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Emily C Somers,1–3 Seetha U Monrad,1 Jeffrey S Warren,4 Maritsa Solano,5 Lourdes Schnaas,6 Mauricio Hernandez-Avila,5 Martha Maria Tellez-Rojo,5 Howard Hu7 1Divison of Rheumatology, Department of Internal Medicine, 2Department of Environmental Health Sciences, 3Department of Obstetrics & Gynecology, 4Division of Clinical Pathology, Department of Pathology, University of Michigan, Ann Arbor, MI, USA; 5Center for Nutrition and Health Research, National Institute of Public Health, Cuernavaca, Morelos, 6Department of Developmental Neurobiology, National Institute of Perinatology, Mexico City, Mexico; 7Occupational and Environmental Health, Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada Objective: To characterize antinuclear antibody (ANA) prevalence according to distinct assay methodologies in a pediatric cohort from Mexico City, and to further examine associations with age and sex.Methods: Serum ANA were measured by indirect immunofluorescence assay (IFA) and multiplex immunoassay in 114 children aged 9–17 years. IFA was considered positive at a cutoff titer of ≥1:80. Agreement between assay methods was assessed by kappa statistic. Sensitivity, specificity, and 95% confidence intervals (CIs) of the multiplex were computed with IFA as the reference standard.Results: Of the 114 children (mean age 14.7 [standard deviation 2.1] years; 54 [47%] female), 18 of 114 (15.8%) were ANA positive by IFA, and 11 of 114 (9.6%) by 11-antigen multiplex assay. ANA prevalence was higher in females compared with males by both of the methods (ratios 1.6–1.9 to 1). Agreement between tests was classified as slight by kappa (κ=0.177 [95% CI −0.051, 0.406]). The multiplex immunoassay had sensitivity of 22.2% (95% CI 6.4, 47.6) and specificity of 92.7% (95% CI 85.6, 97.0), and failed to capture 3 of 4 (75%) of the high-titer (≥1:1280) IFA-positives.Conclusion: Up to 15% of children in this general population cohort were ANA positive, with a higher rate of positivity among females according to both assay methods. Substantial discordance in ANA results was found between IFA and multiplex methods, even for high-titer IFA positives. These findings underscore the need to sufficiently account for assay characteristics when interpreting ANA test results, and support IFA as the more appropriate assay for studies of subclinical autoimmunity. Keywords: Autoreactivity, biomarker, immune dysfunction, preclinical, subclinical autoimmunity, autoantibodies, pediatric, epidemiology

BACKGROUND: The impact of prenatal lead exposure on neurodevelopment remains unclear in terms of consistency, the trimester of greatest vulnerability, and the best method for estimating fetal lead exposure. OBJECTIVE: We studied prenatal lead exposure's impact on neurodevelopment using repeated measures of fetal dose as reflected by maternal whole blood and plasma lead levels. METHODS: We measured lead in maternal plasma and whole blood during each trimester in 146 pregnant women in Mexico City. We then measured umbilical cord blood lead at delivery and, when offspring were 12 and 24 months of age, measured blood lead and administered the Bayley Scales of Infant Development. We used multivariate regression, adjusting for covariates and 24-month blood lead, to compare the impacts of our pregnancy measures of fetal lead dose. RESULTS: Maternal lead levels were moderately high with a first-trimester blood lead mean (+/- SD) value of 7.1 +/- 5.1 microg/dL and 14% of values >or=10 microg/dL. Both maternal plasma and whole blood lead during the first trimester (but not in the second or third trimester) were significant predictors (p < 0.05) of poorer Mental Development Index (MDI) scores. In models combining all three trimester measures and using standardized coefficients, the effect of first-trimester maternal plasma lead was somewhat greater than the effect of first-trimester maternal whole blood lead and substantially greater than the effects of second- or third-trimester plasma lead, and values averaged over all three trimesters. A 1-SD change in first-trimester plasma lead was associated with a reduction in MDI score of 3.5 points. Postnatal blood lead levels in the offspring were less strongly correlated with MDI scores. CONCLUSIONS: Fetal lead exposure has an adverse effect on neurodevelopment, with an effect that may be most pronounced during the first trimester and best captured by measuring lead in either maternal plasma or whole blood. [ABSTRACT FROM AUTHOR]

