Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway | Congenital Defects | JAMA | JAMA Network
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Table.  Characteristics by Modafinil Exposure Status During Pregnancy in Norway (2005-2017) and Sweden (2006-2016)
Characteristics by Modafinil Exposure Status During Pregnancy in Norway (2005-2017) and Sweden (2006-2016)
1.
Teva Pharmaceuticals Ireland. Modafinil: potential risk of congenital malformations when administered during pregnancy. Accessed February 26, 2020. http://www.hpra.ie/docs/default-source/default-document-library/important-safety-information-modafinil99170c2697826eee9b55ff00008c97d0.pdf
2.
European Medicines Agency; Pharmacovigilance Risk Assessment Committee. New product information wording—extracts from PRAC recommendations on signals: 2. modafinil—evaluation of data on foetal outcomes including congenital anomalies from a single observational study in the US (EPITT No. 19367). Accessed February 26, 2020. https://www.ema.europa.eu/en/documents/other/new-product-information-wording-extracts-prac-recommendations-signals-adopted-8-11-april-2019-prac_en.pdf
3.
Government of Canada. Recalls and safety alerts: ALERTEC (modafinil) and the risk of congenital anomalies. Accessed February 26, 2020. https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php
4.
Damkier  P, Broe  A.  First-trimester pregnancy exposure to modafinil and risk of congenital malformations.   JAMA. 2020;323(4):374-376. doi:10.1001/jama.2019.20008PubMedGoogle ScholarCrossref
5.
Furu  K, Kieler  H, Haglund  B,  et al.  Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design.   BMJ. 2015;350:h1798. doi:10.1136/bmj.h1798PubMedGoogle ScholarCrossref
6.
Huybrechts  KF, Bröms  G, Christensen  LB,  et al.  Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium.   JAMA Psychiatry. 2018;75(2):167-175. doi:10.1001/jamapsychiatry.2017.3644PubMedGoogle ScholarCrossref
Research Letter
September 1, 2020

Incidence of Malformations After Early Pregnancy Exposure to Modafinil in Sweden and Norway

Author Affiliations
  • 1Centre for Pharmacoepidemiology, Karolinska Institutet, Stockholm, Sweden
  • 2Department of Chronic Diseases and Aging, Norwegian Institute of Public Health, Bergen, Norway
  • 3Centre for Fertility and Health, Norwegian Institute of Public Health, Oslo, Norway
JAMA. 2020;324(9):895-897. doi:10.1001/jama.2020.9840

Modafinil is used to improve wakefulness in adults with excessive sleepiness due to narcolepsy, for fatigue related to multiple sclerosis, and for the treatment of attention-deficit/hyperactivity disorder. In 2018, an interim report from a manufacturer-established pregnancy registry reported a prevalence of 15% for major malformation in infants exposed to modafinil during pregnancy, spurring regulatory bodies to amend product information.1-3 Recently, a Danish study reported a major malformation rate of 12% (n = 6) among 49 infants exposed to modafinil during early pregnancy compared with 3.9% (n = 32 466) among 828 644 unexposed to modafinil (adjusted odd ratio, 2.7; 95% CI, 1.1-6.9).4 To add to the emerging evidence, we investigated if modafinil use during early pregnancy was associated with major malformations in Norway and Sweden.

Methods

All singleton pregnancies resulting in live births in the nationwide medical birth registers in Norway (2005-2017) and Sweden (2006-2016) were identified and linked to their respective prescribed drug registers (containing data on medication dispensed at pharmacies) and national patient registers (containing data on diagnoses made during hospital-based specialist care). We excluded pregnancies with missing gestational age and those resulting in infants born with chromosomal anomalies (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision [ICD-10] codes Q90-Q99).

Exposure to modafinil (Anatomical Therapeutic Chemical code N06BA07) during the first trimester was defined as 1 or more filled prescriptions within the 30 days before the date of last menstrual period and the end of the first trimester (day 97 of gestation). A secondary exposure definition was 1 or more filled prescriptions during the first trimester. Unexposed pregnant women had no filled prescriptions of modafinil during the year before the last menstrual period to the end of the first trimester.

Characteristics of women, including maternal age at delivery, prepregnancy body mass index, and smoking during early pregnancy, were reported along with diagnoses recorded during the year before the last menstrual period to the end of the first trimester, and filled prescriptions during the 90 days before the last menstrual period to the end of the first trimester.

Major malformations were identified by ICD-10 codes.5 The number and percentage of cases of malformations after exposure or without exposure to modafinil was reported. Crude risk ratios and 2-sided Wald 95% CIs were calculated using SAS version 9.4 (SAS Institute Inc). This study was approved by research ethics committees in Norway and Sweden; register-based studies are exempt from informed consent.

