Odds ratios and 95% CIs comparing first-trimester exposure to modafinil with those who were unexposed and with those who were exposed to methylphenidate. Those who were methylphenidate exposed are also compared with those who were unexposed.
Customize your JAMA Network experience by selecting one or more topics from the list below.
Damkier P, Broe A. First-Trimester Pregnancy Exposure to Modafinil and Risk of Congenital Malformations. JAMA. 2020;323(4):374–376. doi:10.1001/jama.2019.20008
Modafinil is a stimulant drug used in the treatment of excessive daytime sleepiness associated with narcolepsy.1 In Denmark, it is also sometimes used off-label for fatigue in multiple sclerosis. Modafinil has been discouraged during pregnancy because of a lack of safety data. In June 2019, the manufacturer alerted health care professionals that an interim analysis of postmarketing surveillance data detected major malformations among 15% of children exposed to modafinil during pregnancy compared with 3% in the background population.2
We examined the association between first-trimester exposure to modafinil and risk of major congenital malformations.
We identified all pregnancies from 2004 to 2017 using the Danish national health registries. Modafinil exposure was defined as any prescription overlapping with the first trimester (first 91 days) of pregnancy. Duration of treatment was calculated by dividing amount prescribed with the standard daily defined dose of 200 mg. The primary comparison was with pregnancies exposed to an active comparator, methylphenidate, which is not associated with congenital malformations and is used for similar indications.3 It is recommended for treatment of attention-deficit/hyperactivity disorder (ADHD) during pregnancy. A second comparator group was pregnancies unexposed to modafinil and methylphenidate 1 year prior to and during pregnancy. Major malformations were identified during pregnancy, at delivery, or during the first year of life using the EUROCAT classification of malformations.
We excluded women not residing in Denmark for at least 2 years before delivery; pregnancies shorter than 18 weeks or missing information on gestational age; pregnancies exposed to known teratogens (retinoids, angiotensin-converting enzyme inhibitors, vitamin K antagonists, valproic acid, lithium, carbamazepine, oxcarbazepine, phenytoin, phenobarbital); and infants/fetuses with chromosomal malformations. Recording of gestational age in the Danish registries is 99% complete.
Logistic regression was used to calculate odds ratios (ORs), adjusting for diagnosis of diabetes and hypertension, concomitant use of psychotropic drugs (listed in the Table), maternal age, year of delivery, smoking status, and body mass index. Stata release 15.1 (StataCorp) was used for analysis, and a 2-sided 95% CI was used to define a significant association.
Registry-based studies are exempt from informed consent and ethical review in Denmark. The study was approved by the Danish Data Health Authority.
There were 49 pregnancies (0.006%) exposed to modafinil, 963 (0.12%) exposed to methylphenidate, and 828 644 unexposed pregnancies. Among modafinil-exposed women, 27% had a diagnosis of multiple sclerosis, and of methylphenidate exposed women, 11% had a diagnosis of ADHD. Sleep disorders occurred in 39% of modafinil users and 4.5% of methylphenidate users, and use of other psychoanalytics in the modafinil- and methylphenidate-exposed groups was reported to be 41% and 30%, respectively (Table).
There were 6 major congenital malformations in the modafinil-exposed group (no patient with multiple sclerosis received teriflunomide, a suspected teratogen), 43 in the methylphenidate-exposed group, and 32 466 in the unexposed pregnancies group, for absolute risks of 12% for modafinil, 4.5% for methylphenidate, and 3.9% for unexposed. The adjusted ORs were 3.4 (95% CI, 1.2-9.7) comparing modafinil and methylphenidate and 2.7 (95% CI, 1.1-6.9) comparing modafinil with unexposed (Figure).
In this nationwide study, first-trimester in utero exposure to modafinil compared with methylphenidate or no medication was significantly associated with an increased risk of congenital malformations.
In 2 case series totaling 274 patients with narcolepsy, no malformations among 13 modafinil-exposed pregnancies were reported.4,5 Narcolepsy itself does not appear to increase the risk of congenital malformations.6
There are several limitations. First, the potential for residual confounding exists. For example, baseline differences in psychiatric medications were adjusted for, but adjusting for psychiatric diagnoses was not feasible. Although methylphenidate was used as an active comparator to address confounding by indication, methylphenidate is indicated for ADHD as well as narcolepsy. Second, prescription redemptions were a proxy for actual use. Third, the small numbers of exposed women and events reflect the rarity of the exposure and decrease the precision of the point estimates. Fourth, specific malformations were not identifiable.
Although further research is needed, women contemplating pregnancy should currently avoid or discontinue modafinil.
Accepted for Publication: November 18, 2019.
Corresponding Author: Per Damkier, MD, PhD, Department of Clinical Biochemistry and Pharmacology, Odense University Hospital, Odense, DK 5000 Denmark (email@example.com).
Author Contributions: Dr Broe 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: All authors.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Damkier.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: All authors.
Obtained funding: Damkier.
Conflict of Interest Disclosures: None reported.
Funding/Support: This study was partly funded by grant NNF17OC0028866 from the Novo Nordisk Foundation.
Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
Create a personal account or sign in to: