Prenatal exposure to legacy PFAS and neurodevelopment in preschool-aged Canadian children: The MIREC cohort.

BACKGROUND: Exposure to perfluoroalkyl substances (PFAS) has been shown to be neurotoxic in experimental studies, but epidemiological evidence linking prenatal PFAS exposure to child neurodevelopment is equivocal and scarce. OBJECTIVE: To quantify associations between prenatal exposure to legacy PFAS and children's intelligence (IQ) and executive functioning (EF) in a Canadian pregnancy and birth cohort and to determine if these associations differ by child sex. METHODS: We measured first-trimester plasma concentrations of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), and perfluorohexanesulfonic acid (PFHxS) in the Maternal-Infant Research on Environmental Chemicals (MIREC) study and assessed children's full-scale (n = 522), performance (n = 517), and verbal (n = 519) IQ using the Wechsler Preschool and Primary Scale of Intelligence (WPPSI-III). Children's working memory (n = 513) and ability to plan and organize (n = 514) were assessed using a parent-reported questionnaire, the Behavior Rating Inventory of Executive Function - Preschool Version (BRIEF-P). We quantified associations between individual log2-transformed PFAS exposure and children's IQ and EF using multiple linear regression analyses and evaluated effect modification by child sex. We also used Repeated Holdout Weighted Quantile Sum (WQS) regression models with effect modification by child sex to quantify the effect of combined exposure to all three PFAS chemicals on IQ and EF. All models were adjusted for key sociodemographic characteristics. RESULTS: Geometric mean plasma concentrations (IQR) for PFOA, PFOS and PFHxS were 1.68 (1.10-2.50), 4.97 (3.20-6.20) and 1.09 (0.67-1.60) µg/L respectively. We found evidence of effect modification by child sex in all models examining performance IQ (p < .01). Specifically, every doubling of PFOA, PFOS, and or PFHxS was inversely associated with performance IQ, but only in males (PFOA: B = -2.80, 95% CI: -4.92, -0.68; PFOS: B = -2.64, 95% CI: -4.77, -0.52; PFHxS: B = -2.92, 95% CI: -4.72, -1.12). Similarly, every quartile increase in the WQS index was associated with poorer performance IQ in males (B = -3.16, 95% CI: -4.90, -1.43), with PFHxS contributing the largest weight to the index. In contrast, no significant association was found for females (B = 0.63, 95% CI: -0.99, 2.26). No significant associations were found for EF in either males or females. CONCLUSIONS: Higher prenatal PFAS exposure was associated with lower performance IQ in males, suggesting that this association may be sex- and domain-specific.

Iodine Status Modifies the Association between Fluoride Exposure in Pregnancy and Preschool Boys' Intelligence.

In animal studies, the combination of in utero fluoride exposure and low iodine has greater negative effects on offspring learning and memory than either alone, but this has not been studied in children. We evaluated whether the maternal urinary iodine concentration (MUIC) modifies the association between maternal urinary fluoride (MUF) and boys' and girls' intelligence. We used data from 366 mother-child dyads in the Maternal-Infant Research on Environmental Chemicals Study. We corrected trimester-specific MUF and MUIC for creatinine, and averaged them to yield our exposure variables (MUFCRE, mg/g; MUICCRE, µg/g). We assessed children's full-scale intelligence (FSIQ) at 3 to 4 years. Using multiple linear regression, we estimated a three-way interaction between MUFCRE, MUICCRE, and child sex on FSIQ, controlling for covariates. The MUICCRE by MUFCRE interaction was significant for boys (p = 0.042), but not girls (p = 0.190). For boys whose mothers had low iodine, a 0.5 mg/g increase in MUFCRE was associated with a 4.65-point lower FSIQ score (95% CI: -7.67, -1.62). For boys whose mothers had adequate iodine, a 0.5 mg/g increase in MUFCRE was associated with a 2.95-point lower FSIQ score (95% CI: -4.77, -1.13). These results suggest adequate iodine intake during pregnancy may minimize fluoride's neurotoxicity in boys.

