Martha M. Werler

Folic Acid Antagonists during Pregnancy and the Risk of Birth Defects

Background Multivitamin supplementation in pregnant women may reduce the risks of cardiovascular defects, oral clefts, and urinary tract defects in their infants. We evaluated whether the folic acid component of multivitamins is responsible for the reduction in risk by examining the associations between maternal use of folic acid antagonists and these congenital malformations. Methods We assessed exposure to folic acid antagonists that act as dihydrofolate reductase inhibitors and to certain antiepileptic drugs in 3870 infants with cardiovascular defects, 1962 infants with oral clefts, and 1100 infants with urinary tract defects and also in 8387 control infants with malformations the risk of which is not reduced after vitamin supplementation. Mothers were interviewed within six months after delivery about their medication use during pregnancy. Results The relative risks of cardiovascular defects and oral clefts in infants whose mothers were exposed to dihydrofolate reductase inhibitors during the second o...

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.

Maternal obesity, gestational diabetes, and central nervous system birth defects.

Background: Maternal obesity and diabetes are both associated with increased risk of congenital central nervous system (CNS) malformations in the offspring and may share a common underlying mechanism. Our objective was to evaluate whether gestational diabetes influenced the association of prepregnancy maternal obesity and risks for CNS birth defects. Methods: This Texas population-based case-control study evaluated births occurring January 1997 through June 2001. Data came from structured telephone interviews. Cases (n = 477) were mothers of offspring with anencephaly (n = 120), spina bifida (n = 184), holoprosencephaly (n = 49), or isolated hydrocephaly (n = 124). Controls (n = 497) were mothers of live infants without abnormalities randomly selected from the same hospitals as cases. Response rates were approximately 60% for both cases and controls. We evaluated maternal obesity (body mass index ≥30.0 kg/m2) and risks for CNS birth defects, as well as whether gestational diabetes influenced the risks. Results: After adjusting for maternal ethnicity, age, education, smoking, alcohol use, and periconceptional vitamin use, obese women had substantially increased risks of delivering offspring with anencephaly (odds ratio = 2.3; 95% confidence interval = 1.2–4.3), spina bifida (2.8; 1.7–4.5), or isolated hydrocephaly (2.7; 1.5–5.0), but not holoprosencephaly (1.4; 0.5–3.8). Odds ratios were higher for the joint effects of maternal obesity and gestational diabetes, with evidence for interaction on a multiplicative scale. Conclusions: Maternal obesity and gestational diabetes may increase the risk of CNS birth defects through shared causal mechanisms.

Predictive value of minor anomalies. I. Association with major malformations.

We examined 4305 white newborn infants for 114 minor physical features and major malformations to evaluate the hypothesis that the presence of three or more minor anomalies is highly predictive of a major malformation. We confirmed that the infant with three or more minor anomalies is at increased risk for a major malformation. However, this risk (19.6%) was much lower than the risk of 90% popularized by Smith and based on the study of Marden et al. (J Pediatr 1964;64:357). Analysis of the findings in the two studies showed that the lower predictive value was probably related to differences in study design. Nevertheless, some minor anomalies remain essential to the early recognition of several serious malformation syndromes.

