Home Women Health Essential Reads: Modafinil and Armodafinil During Pregnancy Related to Increased Risk of Malformations

Essential Reads: Modafinil and Armodafinil During Pregnancy Related to Increased Risk of Malformations

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Essential Reads: Modafinil and Armodafinil During Pregnancy Related to Increased Risk of Malformations

Modafinil (brand name Provigil) and armodafinil (Nuvigil) are wake-promoting agents used to treat sleepiness attributable to narcolepsy, shift work sleep problem, or obstructive sleep apnea. Also they are utilized in other settings, often together with other medications, to treat ADHD symptoms, depressive symptoms, fatigue, and cognitive dysfunction.  

Danish Study of fifty Modafinil-Exposed Infants

In 2020, a Danish study reported a serious malformation rate of 12% (n = 6) in 50 modafinil-exposed pregnancies, in comparison with a rate of 4.5% in methylphenidate-exposed pregnancies and three.9% in unexposed pregnancies. After adjusting for potential confounders, modafinil was related to a significantly increased risk for malformation in comparison with 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 discover women using modafinil in pregnancy.  All singleton pregnancies leading to live births were identified within the nationwide medical birth registers from Norway (2005- 2017) and Sweden (2006-2016).  

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

Overall, the speed of major malformations within the unexposed group was 2.1%.  Within the modafinil group, there have been three infants diagnosed with a serious malformation, leading to a prevalence rate of two.6% and a crude risk ratio of 1.06 (95% CI, 0.35-3.26). 

Data from the 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 inside 6 weeks prior to conception or while pregnant.  Collected information is assessed as prospective if enrollment occurs before knowledge of the pregnancy end result or detection of a congenital malformation through prenatal testing.  

In contrast to adversarial events reporting carried out by drug manufacturers which might overestimate the prevalence of malformations, these data were collected as a 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 while pregnant.  After these findings were released, regulatory bodies in several countries issued warnings regarding using modafinil in women of reproductive age.

In essentially 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).  On this cohort, 81 women received modafinil, 67 received armodafinil, and one patient received each drugs. Narcolepsy was indicated in 70% of prescriptions.  

Amongst  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 overall population.  Of those live births with malformations, 4 had congenital torticollis, 2 had hypospadias, and three had congenital heart defects.  Adding within the retrospective cases didn’t change the prevalence of malformations.  

These findings are much like those observed within the Danish study published in 2020 which demonstrated a serious malformation rate of 12% (n = 6) in 49 modafinil-exposed pregnancies.  Nonetheless, these data and the present study should not consistent with a more moderen report from Sweden and Norway, which demonstrated an overall risk of major malformations of two.3% (3 out of 133 exposed pregnancies).  There is just not a particular pattern of malformations related to exposure to modafinil, even though it is notable that 4 of the 13 infants in the present study had congenital torticollis.  This kind of malformation is comparatively rare in the overall population and is a malformation not typically reported in these exposure studies.  

Advising Patients on the Use of Modafinil During Pregnancy

Based on these findings, we’d not recommend using modafinil or armodafinil while pregnant.  Ideally we would love to have data from 600-700 exposures to get a greater estimate of risk; basing decisions regarding safety on small sample sizes can result in miscalculations of risk in either direction.  Nonetheless, within the absence of adequate data, it will be sensible to exercise caution when using modafinil and armodafinil in women of reproductive age, on condition that half of all pregnancies are unplanned. In those situations where using modafinil is indicated in a lady of reproductive age, effective contraception is important.

Necessary Reminder: Modafinil and armodafinil are inducers of the CYP-3A4 hepatic enzymes and increase the metabolism of hormonal contraceptives, thus they could decrease the effectiveness of hormonal contraception, including contraception pills, injections, implants, transdermal patches, and vaginal rings.   Women who plan to take modafinil or armodafinil ought to be counseled to make use of an alternate, more practical, approach to contraception, reminiscent of a barrier method or an IUD.

Health Canada has issued the next recommendations regarding using modafinil.     

  • Women who’re pregnant, or plan to change into pregnant, shouldn’t use modafinil.
  • Because hormonal contraception methods, reminiscent of contraception pills, may not work as well when used similtaneously modafinil, women using all these contraception can have the next likelihood of getting pregnant while taking modafinil. Alternative modes of contraception ought to be considered.  
  • Women should take a pregnancy test inside every week before starting treatment with modafinil to make sure they should 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)

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