A multidisciplinary and structured investigation of three suspected clusters of transverse upper limb reduction defects in France.

INTRODUCTION: Between 2019-2021, facing public concern, a scientific expert committee (SEC) reanalysed suspected clusters of transverse upper limb reduction defects (TULRD) in three administrative areas in France, where initial investigations had not identified any risk exposure. We share here the national approach we developed for managing suspicious clusters of the same group of congenital anomalies occurring in several areas. METHODS: The SEC analysed the medical records of TURLD suspected cases and performed spatiotemporal analyses on confirmed cases. If the cluster was statistically significant and included at least three cases, the SEC reviewed exposures obtained from questionnaires, environmental databases, and a survey among farmers living near to cases' homes concerning their plant product use. RESULTS: After case re-ascertainment, no statistically significant cluster was observed in the first administrative areas. In the second area, a cluster of four children born in two nearby towns over two years was confirmed, but as with the initial investigations, no exposure to a known risk factor explaining the number of cases in excess was identified. In the third area, a cluster including just two cases born the same year in the same town was confirmed. DISCUSSION: Our experience highlights that in the event of suspicious clusters occurring in different areas of a country, a coordinated and standardised approach should be preferred.

Longitudinal Associations between Prenatal Exposure to Phthalates and Steroid Hormones in Maternal Hair Samples from the SEPAGES Cohort.

We assessed phthalate-hormone associations in 382 pregnant women of the new-generation SEPAGES cohort (2014-2017, France) using improved exposure and outcome assessments. Metabolites from seven phthalate compounds and the replacement di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH) were measured in within-subject pools of repeated urine samples collected at the second and third pregnancy trimesters (≈21 samples/trimester). Metabolites from five steroid hormones were measured in maternal hair samples collected at delivery, reflecting cumulative levels over the previous weeks to months. Adjusted linear regression and Bayesian weighted quantile sum (BWQS) mixture models were performed. Each doubling in third-trimester urinary mono-benzyl phthalate (MBzP) concentrations was associated with an average increase of 13.3% (95% CI: 2.65, 24.9) for ∑cortisol, 10.0% (95% CI: 0.26, 20.7) for ∑cortisone, 17.3% (95% CI: 1.67, 35.4) for 11-dehydrocorticosterone, and 16.2% (95% CI: 2.20, 32.1) for testosterone, together with a suggestive 10.5% (95% CI: -1.57, 24.1) increase in progesterone levels. Each doubling in second-trimester urinary di-isononyl phthalate (DiNP) concentrations was inversely associated with testosterone levels (-11.6%; 95% CI: -21.6, -0.31). For most hormones, a nonsignificant trend toward a positive phthalate mixture effect was observed in the third but not in the second trimester. Our study showed that exposure to some phthalate metabolites, especially MBzP, may affect adrenal and reproductive hormone levels during pregnancy.

Effects of early exposure to phthalates on cognitive development and visual behavior at 24 months.

BACKGROUND AND OBJECTIVES: Studies focusing on the neurodevelopmental effects of phthalates seldom consider exposure during infancy, a critical period for brain development. Most rely on parent-completed questionnaires to assess child neurodevelopment, which may be subject to reporting error. We studied the associations between prenatal and infancy exposure to phthalates and objective measures of neurodevelopment at the age of two. METHODS: We relied on 151 mother-child pairs from the SEPAGES mother-child cohort. Women were asked to collect three spot urine samples per day over seven consecutive days during the second (median: 18.0 gestational weeks) and third (median: 34.2 gestational weeks) trimesters of pregnancy. They then collected one urine sample per day over seven consecutive days from their infants around the age of 12 months. Metabolites of phthalates and non-phthalate plasticizers were measured in within-subject and within-period pools of repeated urine samples. Eye tracking tasks were performed at two years allowing to compute four indicators linked with cognitive development and visual behavior: mean fixation duration, novelty preference, percent time spent looking at the eyes and mean reaction time. RESULTS: Pre-natal exposure to monobenzyl phthalate at the second and third trimesters was associated with shorter fixation durations. In models allowing for interaction with child sex, these associations were only observed among girls. Exposure to di(2-ethylhexyl) phthalate at the third but not the second trimester was associated with increased time spent looking at a novel face and eyes. We observed faster reaction times and decreased time spent looking at the eyes in a face recognition task, with increased post-natal exposure to monoethyl, mono-iso-butyl and mono-n-butyl phthalates. DISCUSSION: Relying on improved exposure assessment, we highlighted associations of pre- and post-natal exposure to phthalates with indicators derived from eye tracking tasks, mainly in girls. Some of these indicators have been affected in individuals with neurodevelopmental disorders.

