Summary: A large-scale study analyzing over a million births in Sweden found no evidence that prescribed opioid pain medications during pregnancy cause autism or ADHD in children. While earlier data suggested a potential link, those associations largely disappeared after accounting for genetics, parental mental health, and shared family environment.
Comparisons between siblings, as well as children of parents prescribed opioids before but not during pregnancy, supported this conclusion. These findings provide reassurance to pregnant individuals and clinicians that opioid use, when medically necessary, does not substantially increase neurodevelopmental risk.
An Indiana University study brings a comprehensive new perspective to a growing body of evidence suggesting that mild to moderate use of prescribed opioid pain medications during pregnancy does not cause an increased risk for autism spectrum disorder (ASD) or attention-deficit/ hyperactivity disorder (ADHD) in children.
The study explores documented associations between prescribed opioid pain medications during pregnancy and the increased risk for the two neurodevelopmental disorders.
It concludes that other factors, rather than fetal exposure to opioid pain medications, may explain the increased risk for autism and ADHD in the children of individuals who received opioid prescriptions during pregnancy.
This study "helps provide more information to pregnant individuals and their physicians who are trying to make complex decisions about how to best manage pain during pregnancy," said first author Emma Cleary, a graduate student in the lab of the study's co-principal investigator, Professor Brian D'Onofrio in the Department of Psychological and Brain Sciences.
"While they are not able to rule out small increased risks for autism and ADHD with high amounts of exposure, which were rare in our data," Cleary observed, "the results suggest that there is no causal effect of prescribed opioid analgesics on the risk for these two common neurodevelopmental disorders."
The study's findings further suggest, as co-author Ayesha Sujan, a postdoctoral fellow at Stanford University School of Medicine, noted, "that the observed associations between prenatal exposure to opioid analgesics and two major neurodevelopmental disorders -- autism and ADHD -- are largely driven by factors leading up to opioid analgesic use rather than the opioid exposure itself."
Study data and designs
The study drew on the extensive data from Swedish population-based registers, including more than 1.2 million births in Sweden from 2007 to 2018 when analyzing risk of ASD, among whom 4.4% were exposed to prescribed opioid medications during pregnancy. Analyses of ADHD risk included more than 900,000 births from 2007 to 2015.
The researchers estimated risks based on the dose range and duration of cumulative exposure during pregnancy. By analyzing the data from a variety of perspectives, the study also accounted for a range of possible confounding factors.
When comparing children exposed to opioid medication to unexposed children, results suggested increased risk with higher doses, similar to what was observed in previous studies. However, when they statistically adjusted for factors such as parental age and psychiatric conditions, and used a narrower set of comparison groups to that account for shared characteristics between the groups, the observed risks decreased.
Notably, when comparing exposed children to unexposed children whose birthing parent had been prescribed opioids in the year before conception but not during pregnancy, the increased risk for autism and ADHD in the exposed children was markedly diminished. Similarly, the risk for these neurodevelopmental conditions disappeared when comparing differentially exposed siblings.
These designs provide a strong test of the causal effects of these medications because they enabled the researchers to hold constant some of the shared characteristics of individuals who are prescribed opioids around the time of pregnancy and the genetic and environmental factors common to siblings.
The paper, titled "Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden," was published on September 16 in the journal PLOS Medicine.
As Cleary explained, "The way we take our findings together, is that yes, initially, we observe this increased risk for high dose and low doses.
"But as we increase our adjustment for various sources of potential bias, adjusting for proxies of socio-economic status, mental health history of parents, characteristics of the pregnancy, diagnoses of painful conditions, previous opioid pain medication use, and genetics and environmental factors in the sibling comparisons, we're able to account for many of these things that potentially could confound our associations.
"And when doing so, the risks that we initially observe go away. As previous studies have explored, these background characteristics would make you both more likely to be exposed to prescribed opioids and increase risk of ASD and ADHD."
One of the study's innovative features was the use of text-mining algorithms, a novel technique previously used by some of the authors to study ADHD medication use but not yet applied to prescribed opioid use. This technique enabled the researchers to take into account the written instructions on each prescription and thereby consider the possible variations in how patients actually took the medications.
"With these pharmacy-based dispensations," said Cleary, "there's always some uncertainty, but with text-mining of the 'as needed dosages' or prescriptions with a range, such as 1-3 pills a day, we were able to test different possible versions of exposure - and across those analyses we found converging results."
