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

Abstract and Introduction


Several studies have reported associations between prenatal acetaminophen exposure and behavioral outcomes in young children. We aimed to evaluate the associations of prenatal and postnatal exposures to acetaminophen with behavioral problems in children at age 11 years, using behavioral measures reported by parents and children. We studied 40,934 mother-child pairs from the Danish National Birth Cohort enrolled during 1996–2002. Parent-reported and child-reported Strengths and Difficulties Questionnaire (SDQ) responses were collected during the 11-year follow-up. We estimated risk ratios for behavioral problems including total difficulties as well as internalizing or externalizing behaviors following prenatal (during pregnancy) or postnatal (within the first 18 months after birth) acetaminophen exposure. Parent-reported and child-reported SDQ scores were moderately correlated; higher for externalizing (r = 0.59) than internalizing (r = 0.49) behaviors. Prenatal acetaminophen exposure was associated with 10%–40% higher risks for total difficulties and internalizing and externalizing problems based on parent- or child-reported SDQ, with the association being stronger for greater cumulative weeks of acetaminophen use. Postnatal exposure was associated with 16%–19% higher risks for parent-reported internalizing behaviors, but the associations were weak or null for child-reported scores except for prosocial behavior. Our study corroborates published associations between prenatal exposures to acetaminophen and behavioral problems and extends the literature to early adolescence.


Acetaminophen is one of the most common over-the-counter drugs used to treat pain and fever.[1,2] This medication has been considered safe to use in therapeutic doses even for pregnant women.[3–5] In recent years, concerns have been raised by several large-scale birth cohort studies that its use during pregnancy might increase the risk of adverse reproductive and childhood neurodevelopmental outcomes.[3,6–15] Potential underlying mechanisms include its endocrine-disrupting properties, such as its inhibition of androgen and prostaglandin synthesis,[16,17] or its induction of oxidative stress leading to neuronal death in early development.[18,19] The majority of epidemiologic studies addressing neurobehavioral problems included children at ages 7 or younger and relied solely on parent-reported outcomes[3,6,10–12] with a few being able to collect neuropsychological measures in age 5 or younger administered by trained psychologists.[8,9] Only a few cohorts had access to diagnoses or treatment data for attention-deficit/hyperactivity disorder (ADHD) ascertained from medical records through approximate ages 10–15 years.[7,13,20–22]

Debates over the validity of the findings from these cohort studies have focused mostly on uncontrolled confounding, particularly due to unmeasured or unknown factors affecting both maternal acetaminophen intake and child behavioral outcomes.[23–25] Several studies tried to address this bias using a sibling-controlled design and negative-control analyses.[3,10,11,13] These studies suggested that time-fixed confounding factors such as genetics, familial socioeconomic differences, or maternal chronic illnesses were not plausible reasons for the observed associations between prenatal acetaminophen exposure and ADHD-like behaviors in children. However, a recent meta-analysis with bias analysis suggested that the role of unmeasured confounder(s) needs to be further evaluated.[25] Despite such elaborate discussion about unmeasured confounding on this topic, evaluation for another type of bias introduced when both exposures and outcomes are reported by the same informant is scarce. Some efforts were made by comparing results of maternal reports of exposure and child behavioral outcomes measures reported by mothers or teachers[8,9,26,27] but these were studies with less than 3,000 mother-child pairs. Behavioral difficulties self-reported by the children have rarely been available.

Addressing this issue is important given the potential for dependent and possibly differential misclassification[28] due to reporting by the same informant. For instance, mothers who more carefully report their pregnancy drug intake might also be more aware of or likely to later report their child's behavioral problems. A previous study has also shown that mothers' personality traits, such as conscientiousness, are associated with self-reported acetaminophen intake during pregnancy and these personality traits might be related to the perceptions and reports of child behaviours.[29] In addition, the perception and reporting of behavioral and emotional problems differ across informants, with low to moderate agreement found between parent and child reports.[30] Parent-child agreement tends to be higher on observable symptoms (i.e., externalizing problems) than unobservable symptoms (i.e., internalizing problems) and higher with younger children than adolescents.[31] Studies investigating child-reported behavioral outcomes and their associations with prenatal acetaminophen use are lacking, and they would provide invaluable information on the outcomes. Thus, it is imperative to examine behavioral problems reported by children themselves at older ages.

Furthermore, the possible impact of acetaminophen exposure in infancy on neurodevelopment is underexplored. While fetal development is likely the most sensitive period for environmental perturbation of neurodevelopment, the maturation of the central nervous system might be affected by exposures in infancy.[16,17,32] In this context, we conducted a study in the Danish National Birth Cohort (DNBC) to examine the associations of prenatal and/or postnatal exposures to acetaminophen with behavioral problems at age 11 years, assessed using both parent and child reports, based on the Strengths and Difficulties Questionnaire (SDQ).