Prenatal and childhood exposure to ambient air pollution and cognitive function in school-age children: Examining sensitive windows and sex-specific associations.

BACKGROUND: Combined effect of both prenatal and early postnatal exposure to ambient air pollution on child cognition has rarely been investigated and periods of sensitivity are unknown. This study explores the temporal relationship between pre- and postnatal exposure to PM10, PM2.5, NO2 and child cognitive function. METHODS: Using validated spatiotemporally resolved exposure models, pre- and postnatal daily PM2.5, PM10 (satellite based, 1 km resolution) and NO2 (chemistry-transport model, 4 km resolution) concentrations at the mother's residence were estimated for 1271 mother-child pairs from the French EDEN and PELAGIE cohorts. Scores representative of children's General, Verbal and Non-Verbal abilities at 5-6 years were constructed based on subscale scores from the WPPSI-III, WISC-IV or NEPSY-II batteries, using confirmatory factor analysis (CFA). Associations of both prenatal (first 35 gestational weeks) and postnatal (60 months after birth) exposure to air pollutants with child cognition were explored using Distributed Lag Non-linear Models adjusted for confounders. RESULTS: Increased maternal exposure to PM10, PM2.5 and NO2, during sensitive windows comprised between the 15th and the 33rd gestational weeks, was associated with lower males' General and Non-verbal abilities. Higher postnatal exposure to PM2.5 between the 35th and 52nd month of life was associated with lower males' General, Verbal and Non-verbal abilities. Some protective associations were punctually observed for the very first gestational weeks or months of life for both males and females and the different pollutants and cognitive scores. DISCUSSION: These results suggest poorer cognitive function at 5-6 years among males following increased maternal exposure to PM10, PM2.5 and NO2 during mid-pregnancy and child exposure to PM2.5 around 3-4 years. Apparent protective associations observed are unlikely to be causal and might be due to live birth selection bias, chance finding or residual confounding.

In utero exposure to poly- and perfluoroalkyl substances and children respiratory health in the three first years of life.

BACKGROUND: Poly- and perfluoroalkyl substances (PFAS) are used in a wide range of products. Experimental studies suggested impaired lung development and pro-inflammatory response following exposure to some PFAS. We aimed to assess the associations between prenatal exposure to PFAS and children respiratory health. METHODS: The study is based on 433 mother-child pairs. 26 PFAS were measured in maternal serum collected during pregnancy. Lung function parameters were measured at 2 months using tidal breathing flow-volume loops and multiple-breath nitrogen washout and at 36 months using oscillometry. Incidence of respiratory health diseases (asthma, wheeze, bronchitis, bronchiolitis) in the first 36 months of life was assessed by repeated questionnaires. A cluster-based analysis was applied to identify prenatal PFAS exposure patterns. Adjusted linear and logistic regressions were performed to assess the associations between PFAS exposure patterns as well as individual PFAS, and each respiratory health parameter. RESULTS: We excluded 13 PFAS due to low quantification (<5%). Relying on the 13 remaining PFAS, we identified three exposure clusters, characterized by low (N = 163), medium (N = 236) and high (N = 51) pregnancy PFAS concentrations. Compared to children belonging to the low exposure group, children in the moderate exposure group had higher reactance at 7 Hz (X7) and lower frequency dependence of resistance between 7 Hz and 19 Hz (R7-19) at 36 months, suggesting better lung function. No association of any exposure metric was detected with respiratory diseases in the first 3 years of life. CONCLUSIONS: Our study relying on both mixture and uni-pollutant analyses, does not provide evidence for a deleterious effect of prenatal PFAS exposure on respiratory health at an early age.

