Carol Louik

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.

Lack of Relation of Oral Clefts to Diazepam Use during Pregnancy

The hypothesis that in utero exposure to diazepam increases the risk of oral-cleft anomalies was evaluated in a case-control study, in which 445 infants with cleft lip with or without cleft palate and 166 with cleft palate without cleft lip (cleft palate alone) were compared with 2498 control infants having other birth defects. For exposure to diazepam during lunar months 1 through 4 relative to no exposure during pregnancy, the estimated relative risks were 1.0 for cleft lip with or without cleft palate (95 per cent confidence interval, 0.5 to 2.1) and 0.8 for cleft palate alone (0.3 to 2.7). After control for all identified potential confounding factors, the corresponding estimates were 0.8 (0.4 to 1.7) and 0.8 (0.2 to 2.5), respectively. The findings were unchanged when maternal suspicion that diazepam might be a teratogen was taken into account. The data suggest that first-trimester exposure to diazepam does not materially affect the risk of cleft lip with or without cleft palate or of cleft palate alone.

Nonsteroidal antiinflammatory drug use and reduced risk of large bowel carcinoma

Animal experiments and epidemiologic data have suggested that the use of nonsteroidal antiinflammatory drugs (NSAIDs) may decrease the incidence of large bowel carcinoma. Our purpose was to assess the relation of the use of aspirin and nonaspirin NSAIDs with the risk of large bowel carcinoma.

A Pregnancy-Prevention Program in Women of Childbearing Age Receiving Isotretinoin

BACKGROUND Isotretinoin is effective in treating severe acne, but it is also teratogenic. To minimize pregnancies among exposed women, the manufacturer, together with the U.S. Food and Drug Administration, implemented a multicomponent Pregnancy Prevention Program in 1988. We report the results of an ongoing survey designed to assess compliance with this program. METHODS Treated women enrolled in the survey through their physician, by filling out a form in the medication package, or by calling a toll-free telephone number. They were randomly assigned to be followed by telephone or by mail. Telephone interviews were conducted at the start of therapy, in the middle of it, and 6 months after it ended; mailed questionnaires were completed 6 months after therapy ended (median duration of therapy, 20 weeks). RESULTS Between 1989 and 1993, 177,216 eligible women enrolled in the survey. Interviews with 24,503 women within one month of enrollment revealed that 99 percent had been told to avoid pregnancy. At that time, approximately 54 percent were not sexually active (of whom 37 percent used contraception) and 42 percent were sexually active (of whom 99 percent used contraception); 4 percent were infertile. Among 124,216 women with completed telephone or mail follow-up results, there were 402 pregnancies during therapy (3.4 per 1000 courses of isotretinoin); 72 percent of the pregnant women had elective abortions, 16 percent spontaneous abortions, 3 percent ectopic pregnancies, and 8 percent live births. CONCLUSIONS The pregnancy rate among women receiving isotretinoin therapy was substantially lower than that in the general population and was compatible with the characteristics and behavior of the enrolled women.

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.

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.

Oral Contraceptives and Birth Defects

We reviewed the birth certificates and hospital records of 7723 infants those mothers had reported using oral contraceptives. The overall frequency of malformation was 4.3 per cent for infants whose mothers terminated use of oral contraceptives shortly before conception, as compared with 3.3 per cent for infants whose mothers did not take oral conceptives diring the three years before conception. The 90 per cent confidence limits for the prevalence ratio were 1.0 and 1.7. No difference was apparent for major malformations. For specific malformations the most notable difference was for undescented testis, but this excess, like the overall excess, could be explained by sampling variability. Despite the slightly greater rate of minor malformations in the short-interval group, a reasonable interpretation of these data would be that oral contraceptives present no major teratogenic hazard.

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.

Heparin Use as a Risk Factor for Intraventricular Hemorrhage in Low-Birth-Weight Infants

In a systematic review of data on drug use and adverse clinical events in infants with birth weights under 2000 g, we observed an association between germinal matrix-intraventricular hemorrhage and the use of heparin to maintain the patency of vascular catheters. Sixty-six infants with germinal-matrix (periventricular) or intraventricular hemorrhage or both (cases) were matched with 254 infants with other conditions (controls), and analysis, taking the matching factors into account, yielded an odds ratio of 14.0 (95 percent confidence interval, 5.4 to 34). When potential confounding factors were taken into account, the odds ratio was 3.9 (1.4 to 11). The association did not appear to vary according to the severity of hemorrhage or to the method of administration or dose of heparin. The data suggest that the routine use of heparin in neonatal intensive care units is associated with a four-fold increase in the risk of germinal matrix-intraventricular hemorrhage. Because of the possibility that confounding may have been incompletely controlled for, the true risk cannot be determined from these data, and a controlled clinical trial of heparin use in low-birth-weight infants is recommended.

Specific SSRIs and birth defects: bayesian analysis to interpret new data in the context of previous reports

Objective To follow up on previously reported associations between periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and specific birth defects using an expanded dataset from the National Birth Defects Prevention Study. Design Bayesian analysis combining results from independent published analyses with data from a multicenter population based case-control study of birth defects. Setting 10 centers in the United States. Participants 17 952 mothers of infants with birth defects and 9857 mothers of infants without birth defects, identified through birth certificates or birth hospitals, with estimated dates of delivery between 1997 and 2009. Exposures Citalopram, escitalopram, fluoxetine, paroxetine, or sertraline use in the month before through the third month of pregnancy. Posterior odds ratio estimates were adjusted to account for maternal race/ethnicity, education, smoking, and prepregnancy obesity. Main outcome measure 14 birth defects categories that had associations with SSRIs reported in the literature. Results Sertraline was the most commonly reported SSRI, but none of the five previously reported birth defects associations with sertraline was confirmed. For nine previously reported associations between maternal SSRI use and birth defect in infants, findings were consistent with no association. High posterior odds ratios excluding the null value were observed for five birth defects with paroxetine (anencephaly 3.2, 95% credible interval 1.6 to 6.2; atrial septal defects 1.8, 1.1 to 3.0; right ventricular outflow tract obstruction defects 2.4, 1.4 to 3.9; gastroschisis 2.5, 1.2 to 4.8; and omphalocele 3.5, 1.3 to 8.0) and for two defects with fluoxetine (right ventricular outflow tract obstruction defects 2.0, 1.4 to 3.1 and craniosynostosis 1.9, 1.1 to 3.0). Conclusions These data provide reassuring evidence for some SSRIs but suggest that some birth defects occur 2-3.5 times more frequently among the infants of women treated with paroxetine or fluoxetine early in pregnancy.