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Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations: A Cohort Study From the International Pregnancy Safety Study Consortium

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  • Krista F Huybrechts, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
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  • Gabriella Bröms, Centre for Pharmacoepidemiology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  • ,
  • Lotte Brix Christensen
  • Kristjana Einarsdóttir, Centre of Public Health Sciences, Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
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  • Anders Engeland, Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway.
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  • Kari Furu, Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway.
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  • Mika Gissler, Department of Neurobiology, Care Sciences and Society, Division of Family Medicine, Karolinska Institutet, Stockholm, Sweden.
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  • Sonia Hernandez-Diaz, Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
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  • Pär Karlsson, Centre for Pharmacoepidemiology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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  • Øystein Karlstad, Department of Pharmacoepidemiology, Norwegian Institute of Public Health, Oslo, Norway.
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  • Helle Kieler, Centre for Pharmacoepidemiology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
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  • Anna-Maria Lahesmaa-Korpinen, Information Services Department, National Institute for Health and Welfare, Helsinki, Finland.
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  • Helen Mogun, Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • ,
  • Mette Nørgaard
  • Johan Reutfors, Centre for Pharmacoepidemiology, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden.
  • ,
  • Henrik Toft Sørensen
  • Helga Zoega, Medicines Policy Research Unit, Centre for Big Data Research in Health, University of New South Wales, Sydney, New South Wales, Australia.
  • ,
  • Brian T Bateman, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.

Importance: Given the rapidly increasing use of stimulant medications during pregnancy and among women of reproductive age who may become pregnant inadvertently, there is a need to better understand their safety.

Objective: To examine the risk of congenital malformations associated with intrauterine exposure to stimulants.

Design, Setting, and Participants: Cohort study of the Medicaid-insured population in the United States nested in the 2000-2013 US Medicaid Analytic eXtract, with follow-up of safety signals detected in the Medicaid Analytic eXtract data using the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden). A total of 1 813 894 publicly insured pregnancies in the United States and 2 560 069 singleton pregnancies in the 5 Nordic countries ending in live births were included. Relative risks were estimated accounting for underlying psychiatric disorders and other potential confounders. Relative risk estimates for the US and Nordic data were pooled using a fixed-effects meta-analytic approach. The study was conducted from July 1, 2015, to March 31, 2017.

Exposures: Methylphenidate and amphetamines dispensed during the first trimester.

Main Outcomes and Measures: Major congenital malformations and subgroup of cardiac malformations.

Results: In the US data, of the 1 813 894 pregnancies evaluated, 35.0 per 1000 infants not exposed to stimulants were diagnosed as having congenital malformations, compared with 45.9 per 1000 infants for methylphenidate and 45.4 for amphetamines. For cardiac malformations, the risks were 12.7 (95% CI, 12.6-12.9), 18.8 (95% CI, 13.8-25.6), and 15.4 (95% CI, 12.5-19.0) per 1000 infants, respectively. The adjusted relative risks for methylphenidate were 1.11 (95% CI, 0.91-1.35) for any malformation and 1.28 (95% CI, 0.94-1.74) for cardiac malformations. No increased risks were observed for amphetamines: 1.05 (95% CI, 0.93-1.19) for any malformations and 0.96 (95% CI, 0.78-1.19) for cardiac malformations. Findings were confirmed in sensitivity analyses accounting for proxies of unmeasured confounders and increasing the specificity of the exposure and outcome definitions. Replication of the analyses for methylphenidate using the Nordic data including 2 560 069 pregnancies yielded a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations, resulting in a pooled estimate of 1.28 (95% CI, 1.00-1.64).

Conclusions and Relevance: These findings suggest a small increase in the risk of cardiac malformations associated with intrauterine exposure to methylphenidate but not to amphetamines. This information is important when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy.

Original languageEnglish
JournalJAMA Psychiatry
Volume75
Issue2
Pages (from-to)167-175
Number of pages9
ISSN0003-990X
DOIs
Publication statusPublished - 1 Feb 2018

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