Statement of the Polish Society of Gynecologists and Obstetricians on paracetamol use during pregnancy and autism risk.

Autism spectrum disorder (ASD) affecting one in every 59 newborns with significant surge in the prevalence rates over last few decades has complex underlying pathophysiological mechanism which is not fully understood. We hypothesize that such association might be associated with paracetamol-induced alterations in cytokine levels, oxidative stress and dysregulation of neurotransmission, especially dopaminergic pathways. Additionally, disruption of prostaglandin synthesis following paracetamol administration has considerable impact over neurodevelopment. We performed literature review by searching our topic of interest on three databases including PubMed, Embase and the Cochrane library by utilizing keywords. Recent large scale nationwide birth cohort studies implicate link between paracetamol use during pregnancy, most commonly utilized anti-pyretic and analgesic medication at that period, and risk of autism in infants. Alterations at cytokine and prostaglandin levels, elevated oxidative stress and impairment of neurotransmission may have role in ASD pathogenesis, though, it has not been demonstrated in human studies. There is clear need for future comprehensive molecular and clinical studies to investigate the association between paracetamol use in pregnancy and ASD risk. This study is significant by investigating the role of paracetamol use in upward projection in ASD prevalence and providing a hypothetical underlying mechanism for the association between paracetamol use and ASD risk.

Recent political statements linking paracetamol (acetaminophen) use during pregnancy to autism spectrum disorders have created concern among patients and healthcare providers worldwide. This editorial critically examines the scientific evidence, highlighting that the largest and most methodologically rigorous population-based studies employing sibling control analyses demonstrate no causal association between prenatal paracetamol exposure and neurodevelopmental disorders. While some observational studies have suggested potential weak associations, these findings likely reflect confounding by indication and familial genetic factors rather than actual causal relationships. The most robust evidence comes from a Swedish population-based study of 2.48 million children, which found no increased risk when controlling for familial confounding. Major international medical organizations including ACOG, RCOG, and FIGO, and regulatory agencies including the European Medicines Agency continue to recommend paracetamol as the safest analgesic option during pregnancy when clinically indicated. The established risks of untreated pain and fever during pregnancy significantly outweigh theoretical concerns based on methodologically limited studies. Healthcare providers should continue evidence-based counseling while avoiding unnecessary anxiety about this essential medication in obstetric practice.

Several studies suggest that acetaminophen (paracetamol) use during pregnancy may increase risk of neurodevelopmental disorders in children. If true, this would have substantial implications for management of pain and fever during pregnancy. To examine the associations of acetaminophen use during pregnancy with children's risk of autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability. This nationwide cohort study with sibling control analysis included a population-based sample of 2 480 797 children born in 1995 to 2019 in Sweden, with follow-up through December 31, 2021. Use of acetaminophen during pregnancy prospectively recorded from antenatal and prescription records. Autism, ADHD, and intellectual disability based on International Classification of Diseases, Ninth Revision and International Classification of Diseases, Tenth Revision codes in health registers. In total, 185 909 children (7.49%) were exposed to acetaminophen during pregnancy. Crude absolute risks at 10 years of age for those not exposed vs those exposed to acetaminophen were 1.33% vs 1.53% for autism, 2.46% vs 2.87% for ADHD, and 0.70% vs 0.82% for intellectual disability. In models without sibling control, ever-use vs no use of acetaminophen during pregnancy was associated with marginally increased risk of autism (hazard ratio [HR], 1.05 [95% CI, 1.02-1.08]; risk difference [RD] at 10 years of age, 0.09% [95% CI, -0.01% to 0.20%]), ADHD (HR, 1.07 [95% CI, 1.05-1.10]; RD, 0.21% [95% CI, 0.08%-0.34%]), and intellectual disability (HR, 1.05 [95% CI, 1.00-1.10]; RD, 0.04% [95% CI, -0.04% to 0.12%]). To address unobserved confounding, matched full sibling pairs were also analyzed. Sibling control analyses found no evidence that acetaminophen use during pregnancy was associated with autism (HR, 0.98 [95% CI, 0.93-1.04]; RD, 0.02% [95% CI, -0.14% to 0.18%]), ADHD (HR, 0.98 [95% CI, 0.94-1.02]; RD, -0.02% [95% CI, -0.21% to 0.15%]), or intellectual disability (HR, 1.01 [95% CI, 0.92-1.10]; RD, 0% [95% CI, -0.10% to 0.13%]). Similarly, there was no evidence of a dose-response pattern in sibling control analyses. For example, for autism, compared with no use of acetaminophen, persons with low (<25th percentile), medium (25th-75th percentile), and high (>75th percentile) mean daily acetaminophen use had HRs of 0.85, 0.96, and 0.88, respectively. Acetaminophen use during pregnancy was not associated with children's risk of autism, ADHD, or intellectual disability in sibling control analysis. This suggests that associations observed in other models may have been attributable to familial confounding.

