Application of data screening to drug exposure in large risk factor studies of birth defects.

BACKGROUND: Birth defects are the leading cause of infant death. While causes of most are unknown, those that might be due to medication use are among the most preventable. This study describes an approach to identifying those medications that most warrant attention by using a "screen" program that calculates odds ratios for pairs of exposures and specific birth defects. METHODS: We discuss the development of this tool and illustrate its application to two large risk factor studies, the Slone Epidemiology Center's Birth Defects Study and the Centers for Disease Control and Prevention's National Birth Defects Prevention Study, ideal settings for the systematic study of risks and relative safety of drugs in relation to birth defects while recognizing the inherent limitations of such an approach. RESULTS: Suggestions for establishing criteria for exposures and outcomes that balance the need for specific details with the practical considerations of sample size and volume of output are presented. Selection of appropriate exposure reference categories and control groups is also discussed, as well as the need to address potential confounding. An example that motivated a detailed investigation of possible associations between a medication (butalbital) and selected specific birth defects is provided. CONCLUSION: While screening programs such as the one described can be a valuable tool for exploring potential associations in large data bases, they must be applied with caution. The issue of multiple testing and chance findings is a major concern. While statistics are a necessary component, human judgment must be an integral part of the process.

Use of selective serotonin-reuptake inhibitors during pregnancy and the risk of clubfoot.

BACKGROUND: Selective serotonin-reuptake inhibitors (SSRIs) are the most commonly prescribed antidepressants. Previous studies have suggested that SSRIs may increase the risk of birth defects, including clubfoot. Using data from a population-based case-control study, we evaluated whether SSRI use increased the risk of clubfoot. METHODS: Mothers were interviewed within 1 year after delivery about sociodemographic factors, pregnancy events, and exposures. They were specifically asked if they experienced depression or anxiety or if they took any of the following SSRIs: citalopram, escitalopram, fluvoxamine, paroxetine, sertraline, or fluoxetine. We used logistic regression models to calculate odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: We included a total of 622 clubfoot cases and 2002 nonmalformed controls born between 2006 and 2011 in Massachusetts, New York, and North Carolina. For the 2nd or 3rd lunar month of pregnancy (the relevant gestational period), SSRI use for a period of more than 30 days was higher in case mothers (5%) than control mothers (3%). After adjustment for maternal smoking and body mass index, the OR for any SSRI use and clubfoot was 1.8 (95% CI = 1.1-2.8). When individual SSRIs were examined, ORs were elevated for sertraline (1.6 [0.8-3.2]), paroxetine (9.2 [0.7-484.6]), and escitalopram (2.9 [1.1-7.2]). CONCLUSION: Our data suggest an increased risk of clubfoot occurrence in relation to SSRI use. Drug-specific risks varied widely, and some estimates were unstable.

Seasonal influenza vaccination during pregnancy and the risks of preterm delivery and small for gestational age birth.

BACKGROUND: Influenza vaccination is routinely recommended for pregnant women, yet information on perinatal outcomes is sparse. METHODS: We investigated the associations between trivalent (seasonal) influenza vaccination during pregnancy and the risks of preterm delivery (PTD, live birth <37 weeks gestation) and small for gestational age birth (SGA, <10th percentile in weight for sex-specific gestational age) during the influenza seasons 2006-07 through 2009-10. The study population included 1619 mothers of live-born, non-malformed singleton infants interviewed as part of the Slone Epidemiology Center's Birth Defects Study. Associations between influenza vaccination and PTD and SGA were assessed using Cox and logistic regression models, respectively, with propensity scores used to adjust for confounding. Women vaccinated against pandemic H1N1 were excluded from the analysis. RESULTS: Influenza vaccination during pregnancy showed a near null association with PTD for influenza seasons 2006-07 through 2008-09 compared with unvaccinated women [adjusted hazard ratios (aHR) ranged from 0.79 [95% confidence interval (CI) 0.28, 2.21] in 2007-08 to 1.08 [95% CI: 0.40, 2.95] in 2008-09]. For 2009-10, the risk of PTD was higher in vaccinated women (aHR, 7.81 [95% CI: 2.66, 23.0]). Influenza vaccination was not associated with appreciable risks for SGA for all seasons with sufficient numbers of exposed SGA. CONCLUSION: Though limited by study size, these findings add support to previous observations of little or no increased risk of PTD or SGA associated with seasonal influenza vaccination for three of the four influenza seasons in our study. The increased risk of PTD observed for the 2009-10 influenza season warrants further investigation.

