Prenatal Acetaminophen Exposure Tied to Behavior Problems

Diana Phillips

August 15, 2016

Children who are exposed to acetaminophen (paracetamol) in utero may be at higher risk for behavioral problems, according to the results of a prospective study.

"Given the widespread use of acetaminophen among pregnant women, this can have important implications on public health advice. However, the risk of not treating fever or pain during pregnancy should be carefully weighed against any potential harm of acetaminophen to the offspring," write Evie Stergiakouli, PhD, from the University of Bristol in England, and colleagues.

The authors, who reported their findings online August 15 in JAMA Pediatrics, stress that additional studies are needed to determine the mechanisms behind the association.

Previous studies have observed associations between acetaminophen use during pregnancy and an increased risk for hyperkinetic disorders and attention-deficit hyperactivity disorder (ADHD)-like behaviors, as reported byMedscape Medical News. Further, animal models suggest acetaminophen use may disrupt endocrine production in utero, as reported here. "But association doesn't imply causality. We wanted to know if these problems were consistent with intrauterine mechanism or recognized familial or genetic risk factors [for behavioral problems]," Dr. Stergiakouli said in an interview with JAMA Pediatrics.

Using data from the ongoing Avon Longitudinal Study of Parents and Children (ALSPAC) prospective birth cohort, the researchers assessed associations between behavioral problems in offspring at 7 years and maternal pre- and postnatal acetaminophen use, as well as partners' acetaminophen use.

The study sample included 7796 mothers who were enrolled in ALSPAC in 1991 and 1992, along with their children and partners. Acetaminophen use within the previous 3 months was recorded based on maternal self-report at 18 and 32 weeks of pregnancy, and based on maternal and partner self-report when the offspring reached 61 months of age.

Among the mothers, 4415 (53%) reported acetaminophen use at 18 weeks, as did 3381 (42%) at 32 weeks. And 6916 mothers (89%) and 3454 partners (84%) reported using it postnatally. The behavioral status of the offspring was assessed using the Strengths and Difficulties Questionnaire (SDQ) behavioral screening tool, which showed that 5% of children at 7 years of age (mean age 79 months) had behavioral problems based on their total difficulties scores.

The analysis was repeated multiple times, adjusting for a number of potential confounding factors, including maternal age at birth, parity, socioeconomic status, smoking and alcohol consumption during pregnancy, prepregnancy body mass index, self-reported maternal psychiatric illness, possible reasons for acetaminophen use (such as migraine or infection), and genetic risk factors for ADHD, the authors report.

In the initial analysis, maternal prenatal acetaminophen use at 18 weeks of pregnancy was associated with an increased likelihood for offspring conduct problems (risk ratio [RR], 1.20; 95% confidence interval [CI], 1.06 - 1.37) and hyperactivity symptoms (RR, 1.23; 95% CI, 1.08 - 1.39), and maternal acetaminophen use at 32 weeks of pregnancy was associated with higher odds of emotional symptoms (RR, 1.29; 95% CI, 1.09 - 1.53), conduct problems (RR, 1.42; 95% CI, 1.25 - 1.62), hyperactivity symptoms (RR, 1.31; 95% CI, 1.16 - 1.49), and total difficulties (RR, 1.46; 95% CI, 1.21 - 1.77), achieved by summing the SDQ subscales.

"The associations did not change when we included the covariates and also when we adjusted the maternal prenatal acetaminophen use for postnatal maternal or partner use," Dr Stergiakouli said in the interview. Importantly, the results were similar after adjusting for maternal ADHD polygenic risk scores at 18 and 32 weeks' gestation. "These results point to a true intrauterine mechanism."

The stronger association between maternal acetaminophen use and behavioral and emotional problem domains on the SDQ during the third trimester versus the second trimester suggests that the timing of acetaminophen use is important.

"Given that there is active brain development and growth during the third trimester, this finding could indicate that there are developmental periods when the brain is more sensitive to acetaminophen exposure," the authors write.

Although the connection between maternal acetaminophen use during pregnancy and behavioral problems has been observed in other studies, "it was surprising [in this study] that the effects of acetaminophen were not limited, as has been reported in other studies to hyperkinetic and ADHD type disorders, but instead extended to other domains of the SDQ," Dr Stergiakouli said.

The findings, however, are limited by the absence of information on acetaminophen doses or duration of use as well as the lack of maternal reports on the indications for acetaminophen use, although the analysis was adjusted for the most common reasons, including headaches, musculoskeletal problems, and infections.

The mechanism for the influence of acetaminophen on offspring behavior is not known, but the authors hypothesize that the endocrine-disrupting properties of acetaminophen could affect fetal development, as could the development of toxic metabolites by the fetus when the acetaminophen crosses the placenta or the disruption of brain development through oxidative stress.

These possibilities highlight "the need for further experimental research to identify potential causal mechanisms and to test alternate causal explanations," Dr Stergiakouli said.

JAMA Pediatr. Published online August 15, 2016. Full text

The authors have disclosed no relevant financial relationships.

For more news, join us on Facebook and Twitter


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.