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Background: Early childhood development (ECD) is essential in human capacity building and a critical element in the intergenerational process of human development. In some countries, social programs targeted at improving ECD have proven to be successful. Oaxaca is one of the States with the greatest social inequities in Mexico. Therefore, children in Oaxaca are at a high risk of suboptimal ECD. In 2014, the non-governmental organization (NGO) Un Kilo de Ayuda started to implement the Neurological and Psycho-affective Early Childhood Development Program in eighty marginalized communities of Oaxaca. In this article, we present the impact evaluation design to estimate the effect of this program on ECD. Methods: We will use a cluster randomized stepped-wedge design with an allocation ratio of 1:1. Communities will be randomly assigned to each study group: four groups of twenty communities each. We expect that children from intervened communities will show better ECD outcomes. Discussion: This study is one of the few rigorous assessments of the effect of an ECD program on the neurodevelopment of Mexican children recruited in their first 3 years of life from communities of high social vulnerability. Our study design is recommended when the way in which outcomes are measured and assessed depends on age, self-selection is present, and assignment is performed at an aggregate level. Implementation research will be conducted prior to study launch and quality control measures will be in place to maximize the fidelity of study design implementation. Trial registration: ClinicalTrials.gov NCT04210362 [ABSTRACT FROM AUTHOR]

ABSTRACT. The authors determined the secular trend in blood lead levels in a cohort of 91 children born in Mexico City between 1987 and the beginning of 1993. The authors grouped children by calendar year in which they reached 36 mo of age (i.e., 1990-1995), and their blood lead levels were measured every 6 mo during a 66-mo period. The overall geometric mean blood lead level was 8.6 mg/dl (range = 1.0-61.0 Mu g/dl). A repeated measures analysis of variance revealed a significant downward linear trend in blood lead levels by year (p < .001)--from an estimated marginal geometric mean of 14.2 Mu g/dl in 1990 to 6.3 mg/dl in 1995. There was also a significant linear age effect (p < .001); blood lead levels generally fell during the 36th-66th mo. Family use of lead-glazed pottery significantly elevated blood lead levels (p = .006), and the effect magnified as age increased (Age x Pottery Interaction [p = .014]). Although the overall downward trend in blood lead levels during the time period described corresponded to a reduction in various sources of lead exposure, there was no alteration in production, distribution, or use of leaded pottery. Currently, use of lead-glazed ceramic pottery is one of the most profound sources of lead exposure in the Mexican population. [ABSTRACT FROM AUTHOR]

• We investigated the association between prenatal PM 2.5 and behavioral development. • Behavioral development was assessed in 4-6 year olds using the BASC-2. • Higher first trimester PM 2.5 was associated with reduced Adaptive Skills scores. • PM 2.5 effects were consistent across subscales, including Functional Communication. • Our results suggest that PM 2.5 impacts behavioral domains as well as cognition. Childhood exposure to air pollution has been linked with maladaptive cognitive development; however, less is known about the association between prenatal fine particulate matter (PM 2.5) exposure and childhood behavior. Our aim was to assess the association between prenatal PM 2.5 exposure and behavioral development in 4-6 year old children residing in Mexico City. We used data from 539 mother-child pairs enrolled in a prospective birth cohort in Mexico City. We estimated daily PM 2.5 exposure using a 1 km2 satellite-based exposure model and averaged over each trimester of pregnancy. We assessed childhood behavior at 4-6 years of age using the parent-completed Behavioral Assessment Scale for Children (BASC-2) composite scores and subscales. We used linear regression models to estimate change in BASC-2 T-scores with trimester specific 5-μg/m3 increases in PM 2.5. All models were mutually adjusted for PM 2.5 exposures during the other trimesters, maternal factors including age, education, socioeconomic status, depression, and IQ, child's age at study visit, and season. We additionally assessed sex-specific effects by including an interaction term between PM 2.5 and sex. Higher first trimester PM 2.5 exposure was associated with reduced Adaptive Skills scores (β: -1.45, 95% CI: -2.60, -0.30). Lower scores on the Adaptive Skills composite score and subscales indicate poorer functioning. For PM 2.5 exposure during the first trimester, decrements were consistent across adaptive subscale scores including Adaptability (β: -1.51, 95% CI: -2.72, -0.30), Social Skills (β: -1.63, 95% CI: -2.90, -0.36), and Functional Communication (β: -1.21, 95% CI: -2.21, -0.21). The association between 1st trimester PM 2.5 and depression was stronger in males than females (β for males: 1.52, 95% CI: -0.41, 3.45; β for females: -0.13, 95% CI: -1.99, 1.72; p -int: 0.07). Exposure to PM 2.5 during early pregnancy may be associated with impaired behavioral development in children, particularly for measures of adaptive skills. These results suggest that air pollution impacts behavioral domains as well as cognition, and that the timing of exposure may be critical. [ABSTRACT FROM AUTHOR]