Risk Factors for Persistent Pulmonary Hypertension of the Newborn

OBJECTIVE. Persistent pulmonary hypertension of the newborn, a clinical syndrome that results from the failure of the normal fetal-to-neonatal circulatory transition, is associated with substantial infant mortality and morbidity. We performed a case-control study to determine possible antenatal and perinatal predictors of persistent pulmonary hypertension of the newborn. METHODS. Between 1998 and 2003, the Slone Epidemiology Center enrolled 377 mothers of infants with persistent pulmonary hypertension of the newborn and 836 mothers of matched control subjects. Within 6 months of delivery, study nurses interviewed participants regarding demographic, medical, and obstetric characteristics. RESULTS. Factors that were independently associated with an elevated risk for persistent pulmonary hypertension of the newborn were infant male gender and black or Asian maternal race compared with white race. High prepregnancy BMI (>27 vs <20) was also associated with persistent pulmonary hypertension of the newborn, as were diabetes and asthma. Compared with infants who were delivered vaginally, the risk for persistent pulmonary hypertension of the newborn was higher for those who were born by cesarean section. Compared with infants who were born within 37 to 41 gestational weeks, the risk was higher for those who were born between 34 and 37 completed weeks and for those born beyond 41 weeks. Compared with infants within the 10th and 90th percentiles of birth weight for gestational age distribution, the risk was higher for infants above the 90th percentile. CONCLUSIONS. Our findings suggest an increased risk for persistent pulmonary hypertension of the newborn associated with cesarean delivery; late preterm or postterm birth; being large for gestational age; and maternal black or Asian race, overweight, diabetes, and asthma. It remains unclear whether some of these factors are direct causes of persistent pulmonary hypertension of the newborn or simply share common causes with it; however, clinicians should be alert to the increased need for monitoring and intervention among pregnancies with these risk factors.

Use of topiramate in pregnancy and risk of oral clefts

OBJECTIVE The objective of this study was to evaluate the association between the use of monotherapy topiramate in pregnancy and cleft lip with or without cleft palate (CL/P) in the offspring. STUDY DESIGN Data from the Slone Epidemiology Center Birth Defects Study (BDS) from 1997 to 2009 and the National Birth Defects Prevention Study (NBDPS) from 1997 to 2007 were analyzed. Conditional logistic regression was used to compare the first-trimester use of topiramate monotherapy to no antiepileptic drug use during the periconceptional period between the mothers of infants with CL/P and the mothers of controls for each study separately and in pooled data. RESULTS The BDS contained 785 CL/P cases and 6986 controls; the NBDPS contained 2283 CL/P cases and 8494 controls. The odds ratios (exact 95% confidence intervals) for the association between topiramate use and CL/P were 10.1 (1.1-129.2) in the BDS, 3.6 (0.7-20.0) in the NBDPS, and 5.4 (1.5-20.1) in the pooled data. CONCLUSION First-trimester use of topiramate may be associated with CL/P.

Antihypertensive Medication Use During Pregnancy and the Risk of Cardiovascular Malformations

We used data from the National Birth Defects Prevention Study, a population-based, case-control study, to examine whether previously reported associations between antihypertensive medications and cardiovascular malformations could be confirmed and to explore whether new associations might be identified. Cases (n=5021) were ascertained through birth defects surveillance systems from 1997 through 2003 in 10 US states. Controls (n=4796) were live births without birth defects selected randomly from birth certificates or hospital discharge listings in the same geographic regions. Logistic regression was used to examine the relationship between antihypertensive medication treatment and the occurrence of cardiovascular malformations while controlling for confounding variables. First-trimester treatment with antihypertensive medication was associated with pulmonary valve stenosis (odds ratio [OR]: 2.6; 95% CI: 1.3 to 5.4), Ebstein malformation (crude OR: 11.4; exact 95% CI: 2.8 to 34.1), coarctation of the aorta (OR: 3.0; 95% CI: 1.3 to 6.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Treatment initiated after the first trimester was associated with pulmonary valve stenosis (OR: 2.4; 95% CI: 1.1 to 5.4), perimembranous ventricular septal defects (OR: 2.3; 95% CI: 1.2 to 4.6), and secundum atrial septal defects (OR: 2.4; 95% CI: 1.3 to 4.4). Untreated hypertension was associated with Ebstein malformation (OR: 2.1; 95% CI: 1.0 to 4.3) and secundum atrial septal defects (OR: 1.3; 95% CI: 1.0 to 1.6). Antihypertensive medication use and/or the underlying hypertension might increase the risk of having an infant with specific left and right obstructive and septal defects. Additional studies with adequate power will be needed to confirm these findings.

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.

Teratogen update: smoking and reproductive outcomes.