Maternal butalbital use and selected defects in the national birth defects prevention study.

BACKGROUND: Butalbital is a barbiturate contained in combination products with caffeine and an analgesic prescribed for the treatment of migraine and tension-type headaches. Controversy exists as to whether butalbital should continue to be prescribed in the United States because of the potential for abuse, overuse headache, and withdrawal syndromes. Butalbital crosses the placenta but there is limited information about potential teratogenicity. OBJECTIVE: To evaluate associations between butalbital and a wide range of specific birth defects. METHODS: The National Birth Defects Prevention Study is an ongoing, case-control study of nonsyndromic, major birth defects conducted in 10 states. The detailed case classification and large number of cases in the National Birth Defects Prevention Study allowed us to examine the association between maternal self-reported butalbital use and specific birth defects. We conducted an analysis of 8373 unaffected controls and 21,090 case infants with estimated dates of delivery between 1997 and 2007; included were birth defects with 250 or more cases. An exploratory analysis examined groups with 100 to 249 cases. RESULTS: Seventy-three case mothers and 15 control mothers reported periconceptional butalbital use. Of 30 specific defect groups evaluated, adjusted odds ratios for maternal periconceptional butalbital use were statistically significant for 3 congenital heart defects: tetralogy of Fallot (adjusted odds ratio = 3.04; 95% confidence interval = 1.07-8.62), pulmonary valve stenosis (adjusted odds ratio = 5.73; 95% confidence interval = 2.25-14.62), and secundum-type atrial septal defect (adjusted odds ratio = 3.06; 95% confidence interval = 1.07-8.79). In the exploratory analysis, an elevated odds ratio was detected for 1 congenital heart defect, single ventricle. CONCLUSIONS: We observed relationships between maternal periconceptional butalbital use and certain congenital heart defects. These associations have not been reported before, and some may be spurious. Butalbital use was rare and despite the large size of the National Birth Defects Prevention Study, the number of exposed case and control infants was small. However, if confirmed in additional studies, our findings will be useful in weighing the risks and benefits of butalbital for the treatment of migraine and tension-type headaches.

First-trimester exposure to bupropion and risk of cardiac malformations.

PURPOSE: Bupropion is a drug uniquely used both to treat depression and as an aid to smoking cessation. We investigated previously reported associations between first-trimester exposure to bupropion and cardiac defects. METHODS: Using data gathered since 2003 by the Slone Epidemiology Center's Case-control Birth Defects Study, we classified subjects with cardiac defects into subgroups. Exposure categories included first-trimester bupropion alone or in combination with other antidepressants, first-trimester antidepressants other than bupropion, and no exposure to any antidepressant at any time from 2 months prior to pregnancy through delivery. We calculated odds ratios and 95% confidence intervals, controlling for confounding using logistic regression. RESULTS: There were 8611 non-malformed infants and 7913 infants with cardiac defects. Eight cardiac subgroups had sufficient subjects (two or more exposed cases) for analysis. The adjusted odds ratio (aOR) for first-trimester bupropion use in relation to ventricular septal defect (VSD) was slightly elevated (1.6, 95% confidence interval 1.0-2.8); for exposure to bupropion alone, the aOR was 2.5 (95% confidence interval 1.3-5.0). Risks were not materially elevated for bupropion in relation to the other seven cardiac subgroups. CONCLUSIONS: We did not confirm previously reported associations for left-sided defects overall but had too few exposed cases to evaluate specific defects in this category. We did observe an elevated risk of VSD following first-trimester bupropion use, particularly when used without other antidepressants. This pattern for bupropion alone was observed in all our risk comparisons and was not explained by higher doses or gestational timing.

