Maternal Methylphenidate Use May Increase Risk for Congenital Malformations

pregnant woman taking a pill
pregnant woman taking a pill
Weighing the benefits and risks of treatment options for ADHD in women of reproductive age is a clear priority.

Results from a study published in JAMA Psychiatry show that methylphenidate taken by expectant mothers during the first trimester poses a small but significant risk for congenital cardiac malformations in the newborn. This effect was not seen with other amphetamines.

Due to increasing numbers of women prescribed and taking stimulants during pregnancy, as well as women taking stimulants who accidentally become pregnant, researchers aimed to examine the relative risks for all congenital malformations linked to intrauterine stimulant exposure.

This US study was a non-randomized retrospective observational cohort study undertaken by the International Pregnancy Safety Study Consortium. The study was replicated in a Nordic cohort due to the detection of potential safety concerns that indicated the need for confirmation. US Medicaid records and Nordic Health registries from 2000 to 2013 were examined. 

A total of 1,813,894 live births in the US cohort and 2,560,069 live births in the Nordic Health group were included in the study. Women who were exposed to a teratogen (n=3562) or whose fetuses demonstrated chromosomal abnormalities (n=3156) were excluded from the study.

Rates of all congenital malformations per 1000 live births were 35.0 for non-exposed mothers, 45.9 for mothers exposed to methylphenidate, and 45.4 for mothers taking amphetamines. Rates for congenital cardiac malformations 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), respectively.

After adjustment for confounding factors, the relative risk for methylphenidate use was 1.11 for all congenital malformations (95% CI, 0.91-1.35) and 1.28 for congenital cardiac malformations (95% CI, 0.94-1.74). There were no significantly increased risks for amphetamines in terms of either congenital malformations (relative risk [RR] 1.05; 95% CI, 0.93-1.19) or congenital cardiac malformations (RR0.96; 95% CI, 0.78-1.19). The association between methylphenidate and all congenital malformations was found to be insignificant.

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During confirmation analysis in the Nordic cohort, methylphenidate carried a 1.28 RR (95% CI, 0.83-1.97) for congenital cardiac malformations, which produced a final pooled estimated RR of 1.28 (95% CI, 1.00-1.64) for congenital cardiac malformations.

The researchers noted that study strengths included being sufficiently powered to detect data that other, smaller studies may have missed, the absence of recall bias, and minimal to no surveillance bias. Identified limitations included possible misclassification of exposure (resulting in bias toward the null), non-randomization of subjects, and potential underestimation of the relative risk because both cohorts were restricted to live births.

In conclusion, researchers detected a 28% increase in the risk for congenital cardiac malformations when the mother was treated with methylphenidate. The implication is that maternal methylphenidate use resulted in an additional 3 infants per 1000 born with congenital cardiac malformations, in addition to the 10 per 1000 normally seen in live births without methylphenidate exposure — a 30% increase above baseline.

Because this is a substantial uptick, the researchers noted that while the absolute risk is minimal, these findings show that weighing the benefits and risks of treatment options for attention deficit hyperactivity disorder (ADHD) in women of reproductive age are a clear priority.


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 [published online December 13, 2017]. JAMA Psychiatry.doi:10.1001/jamapsychiatry.2017.3644