Exposition médicamenteuse prénatale des enfants ayant suivi un parcours de soin en neuropsychiatrie : une étude cas-témoins dans la parcours de soin en neuropsychiatrie : une étude cas-témoins dans la

cohorte POMME (Résumé de la publication n°4)

Les troubles neuropsychiatriques sont d’origine multifactorielle et une des étiologies mise en évidence à ce jour est l’exposition médicamenteuse pendant la vie intra-utérine. La majorité des études a évalué le risque de troubles neuropsychiatriques chez les enfants après exposition prénatale aux psychotropes. Pourtant, de nombreux médicaments pourraient potentiellement être responsables d’effets sur le fonctionnement du cerveau à long terme. L’objectif de cette étude était de comparer l’exposition prénatale à l’ensemble des classes de médicaments, psychotropes ou non, entre des enfants ayant un parcours de soin en neuropsychiatrie et des témoins.

Une étude cas-témoins a été conduite dans la cohorte française POMME-2010 (PrescriptiOn-Médicaments-Mères-Enfants), qui inclut les enfants nés en Haute-Garonne entre le 1er juillet 2010 et le 30 juin 2011 (N=8372). Les enfants sont suivis pendant la vie intra-utérine et jusqu’à l’âge de 8 ans. Les cas étaient identifiés par le biais : (1) du remboursement de consultation ou de soin en neuropsychiatrie, (2) d’anomalies du développement psychomoteur renseignées sur les certificats de santé à 9 ou 24 mois et (3) du remboursement de méthylphénidate et/ou de neuroleptiques. Les témoins n’avaient aucun de ces critères. L’exposition prénatale à chacune des grandes classes ATC a été comparée entre les cas et les témoins, puis la ou les classe(s) ATC pour laquelle/lesquelles il existait une différence statistiquement significative a été comparée à l’aide d’une régression logistique.

Un total de 723 (8,6%) enfants a eu un parcours de soin en neuropsychiatrie. Le groupe des témoins était constitué de 4924 enfants. En accord avec les nombreuses données de la littérature, cette étude retrouvait une différence statistiquement significative d’exposition prénatale aux médicaments du système nerveux (antalgiques exclus) entre les cas et les témoins (ORa : 2,12 [1,55 ; 2,90]). Des différences ont également été observées pour les classes ATC : système musculo-squelettique, système génito-urinaire et hormones sexuelles, voies digestives et métabolisme et anti-infectieux à usage systémique.

73 par le biais de critères qui n’ont jamais pu être utilisés jusqu’à maintenant du fait du caractère unique de la cohorte POMME. Elle donne des pistes pour l’évaluation des effets neuropsychiatriques à long terme après exposition médicamenteuse prénatale.

Neuropsychiatric Care: A Case-Control Study nested in the POMME Cohort

Justine Beneventa, Pharm.D., Caroline Hurault-Delaruea, Ph.D., Mélanie Araujoa, M.S., Alexis Revet a,b, M.D., Agnès Sommet a, M.D., Ph.D., Isabelle Lacroix a Pharm.D., Ph.D.,

Christine Damase-Michel a, Pharm.D., Ph.D.

Affiliations:

a Department of Medical and Clinical Pharmacology, Toulouse Faculty of Medicine, University Toulouse III, INSERM UMR 1027, CIC 1436, Toulouse, France

b Department of Child and Adolescent Psychiatry, Toulouse University Hospital (CHU de Toulouse), Toulouse, France

Corresponding author:

Justine Benevent, Service de Pharmacologie Médicale et Clinique, Centre Hospitalier Universitaire de Toulouse, 37 allées Jules Guesde, 31000 Toulouse, France

Phone: +33561145656 Email: justine.benevent@univ-tlse3.fr

Question: Which prenatal medication exposure is associated with neuropsychiatric disorders in childhood?

Findings: This case-control study nested in the POMME-cohort (N=8,372), showed that children with neuropsychiatric disorders were prenatally more exposed to the ATC class of Nervous System drugs (excluding analgesics) than controls. It also provides clues for conducting studies to assess the risk of neuropsychiatric disorders in children subsequent to prenatal medication exposure

Meaning: Some medications other than psychotropics cross the placenta and may lead to delayed neuropsychiatric adverse effects.

Importance: Long term medication safety after prenatal exposure raises growing concerns, especially regarding neuropsychiatric disorders in the offspring. Most of the studies focused on psychotropic medications and found conflicting results.

Objective: This study aimed to investigate associations between prenatal medication exposure, psychotropic or not, and neuropsychiatric disorders in childhood.

Design: A case-control study was conducted, to compare prenatal medication exposure between children with a history of neuropsychiatric care between 0 and eight years of age and children in a control group.

Setting: The study was conducted in the French POMME cohort, which includes children born in Haute-Garonne to women covered by the general health insurance scheme, between July 2010 and June 2011 (N=8,372). Children follow-up began at conception up to the age of eight years.

Participants: All the children included in the POMME cohort were eligible participants.

Main outcome(s) and Measure(s) Cases were identified through: (1) reimbursement for neuropsychiatric care; (2) psychomotor development abnormalities as indicated on health certificates; and (3) reimbursement for methylphenidate or neuroleptics. Controls had none of these criteria.

Exposure(s): Prenatal exposure to each of the major “Anatomical Therapeutic Chemical” classes was compared between the groups. Class(es) for which there was a statistically significant difference (after Bonferroni adjustment, ie p<0.0033) was(were) then compared using logistic regression.

Results: A total of 723 (8.6%) cases and 4,924 (58.8%) controls were identified. This study showed a statistically significant difference in prenatal exposure to nervous system drugs (excluding analgesics) between the groups (ORa: 2.12 [1.55; 2.90]). Differences were also observed for the ATC classes, but not statistically significant at the 0.0033 threshold: Musculoskeletal, Genito-urinary System and Sex Hormones, Alimentary Tract and Anti-infectives.

Conclusion and relevance: Through identification of children with neuropsychiatric disorders and of their prenatal medication exposure, this study provides guidance for the assessment of long-term neuropsychiatric effects after prenatal medication exposure without focusing on psychotropic medications.

Neuropsychiatric disorders are a diverse group of conditions that include neurodevelopmental disorders as defined by the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders1 (autism spectrum disorder (ASD), attention deficit/hyperactivity disorder (ADHD), communication disorders, developmental coordination disorder and learning disabilities) but also other psychiatric disorders (anxiety disorders, mood disorders, childhood schizophrenia, etc.). Epidemiological data have shown an increase in the prevalence of childhood neuropsychiatric disorders in recent years.2,3 The origin of neuropsychiatric disorders is multifaceted and certain events that occur during intrauterine life may contribute to the risk of these disorders. 4 For example, prenatal exposure to valproic acid has been shown to increase the risk of ASD in children 5. Recently, the involvement of other psychotropic medications in long-term neuropsychiatric effects has been examined and the results are conflicting. 6–11

Moreover, nearly all studies on the subject have focused on psychotropic drugs, yet many medications cross the placenta and could be responsible for long-term effects on brain function. For example, studies have highlighted associations between childhood neurodevelopmental disorders and prenatal exposure to glucose-lowering or immunosuppressive medications.12–14

The objective of this study was to investigate associations between prenatal medication exposure, psychotropic or not, and neuropsychiatric disorders in childhood. To address that, a comparison of prenatal medication exposure in children with a history of neuropsychiatric care and control children was conducted in the POMME cohort.