Maternal fluoride exposure, fertility and birth outcomes: The MIREC cohort.

Objective: Fluoride exposure >1.5 mg/L from water has been associated with adverse pregnancy and birth outcomes. Little is known, however, about the effect of fluoride at levels consistent with water fluoridation (i.e., 0.7 mg/L) on pregnancy and birth outcomes. We examined the relationship between maternal fluoride exposure, fertility, and birth outcomes in a Canadian pregnancy cohort living in areas where municipal drinking water fluoride concentrations ranged from 0.04 to 0.87 mg/L. Methods: Using data from the Maternal-Infant Research on Environmental Chemicals (MIREC) study, we estimated fluoride exposure during pregnancy using three different metrics: (1) maternal urinary fluoride concentrations standardized for specific gravity (MUFSG) and averaged across all three trimesters (N = 1566), (2) water fluoride concentration (N = 1370), and (3) fluoride intake based on self-reported consumption of water, coffee, and tea, adjusted for body weight (N = 1192). Data on fertility, birth weight, gestational age, preterm birth, and small-for-gestational age (SGA) were assessed. We used multiple linear regression to examine associations between fluoride exposure, birth weight and gestational age, and logistic regression to examine associations with fertility, preterm birth, and SGA, adjusted for relevant covariates. Results: Median (IQR) MUFSG was 0.50 (0.33-0.76) mg/L, median water fluoride was 0.52 (0.17-0.64) mg/L, and median fluoride intake was 0.008 (0.003-0.013) mg/kg/day. MUFSG, water fluoride concentrations, and fluoride intake were not significantly associated with fertility, birth weight, gestational age, preterm birth, or SGA. Fetal sex did not modify any of the associations. Conclusion: Fluoride exposure during pregnancy was not associated with fertility or birth outcomes in this Canadian cohort.

Critical windows of fluoride neurotoxicity in Canadian children.

BACKGROUND: Fluoride has been associated with IQ deficits during early brain development, but the period in which children are most sensitive is unknown. OBJECTIVE: We assessed effects of fluoride on IQ scores across prenatal and postnatal exposure windows. METHODS: We used repeated exposures from 596 mother-child pairs in the Maternal-Infant Research on Environmental Chemicals pregnancy and birth cohort. Fluoride was measured in urine (mg/L) collected from women during pregnancy and in their children between 1.9 and 4.4 years; urinary fluoride was adjusted for specific gravity. We estimated infant fluoride exposure (mg/day) using water fluoride concentration and duration of formula-feeding over the first year of life. Intelligence was assessed at 3-4 years using the Wechsler Preschool and Primary Scale of Intelligence-III. We used generalized estimating equations to examine the associations between fluoride exposures and IQ, adjusting for covariates. We report results based on standardized exposures given their varying units of measurement. RESULTS: The association between fluoride and performance IQ (PIQ) significantly differed across prenatal, infancy, and childhood exposure windows collapsing across child sex (p = .001). The strongest association between fluoride and PIQ was during the prenatal window, B = -2.36, 95% CI: -3.63, -1.08; the association was also significant during infancy, B = -2.11, 95% CI: -3.45, -0.76, but weaker in childhood, B = -1.51, 95% CI: -2.90, -0.12. Within sex, the association between fluoride and PIQ significantly differed across the three exposure windows (boys: p = .01; girls: p = .01); among boys, the strongest association was during the prenatal window, B = -3.01, 95% CI: -4.60, -1.42, whereas among girls, the strongest association was during infancy, B = -2.71, 95% CI: -4.59, -0.83. Full-scale IQ estimates were weaker than PIQ estimates for every window. Fluoride was not significantly associated with Verbal IQ across any exposure window. CONCLUSION: Associations between fluoride exposure and PIQ differed based on timing of exposure. The prenatal window may be critical for boys, whereas infancy may be a critical window for girls.

Fluoride exposure from infant formula and child IQ in a Canadian birth cohort.

