Effects Of Prenatal Phthalate Exposure Research Articles

Prenatal exposure to phthalates and children’s mental health trajectories: Rhea Cohort, Greece

Abstract Background Accumulating evidence suggests that phthalate exposure affects neurodevelopment, including emotional and behavioral outcomes. Our aim was to investigate if prenatal phthalate exposure affects the developmental course of internalizing and externalizing symptoms from early childhood to adolescence. Methods Concentrations of seven phthalate metabolites were measured in first-trimester maternal spot urine samples, and DEHP, and high and low molecular weight phthalate concentrations were calculated (HMW and LMW, respectively). Mothers reported internalizing and externalizing symptoms via the Strengths and Difficulties Questionnaire at 4 years and the Child Behavior Checklist at 6, 11 and 15 years. Group-Based Trajectory Modeling was used to classify 546 participants of the Rhea Cohort (Crete, Greece) into 4 distinct groups (Stable low, Stable high, Low-Increasing, and High-Decreasing symptoms). We evaluated the association of prenatal phthalate exposure with the odds of an adverse (Stable high, Low-Increasing, and High-Decreasing) internalizing and externalizing symptom trajectory in 150 children using multivariable-adjusted logistic regression (reference group: stable low). Results Only for girls, exposure to DEHP and HMW phthalates was associated with higher odds of being grouped in an adverse internalizing symptoms trajectory (OR [95%CI]: 1.52 [1.03, 2.25] and 1.57 [1.03, 2.39], respectively). Regarding externalizing symptoms, interactions with gender emerged for DEHP (p = 0.024) and HMW (p = 0.028) phthalates, and increased odds of being grouped into an adverse trajectory were observed in girls, whereas boys showed the opposite trend, albeit none reached statistical significance. Conclusions The findings suggest programming effects of prenatal phthalate exposure on the developmental course of emotional symptoms in girls. Further research is needed to clarify the association between in utero phthalate exposure and behavioral symptoms. Key messages • Phthalate exposure is linked to adverse trajectories of emotional symptoms, emerging from preschool age and up to adolescence. • Phthalate effect on internalizing and externalizing symptoms varies by gender.

Effect of prenatal exposure to phthalates on birth weight of offspring: A meta-analysis

Prenatal exposure to phthalates is common. However, its effect on birth weight has always been met with conflicting conclusions. To explore the effects of prenatal phthalate exposure on neonatal weight, we searched PubMed, Web of Science (WOS), Cochrane Library, and Embase databases for articles published up to October 24, 2023. Observational studies with 95% confidence intervals (CI) were included. Our findings indicate no significant association between either mixed exposure effects or single phthalate metabolites and offspring birth weight when monitoring maternal urine phthalate metabolites. When stratified by sex, ΣHMWPs and MMP significantly reduced the birth weight of female offspring (ΣHMWPs: Pooled β = −62.08, 95%CI: −123.11 to −1.05, P = 0.046; MMP: Pooled β = −10.77, 95%CI: −18.74 to −2.80, P = 0.008). The results of subgroup analysis showed that ΣPAEs and ΣDEHP significantly decreased birth weight in the specific gravity correction group (ΣPAEs: Pooled estimates = −29.31, 95%CI: −58.52 to −0.10, P = 0.049; ΣDEHP: Pooled estimates = −18.25, 95%CI: −33.03 to −3.47, P = 0.016), and MECPP showed a positive correlation in the creatinine correction group (MECPP: Pooled estimates = 18.45, 95%CI: 0.13 to 36.77, P = 0.048). MEP and MBzP were negatively associated with birth weight in the no adjustment for gestational age group (MEP: Pooled estimates = −7.70, 95%CI: −14.19 to −1.21, P = 0.020; MBzP: Pooled estimates = −9.55, 95%CI: −16.08 to −3.03, P = 0.004). To make the results more convincing, more high-quality studies with large samples are urgently required.

Prenatal exposure to phthalates and child growth trajectories in the first 24 months of life

BackgroundPhthalates are a class of environmental chemicals with endocrine-disrupting properties. Prenatal phthalate exposure has been associated with adverse developmental outcomes in childhood. However, data assessing the effects of prenatal phthalate exposure on postnatal infant growth trajectories are sparse. ObjectivesTo evaluate the associations of prenatal phthalate exposure with child growth trajectories from birth to 24 months old. MethodsWithin a Chinese birth cohort study, 1051 mother-offspring pairs were included. Seven phthalate metabolites were quantified in maternal urine collected between weeks 33 and 39 of gestation. The trajectories for weight-for-age z-score (WAZ), length-for-age z-score (LAZ), weight-for-length z-score (WLZ) and head-circumference-for-age z-score (HCZ) were determined by group-based trajectory modeling (GBTM). Multinomial logistic regression and the weighted quantile sum approach (WQS) were used to investigate the association between individual and phthalate mixture exposure and the growth trajectories of four anthropometric metrics. ResultsFive trajectory groups were identified for each anthropometric measure using GBTM. Higher prenatal exposure to several phthalate metabolites (MEHP, MEHHP, MEOHP, MECCP, summed DEHP metabolites, as well as MBP) was associated with child growth trajectories, especially for WAZ and LAZ in the first 24 months of life. The associations were further confirmed by a mixture analysis of phthalate metabolites and a sex-specific effect was observed in the WAZ and LAZ trajectories. ConclusionPrenatal phthalate exposure had heterogeneous associations with postnatal growth trajectories. More studies are warranted to confirm and elucidate the meaning of our findings.

