Behavioral Problems at Age 11 Years After Prenatal and Postnatal Exposure to Acetaminophen

Parent-Reported and Self-Reported Outcomes

Kosuke Inoue; Beate Ritz; Andreas Ernst; Wan-Ling Tseng; Yuying Yuan; Qi Meng; Cecilia Høst Ramlau-Hansen; Katrine Strandberg-Larsen; Onyebuchi A. Arah; Carsten Obel; Jiong Li; Jørn Olsen; Zeyan Liew


Am J Epidemiol. 2021;190(6):1009-1020. 

In This Article


In this large population-based cohort, maternal acetaminophen use during pregnancy was consistently associated with increased risks for offspring developing behavioral and emotional problems at 11 years of age, using outcome measures reported by the parent or the child. We also observed associations between infant treatment with acetaminophen during the first 18 months of life and internalizing behaviors, but these results were less consistent across parent- and child-reported outcomes.

Associations between maternal intake of acetaminophen during pregnancy and adverse neurobehavioral outcomes in young children have been reported in several birth cohorts, including 3 cohort studies that assessed behavioral problems in children using parent-reported SDQ.[6,7,10] Prior studies neither simultaneously assessed prenatal and postnatal exposures nor used more than 1 informant for the outcome assessments. There was also little information on how much SDQ scores varied by the type of informant in the large population-based samples.[43–45] In our study, we compared the SDQ reported by parents and their index children at 11 years of age in the DNBC. The parent-child correlation for the total difficulties score in this study (r = 0.58) was higher than previous SDQ results in European children (r ≈ 0.40)[46,47] and another meta-analytic mean of 119 studies worldwide on childhood behavioral and emotional problems (r = 0.25).[48] Consistent with the literature,[31] the parent-child agreement was higher for externalizing problems than for internalizing problems, possibly because externalizing problems are more observable by the parents than internalizing problems.[49,50] Despite the relatively high parent-child agreement, there are still nonshared variances between the 2 informants, suggesting that parents and children each provide unique information about the child's behavioral and emotional problems.

We found rather consistent associations between prenatal exposure to acetaminophen and behavioral problems in children, using either parent- or child-reported SDQ. The acetaminophen exposure in pregnancy was based on maternal reports; therefore, a positive association found between the exposure and outcome assessed by different informants provided additional assurance that the finding is unlikely to be driven solely by shared-method variances in parental reports. The concerns for possible correlated errors are not completely resolved in these multiple-informant comparisons, because inherited personality traits or family factors might influence both parent and child outcome reports. However, if the observed association is strongly driven by correlated errors of exposure and outcome reports, we would expect to find stronger association for parent-rated than child-rated SDQ, which was true only for results concerning postnatal acetaminophen exposure but not for prenatal exposure. Moreover, the prevalence of infants exposed to acetaminophen was lower than that in previous reports,[51,52] and there are some discrepancies in results based on different informants for postnatal exposure to acetaminophen. Further evaluation that addresses the possibility of a reporting bias for acetaminophen treatment of infants is needed.

Mechanisms underlying the neurodevelopmental toxicity of acetaminophen have not been established, but several have been proposed. It is known that acetaminophen crosses the placenta[53] and penetrates the blood-brain barrier.[54] Animal and human studies found that acetaminophen has endocrine-disrupting properties, such as inhibiting androgen or prostaglandin synthesis.[16,17] Given that endocrine homeostasis plays an important role in development throughout both the prenatal and postnatal periods, its disruption might affect neurodevelopment of the fetus[55,56] and thus increase the risk of behavioral and emotional difficulties later on. For example, an experimental study in mice showed that paracetamol administration to neonates alters locomotor activity and spatial learning skills in adulthood, possibly through affecting brain-derived neurotrophic factor levels in the neonatal brain (the neonatal period in mice corresponds to the third trimester of brain development in humans).[32] Another rodent study has shown that acetaminophen could interrupt brain development via direct neurotoxicity by inducing oxidative stress leading to neuronal cell deaths.[18]

Consistent with previous studies,[57] we estimated increased risks in childhood behavioral difficulties for greater cumulative weeks of acetaminophen use during pregnancy. However, studies used various classifications to investigate the duration or frequency of exposure in pregnancy according to the data each study collected. Also, it remains unclear whether there is a threshold for an acetaminophen exposure effect on neurodevelopment. The DNBC collected gestational week–specific intake data, and we found a smaller but still elevated risk for child-reported SDQ outcomes associated with less than 5 weeks of acetaminophen intake in pregnancy. The possibility that a lower dose exposure can affect a critical developmental period in pregnancy needs to be considered.[58]

A major strength of our study is that study participants were enrolled in a well-established national longitudinal cohort, and its large sample size provides adequate power to compare results based on parent- and child-reported SDQ. Another strength is the use of multiple informants in outcome assessments as well as a repeated assessment of prenatal and postnatal use of acetaminophen. Moreover, we used IPSW to account for possible selection bias, and we were able to control for a comprehensive set of potential confounders including indications for acetaminophen use by the mother and infant. However, our study also has several limitations. Exposure and outcome were based on reports from the participants, and measurement errors might be expected to occur. We had no information on the number of pills and dosage taken during pregnancy and infancy, which prevented us from conducting more detailed exposure-response analyses. The low prevalence of postnatal acetaminophen use in the DNBC might reflect the true use rate for the Danish population or represent underreporting.[51,52] Last, we cannot rule out the possibility of residual confounding, time-varying confounding by pregnancy-specific factors, and confounding by indications of drug use in our findings. Further investigations are needed to address these limitations due to measurement error and unmeasured confounding.

In conclusion, we found that prenatal exposure to acetaminophen was associated with behavioral problems in children at 11 years of age, extending the previous literature focusing on early childhood to include results for late childhood and early adolescence. A positive association was also observed for the exposure of infants to acetaminophen. Because some findings for postnatal exposure were seen only with parent-reported outcomes, reporting bias is a concern here, and further evaluation in future studies is warranted.