BACKGROUND: Infant consumption of formula reconstituted with fluoridated water can lead to excessive fluoride intake. We examined the association between fluoride exposure in infancy and intellectual ability in children who lived in fluoridated or non-fluoridated cities in Canada. METHODS: We examined 398 mother-child dyads in the Maternal-Infant Research on Environmental Chemicals cohort who reported drinking tap water. We estimated water fluoride concentration using municipal water reports. We used linear regression to analyze the association between fluoride exposure and IQ scores, measured by the Wechsler Primary and Preschool Scale of Intelligence-III at 3-4 years. We examined whether feeding status (breast-fed versus formula-fed) modified the impact of water fluoride and if fluoride exposure during fetal development attenuated this effect. A second model estimated the association between fluoride intake from formula and child IQ. RESULTS: Thirty-eight percent of mother-child dyads lived in fluoridated communities. An increase of 0.5 mg/L in water fluoride concentration (approximately equaling the difference between fluoridated and non-fluoridated regions) corresponded to a 9.3- and 6.2-point decrement in Performance IQ among formula-fed (95% CI: -13.77, -4.76) and breast-fed children (95% CI: -10.45, -1.94). The association between water fluoride concentration and Performance IQ remained significant after controlling for fetal fluoride exposure among formula-fed (B = -7.93, 95% CI: -12.84, -3.01) and breastfed children (B = -6.30, 95% CI: -10.92, -1.68). A 0.5 mg increase in fluoride intake from infant formula corresponded to an 8.8-point decrement in Performance IQ (95% CI: -14.18, -3.34) and this association remained significant after controlling for fetal fluoride exposure (B = -7.62, 95% CI: -13.64, -1.60). CONCLUSIONS: Exposure to increasing levels of fluoride in tap water was associated with diminished non-verbal intellectual abilities; the effect was more pronounced among formula-fed children.

Association Between Maternal Fluoride Exposure During Pregnancy and IQ Scores in Offspring in Canada.

IMPORTANCE: The potential neurotoxicity associated with exposure to fluoride, which has generated controversy about community water fluoridation, remains unclear. OBJECTIVE: To examine the association between fluoride exposure during pregnancy and IQ scores in a prospective birth cohort. DESIGN, SETTING, AND PARTICIPANTS: This prospective, multicenter birth cohort study used information from the Maternal-Infant Research on Environmental Chemicals cohort. Children were born between 2008 and 2012; 41% lived in communities supplied with fluoridated municipal water. The study sample included 601 mother-child pairs recruited from 6 major cities in Canada; children were between ages 3 and 4 years at testing. Data were analyzed between March 2017 and January 2019. EXPOSURES: Maternal urinary fluoride (MUFSG), adjusted for specific gravity and averaged across 3 trimesters available for 512 pregnant women, as well as self-reported maternal daily fluoride intake from water and beverage consumption available for 400 pregnant women. MAIN OUTCOMES AND MEASURES: Children's IQ was assessed at ages 3 to 4 years using the Wechsler Primary and Preschool Scale of Intelligence-III. Multiple linear regression analyses were used to examine covariate-adjusted associations between each fluoride exposure measure and IQ score. RESULTS: Of 512 mother-child pairs, the mean (SD) age for enrollment for mothers was 32.3 (5.1) years, 463 (90%) were white, and 264 children (52%) were female. Data on MUFSG concentrations, IQ scores, and complete covariates were available for 512 mother-child pairs; data on maternal fluoride intake and children's IQ were available for 400 of 601 mother-child pairs. Women living in areas with fluoridated tap water (n = 141) compared with nonfluoridated water (n = 228) had significantly higher mean (SD) MUFSG concentrations (0.69 [0.42] mg/L vs 0.40 [0.27] mg/L; P = .001; to convert to millimoles per liter, multiply by 0.05263) and fluoride intake levels (0.93 [0.43] vs 0.30 [0.26] mg of fluoride per day; P = .001). Children had mean (SD) Full Scale IQ scores of 107.16 (13.26), range 52-143, with girls showing significantly higher mean (SD) scores than boys: 109.56 (11.96) vs 104.61 (14.09); P = .001. There was a significant interaction (P = .02) between child sex and MUFSG (6.89; 95% CI, 0.96-12.82) indicating a differential association between boys and girls. A 1-mg/L increase in MUFSG was associated with a 4.49-point lower IQ score (95% CI, -8.38 to -0.60) in boys, but there was no statistically significant association with IQ scores in girls (B = 2.40; 95% CI, -2.53 to 7.33). A 1-mg higher daily intake of fluoride among pregnant women was associated with a 3.66 lower IQ score (95% CI, -7.16 to -0.14) in boys and girls. CONCLUSIONS AND RELEVANCE: In this study, maternal exposure to higher levels of fluoride during pregnancy was associated with lower IQ scores in children aged 3 to 4 years. These findings indicate the possible need to reduce fluoride intake during pregnancy.

