Antiepileptic treatment with levetiracetam during the first trimester and pregnancy outcome: An observational study.

OBJECTIVE: Levetiracetam is increasingly used in pregnant women with epilepsy. Although teratogenic effects have not been observed so far, data on the risks of spontaneous abortion and major birth defects are still limited, especially for the frequently used dual therapy of levetiracetam and lamotrigine. Our primary aim was to analyze rates of major birth defects and spontaneous abortion after maternal levetiracetam treatment. METHODS: This was a cohort study based on pregnancies recorded by the Embryotox Center from 2000 to 2017. Outcomes of prospectively ascertained pregnancies with first trimester levetiracetam monotherapy (n = 221) were compared to pregnancies with lamotrigine monotherapy for epilepsy (n = 469). In addition, all pregnancies with levetiracetam (n = 364) exposure during the first trimester were analyzed in comparison to a nonexposed cohort (n = 729). Pregnancies with the most frequently used combination therapy comprising levetiracetam and lamotrigine (n = 80) were evaluated separately. RESULTS: There was no significantly increased risk of major birth defects or of spontaneous abortions after first trimester exposure to levetiracetam. Birth weight of male neonates was significantly lower after levetiracetam monotherapy compared to lamotrigine monotherapy. Dual therapy with levetiracetam and lamotrigine resulted in a significantly increased risk of spontaneous abortion (adjusted hazard ratio = 3.01, 95% confidence interval [CI] = 1.43-6.33) and a nonsignificant effect estimate for major birth defects (7.7%, n = 5/65, adjusted odds ratio = 1.47, 95% CI = .48-4.47) compared to a nonexposed cohort. SIGNIFICANCE: Our study confirms the use of levetiracetam as a suitable antiepileptic drug in pregnancy. The lower birth weight of male neonates after maternal levetiracetam monotherapy and the unexpectedly high risk of spontaneous abortion and birth defects after dual therapy with levetiracetam and lamotrigine require further investigation.

Effects of maternal modafinil treatment on fetal development and neonatal growth parameters - a multicenter case series of the European Network of Teratology Information Services (ENTIS).

OBJECTIVE: In recent years, safety concerns about modafinil exposure during pregnancy have emerged. In particular, increased risks for major congenital anomalies (MCA) and impaired fetal growth were reported, although study results were conflicting. Our investigation aims to examine previously reported safety signals. METHOD: Multicenter case series based on data from 18 Teratology Information Services from 12 countries. Modafinil exposed pregnancies with an estimated date of birth before August 2019 were included in this study. For prospectively ascertained pregnancies, cumulative incidences of pregnancy outcomes, rate of nonchromosomal MCA in first trimester exposed pregnancies and percentiles of neonatal/infant weight and head circumference (HC) were calculated. Potential dose-dependent effects on fetal growth were explored by linear regression models. Retrospectively ascertained cases were screened for pattern of MCA and other adverse events. RESULTS: One hundred and seventy-five prospectively ascertained cases were included, of which 173 were exposed at least during the first trimester. Cumulative incidences for live birth, spontaneous abortion and elective termination of pregnancy were 76.9% (95% CI, 68.0%-84.8%), 9.3% (95% CI, 5.0%-16.9%), and 13.9% (95% CI, 8.1%-23.1%), respectively. Nonchromosomal MCA was present in 3/150 live births, corresponding to an MCA rate of 2.0% (95%CI, 0.6%-6.1%), none were reported in pregnancy losses. Compared to reference standards, birth weight (BW) tended to be lower and neonatal HC to be smaller in exposed newborns (data available for 144 and 73 of 153 live births, respectively). In nonadjusted linear regression models, each 100 mg increase of average dosage per pregnancy day was associated with a decrease in standard deviation score (SDS) of -0.28 SDS (95% CI, -0.45 to -0.10) for BW and of -0.28 SDS (95% CI, -0.56 to 0.01) for HC. Screening of 22 retrospectively reported cases did not reveal any specific pattern of MCA or other adverse outcomes. CONCLUSION: The results do not indicate an increased risk of MCA after in utero exposure to modafinil, but a tendency toward lower BW and reduced neonatal HC. However, these findings should be regarded as preliminary. Until further studies allow for a definite conclusion, modafinil should not be used during pregnancy.

Behavioral factors predict all-cause mortality in female coronary patients and healthy controls over 26 years - a prospective secondary analysis of the Stockholm Female Coronary Risk Study.

OBJECTIVE: The prognosis of coronary artery disease (CAD) is related to its severity and cardiovascular risk factors in both sexes. In women, social isolation, marital stress, sedentary lifestyle and depression predicted CAD progression and outcome within 3 to 5 years. We hypothesised that these behavioral factors would still be associated with all-cause mortality in female patients after 26 years. METHODS: We examined 292 patients with CAD and 300 healthy controls (mean age of 56 ± 7 y) within the Fem-Cor-Risk-Study at baseline. Their cardiac, behavioral, and psychosocial risk profiles, exercise, smoking, and dietary habits were assessed using standardized procedures. Physiological characteristics included a full lipid profile, the coagulation cascade and autonomic dysfunction (heart rate variability, HRV). A new exploratory analysis using machine-learning algorithms compared the effects of social and behavioral mechanisms with standard risk factors. Results: All-cause mortality records were completed in 286 (97.9%) patients and 299 (99.7%) healthy women. During a median follow-up of 26 years, 158 (55.2%) patients and 101 (33.9%) matched healthy controls died. The annualized mortality rate was 2.1% and 1.3%, respectively. After controlling for all available confounders, behavioral predictors of survival in patients were social integration (HR 0.99, 95% CI 0.99-1.0) and physical activity (HR 0.54, 95% CI 0.37-0.79). Smoking acted as a predictor of all-cause mortality (HR 1.56, 95% CI 1.03-2.36). Among healthy women, moderate physical activity (HR 0.42, 95% CI 0.24-0.74) and complete HRV recordings (≥50%) were found to be significant predictors of survival. CONCLUSIONS: CAD patients with adequate social integration, who do not smoke and are physically active, have a favorable long-term prognosis. The exact survival times confirm that behavioral risk factors are associated with all-cause mortality in female CAD patients and healthy controls.