What is the risk of congenital malformations associated with intrauterine exposure to stimulant attention-deficit/hyperactivity disorder medications?
Results from this cohort study including 1.8 million pregnancies nested in US Medicaid Analytic eXtract (2000-2013), with replication of initial safety signals in 2.5 million singleton pregnancies in the Nordic Health registries (2003-2013), suggest a potential small increased risk of cardiac malformations associated with methylphenidate use (pooled relative risk, 1.28; 95% CI, 1.00-1.64); an increase in the risk of this malformation type was not found for amphetamines. Neither methylphenidate nor amphetamines were associated with an increased risk for malformations overall.
This study provides important information when weighing the risks and benefits of alternative treatment strategies for attention-deficit/hyperactivity disorder in women of reproductive age and during early pregnancy and illustrates the unique opportunity provided by the International Pregnancy Safety Study network to rapidly follow-up on initial safety signals.
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.
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.
Methylphenidate and amphetamines dispensed during the first trimester.
Main Outcomes and Measures
Major congenital malformations and subgroup of cardiac malformations.
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.
Huybrechts KF, Bröms G, Christensen LB, Einarsdóttir K, Engeland A, Furu K, Gissler M, Hernandez-Diaz S, Karlsson P, Karlstad Ø, Kieler H, Lahesmaa-Korpinen A, Mogun H, Nørgaard M, Reutfors J, Sørensen HT, Zoega H, Bateman BT. Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital MalformationsA Cohort Study From the International Pregnancy Safety Study Consortium. JAMA Psychiatry. 2018;75(2):167–175. doi:10.1001/jamapsychiatry.2017.3644
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