Community Water Fluoridation and Urinary Fluoride Concentrations in a National Sample of Pregnant Women in Canada.

BACKGROUND: Fluoride exposures have not been established for pregnant women who live in regions with and without community water fluoridation. OBJECTIVE: Our aim was to measure urinary fluoride levels during pregnancy. We also assessed the contribution of drinking-water and tea consumption habits to maternal urinary fluoride (MUF) concentrations and evaluated the impact of various dilution correction standards, including adjustment for urinary creatinine and specific gravity (SG). METHODS: We measured MUF concentrations in spot samples collected in each trimester of pregnancy from 1,566 pregnant women in the Maternal-Infant Research on Environmental Chemicals cohort. We calculated intraclass correlation coefficients (ICCs) to assess variability in MUF concentrations across pregnancy. We used regression analyses to estimate associations between MUF levels, tea consumption, and water fluoride concentrations as measured by water treatment plants. RESULTS: Creatinine-adjusted MUF values ([Formula: see text]; milligrams per liter) were almost two times higher for pregnant women living in fluoridated regions ([Formula: see text]) compared with nonfluoridated regions ([Formula: see text]; [Formula: see text]). MUF values tended to increase over the course of pregnancy using both unadjusted values and adjusted values. Reproducibility of the unadjusted and adjusted MUF values was modest ([Formula: see text]). The municipal water fluoride level was positively associated with creatinine-adjusted MUF ([Formula: see text], 95% CI: 0.46, 0.57), accounting for 24% of the variance after controlling for covariates. Higher MUF concentrations correlated with numbers of cups of black ([Formula: see text] but not green tea ([Formula: see text]). Urinary creatinine and SG correction methods were highly correlated ([Formula: see text]) and were interchangeable in models examining predictors of MUF. CONCLUSION: Community water fluoridation is a major source of fluoride exposure for pregnant women living in Canada. Urinary dilution correction with creatinine and SG were shown to be interchangeable for our sample of pregnant women. https://doi.org/10.1289/EHP3546.

Effect of Residential Lead-Hazard Interventions on Childhood Blood Lead Concentrations and Neurobehavioral Outcomes: A Randomized Clinical Trial.