Objective: To explore anthropometric indicators and mental development in very-low-income children in the second year of life.Design: Cross-sectional survey.Setting: Low-income areas (income <20th percentile) in semi-urban Mexico (defined as towns or cities with 2,500-50,000 inhabitants).Subjects: Eight hundred and ninety-six children aged 12.5-23.5 months surveyed from September to December 2001.Methods: Questionnaire survey and anthropometric survey of households. Multivariate regression models evaluated differences across age in anthropometry (height-for-age Z-score (HAZ) and weight-for-height Z-score) and cognitive function (Mental Development Index (MDI) of the Bayley Scales of Infant Development) while controlling for socio-economic and parental characteristics.Results: There was a significant decline in HAZ and in age-adjusted MDI score across the second year of life. Although the children showed MDI scores close to the mean, normed US values at 13-14 months, the scores were significantly lower than expected in older children (P < 0.0001), even after controlling for socio-economic status and parental characteristics. At 13-14 months, only 3% of children received scores below 70 (less than minus two standard deviations), whereas by 19-20 months, almost 17% of children were performing below this level. No socio-economic or parental characteristics were significant predictors of HAZ or MDI.Conclusions: Parallel deficits are evident in both height-for-age and cognitive functioning during the second year of life in low-income Mexican infants. The consistency of these growth and development findings further stresses the need for targeted interventions to reduce the vulnerability of low-income Mexican children very early in life. [ABSTRACT FROM AUTHOR]

We determined the secular trend in blood lead levels in a cohort of 321 children born in Mexico City between 1987 and 1992. Blood lead level was measured every 6 months during a 10-year period. We modeled the effect of yearly air lead concentration nested within the calendar year in which the child was born, family use of lead-glazed pottery, socioeconomic status, year in which the child was born, age of the child at the time of blood lead measurement, place of residence, and an indicator variable for subjects with complete or incomplete blood lead values. The yearly mean of air lead of the Valley of Mexico decreased from its highest level of 2.80 microg/m[3] in 1987 to 0.07 microg/m[3] in 2002. The contribution of air lead to blood lead according to year of birth was strongest for subjects born in 1987 and fell to nearly zero for children born in 1992. The geometric mean of the entire cohort rose from 8.4 microg/dL in the first year of life to 10.1 microg/dL in the second and decreased thereafter until it reached 6.4 microg/dL at 10 years of age. Children of families who used lead-glazed ceramics had blood lead levels 18.5% higher than did children of nonusing families. Children who belonged to the lowest socioeconomic levels had blood lead levels 32.2% higher than did those of highest socioeconomic levels. Children who lived in the northeast part of the city had blood lead levels 10.9% higher compared with those who lived in the southwest. [ABSTRACT FROM AUTHOR]

Objective: This study investigated determinants of bone and blood lead concentrations in 430 lactating Mexican women during the early postpartum period and the contribution of bone lead to blood lead.Methods: Maternal venous lead was measured at delivery and postpartum, and bone lead concentrations, measured with in vivo K-x ray fluorescence, were measured post partum. Data on environmental exposure, demographic characteristics, and maternal factors related to exposure to lead were collected by questionnaire. Linear regression was used to examine the relations between bone and blood lead, demographics, and environmental exposure variables.Results: Mean (SD) blood, tibial, and patellar lead concentrations were 9.5 (4.5) microg/dl, 10.2 (10.1) microg Pb/g bone mineral, and 15.2 (15.1) microg Pb/g bone mineral respectively. These values are considerably higher than values for women in the United States. Older age, the cumulative use of lead glazed pottery, and higher proportion of life spent in Mexico City were powerful predictors of higher bone lead concentrations. Use of lead glazed ceramics to cook food in the past week and increased patellar lead concentrations were significant predictors of increased blood lead. Patellar lead concentrations explained one third of the variance accounted for by the final blood lead model. Women in the 90th percentile for patella lead had an untransformed predicted mean blood lead concentration 3.6 microg/dl higher than those in the 10th percentile.Conclusions: This study identified the use of lead glazed ceramics as a major source of cumulative exposure to lead, as reflected by bone lead concentrations, as well as current exposure, reflected by blood lead, in Mexico. A higher proportion of life spent in Mexico City, a proxy for exposure to leaded gasoline emissions, was identified as the other major source of cumulative lead exposure. The influence of bone lead on blood lead coupled with the long half life of lead in bone has implications for other populations and suggests that bone stores may pose a threat to women of reproductive age long after exposure has declined. [ABSTRACT FROM AUTHOR]