Environmental exposures in early-life and general health in childhood.

BACKGROUND: Early-life environmental exposures are suspected to be involved in the development of chronic diseases later in life. Most studies conducted so far considered single or few exposures and single-health parameter. Our study aimed to identify a childhood general health score and assess its association with a wide range of pre- and post-natal environmental exposures. METHODS: The analysis is based on 870 children (6-12 years) from six European birth cohorts participating in the Human Early-Life Exposome project. A total of 53 prenatal and 105 childhood environmental factors were considered, including lifestyle, social, urban and chemical exposures. We built a general health score by averaging three sub-scores (cardiometabolic, respiratory/allergy and mental) built from 15 health parameters. By construct, a child with a low score has a low general health status. Penalized multivariable regression through Least Absolute Shrinkage and Selection Operator (LASSO) was fitted in order to identify exposures associated with the general health score. FINDINGS: The results of LASSO show that a lower general health score was associated with maternal passive and active smoking during pregnancy and postnatal exposure to methylparaben, copper, indoor air pollutants, high intake of caffeinated drinks and few contacts with friends and family. Higher child's general health score was associated with prenatal exposure to a bluespace near residency and postnatal exposures to pets, cobalt, high intakes of vegetables and more physical activity. Against our hypotheses, postnatal exposure to organochlorine compounds and perfluorooctanoate were associated with a higher child's general health score. CONCLUSION: By using a general health score summarizing the child cardiometabolic, respiratory/allergy and mental health, this study reinforced previously suspected environmental factors associated with various child health parameters (e.g. tobacco, air pollutants) and identified new factors (e.g. pets, bluespace) warranting further investigations.

Pregnancy Exposure to Phenols and Anthropometric Measures in Gestation and at Birth.

BACKGROUND: Some synthetic phenols alter pathways involved in fetal development. Despite their high within-subject temporal variability, earlier studies relied on spot urine samples to assess pregnancy exposure. In this study, we examined associations between prenatal phenol exposure and fetal growth. METHODS: We measured concentrations of two bisphenols, four parabens, benzophenone-3, and triclosan in 478 pregnant women in two weekly pools of 21 samples each, collected at 18 and 34 gestational weeks. We used adjusted linear regressions to study associations between phenol concentrations and growth outcomes assessed twice during pregnancy and at birth. RESULTS: Benzophenone-3 was positively associated with all ultrasound growth parameters in at least one time point, in males but not females. In females, butylparaben was negatively associated with third-trimester abdominal circumference and weight at birth. We observed isolated associations for triclosan (negative) and for methylparaben and bisphenol S (positive) and late pregnancy fetal growth. CONCLUSIONS: Our results suggest associations between prenatal exposure to phenols and fetal growth. Benzophenone-3 was the exposure most consistently (positively) associated across all growth parameters.

Comparison of strategies to efficiently combine repeated urine samples in biomarker-based studies.

BACKGROUND: In biomarker-based studies, collecting repeated biospecimens per participant can decrease measurement error, particularly for biomarkers displaying high within-subject variability. Guidelines to combine such repeated biospecimens do not exist. AIMS: To compare the efficiency of several designs relying on repeated biospecimens to estimate exposure over 7 days. METHODS: We quantified triclosan and bisphenol A (BPA) in all urine voids (N = 427) collected over seven days from eight individuals. We estimated the volume-weighted concentrations for all urine samples collected during a week and compared these gold standards with the concentrations obtained for equal-volume pools (standardized or not for urine dilution), unequal-volume pools (based on sample volume or creatinine concentration), and for the mean of the creatinine-standardized concentrations measured in each spot sample. RESULTS: For both chemicals, correlations with gold standards were similar for equal- and unequal-volume pooling designs. Only for BPA, correlation coefficients were markedly lower after standardization for specific gravity or creatinine of concentrations estimated in equal-volume pools. Averaging BPA creatinine-standardized concentrations measured in each spot sample led also to lower correlations with gold standards compared to those obtained for unstandardized pooling designs. CONCLUSION: For BPA and triclosan, considering individual urine sample volume or creatinine concentrations when pooling is unnecessary because equal-volume pool adequately estimates concentrations in gold standards. Standardization for specific gravity or creatinine of the concentrations assessed in equal-volume pool as well as averaging creatinine-standardized concentrations measured in each individual spot sample are not suitable for BPA. These results provide a practical framework on how to combine repeated biospecimens in epidemiological studies.