Importance: Childhood lead exposure is associated with neurobehavioral deficits. The effect of a residential lead hazard intervention on blood lead concentrations and neurobehavioral development remains unknown. Objective: To determine whether a comprehensive residential lead-exposure reduction intervention completed during pregnancy could decrease residential dust lead loadings, prevent elevated blood lead concentrations, and improve childhood neurobehavioral outcomes. Design, Setting, and Participants: This longitudinal, community-based randomized clinical trial of pregnant women and their children, the Health Outcomes and Measures of the Environment (HOME) Study, was conducted between March 1, 2003, and January 31, 2006. Pregnant women attending 1 of 9 prenatal care clinics affiliated with 3 hospitals in the Cincinnati, Ohio, metropolitan area were recruited. Of the 1263 eligible women, 468 (37.0%) agreed to participate and 355 women (75.8%) were randomized in this intention-to-treat analysis. Participants were randomly assigned to receive 1 of 2 interventions designed to reduce residential lead or injury hazards. Follow-up on children took place at 1, 2, 3, 4, 5, and 8 years of age. Data analysis was performed from September 2, 2017, to May 6, 2018. Main Outcomes and Measures: Residential dust lead loadings were measured at baseline and when children were 1 and 2 years of age. At 1, 2, 3, 4, 5, and 8 years of age, the children's blood lead concentrations as well as behavior, cognition, and executive functions were assessed. Results: Of the 355 women randomized, 174 (49.0%) were assigned to the intervention group (mean [SD] age at delivery, 30.1 (5.5) years; 119 [68.3%] self-identified as non-Hispanic white) and 181 (50.9%) to the control group (mean [SD] age at delivery, 29.2 [5.7] years; 123 [67.9%] self-identified as non-Hispanic white). The intervention reduced the dust lead loadings for the floor (24%; 95% CI, -43% to 1%), windowsill (40%; 95% CI, -60% to -11%), and window trough (47%; 95% CI, -68% to -10%) surfaces. The intervention did not statistically significantly reduce childhood blood lead concentrations (-6%; 95% CI, -17% to 6%; P = .29). Neurobehavioral test scores were not statistically different between children in the intervention group than those in the control group except for a reduction in anxiety scores in the intervention group (ß = -1.6; 95% CI, -3.2 to -0.1; P = .04). Conclusions and Relevance: Residential lead exposures, as well as blood lead concentrations in non-Hispanic black children, were reduced through a comprehensive lead-hazard intervention without elevating the lead body burden. However, this decrease did not result in substantive neurobehavioral improvements in children. Trial Registration: ClinicalTrials.gov identifier: NCT00129324.

Low-level lead exposure and mortality in US adults: a population-based cohort study.

BACKGROUND: Lead exposure is a risk factor for cardiovascular disease mortality, but the number of deaths in the USA attributable to lead exposure is poorly defined. We aimed to quantify the relative contribution of environmental lead exposure to all-cause mortality, cardiovascular disease mortality, and ischaemic heart disease mortality. METHODS: Our study population comprised a nationally representative sample of adults aged 20 years or older who were enrolled in the Third National Health and Nutrition Examination Survey (NHANES-III) between 1988 and 1994 and followed up to Dec 31, 2011. Participants had completed a medical examination and home interview and had results for concentrations of lead in blood, cadmium in urine, and other relevant covariates. Individuals were linked with the National Death Index. This study presents extended follow-up of an earlier analysis. FINDINGS: We included 14 289 adults in our study. The geometric mean concentration of lead in blood was 2·71 µg/dL (geometric SE 1·31). 3632 (20%) participants had a concentration of lead in blood of at least 5 µg/dL (≥0·24 µmol/L). During median follow-up of 19·3 years (IQR 17·6-21·0), 4422 people died, 1801 (38%) from cardiovascular disease and 988 (22%) from ischaemic heart disease. An increase in the concentration of lead in blood from 1·0 µg/dL to 6·7 µg/dL (0·048 µmol/L to 0·324 µmol/L), which represents the tenth to 90th percentiles, was associated with all-cause mortality (hazard ratio 1·37, 95% CI 1·17-1·60), cardiovascular disease mortality (1·70, 1·30-2·22), and ischaemic heart disease mortality (2·08, 1·52-2·85). The population attributable fraction of the concentration of lead in blood for all-cause mortality was 18·0% (95% CI 10·9-26·1), which is equivalent to 412 000 deaths annually. Respective fractions were 28·7% (15·5-39·5) for cardiovascular disease mortality and 37·4% (23·4-48·6) for ischaemic heart disease mortality, which correspond to 256 000 deaths a year from cardiovascular disease and 185 000 deaths a year from ischaemic heart disease. INTERPRETATION: Low-level environmental lead exposure is an important, but largely overlooked, risk factor for cardiovascular disease mortality in the USA. A comprehensive strategy to prevent deaths from cardiovascular disease should include efforts to reduce lead exposure. FUNDING: The Artemis Fund and Simon Fraser University.

Risk Stratification to Decrease Unnecessary Diagnostic Imaging for Acute Appendicitis.

