Association Between Cord Blood Acetaminophen Biomarkers and Childhood Asthma With and Without Allergic Comorbidities

To assess whether biomarkers of acetaminophen exposure in cord blood are associated with later school-aged asthma, considering cases with and without other allergic conditions.The study included 810 mother-child pairs, enrolled between December 2002 and October 2013 from the Boston Birth Cohort, a long-standing prospective US birth cohort that represents an urban, low-income, underserved population in Boston. All study participants were observed until at least age 6 years. Based on the presence or absence of an allergic condition (eczema and/or allergic rhinitis), children with asthma were further classified into 2 groups: those with asthma and allergic comorbidities and those with asthma without allergic comorbidities. A control group consisted of children without asthma.Umbilical cord blood samples were collected at birth and analyzed using liquid chromatography–tandem mass spectrometry to profile 3 acetaminophen-related biomarkers: free acetaminophen, acetaminophen glucuronide, and 3-(N-acetyl-L-cystein-S-yl)-acetaminophen. Multinomial regression models were used to evaluate the associations between asthma subgroups and the detection of each cord acetaminophen metabolite, adjusting for the potential confounders as covariates. Models were adjusted for relevant confounders including child’s biological sex (as assigned at birth), preterm birth (gestational age <37 weeks), low birth weight (birth weight <2500 g), parity, and delivery type; maternal covariates were age at delivery, education, marital status, race and ethnicity, any type or frequency of cigarette smoking during pregnancy, any gestational conditions, intrauterine inflammation, prepregnancy body mass index, history of asthma, and stress level during pregnancy.Of the 810 eligible participants, 142 (17.5%) had asthma and 1 or more allergic conditions, 55 (6.8%) had asthma without allergic conditions, and 613 (75.7%) were asthma-free. Acetaminophen metabolites were detected in cord blood samples (acetaminophen 16.4%, acetaminophen glucuronide 17.5%, and 3-(N-acetyl-L-cysteine-S-yl)-acetaminophen 28.4%). Detection of acetaminophen metabolites in cord blood, reflecting maternal exposure to acetaminophen shortly before delivery, was associated with 3.73 times the odds of developing asthma without allergic comorbidities compared with those without detectable metabolites (95% CI: 1.79–7.80, P = .0004). The presence of acetaminophen metabolites was not associated with asthma with allergic conditions. In sensitivity analyses, participants with maternal conditions associated with acetaminophen use (eg, intrauterine inflammation, intrapartum maternal fever, preeclampsia, maternal asthma) were excluded, and the associations between acetaminophen and childhood asthma persisted. In the stratified analysis, a higher cord acetaminophen level was significantly associated with an increased risk of asthma without allergic comorbidities in all birth weight strata (<2500 g and ≥2500 g, odds ratio [OR] 4.43 per SD increase in intensity of acetaminophen metabolites, 95% CI: 1.39–14.14, P = .0120 and OR 1.81, 95% CI: 1.09–3.02, P = .0224, respectively).This prospective cohort study reported an elevated risk of developing asthma without allergic comorbidities in school-aged children with detected acetaminophen metabolites in cord blood. Sensitivity analyses found that even when maternal conditions in which acetaminophen may be used are excluded, the association between childhood asthma without allergic conditions and acetaminophen biomarkers persisted. The positive association of cord acetaminophen level with the subgroup of asthma without allergic comorbidities was stronger in children with low birth weight.This study provides an important contribution to growing evidence assessing potential links between prenatal acetaminophen exposure and increased risk of asthma in children. Given the common use of acetaminophen in pregnancy, the results of this study offer valuable insights into the need for further research aimed at preventing asthma in children. Future studies are needed to determine the exposure effect of acetaminophen on childhood asthma based on timing, duration, and dosage during pregnancy.