Associations between maternal phthalate exposure and neonatal neurobehaviors: The Taiwan maternal and infant cohort study (TMICS)

Previous studies have shown associations between prenatal phthalate exposure and neurobehavioral changes in children. However, few studies have focused on neonatal neurobehavioral development. This study aimed to examine the associations between prenatal phthalate exposure and neonatal neurobehavioral development in the early days of life after birth.This cohort study included 283 mother-infant pairs who participated in the Taiwan Mother Infant Cohort Study during 2012–2015. Each mother was interviewed, and urine samples were collected during the third trimester of pregnancy (weeks 29–40). Eleven common phthalate metabolites in maternal urine were analyzed. The Chinese version of the Neonatal Neurobehavioral Examination was used to evaluate early infant neurobehavioral development within five days of birth. We performed multiple linear regressions to explore the associations between phthalate exposure and neonatal neurobehavioral development. Sex differences in the association between phthalate metabolites and neonatal neurobehaviors were noted. Among girls, tertiles of phthalate metabolite concentrations were associated with worse behavioral responses and tone and motor patterns in the high-molecular-weight phthalate (HMW) and low-molecular-weight phthalate (LMW) groups. Girls in the highest tertile of di-2-ethylhexyl phthalate (DEHP) and mono-isobutyl phthalate (MiBP) had a negative association with tone and motor patterns. Girls in the highest tertile of mono-n-butyl phthalate (MnBP) and MiBP showed a negative association with behavioral responses. In contrast, tertiles of phthalate metabolite exposure were associated with improved neurobehaviors in mono-methyl phthalate (MMP) among boys. The highest tertile of MMP was positively associated with behavioral responses, primitive reflexes, and tone and motor patterns. Our findings suggest that maternal phthalate exposure affects neonatal neurobehavioral development in a sex-specific manner. Despite the relatively small sample size, our findings add to the existing research linking maternal phthalate exposure to neonatal neurobehavioral development. Additional research is needed to determine the potential long-term effects of prenatal phthalate exposure on children.

Combined effects of prenatal phthalate exposure on cardiometabolic risk score among 4- to 7-year-old children: MABC study

There is currently no consensus about the impact of prenatal phthalate exposure on blood pressure and glycolipids in children. Few studies consider the health effects as an integrated indicator. The combined effect of multiple phthalate exposures is often ignored. Based on the Ma'anshan Birth Cohort, 2298 woman-child pairs were included in this study. Maternal urine was collected in each trimester to analyze 6 phthalate metabolites. The overall cardiometabolic risk (CMR) score was calculated based on serum glycolipids and blood pressure for children aged 4–7 years. A higher score represents a less favorable CMR profile. The restricted cubic spline model was used to explore the relationship between prenatal phthalate exposure and childhood CMR score. In addition, the quantile g-computation and the Bayesian kernel machine regression were used to evaluate the combined effect. The MBP exposure in the 1st trimester (MBP-1st) and the MEP-2nd were non-linearly associated with the CMR score (Fnonlinear = 3.28 and 5.60, Pnonlinear = 0.0378 and 0.0038, respectively). The MBP-3rd (Flinear = 5.31, Plinear = 0.0012) and the ∑LMWP-3rd (Flinear = 4.37, Plinear = 0.0045) were negatively associated with the score in a linear manner. The phthalate mixture in the 2nd trimester increased the score (psil = 0.1747, 95% CI = 0.0077–0.3416), with the MEP being the most common [weights = 0.5290; posterior inclusion probability (PIP) = 0.40]. The phthalate mixture in the 3rd trimester decreased the score (psil = −0.2024, 95% CI = −0.4097－0.0048), with the MEHP (weights = −0.5101; PIP = 0.14) and the MBP (weights = −0.3993, PIP = 1.00) being the greatest contributors. In conclusion, the MBP-1st and the MEP-2nd are non-linearly associated with the cardiometabolic risk in children. The MBP-3rd and the ∑LMWP-3rd decrease the childhood risk. The combined exposure to phthalate mixture in the second and third trimester elevates and decreases the risk of childhood cardiometabolism, respectively.

