Special Edition of Prescrire International

ADVERSE EFFECTS

Methylphenidate during pregnancy: teratogenic and fetotoxic, with concerns about long-term effects

First trimester: cardiac malformations

ABSTRACT

● ● Methylphenidate is an amphetamine-like psy- chostimulant. In animals, at high doses, various amphetamines carry a risk of cardiac malformations. Methylphenidate is teratogenic at toxic doses for the pregnant female, and can lead to skeletal abnor- malities and neural tube closure defects, depend- ing on the species. Behavioural disorders have also been reported. ● ● Two studies, including a total of about 3500 preg- nant women exposed to methylphenidate during the first trimester of pregnancy, have shown that the risk of cardiac malformations is probably great- er in children of exposed mothers compared to those of non-exposed mothers: around 3 addition- al cases per 1000 pregnancies. ● ● When exposure to methylphenidate occurred during the second and third trimesters of preg­ nancy, the risk of preeclampsia and premature birth seemed to be greater than in the absence of expo- sure. At birth, cardiorespiratory and neurological disorders associated with this exposure were observed. ● ● The long-term neuropsychiatric consequences of in utero exposure to methylphenidate are large- ly unknown. ● ● In practice, use of methylphenidate during preg- nancy should be avoided as far as possible. Rev Prescrire 2019; 39 (425): 188-190 M ethylphenidate is an amphetamine-like psychostimulant, used in attention deficit hyperactivity disorder (ADHD) in children and adolescents and, in some cases, in adults. It is also authorised for some types of narcolepsy (1-6). In 2017, several teams around the world published new studies carried out on thousands of pregnant women exposed to methylphenidate .These studies have brought important data to a hitherto poorly documented field (7-9). As of 2019, what are the chief known consequences of in utero exposure to methylphenidate for the unborn child, in the short and long term?

Studies in animals have shown that various am- phetamines have a teratogenic action, with mainly cardiac malformations at high doses (7). In animals: toxic and teratogenic at high doses. According to the French summaries of product char- acteristics (SPCs) from2017 or 2018, “methylphenidate is not considered to be teratogenic in rats or rabbits” (1,2). This is also stated by the French Teratogenic Agent Information Centre (CRAT) on its website as of 4 February 2019 (10). However, in the 2017 US Full Prescribing Information, methylphenidate is described as teratogenic in rabbits at doses higher than the maximum recommended human dose (1,2,11). Indeed, studies of methylphenidate in animals have yielded conflicting results.The oldest studies, in 2 species, did not show any teratogenic effect. More recent studies, in 2008 and 2016, showed that spina bifida (neural tube closure defects) occurred in rabbits, skeletal abnormalities at the highest doses in rats, and polydactyly, skeletal and cerebral abnormalities in mice at doses 4 times the doses recommended in humans. Behavioural abnormalities were observed in mice and rats after in utero exposure to methylpheni­ date (11-15). Thousands of women exposed: a few cardiac malformations. For pregnant women, the available data mainly come from studies using databases in the US and Scandinavia, covering a total of about 3500 women exposed to methylphenidate during the first trimester of pregnancy (7). There did not appear to be an increased risk of malformations (all types combined). However, these studies demonstrated a greater risk of cardiac malformations in exposed children, compared to unexposed children, at the limit of statistical significance. Pooling data from the 2 studies, the estimated relative risk was 1.3, with a 95% confidence interval (95CI) of 1.0 to 1.6. In other words, given that cardiac malformations affect around 10 children per 1000 births, there is a strong probability that around 3 additional children are born with a cardiac malformation for every 1000 women taking methylphenidate during the first trimester of pregnancy (7). The results only covered live births and therefore probably excluded a number of malformations (7). Methylphenidate also may carry a risk of miscar- riage (7,12).

P rescrire I nternational S pecial E dition 2019 • P age 9