Use and validity of child neurodevelopment outcome measures in studies on prenatal exposure to psychotropic and analgesic medications – A systematic review

In recent years there has been increased attention to child neurodevelopment in studies on medication safety in pregnancy. Neurodevelopment is a multifactorial outcome that can be assessed by various assessors, using different measures. This has given rise to a debate on the validity of various measures of neurodevelopment. The aim of this review was twofold. Firstly we aimed to give an overview of studies on child neurodevelopment after prenatal exposure to central nervous system acting medications using psychotropics and analgesics as examples, giving special focus on the use and validity of outcome measures. Secondly, we aimed to give guidance on how to conduct and interpret medication safety studies with neurodevelopment outcomes. We conducted a systematic review in the MEDLINE, Embase, PsycINFO, Web of Science, Scopus, and Cochrane databases from inception to April 2019, including controlled studies on prenatal exposure to psychotropics or analgesics and child neurodevelopment, measured with standardised psychometric instruments or by diagnosis of neurodevelopmental disorder. The review management tool Covidence was used for data-extraction. Outcomes were grouped as motor skills, cognition, behaviour, emotionality, or “other”. We identified 110 eligible papers (psychotropics, 82 papers, analgesics, 29 papers). A variety of neurodevelopmental outcome measures were used, including 27 different psychometric instruments administered by health care professionals, 15 different instruments completed by parents, and 13 different diagnostic categories. In 23 papers, no comments were made on the validity of the outcome measure. In conclusion, establishing neurodevelopmental safety includes assessing a wide variety of outcomes important for the child’s daily functioning including motor skills, cognition, behaviour, and emotionality, with valid and reliable measures from infancy through to adolescence. Consensus is needed in the scientific community on how neurodevelopment should be assessed in medication safety in pregnancy studies.Review registration number: CRD42018086101 in the PROSPERO database.近年来，妊娠用药安全性研究领域对儿童神经发育的关注度日益提升。神经发育是一类多因素结局，可由不同评估者采用多种测评工具进行评估，由此引发了关于各类神经发育测评工具效度的学术争议。本综述旨在实现双重目标：其一，以精神药物与镇痛药物为例，系统梳理产前暴露于作用于中枢神经系统的药物后儿童神经发育的相关研究，重点关注结局测评工具的使用情况与效度；其二，为如何开展并解读包含神经发育结局的妊娠用药安全性研究提供指导建议。本研究对MEDLINE、Embase、PsycINFO、Web of Science、Scopus及Cochrane数据库自建库起至2019年4月的文献进行了系统检索，纳入产前暴露于精神药物或镇痛药物、且采用标准化心理测评工具（psychometric instruments）或神经发育障碍（neurodevelopmental disorder）诊断来评估儿童神经发育的对照研究。本研究采用综述管理工具Covidence进行数据提取。研究结局被划分为运动技能、认知功能、行为表现、情绪状态及"other"类别。最终纳入110篇符合标准的文献（其中精神药物相关82篇，镇痛药物相关29篇）。研究中使用了多种神经发育结局测评工具，包括由医护人员施测的27种不同心理测评工具、由家长填写的15种不同测评工具，以及13种不同的诊断分类标准。其中23篇文献未对所使用的结局测评工具的效度进行说明。综上，确立神经发育安全性需通过可靠且有效的测评工具，从婴儿期至青春期全程评估对儿童日常功能至关重要的各类结局，涵盖运动技能、认知功能、行为表现与情绪状态等维度。学界亟需就妊娠用药安全性研究中儿童神经发育的标准化评估方案达成共识。本综述的注册编号为PROSPERO数据库中的CRD42018086101。