In utero pyrethroid pesticide exposure in relation to autism spectrum disorder (ASD) and other neurodevelopmental outcomes at 3 years in the MARBLES longitudinal cohort.

BACKGROUND: We assessed the relationships between prenatal pyrethroid pesticide exposure and autism spectrum disorders (ASD) or non-typical development (non-TD) at 3 years. METHODS: Participants were mother-child pairs (n = 201) in the MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) cohort. Because familial recurrence risk is high, MARBLES enrolls pregnant women with a family history of ASD. Children from these pregnancies were clinically assessed at 3 years of age and classified into 3 outcome categories: ASD, typically developing (TD), or non-TD (neither TD or ASD). Repeated maternal second and third trimester urine samples were analyzed for pyrethroid metabolite 3-phenoxybenzoic acid (3-PBA). Multinomial logistic regression was used to obtain relative risk ratios (RRR) linking 3-PBA concentrations averaged across each trimester and over pregnancy with child's outcome: ASD or non-TD vs. TD. Models were adjusted for specific gravity, maternal pre-pregnancy BMI, prenatal vitamin use, birth year, home-ownership, and pregnancy concentrations of TCPy (3,5,6-trichloro-2-pyridinol, a metabolite of chlorpyrifos). RESULTS: The median specific gravity corrected 3-PBA concentration of all samples was 1.46 ng/mL. Greater second trimester 3-PBA concentrations were associated with a relative risk ratio (RRR) for ASD of (RRR: 1.50 (95% CI 0.89 to 2.51), p = 0.12). There were no differences between non-TD and TD. CONCLUSIONS: This study found no evidence for differences in 3-PBA comparing non-TD with TD. A modestly elevated RRR was found comparing second trimester urinary 3-PBA concentrations for ASD versus TD; however, the confidence interval was wide and hence, these findings cannot be considered definitive.

An Empirical Validation of the Within-subject Biospecimens Pooling Approach to Minimize Exposure Misclassification in Biomarker-based Studies.

BACKGROUND: Within-subject biospecimens pooling can theoretically reduce bias in dose-response functions from biomarker-based studies when exposure assessment suffers from classical-type error. However, collecting many urine voids each day is cumbersome. We evaluated the empirical validity of a within-subject pooling approach and compared several options to avoid sampling each void. METHODS: In 16 pregnant women who collected a spot of each urine void over several nonconsecutive weeks, we compared concentrations of 10 phenols in daily, weekly, and pregnancy within-subject pools. We pooled either three or all daily samples. In a simulation study using these data, we quantified bias in dose-response functions when using one to 20 urine samples per subject to assess methylparaben (a compound with moderate within-subject variability) and bisphenol A (high variability) exposures. RESULTS: Correlations between exposure estimates from pools of all and of only three voids per day were above 0.80 for all time windows and compounds, except for benzophenone-3 and triclosan in the daily time window (correlations, 0.57-0.68). With one spot sample to assess pregnancy exposure, correlations were all below 0.74. Using only one biospecimen led to attenuation bias in the dose-response functions of 29% (methylparaben) and 69% (bisphenol A); four samples for methylparaben and 18 for bisphenol A decreased bias to 10%. CONCLUSIONS: For nonpersistent chemicals, collecting and pooling three samples per day instead of all daily samples efficiently estimates exposures over a week or more. Collecting around 20 biospecimens can strongly limit attenuation bias for nonpersistent chemicals such as bisphenol A.

Air Pollution Exposure During Pregnancy and Symptoms of Attention Deficit and Hyperactivity Disorder in Children in Europe.

