In utero modafinil, armodafinil exposure increases risk for major congenital malformations

The offspring of women who used modafinil or armodafinil during pregnancy had a higher risk of major congenital malformations than the general population, data show.

“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,” Sigal Kaplan, PhD, BPharm, and colleagues from Teva Pharmaceuticals wrote in JAMA Internal Medicine.

The researchers analyzed data from 148 prospective (n = 122) and retrospective (n = 26) pregnancies documented in post-marketing studies on modafinil or armodafinil. There were 81 women who received modafinil, 67 who received armodafinil, and one patient received both drugs. Narcolepsy was indicated in 70% of prescriptions.

Kaplan and colleagues reported that of 102 prospective live births with data available by the study cutoff date of February 2019, 13% of infants had a major congenital malformation. The researchers noted that this was higher than the prevalence of congenital malformations in the general population, which is about 3%.

Also, among the live births with malformations, four had congenital torticollis and two had hypospadias. Three had congenital heart defects, which yielded a prevalence of cardiac malformation of 3%, compared with just 1% found in the general population, the researchers said. In addition, the prevalence of major congenital malformations in the 97 prospective live births exposed during the first trimester was 13%. Pooling the data for both prospective and retrospective live births resulted in the same major congenital malformation prevalence of 13% that was seen in prospective live births alone.

Kaplan and colleagues noted that narcolepsy has not been associated with an increased risk for abnormal pregnancy outcomes in previous research, suggesting that physicians should look carefully at modafinil and armodafinil use during pregnancy.

“Although the available data are inconclusive for causality, the potential increased risk of major congenital malformations 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,” Kaplan and colleagues wrote.

In a related editorial, Neda Ghaffari, MD, and Patricia A. Robertson, MD, both perinatologists at the University of California, San Francisco, wrote that modafinil and armodafinil “should be avoided or offered along with a reliable contraceptive to individuals who could become pregnant.”

References:
Ghaffari N, Robertson PA. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2020.4206.

Kaplan S, et al. JAMA Intern Med. 2020;doi:10.1001/jamainternmed.2020.4009.