Summary: Researchers report that the widely used pain reliever acetaminophen taken during pregnancy is linked with a higher risk of behavioral problems in children.
Source: JAMA Network.
New analysis published in JAMA Pediatrics finds maternal acetaminophen use during pregnancy is associated with increased risk of behavioral difficulties in offspring.
Acetaminophen (also known as paracetamol) is commonly recommended for fever and pain relief during pregnancy and is widely regarded as safe. However, a large prospective study now suggests prenatal exposure to acetaminophen may be associated with later behavioral problems in children.
Evie Stergiakouli, Ph.D., of the University of Bristol, United Kingdom, and colleagues analyzed data from 7,796 mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC) together with information on their children and partners. The research team examined links between maternal acetaminophen use before birth (prenatal), after birth (postnatal), and partner acetaminophen use, and behavioral outcomes in the children.
Acetaminophen exposure was recorded by questionnaires completed at about 18 and 32 weeks of pregnancy and again when the child was approximately 61 months old. Child behavioral outcomes were measured by maternal report using the Strengths and Difficulties Questionnaire (SDQ) when the children reached age 7.
At 18 weeks of pregnancy, 4,415 mothers (53 percent) reported acetaminophen use; at 32 weeks, 3,381 mothers (42 percent) reported use. Postnatally, 6,916 mothers (89 percent) and 3,454 partners (84 percent) reported acetaminophen use. Overall, roughly 5 percent of the children met criteria for behavioral problems on the SDQ.
The findings indicate that maternal acetaminophen use during pregnancy—both at 18 and 32 weeks—was associated with higher risk of conduct problems and hyperactivity symptoms in children. Maternal use at 32 weeks was also linked to greater risk of emotional symptoms and higher scores for total difficulties. By contrast, maternal acetaminophen use after delivery and partners’ acetaminophen use were not associated with children’s behavioral problems.
Because similar associations were not observed for postnatal maternal use or for partners’ use, the authors propose that the prenatal associations are less likely to be explained by unmeasured social or behavioral confounders shared within families. Instead, the pattern of results suggests a possible intrauterine mechanism by which acetaminophen exposure could influence neurodevelopment leading to behavioral differences in childhood. The researchers emphasize, however, that more studies are needed to confirm these findings and to investigate biological mechanisms.
The study has important limitations. Information about dosage, exact timing beyond the two prenatal checkpoints, and duration of acetaminophen use was not available, so the results cannot describe dose-response relationships or cumulative exposure. As an observational study, it cannot prove causation; residual confounding or other explanations remain possible despite the study’s design to test alternative sources of bias.
The authors summarize: “Children exposed to acetaminophen use prenatally are at increased risk of multiple behavioral difficulties. Our findings suggest that the association between acetaminophen use during pregnancy and offspring behavioral problems in childhood may be due to an intrauterine mechanism. Further studies are required to elucidate mechanisms behind this association as well as to test alternatives to a causal explanation. Given the widespread use of acetaminophen among pregnant women, this can have important implications on public health advice.”
They also caution that untreated fever or pain during pregnancy can pose risks, and decisions about medication use should balance the potential risks and benefits: “The risk of not treating fever or pain during pregnancy should be carefully weighed against any potential harm of acetaminophen to the offspring.”
Study design: Analysis of 7,796 mothers enrolled in the Avon Longitudinal Study of Parents and Children (ALSPAC), a prospective birth cohort established in 1991–1992. Acetaminophen use was reported at 18 and 32 weeks of pregnancy and again when the child was about 61 months old. Child behavioral outcomes were measured via the Strengths and Difficulties Questionnaire at age 7.
Key findings: Prenatal maternal acetaminophen use at 18 and 32 weeks was associated with higher risk of conduct problems and hyperactivity; use at 32 weeks was also associated with greater emotional symptoms and total difficulties. No associations were observed for maternal postnatal use or partner use.
Limitations: No data on acetaminophen dose or duration; observational design cannot establish causation; potential for residual confounding remains.
Funding and support: Authors are affiliated with the Medical Research Council (MRC) Integrative Epidemiology Unit and related research centers at the University of Bristol and Cardiff University. The ALSPAC cohort receives core support from MRC, the Wellcome Trust, and the University of Bristol.
Citation: Stergiakouli E, Thapar A, Davey Smith G. Association of Acetaminophen Use During Pregnancy With Behavioral Problems in Childhood: Evidence Against Confounding. JAMA Pediatrics. Published online August 15, 2016. doi:10.1001/jamapediatrics.2016.1775
Abstract (condensed)
Importance: Acetaminophen is commonly used during pregnancy, and prior research suggests possible effects on fetal neurodevelopment. Objective: To examine associations between offspring behavioral problems and maternal prenatal acetaminophen use, maternal postnatal acetaminophen use, and partner acetaminophen use. Design: Prospective cohort analysis using ALSPAC data. Participants: 7,796 mothers enrolled in 1991–1992 with available exposure and outcome data. Exposures: Self-reported acetaminophen use at 18 and 32 weeks of pregnancy and at child age 61 months. Main outcomes: Maternal reports of child behavioral problems using the SDQ at age 7. Results: Prenatal maternal acetaminophen use was associated with higher odds of conduct problems and hyperactivity; use at 32 weeks was additionally associated with emotional symptoms and overall difficulties. No associations were observed for maternal postnatal or partner use. Conclusions: Prenatal acetaminophen exposure was linked to a modestly increased risk of multiple childhood behavioral difficulties. Further research is needed to replicate findings and to explore mechanisms before changes to clinical practice or public health guidance are made.