RESUMO
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.
RESUMO
BACKGROUND AND OBJECTIVE: A decrease in factor V activity has been reported in some patients treated with azathioprine or 6-mercaptopurine. This may lead to unnecessary treatment discontinuation in otherwise asymptomatic patients. Our aim was to review spontaneously reported cases of decreased factor V activity associated with both drugs and to identify the possible impact on patient care. METHODS: Cases of decrease in prothrombin (PT) or factor V activity involving purine analogs were extracted from the French pharmacovigilance database. Reports with evidence of disseminated intravascular coagulation, signs of acute hepatocellular failure, liver cirrhosis or concomitant vitamin K antagonist treatment were excluded. RESULTS: Twenty-four cases (azathioprine: 13 and 6-mercaptopurine: 11) were retained. Therapeutic indications were inflammatory bowel diseases in 11 patients, acute leukemia in eight, and other autoimmune diseases in five. PT activity before treatment was normal in all nine tested patients. The decrease in PT or factor V activity occurs after a median of 10 weeks of treatment and all patients were asymptomatic. The median PT and factor V activities values were 51.5% and 36.4%, respectively. Other coagulation factors were inconsistently decreased. Full recovery was observed within 3-60 days following purine analogs discontinuation. In four patients, drug rechallenge was associated with recurrence of the coagulation disorders. CONCLUSIONS: Although the mechanism remains unknown, this series that includes cases with positive drug reintroduction strongly suggests the causative role of these drugs. As all patients remained asymptomatic, treatment discontinuation should be carefully considered in patients who clearly benefits from this treatment.