(JAMA. 2024;331(14):1205–1214. doi:10.1001/jama.2024.3172) The potential link between acetaminophen (paracetamol) use during pregnancy and increased risks of neurodevelopmental disorders in children, such as autism, attention-deficit/hyperactivity disorder (ADHD), and intellectual disability, has been a major subject of concern. Confounding bias may play a role in existing findings. If such a link were found, it could significantly impact how fever and pain are managed during pregnancy.

Paracetamol use in pregnancy does not increase risk of ADHD and autism

Maternal use of some drugs, notably paracetamol and drugs for gastroesophageal reflux, has been associated with an increased risk of childhood asthma in the child. We wanted to analyze these associations with consideration to the confounding of maternal asthma. Childhood asthma was identified from the Swedish National Prescription Register and maternal drug use during the latter part of pregnancy from antenatal records, computerized in the Swedish Medical Birth Register. Risks were estimated as odds ratios (OR) with 95% confidence intervals, using Mantel-Haenszel technique with adjustment for year of birth, maternal age, parity, smoking habits, and BMI. A statistical association between maternal use of many different drugs, including paracetamol, and childhood asthma existed but was mainly due to concomitant drug use, related to maternal asthma. The only associations that appeared to be true were with drugs for gastroesophageal reflux (adjusted (OR)=1.32, 95% CI, 1.18-1.54) and with opiates (adjusted OR=1.56 (96% CI, 1.05-2.34). Maternal use of paracetamol did not seem to increase the risk of childhood asthma, but the previously described association with drugs for gastroesophageal reflux was supported. The analysis is complicated by the confounding from maternal asthma.

Many studies have reported an increased risk of autism spectrum disorder (ASD) associated with some maternal diagnoses in pregnancy. However, such associations have not been studied systematically, accounting for comorbidity between maternal disorders. Therefore our aim was to comprehensively test the associations between maternal diagnoses around pregnancy and ASD risk in offspring. This exploratory case-cohort study included children born in Israel from 1997 to 2008, and followed up until 2015. We used information on all ICD-9 codes received by their mothers during pregnancy and the preceding year. ASD risk associated with each of those conditions was calculated using Cox proportional hazards regression, adjusted for the confounders (birth year, maternal age, socioeconomic status and number of ICD-9 diagnoses during the exposure period). The analytic sample consisted of 80 187 individuals (1132 cases, 79 055 controls), with 822 unique ICD-9 codes recorded in their mothers. After extensive quality control, 22 maternal diagnoses were nominally significantly associated with offspring ASD, with 16 of those surviving subsequent filtering steps (permutation testing, multiple testing correction, multiple regression). Among those, we recorded an increased risk of ASD associated with metabolic [e.g. hypertension; HR = 2.74 (1.92-3.90), p = 2.43 × 10-8], genitourinary [e.g. non-inflammatory disorders of cervix; HR = 1.88 (1.38-2.57), p = 7.06 × 10-5] and psychiatric [depressive disorder; HR = 2.11 (1.32-3.35), p = 1.70 × 10-3] diagnoses. Meanwhile, mothers of children with ASD were less likely to attend prenatal care appointment [HR = 0.62 (0.54-0.71), p = 1.80 × 10-11]. Sixteen maternal diagnoses were associated with ASD in the offspring, after rigorous filtering of potential false-positive associations. Replication in other cohorts and further research to understand the mechanisms underlying the observed associations with ASD are warranted.

Maternal infection during pregnancy and likelihood of autism and intellectual disability in children in Sweden: a negative control and sibling comparison cohort study

Acetaminophen (paracetamol) is available over the counter in most countries and is widely considered to be safe for use during pregnancy; studies report gestational exposures to acetaminophen that lie in the 46%-65% range. Acetaminophen influences inflammatory and immunologic mechanisms and may predispose to oxidative stress; these and other effects are hypothesized to have the potential to compromise neurodevelopment in the fetal and infant brain. Two ecological studies suggested that population-level trends in the use of acetaminophen were associated with trends in the incidence/prevalence of autism; one of these studies specifically examined acetaminophen use during pregnancy. One large prospective observational cohort study found that gestational exposure to acetaminophen (especially when the duration of exposure was 28 days or more) was associated with motor milestone delay, gross and fine motor impairments, communication impairment, impairments in internalizing and externalizing behaviors, and hyperactivity, all at age 3 years; however, social and emotional developmental behaviors were mostly unaffected. A very recent large cohort study with a 12.7-year follow-up found that gestational exposure to acetaminophen was associated with an increased risk of autism spectrum disorder, but only when a hyperkinetic disorder was also present. In the light of existing data associating acetaminophen use during pregnancy and subsequent risk of attention-deficit/hyperactivity disorder, this new finding suggests that the predisposition, if any, is toward the hyperkinetic syndrome rather than to autism. In summary, the empirical data are very limited, but whatever empirical data exist do not support the suggestion that the use of acetaminophen during pregnancy increases the risk of autism in the offspring.