The study also entailed work across several fields and disciplines. As D'Onofrio added, "This is a great example of how collaborations among researchers, clinicians, and data engineers can leverage large datasets to help answer key clinical questions, especially when it is not feasible to conduct randomized controlled trials."
Takeaways and future directions
The findings ultimately provide greater clarity for those seeking to treat pain during pregnancy insofar as they suggest that opioid pain medication does not cause substantial increased risk of autism and ADHD. Yet, the findings also beg the question: What are the underlying causes of increased risk for autism and ADHD in this group of children and how can they be addressed?
"We need more explanation," said Cleary. "It could be the pain and underlying pathophysiological processes, it could be genetics. But people who may be more likely to be prescribed an opioid, may also need more support to help manage symptoms throughout their pregnancy."
More research is needed to explain the workings of these factors. And yet, as her co-author Sujan added, "the results elucidate the critical need to provide pregnant individuals experiencing pain with psychosocial support and evidence-based pain management tools, both pharmaceutical and non-pharmaceutical."
Other researchers include Martin E. Rickert, IU Department of Psychological and Brain Sciences; Franziska Fischer, Karolinska Institutet, Stockholm, Sweden; Tyra Lagerberg, Karolinska Institutet and Warneford Hospital, University of Oxford, Oxford, United Kingdom; Zheng Chang, Karolinska Institutet; Paul Lichtenstein, Karolinska Institutet; Patrick D. Quinn, IU School of Public Health; and Anna Sara Öberg, Karolinska Institutet and Harvard University T.H. Chan School of Public Health.
Funding: This research was supported by the National Institute on Drug Abuse of the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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
The extent to which the documented association between prenatal prescribed opioid analgesic (POA) exposure and neurodevelopmental disorders in children is causal or due to confounding is unknown. The objective of this study was to evaluate associations between dose and duration of POA exposure during pregnancy and autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children while minimizing bias due to confounding and other sources.
This retrospective study analyzed a population-based cohort of births using national register data from Sweden. The ASD analysis cohort consisted of 1,267,978 children born in Sweden from July 1st, 2007 to December 31st, 2018, with follow-up through 2021. A shorter eligibility period was used to study ADHD given its later age of typical diagnosis, consisting of 918,771 children born through December 31st, 2015.
Text-mining algorithms were used to derive cumulative dose and duration of POA exposure during pregnancy from filled POA prescriptions, as well as to identify prescriptions that were to be taken on an "as needed" basis.
Outcomes were identified through inpatient or outpatient clinical diagnosis of ASD and ADHD or dispensed ADHD medications. Cox proportional hazards regression models were adjusted for measured covariates from multiple domains.
Several designs were used to help address unmeasured confounding: comparisons with children whose birthing parent had a diagnosed painful condition but did not receive POAs, children whose birthing parent received POAs in the year before but not during pregnancy, and siblings who were not exposed to POAs.
Of the 1,267,978 children, 48.6% were female and 4.4% were exposed to POAs during pregnancy. At age 10, cumulative incidence of ASD was 2.0% among children unexposed to POAs, 2.9% among children exposed to a low dose across pregnancy, and 3.6% among children exposed to a high dose. In unadjusted models (e.g., hazard ratio [HR], 1.74, 95% confidence interval [CI], 1.63, 1.87) and when accounting for measured covariates, cumulative maximum dose was associated with increased risk of ASD (e.g., HR, 1.34, 95% CI, 1.24, 1.44).
However, the associations were largely or fully attenuated when using alternative designs (particularly when comparing to children whose birthing parent received POAs before but not during pregnancy: HR, 1.10, 95% CI, 1.00, 1.21). No associations were observed in the sibling comparison (HR, 0.99, 95% CI, 0.81, 1.21). This overall pattern of associations was also observed when considering duration of exposure, and in numerous sensitivity analyses, as well as for analyses of ADHD.
A main limitation of this study was that the distribution of dose and duration of POAs prescribed to birthing parents in Sweden limited our ability to explore the effects of extremely high dose and duration on risk for neurodevelopmental disorders.
While increased risks with high amounts of POA exposure cannot be ruled out, the results suggest that confounding may largely explain the increased risks of ASD and ADHD associated with prenatal POA exposure at the levels observed in this cohort.