Effects of Prenatal Phthalate Exposure on Early Childhood Expressive Language Development Trajectories

BACKGROUND AND AIM: Phthalates are common endocrine disruptors that can impair neurodevelopment. We investigated potential links between prenatal exposure to phthalates and child language development trajectories given prior inconsistent evidence across individual phthalates. METHODS: We investigated fourteen urinary phthalate metabolites, measured in maternal urine during pregnancy, and child expressive language scores from the Mullen Scales of Early Learning (MSEL) at 6, 12, 24, and 36 months in 231 children from an enhanced autism-risk cohort (19% with autism): Early Autism Risk Longitudinal Investigation (EARLI), born 2009 - 2013 from California, Maryland, and Pennsylvania. We used multiple imputation to handle missingness in MSEL (~37%) and phthalates (~9%), and assigned children to six distinct expressive language trajectories after selecting the latent class growth analysis model with best goodness-of-fit measures. We estimated relative risk ratios (RRR) of being in different language trajectories ("high growth” as reference) associated with two-fold change in creatinine adjusted phthalates using multinomial logistic regression with Firth correction, adjusting for child sex, birth season, income, and maternal age, race, and education. RESULTS: Some low molecular weight phthalates were associated with sub-optimal language trajectories, e.g. RRRs of 1.33 or higher for mono-2-hydroxy-iso-butyl phthalate, peaking at 1.51 (1.02, 2.24) for the delayed growth low trajectory. In contrast, some high molecular weight phthalates exhibited protective effects for delayed growth trajectories but adverse effects for plateau and tracking trajectories: e.g. mono-isononyl phthalate with RRR 0.72 (0.59, 0.89) with delayed growth low but 1.29 (1.08, 1.53) with the tracking low trajectory. Some phthalates exhibited null patterns. CONCLUSIONS: Prenatal phthalate exposure may impact the trajectory of expressive language development in early childhood, with differences by individual phthalates, perhaps by molecular weight group. We observed adverse and protective influences of phthalates that may be influenced by small numbers in each trajectory class. KEYWORDS: phthalates, language development, trajectory analysis

Effects of Prenatal Phthalate Exposure and Childhood Exercise on Maternal Behaviors in Female Rats at Postpartum: A Role of Oxtr Methylation in the Hypothalamus.

Both the detrimental effect of prenatal exposure to di-(2-ethylhexyl)-phthalate (DEHP) and the beneficial effects of physical exercise on brain functions have been reported. The oxytocin pathway has been implicated in the onset of maternal behaviors. Epigenetic modification of the oxytocin receptor gene (OXTR) through DNA methylation has been associated with the pathogenesis of neuropsychiatric disorders. The purpose of this study was to investigate the effects of prenatal DEHP exposure on oxytocin-regulated maternal behaviors and to examine the protective effect of exercise. Pregnant rats (F0) were fed with vehicle or DEHP during gestation and the offspring females (F1) were assessed for their maternal behaviors by pup retrieval test at postpartum. The results showed that reduced pup retrieval activities without significant alteration of stress responses were observed in the prenatally DEHP-exposed females. Prenatal DEHP exposure decreased the expressions of oxytocin, Oxtr mRNA, and oxytocin receptor, and increased Oxtr methylation in the hypothalamus of postpartum female rats. There were no significant effects of exercise on behavioral, biochemical, and epigenetic measurements. These results suggest that prenatal DEHP exposure has a long-term adverse effect on maternal behaviors; Oxtr hyper-methylation may be a potential epigenetic mechanism for this alteration, which cannot be prevented by physical exercise during childhood.

Effect of prenatal phthalate exposure on childhood atopic dermatitis: A systematic review and meta-analysis.

Background: The association between prenatal exposure to phthalate and childhood atopic dermatitis (AD) has previously been investigated; however, the results are inconsistent. Objective: We aimed to perform a systematic review and meta-analysis of birth cohort studies to investigate whether prenatal exposure to phthalate increases the risk of developing AD in children. Methods: We performed an electronic search of medical literature data bases. Studies were critically appraised, and a meta-analysis was performed. Results: Among 129 articles identified, 11 studies met the eligibility criteria. Included studies originated from Europe (n = 5), the United States (n = 4), and Asia (n = 2). The study sample size ranged from 147 to 1024 mother-child pairs. Quality assessment by using the Newcastle-Ottawa scale of all the studies had scores of ≥6. A meta-analysis of data from eight selected studies suggested that monobenzyl phthalate (MBzP) exposure was significantly associated with the risk of AD development (odds ratio 1.16 [95% confidence interval, 1.04-1.31]; I² = 17.36%). However, AD development was not associated with other phthalate metabolites, such as mono-(2-ethylhexyl) phthalate, monoethyl phthalate, mono-isobutyl phthalate, mono-n-butyl phthalate, and the sum of di-[2-ethylhexyl] phthalate on the development of AD (all p values were > 0.05). Conclusion: Our meta-analysis suggested that prenatal exposure to phthalates may be associated with the development of childhood AD. However, further research is needed because only MBzP showed statistical significance and the number of articles in the literature is still insufficient.

