Does exposure to organophosphate esters during pregnancy increase the risk of attention-deficit hyperactivity disorder in offspring?

Abstract

Background. Elevated organophosphate esters (OPEs) during pregnancy has been associated with hyperactivity and attention problems in children. Such behaviors are often found in children with attention-deficit hyperactivity disorder (ADHD). However, no study has investigated OPEs in relation to clinically diagnosed ADHD.Aim. To evaluate associations between prenatal exposure to OPEs and ADHD diagnosis, in a case-cohort substudy of the Norwegian Mother, Father and Child Cohort.Methods. We identified 297 ADHD cases through the Norwegian patient registry and sampled a sub-cohort of 555 participants among the eligible population. Diphenyl phosphate (DPHP), di-n-butyl phosphate (DnBP), bis(2-butoxyethyl) hydrogen phosphate (BBOEP), and bis(1,3-dichloro-2-propyl) phosphate (BDCIPP) were measured in urine collected at 17 gestational weeks. Binary exposure indicators were created for DPHP (cutoff: sub-cohort median), DnBP (limit of quantification, LOQ), BBOEP and BDCIPP (limit of detection, LOD). We estimated ORs using logistic regression, adjusting for the season of urine collection, child sex, birth year, maternal depression, maternal ADHD, and phthalate metabolite concentrations. Missing covariates were multiply imputed and estimates were pooled using Rubin’s rules. Effect measure modification by child sex was investigated.Results. DPHP was detected in nearly all samples (98%>LOD), with a higher geometric mean among ADHD cases (0.70 ng/ml) as compared to the sub-cohort (0.52 ng/ml). DNBP was commonly detected as well (6%<LOD; 39% LOD-LOQ; 55%>LOQ), while BBOEP (51%>LOD) and BDCIPP (21%>LOD) were detected less frequently. Children whose mothers had above the median DPHP concentrations during pregnancy were more likely to be diagnosed with ADHD (aOR: 1.41 [95% CI: 1.00, 1.99]). Similar positive associations were observed for BDCIPP (1.47 [0.99, 2.17]), but near-null associations were observed for DnBP (0.93 [0.67,1.30]) and BBOEP (1.05 [0.75, 1.45]). We did not observe strong evidence of modification by child sex.Conclusions. DPHP and BDCIPP exposure during pregnancy may increase the risk of ADHD in offspring.