• Lead is a neurotoxicant associated with neurodevelopmental deficits. • Prepulse inhibition (PPI) deficits are associated with neurological disorders. • We estimated the causal effect of prenatal lead exposure on PPI in children. • Our findings suggest prenatal lead exposure causes PPI deficits in children. • PPI may be an objective biomarker of neurotoxicant effects on the brain. During pregnancy, maternal lead from earlier exposures mobilizes and crosses placental barriers, placing the developing fetus at risk for lead exposure and neurodevelopmental deficits. Some neuronal circuits known to be affected in neurodevelopment disorders can be probed with simple physiological behavioral paradigms. One such neural biomarker is Pre-Pulse Inhibition (PPI), an indicator of adequate sensorimotor gating processing. In clinical studies, deficits in PPI have been associated with neurodevelopmental disorders in human subjects. To our knowledge, no studies have examined the use of PPI as a biomarker of toxicant effects on the brain in epidemiological studies. We aimed to estimate the causal effect of prenatal lead exposure, assessed by maternal cortical bone lead concentrations, on PPI in 279 children from Mexico City. in vivo maternal cortical bone lead measurements were taken at four weeks postpartum at the mid-tibia shaft using a K-Shell X-ray fluorescence instrument. PPI recording occurred in an isolated clinical setting and eye blink responses were measured using electromyography. We assessed if the conditions for causal inference held in our study and used the results of our assessment to estimate the causal effect of prenatal lead exposure on PPI using an ordinary least squares regression model, a marginal structural model, and the parametric g-formula. Results were consistent across the three modeling approaches. For the parametric g-formula, a one standard deviation (10.0 μg/g) increase in prenatal lead significantly reduced PPI by approximately 19.0 % (95 % CI: 5.4 %, 34.3 %). This decrease is similar in magnitude to clinical studies on schizophrenia, which have observed PPI impairments in patients with schizophrenia as compared to controls. Our results are consistent with findings from other studies establishing an association between lead exposure and neurodevelopmental disorders in children and suggest that PPI may be useful as an objective biomarker of toxicant effects on the brain. [ABSTRACT FROM AUTHOR]

The etiology of child and adolescent anxiety remains poorly understood. Although several previous studies have examined associations between prenatal maternal psychological functioning and infant and child health outcomes, less is known about the impact of maternal anxiety specific to pregnancy and cortisol during pregnancy on childhood anxiety outcomes. Participants included 496 mother-child pairs from the PROGRESS longitudinal birth cohort in Mexico City. Anxiety symptoms were assessed at age 8–11 years during 2018–2019 using the Revised Children's Manifest Anxiety Scale. Pregnancy-specific anxiety was assessed using an expanded version of the Pregnancy Anxiety Scale. Maternal biological stress response during pregnancy was assessed using salivary cortisol measures (area under the curve, cortisol awakening response, and diurnal slope). Linear regression models were used to estimate associations between maternal anxiety and cortisol in relation to continuous child anxiety symptom T-scores. Models were adjusted for maternal age, socioeconomic status, child sex and age, and gestational age at saliva collection. We found that higher levels of pregnancy-specific anxiety in the mother were associated with higher anxiety symptoms in the child (β: 1.30, 95% CI: 0.19, 2.41). We additionally observed an association between higher maternal total cortisol output during pregnancy and higher anxiety symptoms in the child (β: 1.13, 95% CI: 0.25, 2.01). These findings highlight the importance of screening for maternal pregnancy-specific anxiety and the need to identify interventions and support for mothers during pregnancy in order to promote healthy outcomes for mothers and their children. • The etiology of child and adolescent anxiety remains poorly understood. • We studied impacts of maternal cortisol and anxiety on offspring anxiety symptoms. • Maternal pregnancy-specific anxiety was associated with anxiety in the child. • Higher maternal prenatal cortisol was related to greater childhood anxiety symptoms. • These findings highlight the importance of screening for pregnancy-specific anxiety. [ABSTRACT FROM AUTHOR]