BACKGROUND: Exposure to air pollution during pregnancy may increase attention-deficit/hyperactivity disorder (ADHD) symptoms in children, but findings have been inconsistent. We aimed to study this association in a collaborative study of eight European population-based birth/child cohorts, including 29,127 mother-child pairs. METHODS: Air pollution concentrations (nitrogen dioxide [NO2] and particulate matter [PM]) were estimated at the birth address by land-use regression models based on monitoring campaigns performed between 2008 and 2011. We extrapolated concentrations back in time to exact pregnancy periods. Teachers or parents assessed ADHD symptoms at 3-10 years of age. We classified children as having ADHD symptoms within the borderline/clinical range and within the clinical range using validated cutoffs. We combined all adjusted area-specific effect estimates using random-effects meta-analysis and multiple imputations and applied inverse probability-weighting methods to correct for loss to follow-up. RESULTS: We classified a total of 2,801 children as having ADHD symptoms within the borderline/clinical range, and 1,590 within the clinical range. Exposure to air pollution during pregnancy was not associated with a higher odds of ADHD symptoms within the borderline/clinical range (e.g., adjusted odds ratio [OR] for ADHD symptoms of 0.95, 95% confidence interval [CI] = 0.89, 1.01 per 10 µg/m increase in NO2 and 0.98, 95% CI = 0.80, 1.19 per 5 µg/m increase in PM2.5). We observed similar associations for ADHD within the clinical range. CONCLUSIONS: There was no evidence for an increase in risk of ADHD symptoms with increasing prenatal air pollution levels in children aged 3-10 years. See video abstract at, http://links.lww.com/EDE/B379.

In-utero exposure to phenols and phthalates and the intelligence quotient of boys at 5 years.

BACKGROUND: There are concerns that developmental exposure to endocrine disrupting chemicals such as phenolic compounds and phthalates could affect child cognitive function. Epidemiological studies tackling this question have mainly focused on phthalate metabolites and bisphenol A, but not on the other phenolic compounds. Our study aimed to assess the relationship between in-utero exposure to phthalates, bisphenol A and other phenolic compounds (parabens, triclosan, dichlorophenols and benzophenone-3) and the Intelligence Quotient (IQ) of boys at 5-6 years. METHODS: In 452 mother-son dyads from the French EDEN cohort, we measured 11 phthalate metabolites and 9 phenolic compounds (4 parabens, benzophenone-3, bisphenol A, 2 dichlorophenols and triclosan) in spot urine samples collected between 22 and 29 gestational weeks. Verbal and performance IQ of children were assessed at 5-6 years by a psychologist using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI). We used adjusted Structural Equation Models (SEM) combined with Benjamini and Hochberg false discovery rate correction to assess the associations between maternal urine phenol and phthalate metabolite concentrations considered simultaneously and the boys' IQ. RESULTS: No phenol or phthalate metabolite concentration was negatively associated with the boys' verbal or performance IQ (uncorrected p-values ≥0.09). Mono(3-carboxypropyl) phthalate tended to be associated with increased verbal IQ (ß = 0.136, 95% confidence interval, 0.01; 0.27). This association disappeared after correction for multiple comparison (corrected p-value, 0.71). CONCLUSION: Our results did not provide evidence of an inverse association between in-utero exposure to phenols or phthalates and verbal and performance IQ among boys. Since phenols and phthalates may have sex-specific effects, these null findings cannot be generalized to girls. Limitations included use of a single spot urine sample to assess exposures and lack of consideration of postnatal exposures.

Within-subject Pooling of Biological Samples to Reduce Exposure Misclassification in Biomarker-based Studies.

BACKGROUND: For chemicals with high within-subject temporal variability, assessing exposure biomarkers in a spot biospecimen poorly estimates average levels over long periods. The objective is to characterize the ability of within-subject pooling of biospecimens to reduce bias due to exposure misclassification when within-subject variability in biomarker concentrations is high. METHODS: We considered chemicals with intraclass correlation coefficients of 0.6 and 0.2. In a simulation study, we hypothesized that the chemical urinary concentrations averaged over a given time period were associated with a health outcome and estimated the bias of studies assessing exposure that collected 1 to 50 random biospecimens per subject. We assumed a classical type error. We studied associations using a within-subject pooling approach and two measurement error models (simulation extrapolation and regression calibration), the latter requiring the assay of more than one biospecimen per subject. RESULTS: For both continuous and binary outcomes, using one sample led to attenuation bias of 40% and 80% for compounds with intraclass correlation coefficients of 0.6 and 0.2, respectively. For a compound with an intraclass correlation coefficient of 0.6, the numbers of biospecimens required to limit bias to less than 10% were 6, 2, and 2 biospecimens with the pooling, simulation extrapolation, and regression calibration methods (these values were, respectively, 35, 8, and 2 for a compound with an intraclass correlation coefficient of 0.2). Compared with pooling, these methods did not improve power. CONCLUSION: Within-subject pooling limits attenuation bias without increasing assay costs. Simulation extrapolation and regression calibration further limit bias, compared with the pooling approach, but increase assay costs.

