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.

Pregnancy outcomes following maternal macrolide use: A systematic review and meta-analysis.

To determine whether gestational use of all or specific macrolides (azithromycin, clarithromycin, roxithromycin or erythromycin) lead to an increase in rates of overall major congenital malformations, organ-specific malformations, and other adverse pregnancy outcomes in infants. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox® databases were searched. Dichotomous outcomes or calculated log odds ratios and standard errors from observational studies are combined using the random-effects method in Review Manager 5.3. No significant increased risks for major congenital malformation (OR 1.06 [95% CI 0.99, 1.13]) and congenital heart defect (OR 1.05 [95% CI 0.92, 1.19]) following all macrolides use during the first trimester were detected. Prenatal azithromycin use was associated with a significantly increased risk of major congenital malformations in the analysis of cohort studies (OR 1.21 [95% CI 1.08-1.36]). This significance was also present in the sensitivity analysis. There were no statistically significant associations between the risk of organ specific malformations and all or specific macrolide exposures except for the decreased risk in hypospadias following erythromycin use in the meta-analysis of case-control studies (OR 0.38 [95% CI 0.18, 0.81]. Also, a significant 1.5-fold increased risk for spontaneous abortion following macrolide use was detected. A slight yet significantly increased rate of major congenital malformation with azithromycin exposure during pregnancy may be associated with maternal confounders. Nevertheless, level II ultrasound can be suggested following maternal azithromycin use during the first trimester. Future studies should take into account the inclusion of a disease-matched control group and accurate classification of the malformations.

Comparison of relaxant effects of nifedipine and NS11021 on isolated umbilical arteries of healthy and preeclamptic pregnant women.

OBJECTIVES: Potassium (K+) channel openers and calcium (Ca2+) channel blockers are currently used to treat acute severe hypertension in pregnancy. We aimed to investigate the vasorelaxant effect of NS11021, a potent and specific big-conductance Ca2+-activated K+ (BKCa) channel activator, and to compare it with the vasorelaxant effect of nifedipine on human umbilical arteries (HUAs) isolated from healthy and preeclamptic pregnants. STUDY DESIGN: A total of 29 HUAs were isolated immediately after delivery from 14 healthy and 15 preeclamptic pregnant with severe features. The concentration-dependent relaxation responses were obtained to nifedipine and NS11021 on HUAs precontracted with endothelin-1 (ET-1) (10-8 M) in an isolated tissue bath. RESULTS: Both nifedipine and NS11021 caused concentration-dependent relaxation responses in HUAs from healthy and preeclamptic pregnants. While the maximum responses (Emax) and pD2 values of nifedipine did not change significantly in both groups, the Emax and pD2 values of NS11021 were significantly decreased in the preeclampsia group (Emax ± SEM; %75.57 ± 4.53 and %43.75 ± 14.00 and pD2 ± SEM; 6.92 ± 0.26 and 5.24 ± 0.53 respectively, p < 0.05). In addition, the pD2 value of NS11021 was not significantly different from that of nifedipine in the control group, but decreased significantly in the preeclampsia group (pD2 ± SEM 7.1 ± 0.41 and 5.2 ± 0.53, p < 0.05, respectively). CONCLUSIONS: Efficacy and potency of NS11021 decreased in HUAs from preeclamptic pregnants. Also, NS11021 is less potent than nifedipine in the preeclampsia group. BKCa channels may have a role in the pathogenesis of preeclampsia, however, further experimental studies are needed to elucidate that.

Pregnancy outcomes following maternal exposure to statins: A systematic review and meta-analysis.

AIMS: The objective of this meta-analysis was to determine whether maternal exposure to statins is associated with increased rates of major congenital malformations and other adverse pregnancy outcomes. METHODS: PubMed/Medline, Web of Science and Reprotox® databases were searched. Cohort and case control studies with prenatal exposure to statins were included. RESULTS: Analysis of five cohort studies and one case-control study showed no significant increase in rate of major congenital malformations when the exposed group was compared with the control ([OR 1.27; 95% CI 0.80-2.04], [aOR 1.05; 95% CI 0.84-1.31]). A significant increase in heart defect risk was detected in the statin-exposed group when unadjusted ORs were combined (OR 2.47; 95% CI 1.36-4.49). Further analysis of the same outcome by using adjusted ORs showed no significant increase in heart defect risk in the statin-exposed group compared with the controls (aOR 1.24; 95% CI 0.93-1.66). A significantly lower live birth rate (OR 0.60, 95% CI 0.49-0.75) and a higher spontaneous abortion rate (OR 1.36; 95% Cl 1.06-1.75) were detected in the statin-exposed group. CONCLUSIONS: Gestational statin exposure was not associated with a significant increase in risk of major congenital malformations, heart defects and other adverse pregnancy outcomes, except spontaneous abortion and live birth rate, which may be associated with maternal comorbidity and other unadjusted risk factors. Further research focusing on particular statins is needed to draw more definitive conclusions.

Paroxetine overdose during pregnancy.

Paroxetine is a selective serotonin reuptake inhibitor (SSRI) used in the treatment of depression and anxiety disorders. In some epidemiological studies, slightly increased risks of major malformations and cardiac malformations have been reported following paroxetine exposure in the first trimester of pregnancy. However, such findings have been inconsistent. There is only one report of any overdose of an SSRI during pregnancy, and that involved escitalopram. The aim of this case report was to describe the impact of a paroxetine overdose in the first trimester of pregnancy on the health of the foetus. A 21-year-old mother of one child who was pregnant with a second child was prescribed 20 mg/day paroxetine hydrochloride for the treatment of anxiety/depression. The patient ingested 15 or 16 20-mg tablets of paroxetine hydrochloride (300-320 mg) during the 5th week of pregnancy as a suicide attempt. Within 15 min of ingestion, she was admitted to hospital and treated for intoxication. No evidence of maternal SSRI intoxication was observed after treatment. The patient consulted our teratology information service for further risk assessment regarding possible major congenital malformations following the paroxetine overdose. We were unable to find previous reports of paroxetine overdose during pregnancy in the literature. The timely administration of the overdose treatment and the lack of maternal intoxication symptoms were considered positive for the foetal well-being, and the patient was referred for perinatology and psychiatry follow-ups. A healthy, 3 500-g male infant was born at 38 weeks' gestation, and his development at the age of 2 years was normal. This is the first reported case of paroxetine overdose during pregnancy. Comprehensive studies are needed to evaluate pregnancy outcomes after SSRI overdose.Key PointsThere are no reported data on paroxetine overdose during pregnancy.The aim of this case report was to describe the impact of a maternal paroxetine overdose in the first trimester of pregnancy on the health of the foetus. No evidence of maternal SSRI intoxication was observed.No congenital malformations or developmental disorders were observed in the child at 2 years of age.Comprehensive studies are needed to evaluate pregnancy outcomes following SSRI overdose.