Manganese and lead have been cross-sectionally associated with adverse respiratory outcomes in childhood but there is limited data on their combined effects starting in utero. We examined associations between in utero exposure to metals and childhood respiratory symptoms. We assessed 633 mother-child dyads enrolled in the Programming Research in Obesity, Growth, Environment, and Social Stressors (PROGRESS) birth cohort in Mexico City. Blood manganese (BMn) and lead (BPb) were measured in mothers at 2nd and 3rd trimester. Ever wheeze, current wheeze and asthma diagnosis were ascertained at 4–5 and 6–7 year visits through the International Study of Asthma and Allergies in Childhood survey. Logistic mixed model regression was used to assess the association between prenatal metals and respiratory outcomes in children across the 4–5 and 6–7 year visits. Covariates included mother's age, education and asthma, environmental tobacco smoke, child's sex and assessment time. In adjusted models, higher 2nd trimester BPb had a significant association with elevated odds of ever wheeze (Odds Ratio (OR): 1.97, 95% CI: 1.05, 3.67). BMn at 2nd trimester was associated with decreased (OR: 0.06, 95% CI: 0.01, 0.35) odds of current wheeze. We did not find any statistically significant associations with 3rd trimester blood metals. Prenatal exposure to Pb was associated with higher odds of ever wheeze while Mn was negatively associated with odds of current wheeze. These findings underscore the need to consider prenatal metal exposure, including low exposure levels, in the study of adverse respiratory outcomes. • Examined associations between prenatal metals exposure and wheeze in childhood. • Lead was associated with higher odds of wheeze in childhood. • Manganese was associated with lower odds of wheeze in childhood. [ABSTRACT FROM AUTHOR]

Abstract: Globally, organophosphate (OP) pesticide usage and exposure is widespread. Studies have found that fetuses and infants are more sensitive than adults to environmental toxicants and that prenatal exposure to low levels of OPs has been associated with Attention Deficit Hyperactivity Disorder-Like Phenotypes (ADHD-LP). Paraoxonase 1 (PON1) is an enzyme involved in detoxifying some OPs and its polymorphisms influence enzyme activity and quantity. The objective of this study was to examine whether maternal and/or child PON1 genotypes (PON1R192Q and PON1L55M) were associated with ADHD-LP in a Mexico City, Mexico birth cohort. PON1R192Q and PON1L55M genotypes in mothers (PON1R192Q: N=531; PON1L55M: N=458) and children (PON1R192Q: N=532; PON1L55M: N=478) from blood DNA were determined. We assessed ADHD-LP for children between the ages of 6 and 13 using Conners׳ Parent Rating Scales-Revised (CRS-R), Conners׳ Continuous Performance Test (CPT), and the parent scores for Behavior Assessment System for Children-2 (BASC2). Multivariable linear regression models were used to test relationships between ADHD-LP and PON1 polymorphisms. In these models, significant associations were observed with maternal genotypes but not with the child genotypes. A higher DSM IV Hyperactivity/Impulsivity score (β=3.27 points; 95% CI (0.89, 5.65)) and a 2.17 higher score in child DSM IV Total (95% CI (0.05, 4.29)) were observed for maternal PON155MM in comparison to PON155LM+LL. The childattention problems score was 2.27 points higher (95% CI (0.002, 4.53) for maternal PON1192QQ in comparison to PON1192QR+RR. Because maternal PON1 polymorphisms were associated with child ADHD-LP, this may be a viable biomarker of susceptibility for ADHD-LP. [Copyright &y& Elsevier]

Abstract: Attention Deficit Hyperactivity Disorder (ADHD) is the most commonly diagnosed and studied cognitive and behavioral disorder in school-age children. The etiology of ADHD and ADHD-related behavior is unclear, but genetic and environmental factors, such as pesticides, have been hypothesized. The objective of this study was to investigate the relationship between in utero exposure to chlorpyrifos, chlorpyrifos-methyl, and/or 3,5,6-trichloro-2-pyridinol (TCPY) and ADHD in school-age Mexican children using TCPY as a biomarker of exposure. The temporal reliability of repeated maternal urinary TCPY concentrations across trimesters was also explored (N =21). To explore associations with ADHD-related outcomes in children, third trimester urinary TCPY concentrations in were measured in 187 mother-child pairs from a prospective birth cohort. Child neurodevelopment in children 6–11 years of age was assessed using Conners’ Parental Rating Scales-Revised (CRS-R), Conners’ Continuous Performance Test (CPT), and Behavior Assessment System for Children-2 (BASC-2). Multivariable linear regression models were used to test relationships for all children combined and also stratified by sex. Intraclass correlation coefficients (ICC) calculations were based on a random effects model. The ICC was 0.41 for uncorrected TCPY, and ranged from 0.29 to 0.32 for specific gravity-corrected TCPY. We did not observe any statistically significant associations between tertiles of maternal TCPY concentrations and ADHD-related outcomes in children. However, compared to the lowest tertile we found suggestive evidence for increased ADHD index in the highest TCPY tertile in boys (β =5.55 points; 95% CI (−0.19, 11.3); p =0.06) and increased attention problems for the middle tertile in girls (β =5.81 points; 95% CI (−0.75, 12.4); p =0.08). Considering the continued widespread agricultural and possible residential use of chlorpyrifos and chlorpyrifos-methyl in Mexico and the educational implications of cognitive and behavior deficits, these relationships deserve further study. [Copyright &y& Elsevier]

