A large-scale study in siblings showed that the apparent association between prenatal paracetamol use and autism or ADHD disappears when common family-related factors are taken into account, challenging long-held concerns and providing reassurance for the clinically indicated use of paracetamol during pregnancy.
Large population-based cohort study published in a journal JAMA Internal Medicine After accounting for familial confounders, they found that prenatal use of acetaminophen (paracetamol) did not appear to increase the risk of autism or ADHD.
Familial factors complicate prenatal paracetamol research
Acetaminophen (paracetamol) is the most commonly recommended treatment for pain and fever during pregnancy and is considered first choice by obstetric societies and regulatory authorities around the world. But because the drug crosses the placenta, researchers have long investigated whether it could affect fetal neural development.
Over the past decade, several observational studies have reported that prenatal paracetamol use may be associated with an increased risk of autism spectrum disorder (ASD) or attention-deficit/hyperactivity disorder (ADHD) in children. Despite clinical guidance from bodies such as the Medicines and Healthcare products Regulatory Agency (UK) and the World Health Organization (WHO), these findings have raised concerns among expectant parents, who continue to believe that use during pregnancy is reasonable and appropriate when clinically indicated.
One of the biggest challenges in interpreting the evidence is that the symptoms that prompt paracetamol use, such as fever, infection, inflammation, and pain, may themselves be associated with neurodevelopmental outcomes. This problem, known as confounding by indication, makes it difficult to determine whether an observed increased risk is due to the drug or the underlying disease. Furthermore, ASD and ADHD have strong genetic and familial components, and studies that account for these common family-related factors generally find that the apparent association disappears.
This question is especially important because alternative treatments are limited. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) are avoided in some pregnancies because they can increase the risk of complications such as teratogenicity, oligohydramnios, and fetal kidney damage.
Previous systematic reviews have concluded that much of the existing evidence is of low quality and remains vulnerable to these sources of bias. Therefore, the current study aimed to provide stronger evidence using a large population-based cohort from Hong Kong and a sibling-matched study design to better account for common family factors.
The researchers also examined whether the association differed by timing, duration, or cumulative dose of paracetamol exposure. Exposure was classified as sporadic (first trimester only), intermittent (any of the second trimester), or continuous (all three trimesters), and cumulative dose was classified as low, moderate, or high based on the distribution of the study population.
Sibling comparisons tested for prenatal exposures
Researchers now investigated whether taking paracetamol during pregnancy increases the risk of autism spectrum disorder (ASD) or attention-deficit hyperactivity disorder (ADHD) in children. Sibling analyzes included two cohorts: 124,333 children in the ASD analysis and 97,285 children in the ADHD analysis.
They also conducted a traditional cohort analysis, comparing the offspring of women exposed during pregnancy with those of unexposed women, and a negative control analysis, comparing the risk for the offspring of women exposed before or after pregnancy.
In each cohort, children from the same family with different paracetamol exposure histories were followed for at least 2 and 5 years, respectively, to identify ASD and ADHD. Clinical diagnosis or ADHD-specific medication prescriptions were used to identify these conditions.
Electronic health records were used to track paracetamol prescriptions during pregnancy. The association between such diagnoses and paracetamol exposure during intrauterine survival was stratified by timing, pattern of use, and cumulative dose.
No increased neurodevelopmental risk was found in sibling analysis
Sibling matching analysis found no evidence that prenatal paracetamol exposure increased the risk of ASD or ADHD. Children exposed during pregnancy were no more likely to be diagnosed with either condition than their unexposed siblings. This suggests that common familial factors, rather than the drug itself, explain the associations reported in previous observational studies.
Results remained consistent across various additional analyses. No increased risk was observed when the comparison was limited to children whose mothers used paracetamol for a sustained period (more than 7 consecutive days), for more than 7 days cumulatively, or of women who were not prescribed other analgesics during pregnancy.
Previous analyzes pointed out that familial confounding remained.
Conversely, when exposure to paracetamol was considered against ASD/ADHD diagnosis in the traditional cohort, there was an increased risk in the exposed cohort. Similarly, the risk of ASD and ADHD was increased in offspring born to women exposed before or after pregnancy, but not during pregnancy, compared with women who were not exposed during the corresponding period.
Although the observation of a positive association in traditional exposure analysis suggests that unmeasured familial factors are a source of residual confounding, Mainly featured in sibling comparisons.
The same applies in relation to paracetamol use before or after pregnancy, where exposure to the fetus cannot occur, but not for use during pregnancy.
These findings confirm earlier null findings in other sibling-controlled studies in different populations (Nordics and Japanese) and support current clinical guidelines regarding the safety of paracetamol use during pregnancy under medical supervision.
Restrictions remain for in-store use and sibling designs
This population-based cohort study used prospectively recorded electronic health records and supplementary analyzes to account for unmeasured familial confounding. The sibling-matched cohort was adjusted to account for genetic and environmental confounds operating within the family. Matching with sibling cohorts across other populations supports the validity of this evidence.
The long follow-up period of up to 23 years is another strength, as it increases the reliability of risk estimates. Objective and detailed exposure data enabled detailed analysis of timing and usage patterns and dose-response relationships.
This study also had some limitations. The sibling-matched design may allow unmeasured confounding to persist or even be amplified. The sibling plan assumes that paracetamol use during one pregnancy will not affect the outcome of subsequent pregnancies (the ‘carryover effect’). The authors found no evidence of this, but it cannot be completely ruled out. The sibling-matched design may also limit generalizability.
Over-the-counter (OTC) use of paracetamol can lead to misclassification of exposure, as well as uncertainty regarding the use of the drug at the time of prescription. Prescription drug use may present a more challenging situation compared to OTC use. However, based on further analysis, the researchers believe this is unlikely to be a source of bias, although they note that it remains uncertain whether these findings can be applied to OTC use, and that the pattern of OTC paracetamol use by any mother likely remains constant throughout pregnancy.
Evidence supporting current pregnancy prescription recommendations
The researchers concluded that when clinically indicated, paracetamol use during pregnancy is unlikely to be associated with an increased risk of either ASD or ADHD in offspring and is not a major risk factor for these conditions. The apparent associations seen in many early studies were probably due to familial confounding rather than the drug treatment itself.
This suggests that triangulation and sibling-matched cohorts should be used to address familial confounding in such studies. The authors also note that future studies should also examine other neurodevelopmental outcomes, such as intellectual disability.
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