Pregnancy and Fetal Outcomes Following Exposure to Modafinil and Armodafinil During Pregnancy

Although results of animal studies have shown reproductive toxic effects with use of modafinil and armodafinil, data on exposure during pregnancy in humans are limited.^1,2 The US Provigil/Nuvigil Pregnancy Registry, a postmarketing requirement with data annually reported to the US Food and Drug Administration, was established to evaluate pregnancy and fetal outcomes in individuals who could become pregnant and received these drugs during pregnancy. This report provides results from cumulative data as of February 2019.

The US Provigil/Nuvigil Pregnancy Registry is part of an ongoing, prospective cohort study established in February 2010. Enrollment in the registry is open on a voluntary basis to any individual exposed to modafinil and/or armodafinil within 6 weeks prior to conception or during pregnancy. Those wishing to participate are required to provide informed consent and the contact information of their clinician, and must agree to be contacted periodically. The registry is posted on relevant websites, including FDA.gov and ClinicalTrials.gov, as well as on product labeling, which specifies a toll-free telephone number to the registry. Outreach efforts for patient recruitment included direct mail to health care professionals. This study was approved by Advarra Institutional Review Board.

A pregnancy was classified as prospective if enrollment occurred before knowledge of the pregnancy outcome or detection of a congenital malformation at a prenatal test. A pregnancy was classified as retrospective if enrollment occurred after knowledge of the pregnancy outcome or congenital malformation at a prenatal test.

Pregnancy and fetal outcomes were adjudicated by an independent registry advisory committee. The primary end point was major congenital malformations (MCMs) using the Metropolitan Atlanta Congenital Defects Program classification. Additional pregnancy outcomes included spontaneous abortion (<20 weeks’ gestation), elective pregnancy termination, and fetal death (≥20 weeks’ gestation).

From February 2010 to February 2019, 148 individuals were enrolled in the registry; 81 received modafinil during pregnancy, 66 received armodafinil, and 1 received both modafinil and armodafinil (Table 1). Narcolepsy was the main indication reported (102 of 145 [70%]).

Of the 122 prospective pregnancies, 110 had known outcomes at cutoff date (Table 2). Among 102 prospective live births, 13% (n = 13) had MCMs, which is above the prevalence of about 3% in the general population.³ Of these live births with MCMs, 4 had congenital torticollis, 2 had hypospadias, and 3 had congenital heart defects, of which the latter yielded a cardiac malformation prevalence of 3% compared with about 1% in the general population.⁴ The prevalence of MCMs in the 97 prospective live births exposed during the first trimester was 13% (n = 13). Pooling the data for both prospective and retrospective live births resulted in the same MCM prevalence of 13% observed in prospective live births alone.

Results of this analysis demonstrate that there is a potential increased risk of MCMs following in utero exposure to modafinil and/or armodafinil compared with the general population. This potential risk is not likely due to the underlying condition of narcolepsy, because previous data suggest that narcolepsy does not increase the risk of abnormal pregnancy outcomes.^5,6 Moreover, an analysis of first-trimester exposure confirmed the higher potential risk for MCMs. These findings are consistent with a previously published Danish retrospective database study reporting an absolute risk of 12% for MCMs in first-trimester pregnancy exposure to modafinil.² Because no specific organ malformation pattern was identified, a clear causal association between use of modafinil and/or armodafinil and MCMs cannot be established.

The limitations of this study include selection bias owing to voluntary enrollment, information bias owing to incorrect or incomplete data reporting, lack of internal comparison group, and a small sample size.

Although the available data are inconclusive for causality, the potential increased risk of MCMs provides an impetus for health care professionals to enhance the benefit-risk monitoring of modafinil and/or armodafinil use in pregnant individuals and individuals who may become pregnant.

Accepted for Publication: June 23, 2020.

Corresponding Author: Sigal Kaplan, PhD, BPharm, Teva Pharmaceutical Industries Ltd, 12 Hatrufa St, Netanya 4250483, Israel (sigalit.kaplan@teva.co.il).

Published Online: October 19, 2020. doi:10.1001/jamainternmed.2020.4009

Author Contributions: Dr Kaplan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Kaplan, Braverman.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: All authors.

Critical revision of the manuscript for important intellectual content: Kaplan, Braverman, Frishman.

Statistical analysis: Kaplan.

Administrative, technical, or material support: Kaplan, Braverman, Bartov.

Supervision: Kaplan, Braverman, Frishman.

Conflict of Interest Disclosures: All authors are employees of Teva Pharmaceutical Industries Ltd.

Funding/Support: This study was funded by Cephalon Inc.

Role of the Funder/Sponsor: The sponsor had a role in the design and conduct of the study; study supervision, management, analysis, and interpretation of the data; preparation, review, and approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect those of Cephalon Inc and/or its affiliates, including but not limited to Teva Pharmaceutical Industries Ltd.

Additional Contributions: The authors thank John Edwards, BS, Annette Stemhagen, DrPH, and Heather Lang, BS, from United BioSource LLC for study execution, as well as Rukki Mirotznik, PhD, from Teva Pharmaceutical Industries Ltd for providing editorial support. They were not compensated for their assistance in the preparation of this article.