Effect of prenatal phthalate exposure on the association of maternal hormone levels during early pregnancy and reproductive markers in infants at the age of 3 months

Phthalates belong to the endocrine-disrupting chemicals, altering the hormonal balance in humans during pregnancy with further effects on the reproductive system. This study aimed to investigate the associations between maternal hormone levels during early pregnancy (≤15th week of pregnancy) and reproductive markers in infant boys (n = 37; 61.67 %; average age 3.51 ± 0.73 months) and girls (n = 23; 38.33 %; average age 3.30 ± 0.33 months) concerning prenatal exposure to phthalates. We used high-performance liquid chromatography, tandem mass spectrometry (HPLC-MS/MS), and electro-chemiluminescence immunoassay to quantify urinary concentrations of phthalates and serum concentrations of hormones, respectively. In Mother-Infant Study Cohort (PRENATAL), we observed positive and negative correlations between infants' reproductive markers and phthalate metabolites (p ≤ 0.05). Next, we noticed associations between the penile length and maternal testosterone (β = 0.464) and estradiol levels (β = −0.365) with increasing significance after adjustment to maternal mono-n-butyl phthalate (MnBP) and monobenzyl phthalate (MBzP) (p ≤ 0.05). We observed a positive association (β = 0.337) between penile width and maternal testosterone with increasing significance after adjustment to maternal mono-iso-butyl phthalate (MiBP) (p ≤ 0.05). In a group of girls, we reported a negative association between ACD/AFD ratio and maternal follicle-stimulating hormone (FSH) and estradiol levels with increasing significance after adjustment to maternal monoethyl phthalate (MEP), MnBP, and mono(hydroxy-iso-butyl) phthalate (OH-MiBP). Our results highlight that prenatal phthalate exposure may modulate the effects of maternal hormone levels during early pregnancy on infants' reproductive markers.

Domain- and trimester-specific effect of prenatal phthalate exposure on preschooler cognitive development in the Ma’anshan Birth Cohort (MABC) study

BackgroundPhthalates are a group of heavily produced endocrine disruptors that are widely used in personal care products, food packaging, building materials, and medical device. Few epidemiological studies have examined the effect of repeated prenatal exposure to multiple phthalates on preschooler cognitive development. ObjectivesThis study aimed to examine the association between prenatal phthalate exposure measured at multiple time points and the intelligent quotient (IQ) scores of preschoolers, and to further identify the critical windows and specific intelligence domains in which phthalate exposure would affect preschooler cognitive development. MethodsThe current study was based on the Ma’anshan Birth Cohort (MABC) study. Seven phthalate metabolites were measured in 2128 maternal urine samples collected during the first, second, and third trimesters of pregnancy. The IQ score of preschool-aged children were assessed with the Chinese version of the Wechsler Preschool and Primary Scale of Intelligence, Fourth edition (WPPSI-Ⅳ CN). Linear mixed models (LMMs) were used to assess the longitudinal effects of repeated prenatal phthalate exposure on children’s IQ score. Multiple linear regression models were fitted to determine whether critical window phthalate exposure would affect cognitive development of children. ResultsOverall, the repeated measures analysis indicated that the verbal comprehension index (VCI), visual space index (VSI) and full-scale intelligence quotient (FSIQ) decreased by 0.30 (95% CI: −0.60, 0; p = 0.05), 0.32 (95% CI: −0.62, −0.01; p = 0.04), and 0.31 (95% CI:-0.57, −0.04; p = 0.02) points, respectively, with each ln-transformed increase in the metabolite concentration of MBP. The fluid reasoning index (FRI) and processing speed index (PSI) increased by 0.30 (95% CI: 0.07, 0.54; p = 0.01) and 0.28 (95% CI: 0.06, 0.51; p = 0.01) points, respectively, with each ln-concentration increase in MEP. Trimester-specific regression models stratified by the sample collection time during pregnancy generated consistent results. In the first trimester, each ln-transformed MBP increase was associated with reductions in VCI, VSI and FSIQ of 0.56 (95% CI:-1.09, −0.02; p = 0.04), 0.60 (95% CI:-1.15, −0.05; p = 0.03) and 0.49 (95% CI:-0.97, −0.01; p = 0.04) points, respectively. In the third trimester, we observed that only MBzP exposure was associated with an increase in VCI (β: 0.48, 95% CI: 0.03, 0.92; p = 0.04). The gender-stratified analyses revealed that boys drove these associations. ConclusionsOur results suggest that prenatal phthalate exposure impairs the cognitive development of preschoolers. The first trimester of pregnancy might be the most vulnerable period in terms of neurotoxicitydue to phthalate exposure. These findings warrant further confirmation.

