In Utero Exposure to Caffeine and Acetaminophen, the Gut Microbiome, and Neurodevelopmental Outcomes: A Prospective Birth Cohort Study.

Pregnant individuals are exposed to acetaminophen and caffeine, but it is unknown how these exposures interact with the developing gut microbiome. We aimed to determine whether acetaminophen and/or caffeine relate to the childhood gut microbiome and whether features of the gut microbiome alter the relationship between acetaminophen/caffeine and neurodevelopment. Forty-nine and 85 participants provided meconium and stool samples at 6-7, respectively, for exposure and microbiome assessment. Fecal acetaminophen and caffeine concentrations were quantified, and fecal DNA underwent metagenomic sequencing. Caregivers and study staff assessed the participants' motor and cognitive development using standardized scales. Prenatal exposures had stronger associations with the childhood microbiome than concurrent exposures. Prenatal acetaminophen exposure was associated with a trend of lower gut bacterial diversity in childhood [ß = -0.17 Shannon Index, 95% CI: (-0.31, -0.04)] and was marginally associated with differences in the relative abundances of features of the gut microbiome at the phylum (Firmicutes, Actinobacteria) and gene pathway levels. Among the participants with a higher relative abundance of Proteobacteria, prenatal exposure to acetaminophen and caffeine was associated with lower scores on WISC-IV subscales. Acetaminophen during bacterial colonization of the naïve gut is associated with lasting alterations in childhood microbiome composition. Future studies may inform our understanding of downstream health effects.

Association Between Meconium Acetaminophen and Childhood Neurocognitive Development in GESTE, a Canadian Cohort Study.

Acetaminophen is the only over-the-counter pain reliever that is not contraindicated during pregnancy, but recent studies have questioned whether acetaminophen is safe for the fetus, particularly the developing brain. This prospective birth cohort study probed the previously observed association between in utero exposure to acetaminophen and neurodevelopment by using concentrations of acetaminophen measured in meconium, which more objectively captures exposure of the fetus than maternal report. Exposure, measured by liquid chromatography coupled with tandem mass spectrometry, was categorized into nondetection, low detection, and high detection levels. At age 6-8 years, children completed a set of subtests from the Wechsler Intelligence Scale for Children, 4th edition. Additionally, this study examined potential effect modification by child sex on the association between acetaminophen exposure and neurodevelopment. In fully adjusted models, in utero exposure to acetaminophen was not statistically significantly associated with decreased scores on any of the examined subtests in all children combined (n = 118). The effect of in utero acetaminophen exposure on the Coding subtest was marginally significantly different among boys and girls, with girls performing significantly better on the task with higher levels of acetaminophen compared with girls with undetectable levels of exposure (ßgirls, low = 2.83 [0.97, 4.70], ßgirls, high = 1.95 [-0.03, 3.93], ßboys, low = .02 [-1.78, 1.81], ßboys, high = -.39 [-2.09, 1.31], pinteraction = .06). Effect modification by child sex was not observed on other subtests. These results do not support prior reports of adverse neurodevelopmental effects of in utero exposure to acetaminophen.