Prenatal Phthalates, Maternal Thyroid Function, and Risk of Attention-Deficit Hyperactivity Disorder in the Norwegian Mother and Child Cohort
There is growing concern that phthalate exposures, particularly during the prenatal period, may have an impact on child neurobehavioral development. Prenatal exposure to phthalates has been associated with both externalizing and internalizing behaviors using validated behavioral screening instruments, as well as with deficits in executive function as measured by both parental report and performance-based assessments , although not all studies have found evidence of associations. Among the neurobehavioral domains identified in multiple studies are inattention , aggression, conduct problems, and emotional reactivity/regulation, as well as impairments in working memory. Sex differences in the associations of phthalates with neurobehavioral end points have often been noted, although some studies have found stronger associations among boys, whereas others have found stronger associations among girls. The constellation of phthalate-associated behaviors highlighted across studies has led many researchers to note overlap with symptoms of attention-deficit hyperactivity disorder (ADHD).
Despite the observed overlap in affected neurobehavioral domains, there is less consensus on the specific phthalate responsible for neurodisruptive effects, and no prior study has accounted for the correlation among phthalates by mutual adjustment. Some studies have reported significant associations with dibutyl phthalates and/or di-2-ethylhexyl phthalate (DEHP) ; others have highlighted butyl benzyl phthalate (BBzP). Moreover, as of now there have been no studies with biomarkers of exposure in the prenatal period and access to clinically confirmed neurobehavioral end points, such as ADHD diagnoses from a clinical provider. Rather, the bulk of the literature relies on parent-reported symptoms. Because the ages of the children examined have varied substantially across and within studies, relying solely on parental reports to identify nonnormative behavior may be problematic.
A number of mechanisms have been proposed to explain how phthalates may negatively affect brain development, although few have been thoroughly examined in humans or in animal models. One prominent concern is phthalate-induced maternal thyroid hormone disruption. Phthalates have been associated with changes in circulating thyroid hormone levels in adults and in pregnant women. The most consistent finding across studies has been an inverse association between metabolites of DEHP and thyroxine and/or free thyroxine. Maternal prenatal thyroid hormone is essential for fetal neurodevelopment, and clinically diagnosed thyroid hormone disorders (hyperthyroidism and hypothyroidism) in the perinatal period have been linked with ADHD in offspring. Additionally, both higher and lower levels of thyroid hormone concentrations, even within population reference ranges, have been associated with ADHD-like behaviors. Perinatal phthalate exposure has also been associated with preterm delivery, which is itself a risk factor for ADHD.
A true causal association of phthalate exposure with child neurodevelopment would have major public health significance. Phthalates are ubiquitous in consumer products, are components of many food processing and packaging materials, and can be found in both pharmaceuticals, and personal care products. Therefore, to address this critically important public health question, we undertook a prospective, nested case–control study in the Norwegian Mother and Child Study (MoBa) to examine the hypothesis that prenatal biomarkers of phthalate exposure are associated with clinical ADHD in offspring. We further considered whether any associations were mediated by maternal thyroid function or preterm delivery or were modified by child sex.
We undertook an investigation into whether prenatal exposure to phthalates was associated with clinically confirmed ADHD in a population-based nested case–control study of the Norwegian Mother and Child Cohort (MoBa) between the years 2003 and 2008.
Phthalate metabolites were measured in maternal urine collected at midpregnancy. Cases of ADHD (n=297) were obtained through linkage between MoBa and the Norwegian National Patient Registry. A random sample of controls (n=553) from the MoBa population was obtained.
In multivariable adjusted coexposure models, the sum of di-2-ethylhexyl phthalate metabolites (∑DEHP) was associated with a monotonically increasing risk of ADHD. Children of mothers in the highest quintile of ∑DEHP had almost three times the odds of an ADHD diagnosis as those in the lowest [OR=2.99 (95% CI: 1.47, 5.49)]. When ∑DEHP was modeled as a log-linear (natural log) term, for each log-unit increase in exposure, the odds of ADHD increased by 47% [OR=1.47 (95% CI: 1.09, 1.94)]. We detected no significant modification by sex or mediation by prenatal maternal thyroid function or by preterm delivery.
In this population-based case–control study of clinical ADHD, maternal urinary concentrations of DEHP were monotonically associated with increased risk of ADHD. Additional research is needed to evaluate potential mechanisms linking phthalates to ADHD.