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

Abstract

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 non-detection, low detection, and high detection levels. At age six to eight 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 to girls with undetectable levels of exposure [βgirls, low = 2.83 (0.97, 4.70), βgirls, high = 1.95 (-0.03, 3.93), βboys, low = 0.02 (-1.78, 1.81), βboys, high = -0.39 (-2.09, 1.31), pinteraction = 0.06]. 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.

Paracetamol use during pregnancy — a call for precautionary action

“…Effect sizes were generally modest but because exposure is widespread 1,107 , even a small effect size could translate into a large number of affected children. Dose-response has been investigated in 19 studies [112][113][114][116][117][118][119][120][121][122]124,[127][128][129][130]133,[136][137][138] and of these, 16 studies 112,114,[116][117][118][119][120][121][122]124,127,129,130,133,136,137 identified a dose-response association, whereby increased duration of exposure was associated with increased risk. In many of these studies, associations were weak for short-term exposure suggesting that short-term use might be of limited risk.…”

“…Using methods such as sibling control design, polygenic risk scores and negative controls, efforts were made to control genetic confounding in 16 studies with little effect on the reported associations in all but two of these studies 115,116 . APAP exposure assessment relied on maternal self-report in 24 studies, on biomarkers in five studies [127][128][129][130]137 and on prescription records in one study 138 . Although one study that used both biomarkers and self-reported exposure suggested that the two measures of exposure were correlated 127 , exposure misclassification remains a concern in studies using maternal self-report 24 .…”

Paracetamol (Acetaminophen) and the Developing Brain

“…Neonatal meconium collected after birth may actually be the best way to capture prolonged intrauterine exposure to paracetamol and other drugs, as it accumulates chemicals from the fetal bile and the fetal urine passed into the amniotic fluid which is ingested by the fetus. In the Canadian Gestation and the Environment Cohort, paracetamol in meconium was unrelated to the children's intelligence examined at 6-8 years of age [64] but showed a dose-response association with physician-diagnosed ADHD [62]. Each doubling of exposure increased the odds of ADHD by 10% among 345 children analyzed, 199 (57.7%) of whom had detectable paracetamol in meconium, and 33 (9.6%) were diagnosed with ADHD.…”

In Utero Exposure to Persistent Organic Pollutants and Childhood Lipid Levels

“…We conducted analyses using data from the prospective GESTE cohort, which is described in detail elsewhere [34,35,69,70]. In short, GESTE cohort is comprised of (a) women residing in the Eastern Townships (Estrie) of Quebec, Canada having a pregnancy between 2007 and 2009 and (b) children born from these pregnancies.…”