Abstract
This cohort study uses data from the US Provigil/Nuvigil Pregnancy Registry to assess prevalence of fetal major congenital malformations after exposure to modafinil and armodafinil during pregnancy.
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.1,2 The US Provigil/Nuvigil Pregnancy Registry, a postmarketing requirement with data annually reported to the US Food and Drug Administration, was established to evaluate pregnancy and fetal outcomes in individuals who could become pregnant and received these drugs during pregnancy. This report provides results from cumulative data as of February 2019.
Methods
The US Provigil/Nuvigil Pregnancy Registry is part of an ongoing, prospective cohort study established in February 2010. Enrollment in the registry is open on a voluntary basis to any individual exposed to modafinil and/or armodafinil within 6 weeks prior to conception or during pregnancy. Those wishing to participate are required to provide informed consent and the contact information of their clinician, and must agree to be contacted periodically. The registry is posted on relevant websites, including FDA.gov and ClinicalTrials.gov, as well as on product labeling, which specifies a toll-free telephone number to the registry. Outreach efforts for patient recruitment included direct mail to health care professionals. This study was approved by Advarra Institutional Review Board.
A pregnancy was classified as prospective if enrollment occurred before knowledge of the pregnancy outcome or detection of a congenital malformation at a prenatal test. A pregnancy was classified as retrospective if enrollment occurred after knowledge of the pregnancy outcome or congenital malformation at a prenatal test.
Pregnancy and fetal outcomes were adjudicated by an independent registry advisory committee. The primary end point was major congenital malformations (MCMs) using the Metropolitan Atlanta Congenital Defects Program classification. Additional pregnancy outcomes included spontaneous abortion (<20 weeks’ gestation), elective pregnancy termination, and fetal death (≥20 weeks’ gestation).
Results
From February 2010 to February 2019, 148 individuals were enrolled in the registry; 81 received modafinil during pregnancy, 66 received armodafinil, and 1 received both modafinil and armodafinil (Table 1). Narcolepsy was the main indication reported (102 of 145 [70%]).
Table 1. Demographic and Baseline Characteristics for Pregnant Individuals Exposed to Modafinil and Armodafinil, 2010-2019.
| Demographic variables | No. (%)a | ||
|---|---|---|---|
| Prospective (n = 122) | Retrospective (n = 26) | Total (N = 148) | |
| Exposureb | |||
| Total No. | 122 | 26 | 148 |
| Modafinil | 62 (51) | 19 (73) | 81 (55) |
| Armodafinil | 59 (48) | 7 (27) | 66 (45) |
| Modafinil and armodafinil | 1 (1) | 0 | 1 (1) |
| Pregnant individual age | |||
| Total No. | 122 | 26 | 148 |
| Median (range), y | 31 (20-40) | 31 (21-35) | 31 (20-40) |
| Race | |||
| Total No. | 104 | 20 | 124 |
| White | 95 (91) | 20 (100) | 115 (93) |
| Otherc | 9 (9) | 0 | 9 (7) |
| Education | |||
| Total No. | 105 | 20 | 125 |
| High school graduate or higher | 66 (63) | 11 (55) | 77 (62) |
| Prepregnancy BMI | |||
| Total No. | 97 | 15 | 112 |
| Mean (SD) | 27 (6) | 26 (7) | 27 (6) |
| Trimester of exposure | |||
| Total No. | 118 | 25 | 143 |
| First trimester | 115 (97) | 22 (88) | 137 (96) |
| Comorbiditiesd | |||
| Total No. | 120 | 25 | 145 |
| Narcolepsy | 85 (71) | 17 (68) | 102 (70) |
| Depression | 39 (33) | 4 (16) | 43 (30) |
| Preeclampsia or pregnancy-induced hypertension | 15 (13) | 4 (16) | 19 (13) |
| Diabetes | 5 (4) | 1 (4) | 6 (4) |
| Gestational diabetes | 5 (4) | 0 | 5 (3) |
| Concomitant medicationsd | |||
| Total No. | 120 | 25 | 145 |
| Prenatal vitamins | 89 (74) | 16 (64) | 105 (72) |
| Selective serotonin reuptake inhibitors | 33 (28) | 1 (4) | 34 (23) |
| Antihistamines | 21 (18) | 4 (16) | 25 (17) |
| Thyroid hormones | 20 (17) | 4 (16) | 24 (17) |
| 5-HT3 and other antiemeticse | 16 (13) | 5 (20) | 21 (14) |
| Folic acid | 13 (11) | 3 (12) | 16 (11) |
| Antidepressants | 12 (10) | 3 (12) | 15 (10) |
| Antiepileptic | 11 (9) | 1 (4) | 12 (8) |
| Benzodiazepines | 10 (8) | 0 | 10 (7) |
| Proton-pump inhibitors | 8 (7) | 3 (12) | 11 (8) |
| Use during pregnancy | |||
| Tobacco | |||
| Total No. | 111 | 20 | 131 |
| Yes | 11 (10) | 1 (5) | 12 (9) |
| Alcohol | |||
| Total No. | 111 | 20 | 131 |
| Yes | 4 (4) | 1 (5) | 5 (4) |
| Illicit drug | |||
| Total No. | 111 | 20 | 131 |
| Yes | 0 | 1 (5) | 1 (1) |
Abbreviation: BMI, body mass index, calculated as weight in kilograms divided by height in meters squared.
