Emerging evidence suggests that phthalate exposure may be associated with behavior problems in children and that these associations may be sex specific. In a follow up study of 411 inner-city minority mothers and their children, mono-n-butyl phthalate (MnBP), monobenzyl phthalate (MBzP), monoisobutyl phthalate (MiBP), monethyl phthalate (MEP) and four di-2-ethylhexyl phthalate metabolites (DEHP) were quantified in maternal urine samples collected during the third trimester and in child urine samples at ages 3 and 5 years. The Conners' Parent Rating Scale-Revised: Long Form (CPRS) and Child Behavior Checklist (CBCL) were administered to the mothers to assess children's behavior problems at 7 years of age. The analysis included children with available measures of CBCL, CPRS and phthalates measured in maternal urine. We performed both Quasi-Poisson regression and a mixture analysis using Weighted Quantile Sum(WQS) regression to assess the risk for CPRS scores and for internalizing and externalizing behaviors (from the CBCL) following intra-uterine exposure to the phthalate metabolites for boys and girls separately. Among boys, increases in in anxious-shy behaviors were associated with prenatal exposure to MBzP (Mean Ratio [MR] = 1.20, 95%CI 1.05-1.36) and MiBP (Mean Ratio (MR) = 1.22, 95%CI 1.02-1.47). Among girls, increases in perfectionism were associated with MBzP (MR = 1.15, 95%CI 1.01-1.30). In both boys and girls, increases in psychosomatic problems were associated with MiBP (MR = 1.28, 95%CI 1.02-1.60), and MnBP (MR = 1.28, 95%CI 1.02-1.59), respectively. Among girls, decreased hyperactivity was associated with two DEHP metabolites, mono(2-ethyl-5-oxohexyl) phthalate (MR = 0.83, 95%CI 0.71-0.98) and mono(2-ethyl-5-hydroxyhexyl) phthalate (MR = 0.85, 95%CI 0.72-0.99). Using weighted Quantile Sum logistic regression, no associations were found between the Weighted Quantile Sum (WQS) of phthalate metabolites and CPRS scores or externalizing and internalizing behaviors. Nonetheless, when the analysis was performed separately for DEHP and non-DEHP metabolites significant associations were found between the WQS of DEHP metabolites and social problems in boys (OR = 2.15, 95%CI 1.13-4.06, p-value = 0.02) anxious-shy problems in girls (OR = 2.19, 95%CI 1.15-4.16, p = 0.02), and emotional lability problems in all children (OR = 0.61, 95%CI 0.38-0.97, p = 0.04). MEHP and MEOHP were the most highly weighted DEHP metabolites in WQS mixture. The analysis performed with CBCL scale corroborated these associations. Concentration of non-DEHP metabolites was associated with anxious-shy behaviors among boys. DEHP phthalate metabolites were associated with decreased hyperactivity and impulsivity among girls on CPRS scores. These findings lend further support to the adverse associations between prenatal phthalate exposure and childhood outcomes, and clearly suggest that such associations are sex and mixture specific.

Aim: This systematic review aims to estimate the relationship between prenatal exposure to opioids and neurodevelopmental outcomes and examines potential sources of heterogeneity between the studies.Methods: We searched four databases through May 21st, 2022: PubMed, Embase, PsycInfo and the Web of Science according to a specified search strings. Study inclusion criteria include: (1) cohort and case-control peer-reviewed studies published in English; (2) studies comparing neurodevelopmental outcomes among children with prenatal opioid-exposure (prescribed or used non-medically) vs. an unexposed group. Studies investigating fetal alcohol syndrome or a different primary prenatal exposure other than opioids were excluded. Two main performed data extraction using “Covidence” systematic review platform. This systematic review was conducted in accordance with PRISMA guidelines. The Newcastle-Ottawa-Scale was used for quality assessment of the studies. Studies were synthesized based on the type of neurodevelopmental outcome and the instrument used to assess neurodevelopment.Results: Data were extracted from 79 studies. We found significant heterogeneity between studies due to their use of different instruments to explore cognitive skills, motor, and behavioral outcomes among children of different ages. The other sources of heterogeneity included: procedures to assess prenatal exposure to opioids; period of pregnancy in which exposure was assessed; type of opioids assessed (non-medical, medication used for opioid use dis-order, prescribed by health professional), types of co-exposure; source of selection of prenatally exposed study participants and comparison groups; and methods to address lack of comparability between exposed and unexposed groups. Cognitive and motor skills as well as behavior were generally negatively affected by prenatal opioid exposure, but the significant heterogeneity precluded a meta-analysis.Conclusion: We explored sources of heterogeneity in the studies assessing the association between prenatal exposure to opioids and neurodevelopmental outcomes. Sources of heterogeneity included different approaches to participant recruitment as well as exposure and outcome ascertainment methods. Nonetheless, overall negative trends were observed between prenatal opioid exposure and neuro-developmental outcomes.

Phthalates are a group of high production chemicals, generally used as plasticizers and odor enhancers. Phthalates cross the blood-placenta barrier and are associated with deficits in cognitive functions and behavior problems in offspring. We previously reported sex-specific associations with motor function when phthalates are considered singly. Because exposure to phthalates usually occurs as mixtures, here we assess these associations between a mixture of phthalates and motor function at age 11 years. Data come from the prospective cohort study of mothers and offspring who participated in the Columbia Center for Children's Environmental Health birth cohort (CCCEH). Seven phthalate metabolites were measured in maternal spot urine obtained during the third trimester and motor function was evaluated using the short form of the Bruininks-Oseretsky Test of Motor Proficiency, 2nd edition (BOT-2) at the age of 11 years. We used Weighted Quartile Sum (WQS) regression models to examine the effect of phthalate metabolites in males and females separately. The models were adjusted for child age in months, child BMI, maternal race (African-American vs. Dominican), prenatal alcohol consumption, maternal demoralization score, HOME score, and urine specific gravity. In a secondary analysis we used linear regression models to examine the association between the sum of molar concentrations of both DEHP and non-DEHP metabolites, and outcomes of gross and fine motor functions. 209 mother-child pairs were eligible for this analysis. A significant decrease in fine-motor functions was observed among females, but not among males, following exposure to high levels of weighted quartile sum of seven phthalate metabolites (Covariates-adjusted coefficient estimate B = -2.7, 95% Confidence Interval [CI] -4.64 to -0.75, p = 0.01 for females [n = 116] and B = -1.63, 95%CI -3.94 to 0.69, p = 0.16 for males [n = 93]). The most highly weighted phthalate metabolites, associated with fine-motor functions among females, were MBP, MBZP, and MIBP, all non-DEHP phthalates. No significant associations were found between the weighted quartile sum of seven phthalate metabolites and gross-motor functions at the age of 11 years for males (B = -0.81, 95%CI -1.17 to 1.96, p = 0.23). With the molar sum of four non-DEHP phthalates as main predictor of linear regression models, we found significant decrease in gross and fine motor functions among females prenatally exposed to non-DEHP phthalates B = -0.98, 95%CI -1.98 to 0.03, p = 0.05 and B = -0.85, 95%CI -1.49 to -0.20, p = 0.01, respectively). Phthalate exposure during pregnancy was associated with decreased motor functions among 11-year-old girls.