BACKGROUND: There has been an increase in the use of imaging modalities to diagnose appendicitis despite evidence that can help identify children at especially high or low risk of appendicitis who may not benefit. We hypothesized that the passive diffusion of a standardized care pathway (including diagnostic imaging recommendations) would improve the diagnostic workup of appendicitis by safely decreasing the use of unnecessary imaging when compared with historical controls and that an electronic, real-time decision support tool would decrease unnecessary imaging. METHODS: We used an interrupted time series trial to compare proportions of patients who underwent diagnostic imaging (computed tomography [CT] and ultrasound) between 3 time periods: baseline historical controls, after passive diffusion of a diagnostic workup clinical pathway, and after introduction of an electronic medical record-embedded clinical decision support tool that provides point-of-care imaging recommendations (active intervention). RESULTS: The moderate- and high-risk groups showed lower proportions of CT in the passive and active intervention time periods compared with the historical control group. Proportions of patients undergoing ultrasound in all 3 risk groups showed an increase from the historical baseline. Time series analysis confirmed that time trends within any individual time period were not significant; thus, incidental secular trends over time did not appear to explain the decreased use of CT. CONCLUSIONS: Passive and active decision support tools minimized unnecessary CT imaging; long-term effects remain an important area of study.

Utility of Pediatric Appendicitis Score in Female Adolescent Patients.

OBJECTIVES: Acute appendicitis is common in the pediatric population and is difficult to diagnose in adolescent females. The validated Pediatric Appendicitis Score (PAS) has unclear utility in female adolescents. The purpose of this study is to determine the sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) of the PAS for female adolescents compared to all other patients. METHODS: This study examined a retrospective observational cohort of patients ages 3 to 21 years in a pediatric emergency department with prospectively assigned PAS from an existing database. We compared the sensitivity, specificity, PPV, and NPV of the PAS for acute appendicitis among female adolescent patients (13 to 21 years) and all other patients. RESULTS: Of the 1,228 patients enrolled, 901 (73.4%) had a complete PAS. Among the 901 patients, 249 (27.6%) had pathology-proven appendicitis, 494 (54.8%) were female, and 272 (30.2%) were adolescent females. At a cutoff of ≥8, the PAS showed a specificity of 89% for adolescent females and 78% for all other patients (p < 0.001), although the specificities did not differ at a cutoff of ≥7. At both cutoffs, the PPVs were poor in both groups. At a cutoff of ≥3, the PAS showed similar sensitivities in both groups. At a cutoff of <3, the NPVs did not significantly differ between groups. CONCLUSION: At a cutoff of ≥8 (although not ≥7), the PAS demonstrated a higher specificity among female adolescents compared to all other patients. The PPV for both cutoffs in both groups were poor. At a cutoff of ≥3, sensitivities were equivalent. The NPV for a cutoff of <3 was acceptable but similar in both groups. While sensitivities were similar to previously reported, specificities in both groups were lower. This highlights the need for further investigation of the PAS's performance in specific subpopulations.

Prenatal Exposure to Organophosphorous Pesticides and Fetal Growth: Pooled Results from Four Longitudinal Birth Cohort Studies.