Associations between repeated measures of maternal urinary phthalate metabolites during pregnancy and cord blood glucocorticoids

BackgroundPrevious studies have suggested that phthalates might disrupt fetal steroidogenesis. However, the evidence of the effects of prenatal phthalate exposure across pregnancy on fetal glucocorticoids was insufficient. ObjectiveWe investigated the associations between urinary phthalate metabolites across pregnancy and cord blood glucocorticoids in a prospective birth cohort. MethodsOur study included 553 mother-infant pairs from a prospective birth cohort conducted in Wuhan, China. Maternal urine samples were collected at 14, 24 and 36 weeks of gestation (mean). Urinary phthalate metabolites and cord blood glucocorticoids (cortisol and cortisone) were measured. Generalized estimating equation models were conducted to explore the relationships of phthalate metabolite concentrations at each trimester and glucocorticoid levels. ResultsAmong the participants, mono‑benzyl phthalate (MBzP) in the first trimester was associated with higher cortisol/cortisone ratio concentrations, and mono‑(2‑ethyl‑5‑carboxypentyl) phthalate (MECPP) and mono‑(2‑ethyl‑5‑oxohexyl) phthalate (MEOHP) measured in the third trimester were associated with decreased cortisone. Moreover, the associations between phthalates and glucocorticoids varied by sex. Among the female infants, each 10-fold increase in several maternal urinary phthalate metabolite concentrations in 1st and 3rd trimester was associated with the increased glucocorticoid levels with percent changes ranged from 16.2%–55.9%. However, among male infants, each 10-fold increase in maternal urinary MECPP, mono‑(2‑ethyl‑5‑hydroxyhexyl) phthalate (MEHHP) and MEOHP in 3rd trimester was associated with 20.8%–36.3% decreased cortisol and cortisone levels, respectively. ConclusionWe have shown that prenatal phthalate exposure during early and late trimester disrupted the infant steroidogenesis and these associations might be modified by infant sex. To the best of our knowledge, this is the first study to evaluate phthalate exposure at three trimesters during pregnancy in relation to infant glucocorticoids.

Longitudinal assessment of prenatal phthalate exposure on serum and cord thyroid hormones homeostasis during pregnancy - Tainan birth cohort study (TBCS)

An increasing number of studies have revealed that phthalate exposure alters thyroid hormone homeostasis in the general population, but there is insufficient evidence of the effect of longitudinal maternal phthalate exposure on maternal and fetal thyroid hormones during pregnancy. We longitudinally assessed the effect of prenatal phthalate exposure in pregnant women on umbilical cord and maternal thyroid hormones at three trimesters during pregnancy. We recruited 98 pregnant women and collected urine and blood samples at three trimesters in an obstetrics clinic in Southern Taiwan from 2013 to 2014. We analyzed the concentrations of 11 urinary phthalate metabolites, including monoethylhexyl phthalate, mono-(2-ethyl-5-oxo-hexyl) phthalate (MEOHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate, mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP), mono-n-butyl phthalate, monoisobutyl phthalate (MiBP), monoethyl phthalate (MEP), using online liquid chromatography–tandem mass spectrometry. The cord and maternal serum levels of thyroxine (T4), free T4, triiodothyronine (T3), thyroid-stimulating hormone (TSH), and thyroxine-binding globulin were measured using an electrochemiluminescence immunoassay. A mixed-model analysis was utilized to assess the effect of longitudinal phthalate exposure on thyroid hormones and adjusted for significant covariates. We found that urinary MiBP (β=−0.065, 95% confidence interval (CI): −0.124, −0.005), and MEOHP (β=−0.083, 95% CI: −0.157, −0.009) were significantly negatively associated with serum TSH. Urinary MECPP was inversely related to serum T3 (β=−0.027, 95% CI: −0.047, −0.006). Urinary MEP (β=0.014, 95% CI: −0.001, 0.028) and MiBP (β=0.033, 95% CI: 0.018, 0.049) were positively related to free T4. We found that cord serum T3 (β=0.067, 95% CI: 0.003, 0.131) and free T4 (β=0.031, 95% CI: 0.001, 0.062) levels had significant positive associations with maternal ΣDBPm levels at the second trimester. We concluded that different phthalates exposure windows during gestation may alter cord and serum thyroid hormone homoeostasis.