Safety of macrolides during pregnancy.

OBJECTIVE: Prior studies have reported increased risks of congenital heart defects (CHD) and pyloric stenosis (PS) after prenatal exposure to macrolide antibiotics. We sought to assess the association between maternal use of erythromycin and nonerythromycin macrolides and the risks of CHD and PS. STUDY DESIGN: Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 through 2008, we identified 4132 infants with CHD and 735 with PS as cases, and 6952 infants without any malformation as controls. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of erythromycin or nonerythromycin macrolides in each trimester using conditional logistic regression and adjusting for risk factors for CHD and PS, fever, specific types of infections, and their associated treatments. RESULTS: During the first trimester, 0.4% and 0.7% of control women had used erythromycin and nonerythromycin macrolides, respectively. Compared to non-use during pregnancy, first-trimester exposure to erythromycin was not associated with an increased risk of CHD (OR, 1.3; 95% CI, 0.6-2.6) or PS (OR, 0.9; 95% CI, 0.3-3.0). The corresponding ORs for nonerythromycin macrolides were 0.7 (95% CI, 0.4-1.3) for CHD and 1.7 (95% CI, 0.6-4.6) for PS. We found no association between third-trimester exposure to erythromycin or nonerythromycin macrolides and the risk of PS. Hypothesis generation analyses did not identify appreciable associations between maternal use of macrolides and other common specific birth defects. CONCLUSION: We found no meaningful associations between the risks of CHD, PS, and other common malformations in relation to use of macrolides in pregnancy.

Influenza vaccine safety in pregnancy: can we identify exposures?

PURPOSE: To assess the feasibility of identifying influenza vaccine exposure in pregnancy. METHODS: Two study designs were used. (i) Women who contacted the Organization of Teratology Information Specialists (OTIS) network and were referred to their research center or contacted the center directly were invited to participate. (ii) Vaccine exposure information was gathered within an ongoing case-control surveillance program, the Slone Birth Defects Study (BDS). To confirm vaccine exposure and obtain details (e.g., brand name, presence of thimerosal), we requested medical records. If records were not available, we contacted the provider for information regarding the vaccine product used in that setting. If the provider used only one vaccine product during the reported exposure period, we assumed those vaccine details applied to the reported exposure. Otherwise, no details could be inferred. RESULTS: Between September 2006 and February 2008, OTIS enrolled 106 women who reported influenza vaccine exposure during pregnancy. Vaccine was confirmed for 100 (94.3%); brand was confirmed for 87 (82.1%). Among 2177 BDS interviews completed during the same period, 462 (20.8%) reported influenza vaccine exposure; brand and formulation were available for 314 (69.5%). Over one quarter of the BDS women (29%) received their vaccine in nontraditional settings, where influenza vaccine exposure would not likely be recorded in their medical record. CONCLUSIONS: We demonstrated the capacity both to identify influenza vaccine exposure in pregnancy and to obtain important details of the specific vaccine administered. Many women receive influenza vaccines outside of typical health care settings, which has important implications for influenza vaccine studies that rely on medical records.

Maternal exposure to amoxicillin and the risk of oral clefts.