Percentages are calculated using total number reported in each category as the denominator.
Percentage may not add up to 100% because of rounding.
Including Black individuals, Asian individuals, and individuals of unknown race/ethnicity.
Patients can be counted in multiple groups, so percentages do not add to 100%.
Including serotonin 5-HT3 receptor antagonists (eg, ondansetron).
Of the 122 prospective pregnancies, 110 had known outcomes at cutoff date (Table 2). Among 102 prospective live births, 13% (n = 13) had MCMs, which is above the prevalence of about 3% in the general population.3 Of these live births with MCMs, 4 had congenital torticollis, 2 had hypospadias, and 3 had congenital heart defects, of which the latter yielded a cardiac malformation prevalence of 3% compared with about 1% in the general population.4 The prevalence of MCMs in the 97 prospective live births exposed during the first trimester was 13% (n = 13). Pooling the data for both prospective and retrospective live births resulted in the same MCM prevalence of 13% observed in prospective live births alone.
Table 2. Pregnancy Exposure to Modafinil and Armodafinil, 2010-2019.
| Characteristic | No. (%) | ||
|---|---|---|---|
| Prospective | Retrospective | Total | |
| Pregnancies (by individual) | |||
| Total No. | 122 | 26 | 148 |
| Lost to follow-up | 4 (3) | 0 | 4 (3) |
| Pregnancies complete (known outcomes) | 110 (90) | 26 (100) | 136 (92) |
| Outcome pending | 8 (7) | 0 | 8 (5) |
| Pregnancies with known outcomes (by fetus)a | |||
| Total No. | 116 | 26 | 142 |
| Live birth | 102 (88) | 17 (65) | 119 (84) |
| Major congenital malformationsb | 13 (13) | 3 (18) | 16 (13) |
| Spontaneous abortion | 13 (11) | 8 (31) | 21 (15) |
| Elective terminationc | 1 (1) | 1 (4) | 2 (1) |
| Fetal death | 0 | 0 | 0 |
Including 6 twin fetuses.
Percentage is calculated of total live births.
Termination in prospective case was because of diagnosis of trisomy 21 and in retrospective case because of unknown reasons.
Discussion
Results of this analysis demonstrate that there is a potential increased risk of MCMs following in utero exposure to modafinil and/or armodafinil compared with the general population. This potential risk is not likely due to the underlying condition of narcolepsy, because previous data suggest that narcolepsy does not increase the risk of abnormal pregnancy outcomes.5,6 Moreover, an analysis of first-trimester exposure confirmed the higher potential risk for MCMs. These findings are consistent with a previously published Danish retrospective database study reporting an absolute risk of 12% for MCMs in first-trimester pregnancy exposure to modafinil.2 Because no specific organ malformation pattern was identified, a clear causal association between use of modafinil and/or armodafinil and MCMs cannot be established.
The limitations of this study include selection bias owing to voluntary enrollment, information bias owing to incorrect or incomplete data reporting, lack of internal comparison group, and a small sample size.
Although the available data are inconclusive for causality, the potential increased risk of MCMs 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.
References
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