BACKGROUND: Organophosphorous (OP) pesticides are associated with reduced fetal growth in animals, but human studies are inconsistent. OBJECTIVES: We pooled data from four cohorts to examine associations of prenatal OP exposure with birth weight (n = 1,169), length (n = 1,152), and head circumference (n = 1,143). METHODS: Data were from the CHAMACOS, HOME, Columbia, and Mount Sinai birth cohorts. Concentrations of three diethyl phosphate (ΣDEP) and three dimethyl phosphate (ΣDMP) metabolites of OP pesticides [summed to six dialkyl phosphates (ΣDAPs)] were measured in maternal urine. Linear regression and mixed-effects models were used to examine associations with birth outcomes. RESULTS: We found no significant associations of ΣDEP, ΣDMP, or ΣDAPs with birth weight, length, or head circumference overall. However, among non-Hispanic black women, increasing urinary ΣDAP and ΣDMP concentrations were associated with decreased birth length (ß = -0.4 cm; 95% CI: -0.9, 0.0 and ß = -0.4 cm; 95% CI: -0.8, 0.0, respectively, for each 10-fold increase in metabolite concentration). Among infants with the PON1192RR genotype, ΣDAP and ΣDMP were negatively associated with length (ß = -0.4 cm; 95% CI: -0.9, 0.0 and ß = -0.5 cm; 95% CI: -0.9, -0.1). CONCLUSIONS: This study confirms previously reported associations of prenatal OP exposure among black women with decreased infant size at birth, but finds no evidence of smaller birth weight, length, or head circumference among whites or Hispanics. Contrary to our hypothesis, we found stronger inverse associations of DAPs and birth outcome in infants with the less susceptible PON1192RR genotype. The large pooled data set facilitated exploration of interactions by race/ethnicity and PON1 genotype, but was limited by differences in study populations. CITATION: Harley KG, Engel SM, Vedar MG, Eskenazi B, Whyatt RM, Lanphear BP, Bradman A, Rauh VA, Yolton K, Hornung RW, Wetmur JG, Chen J, Holland NT, Barr DB, Perera FP, Wolff MS. 2016. Prenatal exposure to organophosphorous pesticides and fetal growth: pooled results from four longitudinal birth cohort studies. Environ Health Perspect 124:1084-1092; http://dx.doi.org/10.1289/ehp.1409362.

Prenatal Organophosphorus Pesticide Exposure and Child Neurodevelopment at 24 Months: An Analysis of Four Birth Cohorts.

BACKGROUND: Organophosphorus pesticides (OPs) are used in agriculture worldwide. Residential use was common in the United States before 2001. OBJECTIVES: We conducted a pooled analysis of four birth cohorts (children's centers; n = 936) to evaluate associations of prenatal exposure to OPs with child development at 24 months. METHODS: Using general linear models, we computed site-specific and pooled estimates of the association of total dialkyl (ΣDAP), diethyl (ΣDEP), and dimethylphosphate (ΣDMP) metabolite concentrations in maternal prenatal urine with mental and psychomotor development indices (MDI/PDI) and evaluated heterogeneity by children's center, race/ethnicity, and PON1 genotype. RESULTS: There was significant heterogeneity in the center-specific estimates of association for ΣDAP and ΣDMP and the MDI (p = 0.09, and p = 0.05, respectively), as well as heterogeneity in the race/ethnicity-specific estimates for ΣDAP (p = 0.06) and ΣDMP (p = 0.02) and the MDI. Strong MDI associations in the CHAMACOS population per 10-fold increase in ΣDAP (ß = -4.17; 95% CI: -7.00, -1.33) and ΣDMP (ß = -3.64; 95% CI: -5.97, -1.32) were influential, as were associations among Hispanics (ß per 10-fold increase in ΣDAP = -2.91; 95% CI: -4.71, -1.12). We generally found stronger negative associations of ΣDAP and ΣDEP with the 24-month MDI for carriers of the 192Q PON1 allele, particularly among blacks and Hispanics. CONCLUSIONS: Data pooling was complicated by center-related differences in subject characteristics, eligibility, and changes in regulations governing residential use of OPs during the study periods. Pooled summary estimates of prenatal exposure to OPs and neurodevelopment should be interpreted with caution because of significant heterogeneity in associations by center, race/ethnicity, and PON1 genotype. Subgroups with unique exposure profiles or susceptibilities may be at higher risk for adverse neurodevelopment following prenatal exposure. CITATION: Engel SM, Bradman A, Wolff MS, Rauh VA, Harley KG, Yang JH, Hoepner LA, Barr DB, Yolton K, Vedar MG, Xu Y, Hornung RW, Wetmur JG, Chen J, Holland NT, Perera FP, Whyatt RM, Lanphear BP, Eskenazi B. 2016. Prenatal organophosphorus pesticide exposure and child neurodevelopment at 24 months: an analysis of four birth cohorts. Environ Health Perspect 124:822-830; http://dx.doi.org/10.1289/ehp.1409474.