Phthalate pregnancy exposure and male offspring growth from the intra-uterine period to five years of age.

OBJECTIVE: To study associations between prenatal exposure to phthalates and fetal and postnatal growth up to age 5 years in male offspring. METHODS: Eleven phthalate metabolites were quantified in spot maternal urine samples collected during gestation among 520 women of the EDEN mother-child cohort who gave birth to a boy. Fetal growth was assessed from repeated ultrasound measurements and measurements at birth. We used repeated measures of weight and height in the first 5 years of life to model individual postnatal growth trajectories. We estimated adjusted variations in pre and postnatal growth parameters associated with an interquartile range increase in ln-transformed phthalate metabolite concentrations. RESULTS: Monocarboxyisononyl phthalate (MCNP) was positively associated with femoral length during gestation and length at birth. High molecular weight phthalate metabolites were negatively associated with estimated fetal weight throughout pregnancy. Monoethyl phthalate (MEP) showed positive association with weight growth velocity from two to five years and with body mass index at five years (ß=0.17kg/m2, 95% confidence interval, 0.04, 0.30). CONCLUSIONS: We highlighted associations between gestational exposure to some phthalates and growth in boys. The positive association between MEP and postnatal growth in boys was also reported in several previous human studies.

Variability and exposure classification of urinary phenol and paraben metabolite concentrations in reproductive-aged women.

BACKGROUND: Human exposure to phenols and parabens is widespread. Within-person variability of urinary concentrations in healthy women is not well characterized. OBJECTIVES: To characterize the variability of urinary phenol and paraben concentrations across two months and evaluate the ability of a single spot urine sample to characterize exposure. METHODS: 143 women provided 509 spot urine samples collected across two months of study (3-5 samples/woman). We measured urinary concentrations of 8 phenols: bisphenol A (BPA), benzophenone-3 (BP-3), benzophenone-1 (BP-1), 2,4-dichlorophenol (2,4-DCP), 2,5-dichlorophenol (2,5-DCP), 2,4,5-trichlorophenol (2,4,5-TCP), 2,4,6-trichlorophenol (2,4,6-TCP), triclosan (TCS); and 8 parabens and their metabolites (benzyl (BzP), butyl (BuP), ethyl (EtP), heptyl (HeP), methyl (MeP), propyl (PrP), 4-hydroxybenzoic acid (4-HB), 3,4-dihydroxybenzoic acid (3,4-DHB)). Biomarker variability was characterized using the intraclass correlation coefficient (ICC) and surrogate category analyses were conducted. RESULTS: ICCs ranged from very low for BPA (0.04) to moderate for BP-3, BP-1, TCS, BzP, and MeP (0.66, 0.58, 0.55, 0.54, and 0.62, respectively). Surrogate analyses suggested that BP-1, BP-3, TCS, 2,4-DCP, BuP, and PrP may be characterized by a single spot sample (sensitivity range 0.76-0.86) but that additional samples were necessary for BPA, HeP, 4-HB, and 3,4-DHB (sensitivity range 0.47-0.61). CONCLUSIONS: Urinary phenol and paraben metabolite concentrations were variable across two months in healthy women but the degree of reliability differed by the specific biomarker. A small number of samples may sufficiently characterize typical concentrations for BP-3, BP-1, TCS, BuP, and PrP; but additional biospecimens may be necessary to characterize exposure for other compounds, including BPA.