Effects of Prenatal Phthalate Exposure on Thyroid Hormone Concentrations Beginning at The Embryonic Stage

Limited studies have consistently shown an association of phthalates exposure with thyroid hormones (THs) in pregnant women. However, it remains unknown on which specific phthalates can affect THs and whether any effects could differ by gestational age. In the present study, we investigated associations between serum concentrations of phthalate monoesters [monoethyl phthalate (MEP), mono-(n + iso)-butyl phthalate (MBP) and mono(2-ethylhexyl) phthalate (MEHP)] and THs [thyroid-stimulating hormone (TSH), total thyroxine (TT4) and free thyroxine (FT4)] in Chinese pregnant women. 1,397 women were recruited from the China-Anhui Birth Cohort. Maternal serum samples were collected and used to measure phthalate metabolites and THs. Covariate-adjusted linear regression analyses showed that natural log (Ln)-transferred concentrations of MBP and LnMEHP were negatively associated with TT4 (β = −0.277 and –0.461, respectively; p < 0.001). Stratification analyses by gestational weeks showed significant associations of LnMBP and LnMEHP with TT4 in gestational weeks 5 to 8, 9 to 12, and 13 to 20. Our findings suggest an association of serum phthalates with lower TT4. The influence of MBP and MEHP on TT4 concentrations throughout the early pregnancy may begin from the embryonic stage (gestational weeks 5 to 8).

Prenatal phthalate exposure and placental size and shape at birth: A birth cohort study

ObjectiveThere is concern over the potential placental effects of prenatal phthalate exposure, and the potential adverse effects of prenatal phthalate exposure require further study; however, few data are available in humans. We investigated the associations between phthalate exposure in each trimester and both placental size and shape at birth. MethodsWe measured the urinary concentrations of phthalate metabolites among 2725 pregnant women in the Ma’anshan Birth Cohort. Before collecting urine samples from each of the three trimesters, the pregnant women were interviewed via questionnaires. Placental information was obtained from hospital records. We estimated the sex-specific associations between urinary phthalate concentrations in each trimester and both placental size and shape at birth using adjusted multiple regression. A linear mixed model was used for the repeated measures analysis with subject-specific random intercepts and slopes for gestational age at sample collection to test the effect of phthalate levels on placental size and shape and to estimate the effect sizes. ResultsOverall, placental breadth increased by 0.148cm (95% CI: 0.078, 0.218) with each 1 ln-concentration increase in MBP in the first trimester. The difference between placental length and breadth (length–breadth) decreased by 0.086cm (95% CI: −0.159, −0.012) and 0.149cm (95% CI: −0.221, −0.076) with each 1 ln-concentration increase in MMP and MBP, respectively, in the first trimester. In the second trimester, placental thickness increased by 0.017cm (95% CI: 0.006, 0.027), 0.020cm (95% CI: 0.004, 0.036), 0.028cm (95% CI: 0.007, 0.048), and 0.035cm (95% CI: 0.018, 0.053) with each 1 ln-concentration increase in MMP, MBP, MEOHP, and MEHHP, respectively. In the third trimester, placental thickness increased by 0.037cm (95% CI: 0.019, 0.056) and 0.019cm (95% CI: 0, 0.037) with each 1 ln-concentration increase in MBP and MEHP, respectively. Multiple linear regression for each offspring sex indicated that prenatal phthalate exposure increased placental thickness in both the first and second trimesters in males, whereas the corresponding relationship was close to null in females. Linear mixed models (LMMs) yielded similar results. ConclusionOur results suggest the presence of associations between prenatal phthalate exposure and placental size and shape. Exposure to certain phthalates may cause the placenta to become thicker and more circular. Associations appeared stronger for the subsample representing male offspring than those for the subsample representing female offspring. Given the few studies on this topic, additional research is warranted.

Early-Life Phthalate Exposure and Adiposity at 8 Years of Age.

Background:Early-life phthalate exposure may influence child adiposity, but prior studies have not determined if there are periods of enhanced vulnerability to phthalates.Objective:To examine the relationship between child adiposity at 8 y of age and repeated urinary biomarkers of phthalate exposure from gestation through childhood to determine if there are distinct periods of vulnerability.Methods:In 219 mother–child pairs from Cincinnati, Ohio, we quantified nine urinary phthalate metabolites up to two times prenatally and six times from 1–8 y of age. We measured child body mass index (BMI), waist circumference, and percent body fat at 8 y of age. To identify periods of vulnerability, we used two statistical methods to estimate phthalate–adiposity associations at each visit, test differences in phthalate–adiposity associations across visits, and model trajectories of phthalate concentrations for children at different levels of adiposity.Results:Prenatal phthalate concentrations were not associated with excess child adiposity. Monobenzyl phthalate (MBzP) concentrations during pregnancy and childhood were inversely associated with adiposity. The associations of di(2-ethylhexyl) phthalate () metabolites and monoethyl phthalate (MEP) with child adiposity depended on the timing of exposure. A 10-fold increase in at 1 and 5 y was associated with a 2.7% decrease [95% confidence interval (CI): , ] and 2.9% increase (95% CI: 0.3, 5.5) in body fat, respectively. MEP concentrations at 5 and 8 y of age were associated with higher child adiposity, but earlier childhood concentrations were not.Conclusion:In this cohort, we did not find evidence of an obesogenic effect of prenatal phthalate exposure. Positive associations between postnatal MEP and concentrations depended on the timing of exposure. https://doi.org/10.1289/EHP1022

