For women with mild to moderate attention-deficit/hyperactivity disorder (ADHD) symptoms, we often recommend discontinuing stimulant medications and switching to a non-pharmacologic intervention. Many women experience some decrease in their level of functioning; however, they are able to forgo or minimize pharmacologic treatment during pregnancy. There are, however, women who experience more severe symptoms which interfere significantly with their daily functioning. In these women, we may consider maintaining pharmacologic treatment.
The primary reason for limiting the use of stimulants during pregnancy has been that our data regarding the reproductive safety of stimulant medications, including methylphenidate and amphetamines, has been sparse. In JAMA Psychiatry, Huybrechts and colleagues has published the results of a cohort study analyzing data from Medicaid-insured women nested in the 2000-2013 US Medicaid Analytic eXtract and the Nordic Health registries (2003-2013) (Denmark, Finland, Iceland, Norway, and Sweden).
About 1.8 million publicly insured pregnancies in the US and 2.6 million pregnancies in the Nordic countries were included in the analysis. Relative risks were estimated, taking into account underlying psychiatric illness and other potential confounding factors.
The primary analysis focused only on the US data; 35.0 per 1000 or 3.5% of the infants not exposed to stimulants were born with a congenital malformation, as compared to 45.9 per 1000 or 4.59% of the infants exposed to methylphenidate and 45.4 (or 4.54%) of the infants exposed to amphetamines. The researchers also identified an increase in risk for cardiac malformations: 12.7 (95% CI, 12.6-12.9) in unexposed, 18.8 (95% CI, 13.8-25.6) in methylphenidate-exposed, and 15.4 in amphetamine-exposed (95% CI, 12.5-19.0) per 1000 infants.
When the researchers controlled for potential confounding factors, including maternal psychiatric illness, the findings of increased risk were no longer observed. The adjusted relative risks for exposure to 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. This is not emphasized in the abstract, but look at the confidence intervals here. The confidence intervals include 1, which means that there is insufficient evidence to conclude that the two groups are statistically significantly different. In other words, these findings were NOT STATISTICALLY SIGNIFICANT.
They next analyzed data from the Nordic countries and observed a relative risk of 1.28 (95% CI, 0.83-1.97) for cardiac malformations in the methylphenidate exposed infants, again a finding which was not statistically significant. When they combined the US and Nordic cohorts, they calculated a pooled estimate of 1.28 (95% CI, 1.00-1.64), a finding which was borderline statistically significant.
Understanding the Clinical Implications of this Study
Contrary to the grim news headlines reporting that the use of ADHD drugs during pregnancy increases the risk of heart defects, our group has a different, and certainly more positive, view of the findings. The real strength of this study is its size. Thus far we have derived data on the reproductive safety of stimulants from smaller studies. These studies have not documented an increased risk of malformations in children exposed in utero to either methylphenidate or amphetamines; however, given the smaller size of the studies, it might not be possible to identify smaller increases in relative risk. The Huybrechts study included 2072 infants exposed to methylphenidate and 5517 infants exposed to amphetamines in the US cohort, making this study by far the largest we have.
From a statistical vantage point, this study does not demonstrate that infants exposed to stimulants are at greater risk for congenital malformations than unexposed infants. But even if we say that there is a signal here, the increase in risk is very, very small. In this study, the risk of cardiovascular malformation was 1.27% in the unexposed children. Assuming the relative risks calculated in this study are correct, the risk for cardiac malformation in the methylphenidate-exposed children would be around 1.63%. A very small increase in absolute risk.
All in all, I think the findings of this study are quite positive. If there is a risk, it is a small one. Our primary goal is to maintain mental health stability and functioning during pregnancy, and this study provides useful information to women taking stimulants who are pregnant or planning to conceive.
Ruta Nonacs, MD PhD
Huybrechts KF, Bröms G, Christensen LB, Einarsdóttir K, 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. 2017 Dec 13.
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