As soon as we published this article on the use of modafinil during pregnancy, another study was published which included data on the reproductive safety of modafinil and armodafinil from the US Provigil/Nuvigil Pregnancy Registry.  

The US Provigil/Nuvigil Pregnancy Registry was established in February 2010 and has collected data from women exposed to modafinil and/or armodafinil within 6 weeks prior to conception or during pregnancy.  Collected information is classified as prospective if enrollment occurs before knowledge of the pregnancy outcome or detection of a congenital malformation through prenatal testing.  

In this study, researchers analyzed data from 148 pregnancies exposed to modafinil (Provigil) or armodafinil (Nuvigil) which were prospectively followed (n = 122) or retrospectively ascertained (n = 26).  In this cohort, 81 women received modafinil, 67 received armodafinil, and one patient received both drugs. Narcolepsy was indicated in 70% of prescriptions.  

Among  the 97 prospective live births with first trimester cepsore, 13% (n = 13) had major malformations, which is well above the prevalence of about 3%-4% observed in the general population.  Of these live births with malformations, 4 had congenital torticollis, 2 had hypospadias, and 3 had congenital heart defects.  Adding in the retrospective cases did not change the prevalence of malformations.  

These findings are similar to those observed in a Danish study published in January of this year which demonstrated a major malformation rate of 12% (n = 6) in 49 modafinil-exposed pregnancies.  However, these data and the current study are not consistent with a more recent report from Sweden and Norway, which demonstrated an overall risk of major malformations of 2.3% (3 out of 133 exposed pregnancies).  There is not a specific pattern of malformations associated with exposure to modafinil, although it is notable that 4 of the 13 infants in the current study had congenital torticollis, which is relatively rare in the general population and is a malformation not typically reported in these exposure studies.  

Based on these findings, we would not recommend the use of modafinil or armodafinil during pregnancy.  Ideally we would like to have data from 600-700 exposures to get a better estimate of risk; basing decisions regarding safety on small sample sizes can lead to miscalculations of risk in either direction.  Nonetheless, in the absence of adequate data, it would be wise to exercise caution when using modafinil in women of reproductive age, given that half of all pregnancies are unplanned. In those situations where the use of modafinil is indicated in a woman of reproductive age, effective contraception is essential.

Important Reminder: Modafinil and armodafinil are inducers of the CYP-3A4 hepatic enzymes and increase the metabolism of hormonal contraceptives, thus they may decrease the effectiveness of hormonal contraception, including birth control pills, injections, implants, transdermal patches, and vaginal rings.   Women who plan to take modafinil or armodafinil should be counseled to use an alternate, more effective, method of contraception, such as a barrier method or an IUD.

Ruta Nonacs, MD PhD

Kaplan S, Braverman DL, Frishman I, Bartov N.  Pregnancy and Fetal Outcomes Following Exposure to Modafinil and Armodafinil During Pregnancy.  JAMA Intern Med. 2020 Oct 19.

ALERTEC (modafinil) and the Risk of Congenital Anomalies (Health Canada)