Relationship between maternal phthalate exposure and offspring size at birth

Research findings on effects of prenatal phthalate exposure on fetal growth were inconsistent. Increasing evidence from animal studies has indicated a potential sex-specific effect of phthalates on fetal growth, but the current human data was limited. In this study, we aimed to estimate the relationships between maternal phthalate exposure and infant birth size. Six major phthalate metabolite levels of urine samples were measured among pregnant women (n=1002) from the Healthy Baby Cohort (HBC), China. The associations between urinary phthalate metabolites levels and birth size (birth weight, birth length, birth weight z-scores and ponderal index) were estimated using linear regression models. In boys, the ln-transformed di-2-ethylhexyl phthalate (DEHP) metabolite levels were significantly associated with increased birth weight and birth weight z-scores. Additionally, each ln-unit increase in mono-(2-ethyl-5-carbox-ypentyl) phthalate (MECPP) was associated with a 0.25kg/m3 [95% confidence interval (CI): 0.03, 0.47] increase in ponderal index in boys. However, we did not observe any significant association of maternal phthalate metabolite levels with any of the outcomes in girls. Our data suggested potential sex-specific associations of maternal phthalate exposure with increased birth weight and ponderal index, which were merely apparent in boys.

Effects of prenatal phthalate exposure on thyroid hormone levels, mental and psychomotor development of infants: The Hokkaido Study on Environment and Children's Health

Di (2-ethylhexyl) phthalate (DEHP) is commonly used phthalates and concerns of adverse effects of prenatal DEHP exposure on neonatal thyroid hormone (TH) and neurodevelopment are increasing. However, there is no report regarding association between prenatal DEHP exposure and infant neurodevelopment including TH levels in Japanese population. Thus the aim of present study was to evaluate the associations between prenatal DEHP exposure and mental and psychomotor development of infants 6 and 18months along with investigating influence on neonatal free thyroxine (FT4) and thyroid stimulating hormone (TSH) levels in the prospective birth cohort study.Maternal blood samples collected between 23 and 41weeks of gestation was analyzed for mono (2-ethylhexyl) phthalate (MEHP), metabolite of DEHP levels. Neonatal FT4 and TSH were obtained from mass screening data. Infant neurodevelopment was assessed by Bayley Scale of Infant Development second edition at 6 and 18month of age. For the final analysis, 328 participants were included.The median levels of maternal MEHP was 10.6ng/ml, neonatal TSH and FT4 was 2.20 μU/ml and 2.03ng/ml, respectively. We did not find any associations between prenatal DEHP exposure and neonatal TH levels or infant mental and psychomotor development at 6 and 18month.In this study, prenatal DEHP exposure did not show adverse effects on infant TH levels or mental and psychomotor development in early life stage. However, our previous study revealed negative effects of prenatal DEHP exposure on sex hormone levels, continuous investigation on neurodevelopment in later life in association with prenatal DEHP exposure is necessary.

Prenatal exposure to phthalates and neuropsychological development during childhood.

There is inconsistent evidence regarding the effects of prenatal phthalate exposure on children's neuropsychological development. We evaluate the association between prenatal phthalate exposure and the cognitive, psychomotor and behavioral development of 367 children at repeated ages in a prospective birth cohort study. We measured phthalate metabolites (sum of four DEHP metabolites - Σ4DEHP, MBzP, MEP, MiBP and MnBP) in urine samples collected during the 1st and 3rd trimesters of pregnancy in women participating in the INMA-Sabadell birth cohort study. We assessed cognitive and psychomotor development of their children at 1 and 4 years, and social competence, ADHD symptoms and other behavioral problems at 4 and 7 years. No associations were observed between prenatal phthalate exposure and cognitive and psychomotor scores at the age of 1 year and at the age of 4 years, except for an association between MBzP and lower psychomotor scores (β=-1.49 [95% confidence interval (CI)=-2.78, -0.21]). Σ4DEHP concentrations were associated with increased social competence scores at 4 years and with reduced ADHD symptoms at age 4 and 7 years. Increasing MEP concentrations were associated with a reduced risk of inattention symptoms at 4 years. No associations were observed for MBzP, MiBP or MnBP in relation to behavioral problems. This study, with multiple phthalate exposure measurements and measures of neuropsychological domains at different ages, suggest that prenatal phthalate exposure does not adversely affect children's cognitive, psychomotor or behavioral development.

