The association between analgesic drug use in pregnancy and neurodevelopmental disorders: protocol for an umbrella review

Syst Rev. 2020 Sep 2;9(1):202. doi: 10.1186/s13643-020-01465-9.


Background: Maternal prenatal health has been shown to be an important influence on children's developmental outcomes, which has led to an increased emphasis on providing more information to support clinical decisions in pregnancy. Several systematic reviews suggest that analgesic drug use during pregnancy may have neurodisruptive properties. However, no firm conclusions have yet been drawn on the associations between prenatal analgesic drug use and children's long-term development of neurodevelopmental disorders such as autism spectrum disorder (ASD) or attention deficit hyperactivity disorder (ADHD). Therefore, an umbrella review is proposed for the purpose of examining the associations between maternal analgesic drug use during pregnancy and diagnoses of neurodevelopmental disorders.

Methods: Included systematic reviews will consist of studies examining the effect of maternal prenatal analgesic drug use, specifically ibuprofen, acetaminophen, aspirin, naproxen, diclofenac, and ketoprofen, on children's neurodevelopmental disorder status. Examined drugs were restricted to those readily accessible and frequently used by pregnant women, and with characteristics that allow them to cross the placenta and directly affect fetal development. Outcomes will be restricted to formal clinical diagnoses of ASD and/or ADHD. Two reviewers will independently identify eligible reviews from six databases (e.g., PubMed, EMBASE, PsychINFO) from inception dates of databases to the date of data extraction, and conduct manual searches of reference lists, consultation with field experts, and scan of pre-print archives. Extracted data will also include short qualitative summaries by both reviewers. As part of quality assessment, a standardized measurement tool to assess systematic reviews (AMSTAR 2) will be used. A narrative synthesis is proposed to integrate findings from different, potentially methodologically heterogeneous, studies.

Discussion: This umbrella review of associations between maternal prenatal use of analgesic drugs and children's neurodevelopmental disorders could allow for firmer conclusions to be drawn through the synthesis of all relevant published research. The synthesis of findings using high-quality evidence could provide more accurate healthcare information on the long-term effects of analgesic drugs on neurodevelopment, to better guide future clinical decisions during pregnancy. This review will also allow gaps and methodological differences in the literature to be identified, informing recommendations for future research.

Systematic review registration: PROSPERO CRD42020179216 .

Keywords: ADHD; Analgesics; Autism; Maternal; Medication; Painkillers; Pregnancy; Umbrella review.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics / adverse effects
  • Attention Deficit Disorder with Hyperactivity*
  • Autism Spectrum Disorder* / drug therapy
  • Child
  • Female
  • Humans
  • Neurodevelopmental Disorders* / chemically induced
  • Pregnancy
  • Pregnancy Complications* / drug therapy
  • Review Literature as Topic


  • Analgesics