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)

Author:

Onken Marlies1ORCID,Lohse Lukas1,Coulm Bénédicte2,Beghin Delphine2,Richardson Jonathan L.3,Bermejo‐Sánchez Eva4,Aguilera Cristina5,Bosch Montserrat5,Cassina Matteo6,Chouchana Laurent7,De Santis Marco8,Duman Mine Kadioglu9,Gören M. Zafer10,Johnson Diana11,Bera Annie Pierre Jonville12,Kaplan Yusuf C.13,Kennedy Debra14,Kwok Susan14,Lacroix Isabelle15,Lepelley Marion16,Pistelli Alessandra17,Schaefer Christof1,Te Winkel Bernke18,Uysal Nusret13,Winterfeld Ursula19,Yakuwa Naho20,Diav‐Citrin Orna21,Vial Thierry22,Dathe Katarina1

Affiliation:

1. Charité ‐ Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt‐Universität zu Berlin, Institute of Clinical Pharmacology and Toxicology, Embryotox Center of Clinical Teratology and Drug Safety in Pregnancy Berlin Germany

2. AP‐HP.Sorbonne Université, Hôpital Trousseau, Département de Santé Publique, Centre de Référence sur les Agents Tératogènes (CRAT) Paris France

3. UK Teratology Information Service, Newcastle upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne UK

4. Institute of Rare Diseases Research (IIER), Research Unit on Congenital Anomalies‐UIAC and Spanish Teratology Information Services SITTE and SITE, Instituto Salud Carlos III (ISCIII) Madrid Spain

5. Clinical Pharmacology Service Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus Barcelona Spain

6. Clinical Genetics Unit, Department of Women's and Children's Health University of Padova Padova Italy

7. Assistance Publique‐Hôpitaux de Paris, Hôpital Cochin, Service de pharmacologie périnatale, pédiatrique et adulte Centre Régional de Pharmacovigilance Paris France

8. Teratology Information Service Fondazione Policlinico Universitario Agostino Gemelli IRCCS Rome Italy

9. Teratology Information Service, Department of Pharmacology, Faculty of Medicine Karadeniz Technical University Trabzon Turkey

10. Department of Medical Pharmacology, Faculty of Medicine Marmara University İstanbul Turkey

11. Department of Pediatrics University of California San Diego California USA

12. Service de Pharmacosurveillance Centre Régional de Pharmacovigilance Centre‐Val de Loire Tours France

13. Department of Pharmacology, Izmir Katip Celebi University School of Medicine, Training and Research Center Izmir Turkey

14. MotherSafe, The Royal Hospital for Women Randwick New South Wales Australia

15. Service de pharmacologie médicale et clinique, centre régional de pharmacovigilance, faculté de médecine, CHU de Toulouse Toulouse France

16. Université Grenoble Alpes, Centre régional de pharmacovigilance Grenoble France

17. Toxicology Unit and Poison Control Centre, Teratology Information Service Careggi University Hospital Florence Italy

18. Teratology Information Service, Netherlands Pharmacovigilance Centre Lareb 's‐Hertogenbosch The Netherlands

19. Swiss Teratogen Information Service, Service de Pharmacologie Clinique Lausanne University Hospital and University of Lausanne Lausanne Switzerland

20. Japan Drug Information Institute in Pregnancy, National Center for Child Health and Development Tokyo Japan

21. The Israeli Teratology Information Service Ministry of Health, Hebrew University Hadassah Medical School Jerusalem Israel

22. Pharmacovigilance Center Hospital University Pharmacotoxicology Department Lyon France

Abstract

AbstractObjectiveIn 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.MethodMulticenter 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.ResultsOne 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.ConclusionThe 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.

Funder

Bundesinstitut für Arzneimittel und Medizinprodukte

Ministerie van Volksgezondheid, Welzijn en Sport

Instituto de Salud Carlos III

Publisher

Wiley

Subject

Psychiatry and Mental health

Reference28 articles.

1. Adjunctive treatment with psychostimulants and stimulant-like drugs for resistant bipolar depression: a systematic review and meta-analysis

2. Poll results: look who's doping

3. Government of Canada.Recalls and Safety Alerts: ALERTEC (Modafinil) and the Risk of Congenital Anomalies.2019Accessed April 28 2023.https://www.healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php

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1. Progress in perinatal mental health research;Acta Psychiatrica Scandinavica;2024-08-13

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