Summary: A comprehensive population-based study of more than 1.2 million births in Sweden found no clear evidence that prescribed opioid pain medications taken during pregnancy cause autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children. Initial associations seen in simple comparisons largely disappeared after accounting for parental mental health, genetics, and other family-level factors.
Sibling comparisons and analyses that contrasted children whose birthing parent had received opioid prescriptions before but not during pregnancy supported the conclusion that the observed associations are likely due to confounding factors rather than a direct causal effect of opioid exposure in utero. These findings offer reassurance to pregnant people and clinicians when opioids are used for legitimate medical reasons.
Key facts
- Large dataset: The study analyzed over 1.2 million births from Swedish national registers.
- Risk drivers: After adjusting for measured covariates and family-level confounders, most of the apparent increased risks were explained by genetics, parental mental health, and shared environmental factors.
- Robust designs: Sibling comparisons and comparisons with parents prescribed opioids before—but not during—pregnancy reduced or eliminated the associations.
Source: Indiana University
Researchers at Indiana University and collaborators used Swedish population registers to reassess earlier suggestions that prenatal exposure to prescribed opioid analgesics (POAs) raises the risk of ASD or ADHD in offspring. The team concluded that, for the exposure levels observed in this cohort, other factors that lead to opioid prescriptions—such as underlying pain conditions, parental mental health, and familial traits—appear to explain most of the increased risk seen in simpler analyses.
“These results help inform pregnant individuals and clinicians who must weigh complex decisions about pain treatment during pregnancy,” said Emma Cleary, the study’s first author. Cleary emphasized that while rare, very high doses or prolonged exposure could not be fully ruled out by this dataset, the evidence does not support a substantial causal effect of commonly prescribed opioid analgesics on ASD or ADHD risk.
Co-author Ayesha Sujan added that the study suggests the associations reported in prior research are largely driven by the circumstances that led to opioid use—rather than direct fetal effects of the medications themselves.
Study data and design
The research used national Swedish registers to construct large cohorts: 1,267,978 children born between July 1, 2007 and December 31, 2018 for the ASD analyses (followed through 2021), and 918,771 births through December 31, 2015 for ADHD analyses. About 4.4% of children in the ASD cohort were exposed to prescribed opioids during pregnancy.
Investigators estimated cumulative dose and duration of prenatal POA exposure using filled prescription records. They applied text-mining algorithms to prescription instructions to better model “as needed” dosing ranges and how patients may actually have taken medications—an innovative approach that improved exposure measurement.
Initial comparisons between exposed and unexposed children showed higher cumulative incidence of ASD and ADHD with greater opioid dose, echoing earlier reports. However, the team then adjusted for a broad set of measured covariates including parental age, psychiatric history, socio-economic proxies, pregnancy characteristics, diagnoses of painful conditions, and prior opioid use. They also used alternative comparison designs to account for unmeasured familial confounding:
- Comparisons to children whose birthing parent had a diagnosed painful condition but did not receive POAs during pregnancy.
- Comparisons to children whose birthing parent received POAs in the year before conception but not during pregnancy.
- Sibling comparisons that held constant genetic and many environmental influences.
These approaches reduced the observed associations. For example, comparing exposed children to those whose parent had been prescribed opioids before but not during pregnancy lowered the hazard ratios substantially. In sibling comparisons—where genetic and shared environmental factors are controlled—the elevated risks were not observed.
The study authors note a limitation: the Swedish prescription patterns limited the ability to evaluate extremely high doses or very long durations of opioid exposure, so small effects at those rare extremes cannot be completely excluded.
The paper, “Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden,” was published in PLOS Medicine on September 16.
Takeaways and future directions
Overall, the findings suggest that commonly prescribed opioid analgesics used during pregnancy do not substantially increase the risk of ASD or ADHD for most exposures observed in this large cohort. The results instead point researchers and clinicians toward the underlying causes—such as the effects of chronic pain, mental health conditions, socio-economic factors, and genetic liability—that both increase the likelihood of opioid prescriptions and are independently associated with neurodevelopmental outcomes.
Cleary noted the need for more research to identify and address these underlying factors, and Sujan emphasized the importance of providing pregnant individuals with comprehensive pain management resources—both pharmaceutical and non-pharmaceutical—and psychosocial support.
Co-authors include researchers from Indiana University, Karolinska Institutet, University of Oxford, Harvard T.H. Chan School of Public Health, and other institutions. The research was supported by the National Institute on Drug Abuse of the National Institutes of Health, which did not influence study design, data collection, analysis, or publication decisions.
About this neuropharmacology, autism, and ADHD research news
Author: Christiane Wisehart
Source: Indiana University
Contact: Christiane Wisehart – Indiana University
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden” by Brian D’Onofrio et al. PLOS Medicine
Abstract
Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden
Background
The degree to which prenatal exposure to prescribed opioid analgesics (POAs) causally raises the risk of neurodevelopmental disorders in children—versus reflecting confounding influences—is uncertain. This study evaluated associations between dose and duration of POA exposure during pregnancy and the risk of ASD or ADHD while minimizing bias from measured and unmeasured confounders.
Methods and findings
This retrospective, register-based cohort study included 1,267,978 children for ASD analyses and 918,771 children for ADHD analyses. Text-mining of prescription records estimated cumulative dose and duration, and identified “as needed” instructions. Outcomes were clinical diagnoses of ASD and ADHD or dispensed ADHD medications. Cox proportional hazards models adjusted for extensive measured covariates, and alternative designs addressed unmeasured confounding through comparisons with pain-diagnosed but unexposed children, pre-pregnancy opioid recipients, and differentially exposed siblings.
Unadjusted and conventionally adjusted models showed increased ASD and ADHD incidence with higher cumulative opioid doses. However, associations were largely attenuated or absent in designs that controlled for familial and pre-pregnancy factors, and in sibling comparisons. Sensitivity analyses produced consistent results. A primary limitation was limited exposure to extremely high-dose or long-duration prescriptions in this population, constraining inference about rare, extreme exposures.
Conclusions
While the study cannot fully exclude increased risks at very high levels of POA exposure, the evidence indicates that confounding—rather than prenatal opioid exposure itself—likely explains most of the observed associations between prescribed opioid analgesic use in pregnancy and ASD or ADHD at the exposure levels represented in this cohort.