiac dapat terjadi sebagai cacat "terisolasi", sebagai salah satu beberapa cacat utama yang tidak berhubungan, atau sebagai komponen dari sindrom atau pola kompleks lainnya (baik dari terakhir menjadi "nonisolated") .28 Untuk cacat jantung bawaan, klasifikasi juga terjadi pada sumbu kedua berfokus pada jantung untuk menggambarkan kompleksitas keterlibatan jantung. "Sederhana" cacat jantung secara anatomi diskrit baik yang diakui atau entitas tunggal; "asosiasi" didefinisikan sebagai umum, tidak rumit kombinasi cacat jantung, dan cacat jantung yang tidak masuk dalam kategori baik dianggap "kompleks" (2 terakhir dianggap "nonsimple" untuk analisis ini); b Jumlah kasus termasuk orang dengan nonmissing data eksposur dan tidak termasuk hamil penderita diabetes (tipe 1 atau 2) dan ibu pelaporan paparan opioid narkoba; c Odds rasio yang disesuaikan untuk ibu, usia ras / etnis, pendidikan, ada atau tidak adanya hamil, kehadiran obesitas atau tidak adanya periconceptional merokok, dan pusat studi. Broussard. Opioid analgesik dan risiko cacat lahir. Am J Obstet Gynecol 2011.