Opioids in Pregnancy: Huge Study Rules Out Link to Autism and ADHD

This study investigated whether the use of prescription opioids for pain during pregnancy increases the risk of autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) in children. Analyzing more than 1.2 million births in Sweden, researchers found that, although a higher risk appeared in initial analyses, it virtually disappeared when comparing siblings and other control groups. In other words, the results suggest that family and environmental factors, rather than the medications themselves, explain much of the association. Only in cases of very high opioid use can an increased risk be ruled out.

Pain is a common condition affecting many people who give birth, and when not properly treated, it can negatively impact quality of life and daily well-being. Although the use of prescription opioid painkillers (called OA) has decreased in recent years, it is still relatively common during pregnancy.

The prevalence of use varies greatly between countries: for example, approximately 3% of pregnant women in Norway between 2005 and 2015 received this type of medication, while in the United States in 2019, approximately 9% of Medicaid beneficiaries used prescription opioids during pregnancy.

Both prescribing physicians and pregnant patients face significant dilemmas when deciding whether to use prescription opioid analgesics during this period, as they must balance the benefits of pain relief with the potential risks to the developing baby.

Animal studies have shown that opioid exposure during pregnancy can affect cellular and molecular processes at critical stages of central nervous system development. These changes can lead to structural and functional changes in the brain, increasing the risk of conditions such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD), which are among the most common neurodevelopmental disorders.

In humans, some studies have also found an increased risk of ASD and ADHD in children exposed to prescription opioid analgesics in utero, especially when exposure occurred at higher doses or for longer periods. However, results remain inconsistent, and it is unclear to what extent this association is directly caused by the medications or reflects other confounding factors, such as genetic or environmental characteristics.

Some studies reinforce this uncertainty. For example, research on a national birth cohort in South Korea found a slightly increased risk of neuropsychiatric disorders overall (7%), but this risk disappeared when researchers compared siblings, suggesting that familial factors rather than opioids could explain the association.

In the United States, an analysis of health insurance data showed that children exposed to opioids for more than 14 days during pregnancy had a 70% higher risk of developing neurodevelopmental disorders. Furthermore, higher doses were also associated with a higher risk. In Norway, another study found a 60% higher risk of ADHD in cases of prolonged exposure (five weeks or more).

Given these uncertainties, the present study's main objective was to investigate whether the use of prescription opioid analgesics during pregnancy actually increases the risk of ASD and ADHD in children. To this end, the researchers sought to minimize biases and confounding factors that affected previous studies.

They used different comparison groups, such as children of mothers who had painful conditions but did not receive opioids, children of mothers who took opioids before pregnancy but not during pregnancy, and unexposed siblings.

They also used advanced data analysis techniques, such as text mining on prescriptions, which allowed them to assess not only whether the woman took prescribed opioid analgesics, but also the cumulative dose, duration of treatment, and whether the prescription was for continuous use or "as needed."

Furthermore, the diagnoses of ASD and ADHD were based on validated clinical records, and the follow-up period was sufficient to ensure reliability.

This study was conducted in Sweden and analyzed a large population-based cohort. To investigate ASD, they included more than 1.2 million children born between 2007 and 2018 and followed until 2021. For ADHD, the number was slightly lower, around 918,000 children, as diagnosis tends to occur later and required a different follow-up period.

The researchers identified exposure to prescription opioid analgesics from prescription records. Among the children analyzed, almost half were female, and 4.4% were exposed to prescription opioid analgesics during pregnancy.

The results showed that by age 10, 2% of children who were not exposed to prescription opioid analgesics had a diagnosis of ASD, compared with 2.9% of those exposed to low doses and 3.6% of those exposed to high doses. In initial analyses, without adjustment for confounding factors, the association seemed clear: the higher the dose, the greater the risk.

Even after adjusting for some measured variables, the associations still appeared. However, when the researchers used more sophisticated models, such as comparing children of mothers who used opioids before but not during pregnancy, or comparing siblings, the associations disappeared or became minimal. This same pattern was found when analyzing ADHD.

A limitation of the study is that, in Sweden, the distribution of doses and duration of use of opioid analgesics prescribed during pregnancy did not include many situations of extremely high exposure, making it difficult to determine whether the risk might be greater in more severe cases.

In conclusion, the results indicate that, although risks associated with the use of very high doses of opioids during pregnancy cannot be completely ruled out, much of the association observed in previous studies is likely due to familial or environmental confounding factors rather than a direct effect of the medications.

This means that, at the exposure levels observed in this cohort, the relationship between opioid analgesics prescribed during pregnancy and ASD or ADHD appears to be weaker than previously assumed.

READ MORE:

Prescribed opioid analgesic use in pregnancy and risk of neurodevelopmental disorders in children: A retrospective study in Sweden. 

Emma N. Cleary, Ayesha C. Sujan, Martin E. Rickert, Franziska Fischer, Tyra Lagerberg, Zheng Chang, Paul Lichtenstein, Patrick D. Quinn, Anna Sara Öberg, and Brian M. D’Onofrio

PLoS Med 22(9): e1004721. 

https://doi.org/10.1371/journal.pmed.1004721

Abstract: 

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]high, 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., HRhigh, 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: HRhigh, 1.10, 95% CI, 1.00, 1.21). No associations were observed in the sibling comparison (HRhigh, 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.