Special Edition of Prescrire International

ADVERSE EFFECTS

Three other studies, each dealing with only about 200 women exposed to methylphenidate, lack suf- ficient statistical power to detect a small increase in a rare malformation. There appeared to be a greater risk of cardiac malformations, major mal- formations or miscarriage, but this did not reach statistical significance (7,12-15).

including seizures (6 cases), hypotonia (2 cases), hypoxic ischaemic encephalopathy (1 case), and unspecified conditions (7 cases), i.e. about a 2-fold greater risk than in the control groups (8).

In the long term: perhaps more attention disorders, and many unknowns

Pre-eclampsia, prematurity, and neuropsychiatric disorders

Methylphenidate is an amphetamine-like psycho- stimulant. It crosses into the central nervous system (CNS) and can lead to so-called CNS stimulatory effects: anxiety, fear, agitation, insomnia, and hal- lucinations (17,18). Animals exposed to methylphenidate in utero had behavioural problems more often than unexposed animals (14). According to a conference abstract, a study in Quebec identified 25 000 children with ADHD out of about 166 000 children born at term. After adjustment for various confounding factors, including a maternal history of hyperactivity, the diagnosis of ADHD during childhood was twice as frequent in those exposed to ADHD drugs in utero (estimated relative risk = 2.0; 95CI: 1.3-3.3). The authors of the study attributed this finding to methyl­ phenidate (though with no numerical data) (21).  In practice  Avoid in utero exposure. When a pregnant woman takes methylphenidate, the unborn child is exposed to a risk of serious adverse effects, irrespective of the stage of pregnancy. As of early 2019, there have still been very few studies of the long-term effects on the neuropsychological devel- opment of the child. In addition, methylphenidate seems to expose women to a greater risk of pre- eclampsia. In those rare situations where methylphenidate is justified in a woman who could become pregnant, effective contraception is important. Where exposure during pregnancy has occurred, an effect on the child’s heart must be anticipated, and morphology ultrasound scanning should be carried out to monitor the fetus. When used towards the end of pregnancy and up to delivery, management of the pregnancy must be adjusted to take account of the effects of methyl­ phenidate and to monitor the newborn accordingly. Review produced collectively by the Editorial Staff: no conflicts of interest ©Prescrire ▶▶ Translated from Rev Prescrire March 2019 Volume 39 N° 425 • Pages 188-190 Literature search up to 11 December 2018 1- ANSM“RCP-Concerta LP 18 mg” 13 November 2018: 11 pages. 2- ANSM“RCP-Ritaline LP 10 mg” 15 November 2017: 12 pages. 3- Prescrire Editorial Staff “Methylphenidate and narcolepsy: when modafinil fails” Prescrire Int 2001; 10 (51): 7-9. 4- PrescrireRédaction“Méthylphénidate: banalisémalgré les dangers” Rev Prescrire 2017; 37 (406): 616. 5- Anderson NK et al. “Attention-deficit/hyperactivity disorder medi- cation prescription claims among privately insured women aged 15-44 years - United States, 2003-2015” MorbMortalWkly Rep 2018; 67 (2): 66-70.

The fetus is exposed to the sympathomimetic effects of methylphenidate, common to all amphetamines, which are difficult to demonstrate in utero. These are mainly neuropsychiatric disorders, cardiac disorders with hypertension and arrhythmia, and vasoconstriction (16-18). Cases of neonatal cardiorespiratory disorders, in particular tachycardia and respiratory distress, have been reported (19). Given the adverse effect profile of methylphenidate , intrauterine growth retardation, premature birth and withdrawal symptoms can be predicted (16-18). Epidemiological data concerning methylphenidate exposure during the third trimester of pregnancy are very limited. Preeclampsia. Using the US Medicaid database, a cohort study compared the occurrence of various obstetric complications (preeclampsia, placental abruption, fetal growth restriction, and preterm birth) in 3331 women exposed to an amphetamine- dextroamphetamine combination, 1515 exposed to methylphenidate and 453 to atomoxetine, prescribed for ADHD, during the first two trimesters of preg- nancy (9). Compared to about 1 500 000 unexposed pregnant women, the relative risk of preeclampsia was about 1.3 (95CI: 1.1-1.5) with all of the amphet- amines studied, after adjustment for various con- founding factors. The relative risk associated with at least 2 prescriptions of methylphenidate was of the same order of magnitude. Results following exposure during the third trimester of pregnancy are not available, whereas preeclampsia is more frequent after 34 weeks of pregnancy (20). Premature birth and admission to a neonatal intensive care unit (ICU). A study carried out using Swedish registries compared 1591 children exposed in utero to drugs used for ADHD with 2 control groups: 9475 children of mothers exposed to such drugs before or after pregnancy; and one million children born to mothers who had never been ex- posed (8).The 1591 children were mainly exposed to methylphenidate (92%), about 16% during the third trimester. After taking account of various confounding fac- tors, there was a greater risk of preterm birth and admission to a neonatal ICU as compared to the control groups: estimated relative risk of 1.3 (95CI:1.1- 1.6) and 1.5 (95CI: 1.3-1.7), respectively (8). Sixteen children exposed in utero had neurological disorders

P age 10 • P rescrire I nternational S pecial E dition 2019