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For our next Quick Take, let’s look at the risk of major malformations—fetal teratogenicity—from stimulant medications for the treatment of ADHD. This is an important question given that many of our patients with adult ADHD, who are likely to be treated with stimulants or might be candidates for that, are women of reproductive age. So, how much risk does it pose to take a stimulant medication like methylphenidate or one of the amphetamine salts while pregnant? What’s the first trimester risk?
As you know, to answer this question, you need a really big sample, a huge registry. We are fortunate to have a new study by Krista Huybrechts and colleagues looking at very large databases from the United States Medicaid Program and from a collection of Nordic countries. They are 2 different samples, so we can get 2 different perspectives.
The question then is: What is the risk of major congenital malformations in patients who are exposed to methylphenidate or amphetamines during the first trimester? And the answer is, if you adjust for confounding variables, as the authors did—and I’m not sure exactly how this is done statistically; I would imagine it’s challenging because you’re trying to account for how much risk ADHD itself and the behaviors that go with ADHD contribute to a potential fetal teratogenicity independent of the stimulant—we can say then that when such adjusting is done, there is no greater risk amongst exposed women than nonexposed women for fetal malformations in the first trimester of pregnancy.
This was studied first in a US Medicaid population and then replicated in the Nordic data from the countries of Finland, Iceland, Norway, Sweden, and Denmark. Sample sizes in the Nordic countries are 2.6 million unexposed controls versus about 1500 exposed pregnancies and a similar huge sample in the United States. However, we have to consider that when both of those databases were combined, there was a signal. They found a 28% increased risk of cardiovascular malformations associated with methylphenidate exposure. Now, this requires a lot of assumptions. And it’s the first time this is seen. It was not seen in the Nordic data; it was not seen in the United States alone. Only when you combine these data did that signal emerge. What does this mean? Frankly, I don’t think we really know. It means there may be some risk. Cardiovascular malformations may be an issue.
It would be wonderful to have a replication of this study. Remember that, for example, lamotrigine was associated with a possible risk of cleft palate in 1 of the registry studies. There are now about 4 of those. And in the other 3 registries, that risk was not found. So, the current working conclusion is that lamotrigine does not pose an increased risk of cleft lip or cleft palate. Having 1 study like this from Huybrechts and colleagues gives us pause, but I don’t think it’s necessarily enough to guide our clinical decision making. On the other hand, it is useful to know. Patients may be asking about this, and how you handle that with any given patient is a challenging clinical process.
In summary, we could say that stimulants used for the treatment of ADHD in women of reproductive age carry very little to zero risk of causing major fetal malformations, including cardiovascular malformations in developing fetuses. This comes with a caution that statistical adjustments for confounding variables were necessary in order to arrive at this conclusion and that having a replication and an additional database would be useful before we can really relax about that risk.
Abstract
Association Between Methylphenidate and Amphetamine Use in Pregnancy and Risk of Congenital Malformations A Cohort Study From the International Pregnancy Safety Study Consortium
Krista F. Huybrechts, MS, PhD, Gabriella Bröms, MD, PhD, Lotte Brix Christensen, MSc, Kristjana Einarsdóttir, PhD, Anders Engeland, MSc, PhD, Kari Furu, MScPharm, MPH, PhD, Mika Gissler, PhD, Sonia Hernandez-Diaz, MD, DrPH, Pär Karlsson, MSc, Øystein Karlstad, MScPharm, PhD, Helle Kieler, MD, PhD, Anna-Maria Lahesmaa-Korpinen, PhD, Helen Mogun, MS, Mette Nørgaard, MD, PhD, Johan Reutfors, MD, PhD, Henrik Toft Sørensen, DMSc, PhD, Helga Zoega, MA, PhD, and Brian T. Bateman, MD, MSc
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.
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Reference
Huybrechts, K. F., Bröms, G., Christensen, L. B., 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, H. T., Zoega, H., & Bateman, B. T. (2018). Association between methylphenidate and amphetamine use in pregnancy and risk of congenital malformations. JAMA Psychiatry, 75(2), 167