Maternal diabetes during pregnancy and offspring's risk of autism spectrum disorder: A systematic review and meta-analysis.

Etiologic hypotheses in infantile autism suggest a strong genetic component, as well as possible environmental risks linked to early fetal development. We evaluated the association of maternal, pregnancy, delivery, and infant characteristics and risk of infantile autism. We conducted a case-control study nested within a population-based cohort (all Swedish children born in 1974-1993). We used prospectively recorded data from the Swedish Birth Register, which were individually linked to the Swedish Inpatient Register. Cases were 408 children (321 boys and 87 girls) discharged with a main diagnosis of infantile autism from any hospital in Sweden before 10 years of age in the period 1987-1994, plus 2,040 matched controls. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). The risk of autism was associated with daily smoking in early pregnancy (OR = 1.4; CI = 1.1-1.8), maternal birth outside Europe and North America (OR = 3.0; CI = 1.7-5.2), cesarean delivery (OR = 1.6; CI = 1.1-2.3), being small for gestational age (SGA; OR = 2.1; CI = 1.1-3.9), a 5-minute Apgar score below 7 (OR = 3.2, CI = 1.2-8.2), and congenital malformations (OR = 1.8, CI = 1.1-3.1). No association was found between autism and head circumference, maternal diabetes, being a twin, or season of birth. Our findings suggest that intrauterine and neonatal factors related to deviant intrauterine growth or fetal distress are important in the pathogenesis of autism.

Ahlqvist VH, Sjöqvist H, Dalman C, et al. Acetaminophen use during pregnancy and children's risk of autism, ADHD, and intellectual disability. JAMA. 2024;331:1205-1214. 38592388.

Prenatal exposure to maternal immune activation (MIA) has been implicated as a risk factor for the development of autism spectrum disorder (ASD), though the conditions under which this elevated risk occurs are unclear. Animal literature demonstrates that antibiotic use, which affects the composition of the maternal gut microbiota, modifies the effect of MIA on neurodevelopmental outcomes in the offspring. The aim of this study was to assess whether antibiotic use during pregnancy modifies the association between MIA and subsequent risk of ASD, in a prospective birth cohort with 116 ASD cases and 860 typically developing (TD) child controls. There was no evidence of interaction between fever or genitourinary infection and antibiotic use on the odds of ASD in unadjusted or adjusted analyzes. However, we found evidence of an interaction between flu, specifically in second trimester, and antibiotic use at any point during pregnancy on the odds of ASD in the child. Among women who received an antibiotic during pregnancy, flu in trimester two was not associated with ASD (adjusted odds ratio [aOR] = 0.99 [0.43-2.28]). Among women who were not exposed to an antibiotic at any point during pregnancy, flu in second trimester was significantly associated with increased odds of ASD (aOR = 4.05 [1.14-14.38], P = .03), after adjustment for child sex, child birth year, maternal age, gestational age, C-section delivery, and low birthweight. These findings should be treated as hypothesis-generating and suggest that antibiotic use may modify the influence that MIA has on autism risk in the child. LAY SUMMARY: We looked at whether the association between activation of the immune system during pregnancy and risk of the child developing autism spectrum disorder (ASD) differed among women who did or did not take an antibiotic at any point during pregnancy. We examined 116 children with ASD and 860 without ASD and found that flu in second trimester was associated with increased ASD, but only among women who did not take an antibiotic during pregnancy. No other immune activation exposures seemed to interact with antibiotic use.

A review and meta‐analysis encompassing 10 studies has found an association between mothers' use of antidepressants in pregnancy and higher risk of autism spectrum disorders (ASDs) in their children, but has concluded that this risk appears more consistent with antidepressant use in the preconception period. This finding, according to authors of the review, suggests that the increased risk for autism might be more closely associated with mothers' psychiatric diagnoses than with antidepressant exposure.

Pregnancy risk factors in relation to oppositional-defiant and conduct disorder symptoms in the Avon Longitudinal Study of Parents and Children