Can Computerized Neuropsychological Testing in the Emergency Department Predict Recovery for Young Athletes With Concussions?

OBJECTIVE: The objective of this study was to determine if computerized neurocognitive testing (Immediate Post-Concussion Assessment and Cognitive Testing [ImPACT]) in the emergency department (ED) can be used as a prognostic tool to detect young athletes at risk of having protracted concussive symptoms. METHODS: This was a prospective cohort study of athletes aged 11 to 18 years who presented to an ED less than 24 hours after sustaining a sports-related concussion. ImPACT was administered in the ED, and performance was categorized as "poor" if the athlete had 3 (of 4) or greater low domain scores. Participants completed the Post-Concussion Symptom Scale (PCSS) in the ED and by phone at 1 and 2 weeks after injury. Athletes were symptomatic if their PCSS score was more than 6 in males and more than 8 in females. RESULTS: One hundred nine patients were enrolled; 60% and 36% remained symptomatic at 1 and 2 weeks after injury, respectively. "Poor" ImPACT performance was not particularly useful in predicting athletes with protracted symptoms (at 1 week: positive predictive value, 70.8%; negative predictive value, 43.5%; at 2 weeks: positive predictive value, 47.8%; negative predictive value, 68.9%). In bivariate analysis, a higher ED PCSS score was associated with protracted symptoms (at 1 week: odds ratio, 1.1 [confidence interval, 1.0-1.1]; at 2 weeks: odds ratio, 1.0 [confidence interval, 1.0-1.1]). CONCLUSIONS: Computerized neurocognitive testing in the ED has limited usefulness in predicting protracted symptoms. Total acute symptom burden may be a useful prognostic tool in the ED evaluation of concussed young athletes, yet further research is necessary.

Affected twins in the familial intracranial aneurysm study.

BACKGROUND AND PURPOSE: Very few cases of intracranial aneurysms (IAs) in twins have been reported. Previous work has suggested that vulnerability to IA formation is heritable. Twin studies provide an opportunity to evaluate the impact of genetics on IA characteristics, including IA location. We therefore sought to examine IA location concordance, multiplicity, and rupture status within affected twin-pairs. METHODS: The Familial Intracranial Aneurysm study was a multicenter study whose goal was to identify genetic and other risk factors for formation and rupture of IAs. The study required at least three affected family members or an affected sibling pair for inclusion. Subjects with fusiform aneurysms, an IA associated with an AVM, or a family history of conditions known to predispose to IA formation, such as polycystic kidney disease, Ehlers-Danlos syndrome, Marfan syndrome, fibromuscular dysplasia, or moyamoya syndrome were excluded. Twin-pairs were identified by birth date and were classified as monozygotic (MZ) or dizygotic (DZ) through DNA marker genotypes. In addition to zygosity, we evaluated twin-pairs by smoking status, major arterial territory of IAs, and rupture status. Location concordance was defined as the presence of an IA in the same arterial distribution (ICA, MCA, ACA, and vertebrobasilar), irrespective of laterality, in both members of a twin-pair. The Fisher exact test was used for comparisons between MZ and DZ twin-pairs. RESULTS: A total of 16 affected twin-pairs were identified. Location concordance was observed in 8 of 11 MZ twin-pairs but in only 1 of 5 DZ twin-pairs (p = 0.08). Three MZ subjects had unknown IA locations and comprised the three instances of MZ discordance. Six of the 11 MZ twin-pairs and none of the 5 DZ twin-pairs had IAs in the ICA distribution (p = 0.03). Multiple IAs were observed in 11 of 22 MZ and 5 of 10 DZ twin-pairs. Thirteen (13) of the 32 subjects had an IA rupture, including 10 of 22 MZ twins. CONCLUSIONS: We found that arterial location concordance was greater in MZ than DZ twins, which suggests a genetic influence upon aneurysm location. The 16 twin-pairs in the present study are nearly the total of affected twin-pairs that have been reported in the literature to date. Further studies are needed to determine the impact of genetics in the formation and rupture of IAs.