Background: Reducing the risk of respiratory disease during the plastic stages of lung development could have long-term health impacts. Psychosocial stress has been previously linked to adverse childhood respiratory outcomes, but the influence of child's anxiety and sex differences has not been completely elucidated., Objective: To evaluate the association among maternal stress, child anxiety, and lung function in children and to explore differences by sex., Methods: Cross-sectional analyses included 294 mother-child pairs from the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) birth cohort in Mexico City. Children's lung function was tested once at ages 8 to 13 years of age, and height- and sex-adjusted z-scores were estimated for forced vital capacity, forced expiratory volume in 1 second, forced expiratory volume in 1 second/forced vital capacity and forced expiratory flow between 25% and 75%. Maternal stress was assessed through the Crisis in Family Systems-Revised (CRISYS-R) survey, used to report negative life events experienced in the past 6 months and dichotomized at the median (<3 and ≥3). Child's self-reported anxiety was assessed using the Revised Children's Manifest Anxiety Scale short form and dichotomized at the clinically relevant cutoff (T-score ≥ 60). The association among maternal stress, child anxiety, and lung function outcomes was evaluated using linear models. Effect modification by sex was evaluated with interaction terms and in stratified analyses., Results: We did not find any association between maternal stress and any lung function outcome. Clinically elevated child anxiety symptoms were associated with lower forced expiratory volume in 1 second (β = -0.36, 95% CI -0.69 to -0.02). We found no evidence of effect modification by sex., Conclusion: Results highlight the importance of considering childhood mental health in relation to lung function outcomes., Competing Interests: Disclosures The authors have no conflicts of interest to report., (Copyright © 2024 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Introduction: Neurotoxicity resulting from air pollution is of increasing concern. Considering exposure timing effects on neurodevelopmental impairments may be as important as the exposure dose. We used distributed lag regression to determine the sensitive windows of prenatal exposure to fine particulate matter (PM 2.5 ) on children's cognition in a birth cohort in Mexico., Methods: Analysis included 553 full-term (≥37 weeks gestation) children. Prenatal daily PM 2.5 exposure was estimated using a validated satellite-based spatiotemporal model. McCarthy Scales of Children's Abilities (MSCA) were used to assess children's cognitive function at 4-5 years old (lower scores indicate poorer performance). To identify susceptibility windows, we used Bayesian distributed lag interaction models to examine associations between prenatal PM 2.5 levels and MSCA. This allowed us to estimate vulnerable windows while testing for effect modification., Results: After adjusting for maternal age, socioeconomic status, child age, and sex, Bayesian distributed lag interaction models showed significant associations between increased PM 2.5 levels and decreased general cognitive index scores at 31-35 gestation weeks, decreased quantitative scale scores at 30-36 weeks, decreased motor scale scores at 30-36 weeks, and decreased verbal scale scores at 37-38 weeks. Estimated cumulative effects (CE) of PM 2.5 across pregnancy showed significant associations with general cognitive index ( C E ^ = -0.35, 95% confidence interval [CI] = -0.68, -0.01), quantitative scale ( C E ^ = -0.27, 95% CI = -0.74, -0.02), motor scale ( C E ^ = -0.25, 95% CI = -0.44, -0.05), and verbal scale ( C E ^ = -0.2, 95% CI = -0.43, -0.02). No significant sex interactions were observed., Conclusions: Prenatal exposure to PM 2.5 , particularly late pregnancy, was inversely associated with subscales of MSCA. Using data-driven methods to identify sensitive window may provide insight into the mechanisms of neurodevelopmental impairment due to pollution., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