Exposure to select phthalates and phenols through use of personal care products among Californian adults and their children.

INTRODUCTION: Certain phenols and phthalates are used in many consumer products including personal care products (PCPs). AIMS: We aimed to study the associations between the use of PCPs and urinary concentrations of biomarkers of select phenols and phthalates among Californian adults and their children. As an additional aim we compared phenols and phthalate metabolites concentrations measured in adults and children urine samples collected the same day. METHODS: Our study relied on a subsample of 90 adult-child pairs participating in the Study of Use of Products and Exposure Related Behavior (SUPERB). Each adult and child provided one to two urine samples in which we measured concentrations of selected phenols and phthalate metabolites. We computed Spearman correlation coefficients to compare concentrations measured in adults and children urine samples collected the same day. We used adjusted linear and Tobit regression models to study the associations between the use of PCPs in the past 24h and biomarker concentrations. RESULTS: Benzophenone-3 and parabens concentrations were higher in adults compared to their children. Conversely children had higher mono-n-butyl phthalate and mono-isobutyl phthalate concentrations. No significant difference was observed for the other compounds. The total number of different PCPs used was positively associated with urinary concentrations of methyl, propyl and butyl parabens and the main metabolite of diethyl phthalate in adults. Among children, the use of a few specific products including liquid soap, hair care products and sunscreen was positively associated with urinary concentrations of some phenols or phthalate metabolites. DISCUSSION: These results strengthen the body of evidence suggesting that use of PCPs is an important source of exposure to parabens and diethyl phthalate in adults and provide data on exposure to selected phenols and phthalates through use of PCPs in children.

Phthalate concentrations in house dust in relation to autism spectrum disorder and developmental delay in the CHildhood Autism Risks from Genetics and the Environment (CHARGE) study.

BACKGROUND: Phthalates are endocrine-disrupting chemicals that influence thyroid hormones and sex steroids, both critical for brain development. AIM: We studied phthalate concentrations in house dust in relation to the risks of developing autism spectrum disorder (ASD) or developmental delay (DD). METHODS: Participants were a subset of children from the CHARGE (CHildhood Autism Risks from Genetics and the Environment) case-control study. ASD and DD cases were identified through the California Department of Developmental Services system or referrals; general population controls were randomly sampled from state birth files and frequency-matched on age, sex, and broad geographic region to ASD cases. All children (50 ASD, 27 DD, 68 typically developing (TD)) were assessed with Mullen Scales of Early Learning, Vineland Adaptive Behavior Scales (VABS) and Aberrant Behavior Checklist. We measured 5 phthalates in dust collected in the child's home using a high volume small surface sampler. RESULTS: None of the phthalates measured in dust was associated with ASD. After adjustment, we observed greater di(2-ethylhexyl) phthalate (DEHP) and butylbenzyl phthalate (BBzP) concentrations in indoor dust from homes of DD children: Odds ratios (OR) were 2.10 (95% confidence interval (CI); 1.10; 4.09) and 1.40 (95% CI; 0.97; 2.04) for a one-unit increase in the ln-transformed DEHP and BBzP concentrations, respectively. Among TD children, VABS communication, daily living, and adaptive composite standard scores were lower, in association with increased diethyl phthalate (DEP) concentrations in dust. Participants with higher dibutyl phthalate (DBP) concentrations in house dust also trended toward reduced performance on these subscales. Among ASD and DD boys, higher indoor dust concentrations of DEP and DBP were associated with greater hyperactivity-impulsivity and inattention. DISCUSSION AND CONCLUSION: House dust levels of phthalates were not associated with ASD. The inability to distinguish past from recent exposures in house dust and the fact that house dust does not capture exposure from all sources, limit the interpretation of both positive and null findings and further work is needed. However, the associations observed for DEP and DBP with impairments in several adaptive functions and greater hyperactivity, along with evidence for increased risk of DD raise concerns that these chemicals may affect neurodevelopment in children.

Epidemiologic tools to study the influence of environmental factors on fecundity and pregnancy-related outcomes.