Results

In a cohort of 1 917 605 pregnancies (744 311 in Norway and 1 173 294 in Sweden), 133 (0.007%; 38 in Norway and 95 in Sweden) were exposed to modafinil during early pregnancy. Compared with pregnant women who had not taken modafinil, pregnant women who had taken modafinil were more often overweight or obese and had higher rates of smoking and diagnoses of narcolepsy, multiple sclerosis, and attention-deficit/hyperactivity disorder (Table).

Overall, the rate of major malformations in the unexposed group was 2.1% (n = 40 697). There were 3 modafinil-exposed infants diagnosed as having a major malformation, resulting in a prevalence rate of 2.3% and a crude risk ratio of 1.06 (95% CI, 0.35-3.25). When restricted to only filled prescriptions during the first trimester, 75 pregnancies were exposed and 1 modafinil-exposed infant was diagnosed as having a major malformation (risk ratio, 0.63; 95% CI, 0.09-4.40).

Discussion

In this study, modafinil use during early pregnancy was not significantly associated with increased risk of major malformations. The combined Norwegian and Swedish study population had a similar proportion of modafinil-exposed pregnancies compared with the Danish study, allowing for more than double the number of exposed infants to be followed up. However, the 95% CIs estimated in this study overlap with those from the Danish study and allow for the possibility of a greater than 3-fold risk as previously reported.4

The limitations include that filled prescriptions were used as a proxy for medication use; any nonuse of modafinil would bias the results toward the null. Overall, the absolute number of exposed infants and malformations was low, hindering rigorous analyses accounting for potential confounding factors.

These results illustrate the need to focus on performing large and sufficiently powered studies for drug safety in pregnancy research, preferably from several countries, when exposures and outcomes are rare.6

Section Editor: Jody W. Zylke, MD, Deputy Editor.
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Article Information

Correction: This article was corrected on January 5, 2021, to update data in the Table and in the Results section.

Corresponding Author: Kari Furu, PhD, Norwegian Institute of Public Health, Marcus Thranes Gate 6, 0473 Oslo, Norway (kari.furu@fhi.no).

Accepted for Publication: May 20, 2020.

Author Contributions: Mr Karlsson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: All authors.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Cesta, Kieler, Furu.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Cesta, Engeland, Karlsson.

Obtained funding: Kieler, Furu.

Administrative, technical, or material support: Cesta, Kieler.

Supervision: Kieler, Furu.

Conflict of Interest Disclosures: None reported.

Funding/Support: This study was funded by NordForsk as part of the Nordic Pregnancy Drug Safety Studies project No. 83539 and by the Research Council of Norway as part of the International Pregnancy Drug Safety Studies project No. 273366. All funding was awarded to Dr Furu.

Role of the Funder/Sponsor: The funders/sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

References
1.
Teva Pharmaceuticals Ireland. Modafinil: potential risk of congenital malformations when administered during pregnancy. Accessed February 26, 2020. http://www.hpra.ie/docs/default-source/default-document-library/important-safety-information-modafinil99170c2697826eee9b55ff00008c97d0.pdf
2.
European Medicines Agency; Pharmacovigilance Risk Assessment Committee. New product information wording—extracts from PRAC recommendations on signals: 2. modafinil—evaluation of data on foetal outcomes including congenital anomalies from a single observational study in the US (EPITT No. 19367). Accessed February 26, 2020. https://www.ema.europa.eu/en/documents/other/new-product-information-wording-extracts-prac-recommendations-signals-adopted-8-11-april-2019-prac_en.pdf
3.
Government of Canada. Recalls and safety alerts: ALERTEC (modafinil) and the risk of congenital anomalies. Accessed February 26, 2020. https://healthycanadians.gc.ca/recall-alert-rappel-avis/hc-sc/2019/70201a-eng.php
4.
Damkier  P, Broe  A.  First-trimester pregnancy exposure to modafinil and risk of congenital malformations.   JAMA. 2020;323(4):374-376. doi:10.1001/jama.2019.20008PubMedGoogle ScholarCrossref
5.
Furu  K, Kieler  H, Haglund  B,  et al.  Selective serotonin reuptake inhibitors and venlafaxine in early pregnancy and risk of birth defects: population based cohort study and sibling design.   BMJ. 2015;350:h1798. doi:10.1136/bmj.h1798PubMedGoogle ScholarCrossref
6.
Huybrechts  KF, Bröms  G, Christensen  LB,  et al.  Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations: a cohort study from the International Pregnancy Safety Study Consortium.   JAMA Psychiatry. 2018;75(2):167-175. doi:10.1001/jamapsychiatry.2017.3644PubMedGoogle ScholarCrossref
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