Assessing the status and determinants of early child development (ECD) requires accurate and regularly updated measurements. Yet, little information has been published on the subject in low- and middle-income countries, particularly regarding the proximal determinants of childhood development in contexts of high social marginalization. This article analyzes the factors that favor or mitigate suboptimal ECD outcomes in Mexico. A cross-sectional study was conducted using recently collected data for 918 children aged 0-38 months from socially marginalized communities in 23 Mexican municipalities. The ECD outcomes of the children were estimated based on indicators of chronic undernutrition and neurodevelopment (normal, lagging and at risk of delay). The distribution of outcomes was described across the ECD proximal determinants analyzed, including the co-occurrence of chronic undernutrition and suboptimal neurodevelopment. Covariate-adjusted prevalence of the ECD outcomes and co-occurrences were calculated as post-estimations from a multiple multinomial logistic regression. The prevalence of chronic undernutrition was 23.5%; 45.9% of children were classified with neurodevelopmental lag, and 11% at risk of neurodevelopmental delay. The prevalence of stunting co-occurring with suboptimal neurodevelopment came to 15.4%. The results of the multinomial logistic regression model indicated that early gestational age, low birth weight, a low household socioeconomic level, being male and having numerous siblings were all associated with the co-occurrence of chronic undernutrition and suboptimal child neurodevelopment. This study identified important predictors of child development in the first three years of life, specifically in two of its principal indicators: nutritional and neurodevelopmental status. Most of the predictors observed can be improved by means of social programs and interventions. Trial registration: ClinicalTrials.gov ID: NCT04210362., Competing Interests: The authors declare that they have no competing interests., (Copyright: © 2023 Serván-Mori et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: We assessed associations between maternal stress, social support, and child resiliency during the COVID-19 pandemic in relation to changes in anxiety and depression symptoms in children in Mexico City., Methods: Participants included 464 mother-child pairs from a longitudinal birth cohort in Mexico City. At ages 8-11 (pre-COVID, 2018-2019) and 9-12 (during COVID, May-Nov 2020) years, depressive symptoms were assessed using the child and parent-reported Children's Depressive Inventory. Anxiety symptoms were assessed using the child-reported Revised Manifest Anxiety Scale. Linear regression models were used to estimate associations between maternal stress, social support, and resiliency in relation to changes in depressive and anxiety symptoms. We additionally assessed outcomes using clinically relevant cut-points. Models were adjusted for child age and sex and maternal socioeconomic status and age., Results: Higher continuous maternal stress levels during the COVID-19 pandemic were associated with increases in depressive symptoms (β: 0.72; 95% CI: 0.12, 1.31), and higher odds of clinically relevant depressive and anxiety symptoms in the children., Conclusions: Maternal stress during the pandemic may increase mental health symptoms in pre-adolescent children. Additional studies are needed that examine the long-term pandemic-related impacts on mental health throughout the adolescent years., Impact: In this longitudinal cohort study of children in Mexico City, we observed that depressive symptoms were higher from before to during the pandemic. Maternal stress surrounding the pandemic may increase mental health symptoms in pre-adolescent children. Child resiliency may help to protect against pandemic-related stressors., (© 2022. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

Background: Studies report associations between maternal mental health and adverse respiratory outcomes in children; however, the impact of timing and duration of maternal distress remains understudied. We sought to longitudinally examine associations between maternal depression and childhood asthma and wheeze, and explore sex differences., Methods: Maternal depression (n = 601) was assessed using the Edinburgh Depression Scale questionnaire, dichotomized at a clinically relevant cutoff (>12) (a) during pregnancy, (b) postpartum, and (c) postpartum and subsequent time points postnatally (recurrent depression). Report of wheeze in the past 12 months (current wheeze) and asthma were obtained using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire at 48 and 72 months. Associations were analyzed using a modified Poisson regression adjusted for covariates, and in interaction models., Results: Both postpartum and recurrent depression were associated with higher risk of current wheeze (relative risk [RR]: 1.87, 95% confidence interval [CI]: 1.21, 2.90; RR: 2.41, 95% CI: 1.53, 3.79) and asthma at 48 months (RR: 2.42, 95% CI: 1.01, 5.84; RR: 2.45, 95% CI: 1.02, 5.84). In interaction analyses, associations were stronger in females. Recurrent depression was associated with a higher risk of current wheeze at 48 months in females (RR: 4.34, 95% CI: 2.02, 9.32) when compared to males (RR: 1.89, 95% CI: 1.05, 3.39)., Conclusions: Postpartum and recurrent depression were associated with a higher risk of wheeze and asthma in children. Understanding the temporal- and sex-specific effects of maternal depression may better inform prevention strategies., (© 2022 The Authors. Pediatric Pulmonology published by Wiley Periodicals LLC.)

