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More than 6 million American children have been diagnosed with ADHD. As the girls among them grow up and have children of their own, concern has been rising that taking ADHD medication in early pregnancy could heighten the risk of birth defects.
Now, a major study out in the journal JAMA Psychiatry finds a small added risk of heart malformations, but only from methylphenidate — better known as Ritalin and Concerta — not from amphetamines, aka Adderall.
The study looked at more than 4 million pregnancies, among American women on Medicaid and Nordic women in five countries.
I spoke with professor Krista Huybrechts of Brigham and Women's Hospital and Harvard Medical School, who led the research. Our conversation, lightly edited:
How would you sum up what you found?
In a nationwide cohort of 1.8 million publicly insured pregnant women who gave birth in the U.S., we found a 28 percent increased prevalence of cardiac malformations after first-trimester exposure to methylphenidate. And after replication of these analyses in a cohort of 2.5 million women who gave birth in the Nordic countries, the relative risk increase remained at 28 percent based on the pooled data.
Since cardiac malformations affect approximately 10 per thousand births, this increase corresponds to three additional infants born with congenital cardiac malformations for every thousand women treated with methylphenidate during the first trimester of pregnancy.
But no association was observed for methylphenidate and congenital malformations overall, or for amphetamines and any congenital or cardiac malformations.
If you found the significant increase in cardiac malformations, how could there not be an increase overall in malformations?
Because cardiac malformations are only one component of the overall malformations; the effect gets diluted.
So what does this mean for pregnant women?
Our findings suggest that if pregnant women take methylphenidate during the first trimester of pregnancy, they have a small increased risk of having a baby born with a cardiac malformation, but no such increase in risk was seen for amphetamines. So we feel this is important evidence to consider for pregnant women, and for young women of reproductive age when they are weighing the potential risks and benefits of different treatment strategies for ADHD.
About 10 in every 1,000 babies are born with heart defects. Among mothers who take methylphenidate -- Ritalin and Concerta -- for ADHD, that rises to 13 per 1,000, the study finds.
But as we just talked about, we feel it's important to emphasize that although cardiac malformations are a serious adverse outcome, they are quite rare. They affect approximately 10 per thousand births. And with use of methylphenidate, this risk appears to increase to about 13 per thousand births. But this risk would have to be weighed against the risk associated with discontinuing treatment during pregnancy when symptoms are severe and interfere significantly with daily functioning.
Is this study a first in any way?
This is the first study to issue from the International Pregnancy Safety Study Consortium, known as InPreSS. That is a collaboration among research groups with access to health care databases with demonstrated ability to study the safety of medications in pregnancy.
Given the increasing use of prescription medications during pregnancy worldwide, and the exclusion of pregnant women from clinical trials for ethical reasons, there is a pressing need for the rapid generation of high-quality evidence on the safety and effectiveness of prescription medication used during pregnancy. So the goal of InPreSS is to provide the best available human data on the safety of prescription medications during pregnancy by combining large-scale data from several countries.
Currently in InPreSS, we have nationwide Medicaid data that cover close to 50 percent of pregnancies in the U.S. and the national registries in the five Nordic countries that cover virtually all pregnancies resulting in live births or stillbirths in these countries.
In this initial InPreSS study, we used the collaborative network to follow up on a potential safety signal that was initially identified in the US cohort. The opportunity provided by the InPreSS network to rapidly follow up on initial safety signals that may or may not be causal is unique. And it's likely to reduce the widespread dissemination of alarming early findings that are not confirmed or substantially weakened in subsequent studies; premature dissemination of such early findings creates challenges for pregnant women and clinicians who are trying to weigh the risks and benefits of treatment.
In other words, pregnant women won't have to freak out as much. That's good. How else is this a first?
The second issue relates more to the specific medication we studied. There is very limited evidence available to date on the safety of stimulant medications in pregnant women. The few studies that exist include less than 250 exposed women, and our study markedly expands on this evidence base by reporting on the outcome of 2,072 pregnancies exposed to this medication during the first trimester in the U.S. cohort and 1,402 in the Nordic validation cohort. This allowed us to detect a small increase in the risk of cardiac malformations which prior studies may have been under-powered to detect.
Drugs have been rated according to their safety in pregnancy — A, B, C. Could this change their ratings?
These letters have been replaced by a more narrative description of the evidence base that is available for the drugs. And so hopefully our study results will inform the narrative that will be included in the labeling.
I imagine many women will immediately think about switching drugs...
I think it is important to keep in mind that this study is looking at just one potential adverse effect. There are many other potential adverse effects for both the infant and the mom that have not been studied and that weigh into this risk-benefit consideration.
While it is important information to take into account, in the end it's really a decision that is up to the individual women and their clinicians, based on the severity of their symptoms and based on how well their response to methylphenidate has been.
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