Adverse pregnancy outcomes entail a large health burden for the mother and offspring; a part of it might be avoided by better understanding the role of environmental factors in their etiology. Our aims were to review the assessment tools to characterize fecundity troubles and pregnancy-related outcomes in human populations and their sensitivity to environmental factors. For each outcome, we reviewed the possible study designs, main sources of bias, and their suggested cures. In terms of study design, for most pregnancy outcomes, cohorts with recruitment early during or even before pregnancy allow efficient characterization of pregnancy-related events, time-varying confounders, and in utero exposures that may impact birth outcomes and child health. Studies on congenital anomalies require specific designs, assessment of anomalies in medical pregnancy terminations, and, for congenital anomalies diagnosed postnatally, follow-up during several months after birth. Statistical analyses should take into account environmental exposures during the relevant time windows; survival models are an appropriate approach for fecundity, fetal loss, and gestational duration/preterm delivery. Analysis of gestational duration could distinguish pregnancies according to delivery induction (and possibly pregnancy-related conditions). In conclusion, careful design and analysis are required to better characterize environmental effects on human reproduction.

Prenatal exposure to phenols and growth in boys.

BACKGROUND: Phenols interact with nuclear receptors implicated in growth and adipogenesis regulation. Only a few studies have explored their effects on growth in humans. OBJECTIVES: We studied the associations of maternal exposure to phenols during pregnancy with prenatal and postnatal growth of male newborns. METHODS: Within a cohort of women recruited during pregnancy, we selected 520 mother-son pairs and quantified 9 phenols in spot urine samples collected during pregnancy. We used ultrasonography during pregnancy, together with birth measurements, to assess fetal growth. We modeled individual postnatal growth trajectories from repeated measures of weight and height in the first 3 years of life. RESULTS: Triclosan concentration was negatively associated with growth parameters measured at the third ultrasound examination but not earlier in pregnancy. At birth, this phenol tended to be negatively associated with head circumference (-1.2 mm for an interquartile range [IQR] increase in ln-transformed triclosan concentration [95% confidence interval = -2.6 to 0.3]) but not with weight or height. Parabens were positively associated with weight at birth. This positive association remained for 3 years for methylparaben (ß = 193 g [-4 to 389]) for an IQR increase in ln-transformed concentrations. CONCLUSION: We relied on only 1 spot urine sample to assess exposure; because of the high variability in phenol urinary concentrations reported during pregnancy, using only 1 sample may result in exposure misclassification, in particular for bisphenol A. Our study suggested associations between prenatal exposure to parabens and triclosan and prenatal or early postnatal growth.

Parents' Sleep Multi-Trajectory Modelling from 3 to 36 Months Postpartum in the SEPAGES Cohort.

Objective: We investigated maternal and paternal sleep evolution from 3 to 36 months postpartum, their interrelations and predictors in the SEPAGES cohort. Methods: Sleep information (night sleep duration [NSD], weekend daytime sleep duration [DSD] and subjective sleep loss [SSL]) was collected by self-administered questionnaires at 3, 18, 24 and 36 months postpartum in the SEPAGES French cohort that included 484 mothers and 410 fathers. Group-based multi-trajectory modelling was used to identify maternal, paternal and couple sleep multi-trajectory groups among 188 couples reporting sleep data for at least 2 time points. Multinomial logistic regression was used to assess associations between parental sleep multi-trajectories and early characteristics such as sociodemographic, chronotypes, child sex, birth seasonality or breastfeeding duration. Results: We identified three maternal (M1-M3), paternal (F1-F3) and couple (C1-C3) sleep multi-trajectory groups with similar characteristics: a group with short NSD and high SSL prevalence (M1, F2, C2), a group with long NSD but medium SSL prevalence (M2, F3, C3) and a group with long NSD and low SSL prevalence (M3, F1, C1). Mothers with the shortest NSD (M1) were less likely to have a partner with long NSD (F2). As compared with long NSD and low SSL prevalence (C1), couples with short NSD and high SSL prevalence (C2) were less likely to have had a first child born in the autumn and fathers in C2 had a later chronotype. Conclusion: We identified distinct sleep multi-trajectory groups for mothers, fathers and couples from 3- to 36-month postpartum. Sleep patterns within couples were homogeneous.