Background and Aim: An association between lead (Pb) exposure and antisocial behaviors has been documented, but findings have been inconclusive. We aimed to estimate the association between prenatal, early childhood, and preadolescent/adolescent (periadolescent) Pb exposure and aggression and conduct problems in periadolescent residents of Mexico City., Methods: Using information from the ELEMENT cohort study, we assessed prenatal Pb exposure through maternal patella Pb (MPPb) measurement during the puerperium, early childhood (birth to 5 years of age) exposure through a cumulative blood lead index (CBLI), and periadolescent exposure through a blood Pb (BPb) measurement concurrent with the evaluation of the outcomes. Outcomes were assessed during periadolescence using the parent-reported scales of aggression and conduct problems of the Behavioral Assessment System for Children-2nd version (BASC-2). We modeled the association between Pb exposure at each stage and each outcome (defined as a T-score ≥60 in the corresponding behavioral scale) using logistic regression, adjusting for sex, maternal age at delivery, maternal education, and household socioeconomic status (SES). The differential effect by sex was assessed with an interaction term in the models., Results: 743, 704, and 595 participants were respectively eligible for inclusion in final models of prenatal, early childhood, and periadolescent Pb exposure. Median Pb exposure at each stage was 9.9 µg/g for MPPb (prenatal), 5.19 µg/dl for CBLI (early childhood), and 2.62 µg/dl for concurrent BPb (periadolescence). 12 % of participants met the criterion for aggression, and 15 % for conduct problems. In adjusted models, a one interquartile range increase in MPPb increased the odds of conduct problems (OR:1.31; 95 % CI: 1.01, 1.70) and aggression (OR=1.24; 95 % CI: 0.93, 1.65) during periadolescence. Pb exposure during early childhood or periadolescence was not associated with either outcome. We found no evidence of interactions by sex., Conclusions: Exposure to Pb during the prenatal stage was associated with aggression and conduct problems during periadolescence., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Lead (Pb), mercury (Hg), and manganese (Mn) are neurotoxic, but little is known about the neurodevelopmental effects associated with simultaneous prenatal exposure to these metals. We aimed to study the associations of Pb, Hg, and Mn prenatal levels (jointly and separately) with neurodevelopment in the first year of life. Methods: Pb, Hg, and Mn blood lead levels were measured in 253 pregnant women. Their offspring's neurodevelopment was assessed through the Bayley Scale of Infant Development III ® at one, three, six, and twelve months. The metals' mean blood levels (µg/L) were Pb = 11.2, Hg = 2.1, and Mn = 10.2. Mean language, cognitive, and motor development scores of the infants at each age were between low-average and average. Multilevel models' results showed that language development coefficients of the offspring decreased by 1.5 points per 1 µg/dL increase in maternal blood lead levels ( p = 0.002); the magnitude of the aforementioned association increased in children with maternal blood Mn < 9.6 µg/L (ß = -1.9, p = 0.003) or Hg > 1.9 µg/L (ß = -1.6, p = 0.013). Cognitive and motor development had negative associations with maternal blood Pb levels; the latter was statistically significant when the interaction term between Pb, Mn, and Hg was included (ß = -0.037, p = 0.03). Prenatal exposure to low Pb levels may impair infants' neurodevelopment in the first year of life, even more so if they are exposed to Hg or deficient in Mn.