BACKGROUND: Prior studies have suggested an increased risk of oral clefts after exposure to amoxicillin in early pregnancy, but findings have been inconsistent. METHODS: Among participants in the Slone Epidemiology Center Birth Defects Study from 1994 to 2008, we identified 877 infants with cleft lip with/without cleft palate and 471 with cleft palate alone. Controls included 6952 nonmalformed infants. Mothers were interviewed about demographic, reproductive and medical factors, and details of medication use. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) associated with use of amoxicillin in the first trimester using conditional logistic regression and adjusting for known risk factors for oral clefts, as well as for infections, fever, and concomitant treatments. RESULTS: In the control group, 2.1% of women had used amoxicillin in the first trimester. Maternal use of amoxicillin was associated with an increased risk of cleft lip with/without cleft palate (adjusted OR = 2.0 [95% confidence interval = 1.0-4.1]), with an OR of 4.3 (1.4-13.0) for third-gestational-month use. Risks were not elevated for use of other penicillins or cephalosporins. For cleft palate, the OR for first-trimester amoxicillin was 1.0 (0.4-2.3) with an OR of 7.1 (1.4-36) for third-gestational month use. CONCLUSIONS: Amoxicillin use in early pregnancy may be associated with an increased risk of oral clefts.

Medications used to treat nausea and vomiting of pregnancy and the risk of selected birth defects.

BACKGROUND: Nausea and vomiting of pregnancy (NVP) occurs in up to 80% of pregnant women, but its association with birth outcomes is not clear. Several medications are used for the treatment of NVP; however, data are limited on their possible associations with birth defects. METHODS: Using data from the National Birth Defects Prevention Study (NBDPS)-a multi-site, population-based, case-control study-we examined whether NVP or its treatment was associated with the most common noncardiac defects in the NBDPS (nonsyndromic cleft lip with or without cleft palate [CL/P], cleft palate alone [CP], neural tube defects, and hypospadias) compared with randomly selected nonmalformed live births. RESULTS: Among the 4524 cases and 5859 controls included in this study, 67.1% reported first-trimester NVP, and 15.4% of them reported using at least one agent for NVP. Nausea and vomiting of pregnancy was not associated with CP or neural tube defects, but modest risk reductions were observed for CL/P (adjusted odds ratio [aOR] = 0.87; 95% confidence interval [CI], 0.77-0.98) and hypospadias (aOR = 0.84; 95% CI, 0.72-0.98). Regarding treatments for NVP in the first trimester, the following adjusted associations were observed with an increased risk: proton pump inhibitors and hypospadias (aOR = 4.36; 95% CI, 1.21-15.81), steroids and hypospadias (aOR = 2.87; 95% CI, 1.03-7.97), and ondansetron and CP (aOR = 2.37; 95% CI, 1.18-4.76), whereas antacids were associated with a reduced risk for CL/P (aOR = 0.58; 95% CI, 0.38-0.89). CONCLUSIONS: NVP was not observed to be associated with an increased risk of birth defects; however, possible risks related to three treatments (i.e., proton pump inhibitors, steroids and ondansetron), which could be chance findings, warrant further investigation.

Case-control studies for identifying novel teratogens.

The case-control study design offers an operationally efficient approach to measuring an association between an exposure and an outcome, especially when the outcome is rare, as is true for specific birth defects. For example, instead of following 50,000 pregnant women to have sufficient statistical power to identify a doubling in risk of oral clefts associated with a common exposure (e.g., cigarette smoking), 75 cases and 3 controls per case could be studied with equal statistical power. Examples of case sources include hospital or clinical series, or birth defect registries. For validity, control subjects should represent the population base of the cases, which can be difficult to identify for non-population-based case groups. Case-control studies typically rely on retrospective exposure measurement, which presents a major challenge and sets up the possibility of recall bias. Approaches are discussed to keep sources of bias to a minimum, including recall, non-differential information, and selection biases. Case-control studies can play an important role in this process for both hypothesis-generation and hypothesis-testing of potential teratogens. Examples of case-control studies and their contributions to the field are presented. © 2011 Wiley-Liss, Inc.

Safety of influenza immunizations and treatment during pregnancy: the Vaccines and Medications in Pregnancy Surveillance System.