Prenatal exposure to fine particulate matter air pollution (PM2.5) is an important, under-studied risk factor for neurodevelopmental dysfunction. We describe the relationships between prenatal PM2.5 exposure and vigilance and inhibitory control, executive functions related to multiple health outcomes in Mexico City children. We studied 320 children enrolled in Programming Research in Obesity, GRowth, Environment and Social Stressors, a longitudinal birth cohort study in Mexico City. We used a spatio-temporal model to estimate daily prenatal PM2.5 exposure at each participant's residential address. At age 9–10 years, children performed three Go/No-Go tasks, which measure vigilance and inhibitory control ability. We used Latent class analysis (LCA) to classify performance into subgroups that reflected neurocognitive performance and applied multivariate regression and distributed lag regression modeling (DLM) to test overall and time-dependent associations between prenatal PM2.5 exposure and Go/No-Go performance. LCA detected two Go/No-Go phenotypes: high performers (Class 1) and low performers (Class 2). Predicting odds of Class 1 vs Class 2 membership based on prenatal PM2.5 exposure timing, logistic regression modeling showed that average prenatal PM2.5 exposure in the second and third trimesters correlated with increased odds of membership in low-performance Class 2 (OR = 1.59 (1.16, 2.17), p = 0.004). Additionally, DLM analysis identified a critical window consisting of gestational days 103–268 (second and third trimesters) in which prenatal PM2.5 exposure predicted poorer Go/No-Go performance. Increased prenatal PM2.5 exposure predicted decreased vigilance and inhibitory control at age 9–10 years. These findings highlight the second and third trimesters of gestation as critical windows of PM2.5 exposure for the development of vigilance and inhibitory control in preadolescent children. Because childhood development of vigilance and inhibitory control informs behavior, academic performance, and self-regulation into adulthood, these results may help to describe the relationship of prenatal PM2.5 exposure to long-term health and psychosocial outcomes. The integrative methodology of this study also contributes to a shift towards more holistic analysis. [Display omitted] • Prenatal PM2.5 exposure predicted lower vigilance and inhibitory control at age 9–10. • Cognitive results of the Go/No-Go task revealed two groups: low and high performers. • Trimester 2–3 exposures increased odds of membership in the low-performance group. • Latent class analysis plus distributed lag modeling offers a holistic analytical paradigm. • Prenatal pollution is linked to distinct neurodevelopmental phenotypes in children. [ABSTRACT FROM AUTHOR]

Phthalate exposure has been associated with increased childhood behavioral problems. Existing studies failed to include phthalate replacements and did not account for high correlations among phthalates. Phthalates' exposure is higher in Mexico than in U.S. locations, making it an ideal target population for this study. To examine associations between 15 maternal prenatal phthalate metabolite concentrations and children's behavioral problems. We quantified phthalate metabolites in maternal urine samples from maternal-child dyads (n = 514) enrolled in the Programming Research in Obesity, Growth Environment and Social Stress (PROGRESS) birth cohort in Mexico City. We performed least absolute shrinkage and selection operator (LASSO) regressions to identify associations between specific-gravity adjusted log 2 -transformed phthalate metabolites and parent-reported 4–6 year old behavior on the Behavior Assessment System for Children (BASC-2), accounting for metabolite correlations. We adjusted for socio-demographic and birth-related factors, and examined associations stratified by sex. Higher prenatal mono-2-ethyl-5-carboxypentyl terephthalate (MECPTP) urinary concentrations were associated with increased hyperactivity scores in the overall sample (β = 0.57, 95% CI = 0.17, 1.13) and in girls (β = 0.54, 95% CI = 0.16, 1.08), overall behavioral problems in boys (β = 0.58, 95% CI = 0.20, 1.15), and depression scores in boys (β = 0.44, 95% CI = 0.06, 0.88). Higher prenatal monobenzyl phthalate (MBzP) concentrations were associated with reduced hyperactivity scores in girls (ß = −0.54, 95% CI = −1.08, −0.21). Our findings suggested that prenatal concentrations of phthalates and their replacements altered child neurodevelopment and those associations may be influenced sex. • Prenatal concentrations of phthalates and their novel replacements altered 4-6 year old child behavior. • Children exposed to higher prenatal MECPTP levels showed increased overall behavioral, depression, and hyperactivity scores. • Both magnitude and significance of the MECPTP-behavior associations differed by sex. • Girls born to mothers with higher prenatal MBzP concentrations were associated with reduced hyperactivity. [ABSTRACT FROM AUTHOR]