Introduction: Efforts to identify the predictors of maternal knowledge on Early Child Development (ECD) have proven inconclusive thus far, particularly with respect to socially deprived contexts in Low- and Middle-Income Countries (LMICs). We quantified the extent of ECD knowledge among mothers who were the primary caregivers of 0-38-month-old infants in marginalized communities in Mexico. We also explored the characteristics of the children, both individually and with regard to their households, given the influence of these factors on childhood development., Methods: We analyzed primary data obtained through a questionnaire administered to mothers who were the primary caregivers of 1045 girls and boys 0-38 months of age. The instrument was specifically designed for our study in order to explore the knowledge of participants about physical, neurological and psycho-affective development during childhood. We performed fractional regression analysis to assess the predictors of ECD knowledge., Results: The mean score of maternal ECD knowledge increased with their age and schooling as well as with their levels of cognitive ability and self-esteem. Irrespective of age at first birth, mean knowledge was relatively high for women with high school education and low for women with elementary or no formal education, a gradient with respect to age at fist birth was more marked among women with middle school education. ECD knowledge scores increased among mothers from households enjoying higher socioeconomic levels and from households with health insurance. Scores were lower for indigenous households regardless of their participation in social programs., Conclusion: Public policies on ECD should promote programs that are not only adapted to specific contexts, but also designed to improve shared child-rearing, early childhood care and as well as psycho-emotional education skills as a pathway to healthier ECD. The participation of families and communities in sensitive childhood care should form part of multisectoral programs involving education, health and wellbeing., Competing Interests: Competing interest The authors declare that they have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Prenatal exposure to fluoride has been associated with adverse neurodevelopmental outcomes. However, the neuropsychological profile of fluoride's developmental neurotoxicity at low levels and the stability of this relationship across childhood has not been characterized. We investigated the longitudinal and domain specific effect of prenatal fluoride exposure on IQ among children ages 4, 5, and 6-12 years in the Early Life Exposures in Mexico to Environmental Toxicants (ELEMENT) cohort., Methods: We measured the average of maternal urinary fluoride at each trimester of pregnancy adjusted for creatinine (MUF CRE ). Children were administered the McCarthy Scales of Children's Abilities at ages 4 (N = 386) and 5 (N = 308), and the Wechsler Abbreviated Scale of Intelligence at age 6-12 (N = 278). We used generalized estimating equation (GEE) models to estimate the population averaged effect of MUF CRE concentration on longitudinal General Cognitive Index (GCI)/Full-Scale IQ (FSIQ), Verbal IQ (VIQ), and Performance IQ (PIQ) scores (N = 348). We tested for possible interactions between MUF CRE and child sex as well as for MUF CRE and time point on children's IQ. All models controlled for relevant available covariates., Results: The mean/median MUF CRE concentration was 0.90/0.83 mg/L (SD = 0.39; IQR, 0.64-1.11 mg/L). A 0.5 mg/L increase in MUF CRE predicted an average 2.12-point decrease in GCI/FSIQ (95% CI: -3.49, -0.75) and 2.63-point decrease in PIQ (95% CI: -3.87, -1.40). MUF CRE was marginally associated with VIQ across time (B = -1.29, 95% CI: -2.60, 0.01). No interactions between MUF CRE and child sex or MUF CRE and time were observed., Conclusion: The negative association between prenatal fluoride exposure and longitudinal IQ was driven by decrements in non-verbal intelligence (i.e. PIQ), suggesting that visual-spatial and perceptual reasoning abilities may be more impacted by prenatal fluoride exposure as compared to verbal abilities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Early childhood development (ECD) is a critical stage in the intergenerational process of human development. Targeted interventions depend on accurate and up-to-date ECD measurements. This paper presents estimates for the nutritional and neurodevelopmental status of socially marginalized children in Mexico. We performed a cross-sectional study based on data collected in 2019-2020 during home visits to 1,176 children aged 0-38 months across 24 highly marginalized locations in Oaxaca. We assessed nutritional status according to the World Health Organization 2006 child-growth standards and ECD status using the Child Development Evaluation Test, 2nd Edition. We stratified results by sex. Prevalence of stunting was 5.3 percentage points (p.p.) higher (p = 0.023) in males (25.3%; 95% CI: 20.2%, 31.1%) compared to females (20.0%; 95% CI: 15.0%, 26.1%). Overall prevalence rates stood at 5.7% (95% CI: 4.0%, 8.1%) for underweight, 1.5% (95% CI: 0.9%, 2.7%) for wasting and 3.6% (95% CI: 2.3%, 5.7%) for overweight/obesity, with no significant differences by sex. Prevalence of normal development was 8.3 p.p. lower (p = 0.001) in males (39.3%; 95% CI: 34.5%, 44.4%) compared to females (47.6%; 95% CI: 41.6%, 53.6%). By development area, the highest prevalence of suboptimal outcomes among children with developmental lag or at risk of delay was observed in their gross motor and language skills: 24.1% (95% CI: 20.0%, 28.8%) and 38.6% (95% CI: 34.0%, 43.3%), respectively. The largest difference between the sexes was found in the language area. Our results show that childhood development strategies have been insufficient thus far in the studied population. Programs specifically designed to prevent ECD lags and bridge inequality gaps are urgently needed. Trial registration: ClinicalTrials.gov ID: NCT04210362., Competing Interests: The authors have declared that no competing interests exist.

Background: 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., Methods: 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., Results: 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)., Discussion: 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., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Introduction: 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., Methods: 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 2 nd and 3 rd 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., Results: In adjusted models, higher 2 nd 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., Conclusion: 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., (Copyright © 2021 Elsevier Inc. All rights reserved.)

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., (© 2022. The Author(s).)

