The relationship of prenatal acetaminophen exposure and attention-related behavior in early childhood

Abstract

Acetaminophen is currently the only analgesic considered safe for use throughout pregnancy, but recent studies indicate that prenatal exposure to acetaminophen may be related to poorer neurodevelopmental outcomes. Multiple studies have suggested that it may be associated with attention problems, but few have examined this association by trimester of exposure. The Illinois Kids Development Study is a prospective birth cohort located in east-central Illinois. Exposure data were collected between December 2013 and March 2020, and 535 newborns were enrolled during that period. Mothers reported the number of times they took acetaminophen at six time points across pregnancy. When children were 2, 3, and 4 years of age, caregivers completed the Child Behavior Checklist for ages 1.5-5 years (CBCL). Associations of acetaminophen use during pregnancy with scores on the Attention Problems and ADHD Problems syndrome scales, the Internalizing and Externalizing Behavior composite scales, and the Total Problems score were evaluated. Higher acetaminophen exposure during the second trimester of fetal development was associated with higher Attention Problems, ADHD Problems, Externalizing Behavior, and Total Problems scores at ages 2 and 3. Higher second trimester exposure was only associated with higher Externalizing Behavior and Total Problems scores at 4 years. Higher cumulative exposure across pregnancy was associated with higher Attention Problems and ADHD Problems scores at ages 2 and 3. Findings suggest that prenatal acetaminophen exposure, especially during the second trimester, may be related to problems with attention in early childhood.

Keywords: Acetaminophen; Attention; CBCL; Early childhood; Paracetamol; Prenatal.

Figure 1.

Flowchart of recruitment and retention to IKIDS study visits at 2, 3, and 4 years as of January 2023.

Figure 2.

Associations of acetaminophen use during pregnancy and Attention Problems scores on the CBCL at 2 (left panel), 3 (middle panel), and 4 years of age (right panel).^a At 2 years of age, higher acetaminophen exposure during the second trimester (β=0.009, 95% CI: 0.003, 0.015) and throughout pregnancy (β=0.004, 95% CI: 0.001, 0.008) were related to higher Attention Problems scores. Higher acetaminophen exposure during the second trimester (β=0.009, 95% CI: 0.004, 0.014) and throughout pregnancy (β=0.004, 95% CI: 0.001, 0.007) were also associated with higher Attention Problems scores at 3 years of age. ^aAll models were adjusted for child sex, age at assessment, and gestational age, maternal age, maternal parity (nulliparous vs. ≥1), maternal education (<bachelor’s degree vs. ≥bachelor’s degree), mean perceived stress score during pregnancy, mean Edinburgh Postnatal Depression Scale score during pregnancy, and indication (N/A, pain, other, or multiple). *p < 0.05, **p < 0.01

Figure 3.

Associations of acetaminophen use during pregnancy and ADHD Problems scores on the CBCL at 2 (left panel), 3 (middle panel), and 4 years of age (right panel).^a Per unit increase in prenatal acetaminophen exposure during the second trimester (i.e., report of number of times taking acetaminophen), children had a 0.010-point increase (95% CI: 0.002, 0.019) in ADHD Problems scores at age 2. Increasing use throughout pregnancy was also associated with an increase in scores (β=0.004, 95% CI: −0.001, 0.009) at 2 years of age. Similarly, more acetaminophen use during the second trimester (β=0.013, 95% CI: 0.005, 0.021) and throughout pregnancy (β=0.006, 95% CI: 0.001, 0.010) were related to higher ADHD Problems scores at age 3. While the trend was present at 46-48 months as well, neither was p <0.10. ^aAll models were adjusted for child sex, age at assessment, and gestational age, maternal age, maternal parity (nulliparous vs. ≥1), maternal education (<bachelor’s degree vs. ≥bachelor’s degree), mean perceived stress score during pregnancy, mean Edinburgh Postnatal Depression Scale score during pregnancy, and indication (N/A, pain, other, or multiple). # p < 0.10, *p < 0.05

Figure 4.

Associations of acetaminophen use during pregnancy and Externalizing Behavior scores on the CBCL at 2 (left panel), 3 (middle panel), and 4 years of age (right panel).^a Higher acetaminophen exposure during the second trimester was associated with higher scores at ages 2 (β=0.026, 95% CI: 0.004, 0.048), 3 (β=0.025, 95% CI: 0.003, 0.047), and 4 (β=0.026, 95% CI: 0.003, 0.049). ^aAll models were adjusted for child sex, age at assessment, and gestational age, maternal age, maternal parity (nulliparous vs. ≥1), maternal education (<bachelor’s degree vs. ≥bachelor’s degree), mean perceived stress score during pregnancy, mean Edinburgh Postnatal Depression Scale score during pregnancy, and indication (N/A, pain, other, or multiple). * p < 0.05

Figure 5.

Associations of acetaminophen use during pregnancy and Internalizing Behavior scores on the CBCL at ages 2 (left panel), 3 (middle panel), and 4 (right panel).^a Higher acetaminophen exposure during the first trimester was associated with lower Internalizing Behavior scores (β=−0.021, 95% CI: −0.045, 0.002). ^aAll models were adjusted for child sex, age at assessment, and gestational age, maternal age, maternal parity (nulliparous vs. ≥1), maternal education (<bachelor’s degree vs. ≥bachelor’s degree), mean perceived stress score during pregnancy, mean Edinburgh Postnatal Depression Scale score during pregnancy, and indication (N/A, pain, other, or multiple). # p < 0.10

Figure 6.

Associations of acetaminophen use during pregnancy and Total Problems scores on the CBCL at 2 (left panel), 3 (middle panel), and 4 years of age (right panel).^a Higher acetaminophen exposure during the second trimester was related to higher scores at 2 (β=0.052, 95% CI: −0.009, 0.113), 3 (β=0.066, 95% CI: 0.019, 0.112), and 4 years (β=0.066, 95% CI: 0.011, 0.121). Increasing cumulative exposure throughout pregnancy was associated with higher scores only at age 3 (β=0.028, 95% CI: 0.0002, 0.056). ^aAll models were adjusted for child sex, age at assessment, and gestational age, maternal age, maternal parity (nulliparous vs. ≥1), maternal education (<bachelor’s degree vs. ≥bachelor’s degree), mean perceived stress score during pregnancy, mean Edinburgh Postnatal Depression Scale score during pregnancy, and indication (N/A, pain, other, or multiple). # p < 0.10, *p < 0.05, **p < 0.01