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 our study sample, 53% of mothers reported using acetaminophen at least once during pregnancy, and 10% of the offspring received acetaminophen during the first 18 months after birth (Table 1).

Parent- and Child-reported Behavioral Problems

The medians of child-reported SDQ scores at age 11 years tended to be higher than the parent-reported measures (Table 2). However, using the binary classification of atypical behavior with the recommended cutoffs for the instrument, a higher proportion of children were classified as having emotional problems (9.3% vs. 2.3%), peer problems (4.5% vs. 1.9%), and lack of prosocial behavior (5.5% vs. 3.3%) based on parent report than child report. The Pearson correlation coefficient between parent- and child-reported SDQ total difficulty scores at 11 years was moderate (r = 0.58), with a higher correlation for externalizing behaviors (r = 0.59) than internalizing behaviors (r = 0.49); among all SDQ subdomains, measures for hyperactivity had the highest correlation (r = 0.57), and the prosocial subscale had the lowest correlation (r = 0.34). We found a consistent trend for α reliability and κ coefficients.

Linking Acetaminophen use During Pregnancy to Parent- and Child-reported SDQ

For both parent- and child-reported SDQ, maternal acetaminophen use during pregnancy was positively associated with the risks of SDQ total difficulties (parent-reported, risk ratio (RR) = 1.14, 95% confidence interval (CI): 1.01, 1.29; child-reported, RR = 1.40, 95% CI: 1.20, 1.63), internalizing problems (parent-reported, RR = 1.09, 95% CI: 1.00, 1.19; child-reported, RR = 1.13, 95% CI: 1.04, 1.23), and externalizing problems (parent-reported, RR = 1.07, 95% CI: 0.99, 1.15; child-reported, RR = 1.13, 95% CI: 1.05, 1.22) (Table 3). We did not find evidence of heterogeneity in most of the rater-specific risk ratios comparisons except for the SDQ total difficulties (P = 0.01). Some sex-specific differences were found (i.e., the exposure effect estimates of total difficulties for child-reported SDQ and externalizing behavior for both parent-reported and child-reported SDQ were stronger in boys and null for girls (Web Table 2)).

In analyses by trimester of use, associations between acetaminophen intake in the first or the third trimester only and SDQ total difficulties, internalizing or externalizing problems were slightly stronger compared with exposure in the second trimester (Table 4). The estimated risk ratios were higher for all parent-reported outcomes and some child-reported outcomes when acetaminophen was used in more than 1 pregnancy trimester. Greater cumulative weeks of acetaminophen use in pregnancy were also associated with SDQ total difficulties and internalizing behavioral problems, and the findings were consistently seen with both parent- and child-reported SDQ (Table 5).

Linking Acetaminophen use During Infancy to Parent- and Child-reported SDQ

Postnatal acetaminophen use in the first 18 months of life was associated with parent-reported total difficulties (RR = 1.18, 95% CI: 0.95, 1.48) and internalizing problems (RR = 1.15, 95% CI: 0.98, 1.35), but the 95% confidence intervals of these effect estimates included the null (Table 3). There was no association between postnatal acetaminophen use and child-reported total difficulties, internalizing problems, or externalizing problems. There was no evidence of heterogeneity comparing the risk ratios by raters. Concerning SDQ subdomains, a positive association with peer problems (RR = 1.19, 95% CI: 1.00, 1.42) was found only in parent-reported but not child-reported outcomes. In contrast, postnatal acetaminophen exposure was associated with the lack of prosocial behavior only in child-reported SDQ (RR = 1.22, 95% CI: 1.00, 1.49), with no association for parental reports. Some inconsistencies were also found in analyses by child sex, such that the associations of postnatal acetaminophen exposure with total difficulties or internalizing behaviors were higher in boys based on parent reports and higher in girls based on child reports (Web Table 2).

Sensitivity Analyses

When using a combined outcome based on parent- and child-reported scores, we found that prenatal acetaminophen exposure consistently showed positive associations with total difficulties and internalizing and externalizing behaviors (Web Table 3). Results did not change when we additionally adjusted for parents' childhood behavioral scores or duration of breastfeeding (Web Table 4–5). Analyses using continuous SDQ scores as the outcome were also consistent for the associations between acetaminophen exposure during pregnancy and the parent- or the child-reported measures (Web Table 6). For postnatal exposure, positive associations were found only for parent- and not child-reported measures. Results did not change substantially in models without IPSW (Web Table 7). Our main findings were also robust to changing the SDQ cutoff by ±2 to define behavioral difficulties (Web Figure 2–3).