The potential effects of cigarette smoke exposure on reproductive outcomes are a major scientific and public health concern, as evidenced by the myriad of published studies on outcomes ranging from germ cell morphology to morbidity among subsequent generations of offspring. Although the prevalence of maternal smoking has decreased over the past two decades, ,15% of women smoke throughout pregnancy (Kendrick and Merritt, ’96). Given that cigarette smoke contains hundreds of toxic components, it follows that maternal smoking may have adverse effects on certain reproductive outcomes. For the most part, specific components of cigarette smoke have not been studied in humans, but pieces of evidence point toward certain pathways. Some examples include: nicotine is known to be vasoactive and is thought to reduce placental and fetal circulation (Lehtovirta and Forss, ’78; Goodman, ’90; Mochizuki et al., ’94; Philipp et al., ’94); cotinine, a major metabolite of nicotine, has been measured in follicular fluid (Bureau et al., ’82; Weiss and Eckert, ’89); cyanide is a known toxin and has been studied as a marker for smoking because thiocyanate correlates well with smoking exposure (Sophian, ’68; Andrews and McGarry, ’72; Bottoms et al., ’82); carbon monoxide is known to deplete both maternal and fetal oxygen supplies (Bartlett, ’68; Meyer, ’78; Bureau et al., ’84); excess cadmium has been observed in the ovaries, follicular fluid, and placentas of smokers (Van der Velde et al., ’83; Kuhnert et al., ’88; Zenzes et al., ’93); lead is a known neurotoxin (Doull et al., ’80); and some polycyclic aromatic hydrocarbons are mutagenic (USDHHS, ’82). The more general exposure—cigarette smoking—is the focus of this review. Because of the abundance of published papers on smoking, the outcomes presented here were selected on the basis of public health relevance and the availability of published data from epidemiologic studies in humans. For each reproductive outcome covered, important epidemiologic issues are described and the findings are summarized in terms of an estimated relative effect of smoking (i.e., relative risk) (Rothman, ’86). For those outcomes that have been linked to smoking consistently across studies, the proportion of the outcome attributed to the exposure (i.e., attributable proportion) is estimated (Rothman, ’86).

Selective serotonin reuptake inhibitor use and risk of gestational hypertension.

OBJECTIVE The purpose of this study was to assess the effects of treatment with selective serotonin reuptake inhibitors (SSRIs) on the risks of gestational hypertension and preeclampsia. METHOD The authors analyzed data from 5,731 women with nonmalformed infants and no underlying hypertension who participated in the Slone Epidemiology Center Birth Defects Study from 1998 to 2007. Gestational hypertension was defined as incident hypertension diagnosed after 20 weeks of pregnancy, with and without proteinuria (i.e., with and without preeclampsia). The risks of gestational hypertension and preeclampsia were compared between women who did and did not receive SSRI treatment during pregnancy. Relative risks and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model, adjusting for prepregnancy sociodemographic, lifestyle, reproductive, and medical factors. RESULTS Gestational hypertension was present in 9.0% of the 5,532 women who were not treated with SSRIs and 19.1% of the 199 women who were treated with SSRIs. Among women who received treatment, gestational hypertension was present in 13.1% of the 107 women who received treatment only during the first trimester and in 26.1% of the 92 women who continued treatment beyond the first trimester. The occurrence of preeclampsia was 2.4% among women who were not treated with SSRIs, 3.7% among women who were exposed to SSRIs only during the first trimester, and 15.2% among women who continued SSRI treatment beyond the first trimester. Relative to women who did not receive treatment, the adjusted relative risk of preeclampsia was 1.4 for women who discontinued treatment and 4.9 for women who continued treatment. CONCLUSION SSRI exposure during late pregnancy-whether a causal factor or not-might identify women who are at an increased risk for gestational hypertension and preeclampsia. Further investigation is needed in order to separate the effects of treatment with SSRIs from those of underlying mood disorders.