Reward motivation is a complex umbrella term encompassing the cognitions, emotions, and behaviors involved in the activation, execution, and persistence of goal-directed behavior. Altered reward motivation in children is characteristic of many neurodevelopmental and psychiatric disorders. Previously difficult to operationalize, the Progressive Ratio (PR) task has been widely used to assess reward motivation in animal and human studies, including children. Because the neural circuitry supporting reward motivation starts developing during pregnancy, and is sensitive to disruption by environmental toxicants, including metals, the goal of this study was to examine the association between prenatal concentrations of a mixture of neurotoxic metals and reward motivation in children. We measured reward motivation by administering a PR test to 373 children ages 6-8 years enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) Study in Mexico City. Children were asked to press a response lever for a token reward; one press on the response lever was required to earn the first token and each subsequent token required an additional 10 lever presses. Maternal blood concentrations of lead, manganese, zinc, arsenic, cadmium, and selenium were measured using inductively-coupled plasma mass spectrometry during the 2nd and 3rd trimesters of pregnancy. We performed generalized Weighted Quantile Sum (gWQS) regression analyses to examine associations between the prenatal metal mixture and reward motivation; adjusting for child sex, birthweight and age; and maternal IQ, education, and socioeconomic status. The prenatal metal mixture was significantly associated with higher motivation as indicated by more lever presses (ß = 0.02, p < 0.001) and a shorter time between receiving the reinforcer and the first press (ß = 0.23, p = 0.01), and between subsequent presses (ß = 0.07, p = 0.005). Contributions of different metals to this association differed by trimester and child sex. These findings suggest that children with increased exposure to metal during the 2nd and 3rd trimesters of gestation demonstrate increased reward motivation, which may reflect a tendency to perseverate or hypersensitivity to positive reinforcement., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Foods and beverages provide a source of fluoride exposure in Mexico. While high fluoride concentrations are neurotoxic, recent research suggests that exposures within the optimal range may also pose a risk to the developing brain. This prospective study examined whether dietary fluoride intake during pregnancy is associated with toddlers' neurodevelopment in 103 mother-child pairs from the PROGRESS cohort in Mexico City. Food and beverage fluoride intake was assessed in trimesters 2 and 3 using a food frequency questionnaire and Mexican tables of fluoride content. We used the Bayley-III to evaluate cognitive, motor, and language outcomes at 12 and 24 months of age. Adjusted linear regression models were generated for each neurodevelopment assessment time point (12 and 24 months). Mixed-effects models were used to consider a repeated measurement approach. Interactions between maternal fluoride intake and child sex on neurodevelopmental outcomes were tested. Median (IQR) dietary fluoride intake during pregnancy was 1.01 mg/d (0.73, 1.32). Maternal fluoride intake was not associated with cognitive, language, or motor outcomes collapsing across boys and girls. However, child sex modified the association between maternal fluoride intake and cognitive outcome (p interaction term = 0.06). A 0.5 mg/day increase in overall dietary fluoride intake was associated with a 3.50-point lower cognitive outcome in 24-month old boys (95 % CI: -6.58, -0.42); there was no statistical association with girls (β = 0.07, 95 % CI: -2.37, 2.51), nor on the cognitive outcome at 12-months of age. Averaging across the 12- and 24-month cognitive outcomes using mixed-effects models revealed a similar association: a 0.5 mg/day increase in overall dietary fluoride intake was associated with a 3.46-point lower cognitive outcome in boys (95 % CI: -6.23, -0.70). These findings suggest that the development of nonverbal abilities in males may be more vulnerable to prenatal fluoride exposure than language or motor abilities, even at levels within the recommended intake range., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

An altered mitochondrial DNA copy number (mtDNAcn) at birth can be a marker of increased disease susceptibility later in life. Gestational exposure to acute stress, such as that derived from the earthquake experienced on 19 September 2017 in Mexico City, could be associated with changes in mtDNAcn at birth. Our study used data from the OBESO (Biochemical and Epigenetic Origins of Overweight and Obesity) perinatal cohort in Mexico City. We compared the mtDNAcn in the umbilical cord blood of 22 infants born before the earthquake, 24 infants whose mothers were pregnant at the time of the earthquake (exposed), and 37 who were conceived after the earthquake (post-earthquake). We quantified mtDNAcn by quantitative real-time polymerase chain reaction normalized with a nuclear gene. We used a linear model adjusted by maternal age, body mass index, socioeconomic status, perceived stress, and pregnancy comorbidities. Compared to non-exposed newborns (mean ± SD mtDNAcn: 0.740 ± 0.161), exposed and post-earthquake newborns (mtDNAcn: 0.899 ± 0.156 and 0.995 ± 0.169, respectively) had increased mtDNAcn, p = 0.001. The findings of this study point at mtDNAcn as a potential biological marker of acute stress and suggest that experiencing an earthquake during pregnancy or before gestation can have programing effects in the unborn child. Long-term follow-up of newborns to women who experience stress prenatally, particularly that derived from a natural disaster, is warranted.

Introduction: 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., Methods: 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., Results: 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., Discussion: 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., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Variability in the FADS2 gene, which codifies the Delta-6 Desaturases and modulates the conversion of essential n-3 and n-6 fatty acids into long-chain polyunsaturated fatty acids, might modify the impact of prenatal supplementation with n-3 docosahexaenoic acid (DHA) on neurodevelopment., Objective: To assess if maternal FADS2 single nucleotide polymorphisms (SNPs) modified the effect of prenatal DHA on offspring development at 5 years., Design: We conducted a post-hoc interaction analysis of the POSGRAD randomized controlled trial (NCT00646360) of prenatal supplementation with algal-DHA where 1094 pregnant women originally randomized to 400 mg/day of preformed algal DHA or a placebo from gestation week 18-22 through delivery. In this analysis, we included offspring with information on maternal genotype and neurodevelopment at 5 years (DHA = 316; Control = 306) and used generalized linear models to assess interactions between FADS2 SNPs rs174602 or rs174575 and prenatal DHA on neurodevelopment at 5 years measured with McCarthy Scales of Children's Abilities (MSCA)., Results: Maternal and offspring characteristics were similar between groups. At baseline, mean (±standard deviation) maternal age was 26 ± 5 years and schooling was 12 ± 4 years. Forty-six percent (46%) of the children were female. Maternal minor allele frequencies were 0.37 and 0.33 for SNPs rs174602 and rs174575, respectively. There were significant variations by SNP rs174602 and intervention group (p for interactions <0.05) where children in the intervention group had higher MSCA scores on the quantitative (DHA: mean ± SEM = 22.6 ± 0.9 vs. Control = 19.1 ± 0.9, mean difference (Δ) = 3.45; p = 0.01) and memory (DHA = 27.9 ± 1.1 vs. Control = 23.7 ± 1.1, Δ = 4.26; p = 0.02) scales only among offspring of TT (minor allele homozygotes)., Conclusions: Maternal FADS2 SNP rs174602 modified the effect of prenatal DHA on cognitive development at 5 years. Variations in the genetic make-up of target populations could be an important factor to consider for prenatal DHA supplementation interventions., (Copyright © 2021. Published by Elsevier Ltd.)