Sexually-Dimorphic Associations of Prenatal Phthalate Exposure and Neurobehavioral Development in 6-10 Year Olds

Background: Concern has been raised over the potential neurobehavioral effects of prenatal phthalate exposure but available data are inconsistent. Aims: To examine associations between prenatal urinary concentrations of phthalate metabolites and neurobehavioral outcomes among children. Methods: We analyzed data on 153 children, aged 6 to 10 years, born to participants in the Study for Future Families, a multicenter pregnancy cohort study. Maternal urinary phthalate metabolite levels were measured during late pregnancy by high performance liquid chromatography-tandem mass spectrometry. Children were evaluated with the Child Behavior Checklist. With a useful re-parameterization of a standard regression interaction model, we estimated sex-specific associations between neurobehavioral outcomes and phthalate metabolites levels, adjusting for the child’s age, mother’s education, family stress, and urinary creatinine. Results: Concentration of monoisobutyl phthalate was associated in boys (but not girls) with inattention (b=0.27 (95% CI=0.04, 0.50)), rule-breaking behavior (b=0.20 (95% CI=0.01, 0.38)), aggression (b=0.34 (95% CI=0.09, 0.59)), and conduct problems (b=0.39 (95% CI=0.20, 0.58)). Among boys, the (molar) sum of di-2-ethylhexyl phthalate metabolites was associated with somatic problems (b=0.15, 95% CI=(0.03, 0.28), while in girls, it was negatively associated with anxiety problems (b=-0.21, 95% CI=-0.38, -0.04). Higher monobenzyl phthalate concentration was associated in boys with more oppositional behavior (b=0.16 (95% CI=0.01, 0.32)) and conduct problems (b=0.21 (95% CI=0.06, 0.37)), but with reduced anxiety in girls (b=-0.20, 95% CI=-0.39, -0.01). Higher monoethyl phthalate concentration was associated with fewer affective problems in boys (b=-0.12, 95% CI=-0.24, -0.01). Conclusions: Our results suggest associations between exposure to certain phthalates in late pregnancy and behavioral problems in boys.

Prenatal urinary phthalate metabolites levels and neurodevelopment in children at two and three years of age

BackgroundPrevious studies suggest that prenatal phthalate exposure affects neurodevelopment and behavior during the first years of life. ObjectivesTo evaluate the effect of maternal urinary concentrations of phthalate metabolites during pregnancy on mental and psychomotor development in children 24–36months of age. MethodsThis analysis was conducted on the first three years of life among a subsample of 136 mother–child pairs from the ELEMENT cohort studies conducted in Mexico City. Maternal urine samples collected during the third trimester of pregnancy were analyzed for 9 phthalate metabolites: Mono-ethyl phthalate (MEP), Mono-n-butyl phthalate (MnBP), mono-isobutyl phthalate (MiBP), mono-benzyl phthalate (MBzP), Mono-3-carboxypropyl phthalate (MCPP), and four di-2-ethylhexyl phthalate (DEHP) metabolites [mono-2-ethylhexyl-phthalate (MEHP), mono-(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), mono-(2-ethyl-5-oxohexyl) phthalate (MEOHP), and mono-(2-ethyl-5-carboxypentyl) phthalate (MECPP)]. Among the 136 children, 135 (99.3%) completed the study period. Child neurodevelopment was assessed using mental and psychomotor development indexes (MDI and PDI) from a Bayley (BSID II) test at 24, 30, and 36months of age. The effect of prenatal phthalate exposure on neurodevelopment was estimated using linear regression models for longitudinal data clustered at the individual level. ResultsNo significant associations were observed among all children combined, but differential effects by gender were found. Among girls, there was a negative association between MDI and DEHP metabolites MEHP (β=−2.11 [95% CI: −3.73, −0.49]), MEHHP (β=−1.89 [95% CI: −3.64, −0.15]), MEOHP (β=−1.80 [95% CI: −3.58, −0.03]) MECPP (β=−2.52 [95% CI: −4.44, −0.61]), and ΣDEHP (β=−3.41 [95% CI: −5.26, −1.55]); there was no significant effect among boys. Male PDI was positively related to MBzP (β=1.79 [95% CI: 0.14, 3.45]) and MCPP (β=1.64 [95% CI: 0.15, 3.12]); there was no significant effect on PDI among girls. ConclusionThis study demonstrates that sex plays a role of an effect modifier in the association between prenatal phthalate exposure and neurodevelopment.