Essential Reads: Modafinil and Armodafinil During Pregnancy Associated with Increased Risk of Malformations

By | September 14, 2021

Modafinil (brand name Provigil) and armodafinil (Nuvigil) are wake-promoting agents used to treat sleepiness due to narcolepsy, shift work sleep disorder, or obstructive sleep apnea. They are also used in other settings, often in combination with other medications, to treat ADHD symptoms, depressive symptoms, fatigue, and cognitive dysfunction.  

Danish Study of 50 Modafinil-Exposed Infants

In 2020, a Danish study reported a major malformation rate of 12% (n = 6) in 50 modafinil-exposed pregnancies, compared to a rate of 4.5% in methylphenidate-exposed pregnancies and 3.9% in unexposed pregnancies. After adjusting for potential confounders, modafinil was associated with a significantly increased risk for malformation compared to methylphenidate or no exposure.

Data from the Swedish and Norwegian Study of 133 Modafinil-Exposed Infants

Researchers have used Swedish and Norwegian birth registers to identify women using modafinil in pregnancy.  All singleton pregnancies resulting in live births were identified in the nationwide medical birth registers from Norway (2005- 2017) and Sweden (2006-2016).  

In this cohort of nearly 2 million pregnancies, researchers used national prescribed drug registries to identify 133 pregnancies exposed to modafinil during early pregnancy. Compared to pregnant women who had not received modafinil, pregnant women using modafinil were more likely to be overweight or obese, had higher rates of smoking, and were more likely to be diagnosed with narcolepsy, multiple sclerosis, or ADHD.

Overall, the rate of major malformations in the unexposed group was 2.1%.  In the modafinil group, there were three infants diagnosed with a major malformation, resulting in a prevalence rate of 2.6% and a crude risk ratio of 1.06 (95% CI, 0.35-3.26). 

Data from the Provigil/Nuvigil Pregnancy Registry

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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 contrast to adverse events reporting carried out by drug manufacturers which can overestimate the prevalence of malformations, these data were collected as part of a pregnancy registry which recruited pregnant patients prior to the detection of a congenital malformation. In 2018, preliminary data from the registry released data indicating a prevalence of 15% for major malformations in infants exposed to modafinil during pregnancy.  After these findings were released, regulatory bodies in several countries issued warnings regarding the use of modafinil in women of reproductive age.

In the most recent report from the registry, 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 exposure, 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 the Danish study published in 2020 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.  This type of malformation is relatively rare in the general population and is a malformation not typically reported in these exposure studies.  

Advising Patients on the Use of Modafinil During Pregnancy

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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 and armodafinil 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.

Health Canada has issued the following recommendations regarding the use of modafinil.     

  • Women who are pregnant, or plan to become pregnant, should not use modafinil.
  • Because hormonal birth control methods, such as birth control pills, may not work as well when used at the same time as modafinil, women using these types of birth control may have a higher chance of getting pregnant while taking modafinil. Alternative modes of birth control should be considered.  
  • Women should take a pregnancy test within a week before starting treatment with modafinil to ensure they are not pregnant.

Ruta Nonacs, MD PhD

Cesta CE, Engeland A, Karlsson P, Kieler H, Reutfors J, Furu K.  Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway. JAMA. 2020 Sep 1;324(9):895-897.

Damkier P, Broe A.  First-Trimester Pregnancy Exposure to Modafinil and Risk of Congenital Malformations.  JAMA Psychiatry, January 2020.

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)

US Provigil/Nuvigil Pregnancy Registry

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)

MGH Center for Women's Mental Health

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