The Vaccines and Medications in Pregnancy Surveillance System (VAMPSS) has been designed to assess systematically the safety of vaccines and medications during pregnancy and is suited ideally to evaluate the gestational safety of seasonal and pandemic influenza vaccine and influenza antivirals. VAMPSS is coordinated by the American Academy of Allergy Asthma and Immunology and includes 2 complimentary data collection arms (prospective cohort and case-control surveillance) and a standing independent advisory committee. Both data collection arms obtain information directly from the mother, which facilitates accurate capture of exposures and potential confounders. The full range of perinatal outcomes, which includes specific birth defects, is assessed. Information that is obtained from VAMPSS should allow enhanced prevention and improved treatment of influenza during pregnancy by the identification of any exposures that might be associated with important risks and the provision of reassurance for exposures that are found to be relatively safe.

Medication use during pregnancy, with particular focus on prescription drugs: 1976-2008.

OBJECTIVE: The objective of the study was to provide information on overall medication use throughout pregnancy, with particular focus on the first trimester and specific prescription medications. STUDY DESIGN: The study design included the Slone Epidemiology Center Birth Defects Study, 1976-2008, and the National Birth Defects Prevention Study, 1997-2003, which together interviewed more than 30,000 women about their antenatal medication use. RESULTS: Over the last 3 decades, first-trimester use of prescription medication increased by more than 60%, and the use of 4 or more medications more than tripled. By 2008, approximately 50% of women reported taking at least 1 medication. Use of some specific medications markedly decreased or increased. Prescription medication use increased with maternal age and education, was highest for non-Hispanic whites, and varied by state. CONCLUSION: These data reflect the widespread and growing use of medications by pregnant women and reinforce the need to study their respective fetal risks and safety.

Drug certainty-response in interview-based studies.

PURPOSE: Imperfect recall of exposure timing challenges the ascertainment of medications in interview-based studies. METHODS: We propose an algorithm to classify medication exposure, taking into account recall certainty. The availability of medication use details, including duration of use, start and stop dates, and maternal estimates of how certain they were about these dates, allowed classification of subjects as either likely or possibly exposed in the first trimester of pregnancy. We applied the algorithm to study an association between prenatal tetracycline exposure and risk of congenital heart defects previously reported by the National Birth Defects Prevention Study, using 1993-2008 data from 11,517 subjects in the Slone Epidemiology Center Birth Defects Study. RESULTS: Among women exposed to tetracyclines during pregnancy (n = 58), 50% and 19% were likely and possibly exposed, respectively, in the first trimester, and 31% were exposed outside the first trimester. Compared with non-use during pregnancy, the crude OR for exposure outside the first trimester was 1.0 (95%CI 0.4-2.5), and that for exposed (likely or possibly, combined) in the first trimester was 1.7 (95%CI 0.9-3.2); however, the ORs based on the algorithms were 0.9 (95%CI 0.3-3.0) for possibly exposed and 2.2 (95%CI 1.0-4.6) for likely exposed. CONCLUSIONS: A "certainty-response" (stronger association with higher level of certainty) was found within exposures in the window of etiological interest. Algorithms for exposure classification that incorporate recall certainty may be useful in interview-based studies.

First-trimester use of selective serotonin-reuptake inhibitors and the risk of birth defects.

BACKGROUND: The risk of birth defects after antenatal exposure to selective serotonin-reuptake inhibitors (SSRIs) remains controversial. METHODS: We assessed associations between first-trimester maternal use of SSRIs and the risk of birth defects among 9849 infants with and 5860 infants without birth defects participating in the Slone Epidemiology Center Birth Defects Study. RESULTS: In analyses of defects previously associated with SSRI use (involving 42 comparisons), overall use of SSRIs was not associated with significantly increased risks of craniosynostosis (115 subjects, 2 exposed to SSRIs; odds ratio, 0.8; 95% confidence interval [CI], 0.2 to 3.5), omphalocele (127 subjects, 3 exposed; odds ratio, 1.4; 95% CI, 0.4 to 4.5), or heart defects overall (3724 subjects, 100 exposed; odds ratio, 1.2; 95% CI, 0.9 to 1.6). Analyses of the associations between individual SSRIs and specific defects showed significant associations between the use of sertraline and omphalocele (odds ratio, 5.7; 95% CI, 1.6 to 20.7; 3 exposed subjects) and septal defects (odds ratio, 2.0; 95% CI, 1.2 to 4.0; 13 exposed subjects) and between the use of paroxetine and right ventricular outflow tract obstruction defects (odds ratio, 3.3; 95% CI, 1.3 to 8.8; 6 exposed subjects). The risks were not appreciably or significantly increased for other defects or other SSRIs or non-SSRI antidepressants. Exploratory analyses involving 66 comparisons showed possible associations of paroxetine and sertraline with other specific defects. CONCLUSIONS: Our findings do not show that there are significantly increased risks of craniosynostosis, omphalocele, or heart defects associated with SSRI use overall. They suggest that individual SSRIs may confer increased risks for some specific defects, but it should be recognized that the specific defects implicated are rare and the absolute risks are small.