Background: 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., Aim: To examine associations between 15 maternal prenatal phthalate metabolite concentrations and children's behavioral problems., Methods: 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., Results: 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)., Discussion: Our findings suggested that prenatal concentrations of phthalates and their replacements altered child neurodevelopment and those associations may be influenced sex., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The aim of this study was to examine changes in depression, stress and social support levels before and during the COVID-19 pandemic in women living in Mexico City. We studied 466 women enrolled in the Programming Research in Obesity, Growth, Environment and Social Stressors (PROGRESS) study who completed the Edinburgh Depression Scale (EDS) questionnaire prior (2018-2019) and during the lockdown period of the pandemic (May-November 2020). Psychosocial stress and social support for both time periods were ascertained using the Crisis in Family Systems (CRISYS) questionnaire and the Social Support Network (SSN) Scale, respectively. Associations between stress, social support and change in EDS score/depression were analyzed using generalized linear models adjusting for covariates. Higher stress (>median) during the pandemic was associated with an increase in EDS score (β: 2.13; 95% CI (1.06, 3.19), p < 0.001), and higher odds of depression (OR: 3.75; 95% CI (2.17, 6.50), p < 0.001), while social support was associated with lower odds of depression (OR: 0.56, 95% CI (0.32, 0.97), p = 0.037). Higher levels of stress during the pandemic were associated with depression. Social support may act as a buffer for the effects of psychosocial stress. Future studies should examine the long-term effects of stress associated with the pandemic on mental and overall health.

Early-life lead (Pb) exposure has been linked to adverse neurodevelopmental outcomes. Recent evidence has indicated a critical role of DNA methylation (DNAm) in cognition, and Pb exposure has also been shown to alter DNAm. However, it is unknown whether DNAm is part of the mechanism of Pb neurotoxicity. This longitudinal study investigated the associations between trimester-specific (T1, T2, and T3) maternal blood Pb concentrations, gene-specific DNAm in umbilical cord blood, and infant neurodevelopmental outcomes at 12 and 24 months of age (mental development index, psychomotor development index, and behavioral rating scale of orientation/engagement and emotional regulation) among 85 mother-infant pairs from the Early Life Exposure in Mexico to Environmental Toxicants (ELEMENT) study. In the mediation analysis for this pilot study, P  < 0.1 was considered significant. DNAm at a locus in CCSER1 (probe ID cg02901723) mediated the association between T2 Pb on 24-month orientation/engagement [indirect effect estimate 4.44, 95% confidence interval (-0.09, 10.68), P  = 0.06] and emotional regulation [3.62 (-0.05, 8.69), P  = 0.05]. Cg18515027 ( GCNT1 ) DNAm mediated the association of T1 Pb [-4.94 (-10.6, -0.77), P  = 0.01] and T2 Pb [-3.52 (-8.09, -0.36), P  = 0.02] with 24-month EMOCI, but there was a positive indirect effect estimate between T2 Pb and 24-month psychomotor development index [1.25 (-0.11, 3.32), P  = 0.09]. The indirect effect was significant for cg19703494 ( TRAPPC6A ) DNAm in the association between T2 Pb and 24-month mental development index [1.54 (0, 3.87), P  = 0.05]. There was also an indirect effect of cg23280166 ( VPS11 ) DNAm on T3 Pb and 24-month EMOCI [2.43 (-0.16, 6.38), P  = 0.08]. These associations provide preliminary evidence for gene-specific DNAm as mediators between prenatal Pb and adverse cognitive outcomes in offspring., (© The Author(s) 2021. Published by Oxford University Press.)