Use of oral contraceptives in pregnancy and major structural birth defects in offspring.

BACKGROUND: Oral contraceptives (OCs) are the most commonly used reversible contraceptive method among US women. Although the majority of previous studies have reported no association between OC use during pregnancy and birth defects, some studies have reported increased occurrence of neural tube defects, limb reduction defects, and urinary tract anomalies. METHODS: We assessed OC use among mothers who participated in the multisite, case-control, National Birth Defects Prevention Study. Mothers of 9986 infants with 32 types of birth defects and 4000 infants without birth defects were included. RESULTS: Maternal OC use during the first 3 months of pregnancy was associated with an increased odds ratio for 2 of 32 birth defects: hypoplastic left heart syndrome (adjusted odds ratio = 2.3 [95% confidence interval = 1.3-4.3) and gastroschisis (1.8 [1.3-2.7]). CONCLUSION: Previous reports of associations between OC use and specific types of anomalies were not corroborated. Given that associations were assessed for 32 types of birth defects, our findings of 2 increased associations between OC use and gastroschisis and hypoplastic left heart syndrome should be interpreted as hypotheses until they can be evaluated further. Overall, our findings are consistent with the majority of previous studies that found women who use OCs during early pregnancy have no increased risk for most types of major congenital malformations.

Use of herbal treatments in pregnancy.

OBJECTIVE: Interest in herbal treatments has increased without data on safety, efficacy, or rates of use in pregnancy. We examined antenatal herbal and natural product use among mothers of nonmalformed infants in 5 geographic centers. STUDY DESIGN: We used data on nonmalformed infants from the Slone Epidemiology Center's case-control surveillance program for birth defects to examine rates and predictors of herbal use. Exposures were identified through maternal interview. In addition to overall use, 5 categories based on traditional uses and 2 natural product categories were created; topical products and herbal-containing multivitamins were excluded. RESULTS: Among 4866 mothers of nonmalformed infants, 282 (5.8%) reported use of herbal or natural treatments. Use varied by study center and increased with increasing age. CONCLUSION: Although rates of use are low, there remains a need for investigation of the safety of these products. Given sparse data on efficacy, even small risks might well outweigh benefits.

Herbal use before and during pregnancy.

OBJECTIVE: We estimated the prevalence and patterns of herbal use among US women before and during pregnancy. STUDY DESIGN: The National Birth Defects Prevention Study is an ongoing, population-based, case-control study. This analysis included 4239 women from 10 centers in the United States who delivered infants without major birth defects from 1998-2004. RESULTS: The prevalence of reported herbal use 3 months before or during pregnancy was 10.9%. During pregnancy, prevalence was 9.4% and was highest in the first trimester. Higher prevalence was associated with age greater than 30 years and education greater than 12 years. Use varied considerably by state (5-17%). Ginger and ephedra were the most commonly reported products early in pregnancy; teas and chamomile were most commonly reported throughout pregnancy. CONCLUSION: Potentially 395,000 US births annually involve antenatal exposure to herbal products. Health care providers should inquire routinely about herbal use and educate patients about what little is known regarding risks of these products.