The importance of neurosurgical intervention and surgical timing for management of pediatric patients with myelomeningoceles in Bangladesh.

OBJECTIVE: Reports on the management and survival of children with myelomeningocele defects in Bangladesh are limited. This study describes the characteristics and outcomes of these children, focusing on the timing of surgical repair and factors affecting survival. METHODS: We enrolled patients with myelomeningoceles in a case-control study on arsenic exposure and spina bifida in Bangladesh. Cases were subsequently followed at regular intervals to assess survival. Demographic, clinical, and surgical characteristics were reviewed. Univariate tests identified factors affecting survival. RESULTS: Between 2016-2022, we enrolled 272 patients with myelomeningocele. Postnatal surgical repair was performed in 63% of cases. However, surgery within 5 days after birth was infrequent (<10%) due to delayed presentation, and there was a high rate (29%) of preoperative deaths. Surgical repair significantly improved patient survival (p<0.0001). Older age at time of surgery was also associated with improved survival rates, which most likely represents that those who survived to older ages prior to surgery accommodated better with their lesions. Patients who presented with ruptured lesions had lower survival rates. CONCLUSIONS: Timely neurosurgical repair of myelomeningoceles in Bangladesh is hindered by late patient presentation, resulting in a high preoperative patient death rate. Neurosurgical intervention remains a significant predictor of survival. Increased access to neurosurgical care and education of families and non-neurosurgical providers on the need for timely surgical intervention are important for improving the survival of infants with myelomeningoceles.

Genome-wide analysis of spina bifida risk variants in a case-control study from Bangladesh.

BACKGROUND: Human studies of genetic risk factors for neural tube defects, severe birth defects associated with long-term health consequences in surviving children, have predominantly been restricted to a subset of candidate genes in specific biological pathways including folate metabolism. METHODS: In this study, we investigated the association of genetic variants spanning the genome with risk of spina bifida (i.e., myelomeningocele and meningocele) in a subset of families enrolled from December 2016 through December 2022 in a case-control study in Bangladesh, a population often underrepresented in genetic studies. Saliva DNA samples were analyzed using the Illumina Global Screening Array. We performed genetic association analyses to compare allele frequencies between 112 case and 121 control children, 272 mothers, and 128 trios. RESULTS: In the transmission disequilibrium test analyses with trios only, we identified three novel exonic spina bifida risk loci, including rs140199800 (SULT1C2, p = 1.9 × 10-7), rs45580033 (ASB2, p = 4.2 × 10-10), and rs75426652 (LHPP, p = 7.2 × 10-14), after adjusting for multiple hypothesis testing. Association analyses comparing cases and controls, as well as models that included their mothers, did not identify genome-wide significant variants. CONCLUSIONS: This study identified three novel single nucleotide polymorphisms involved in biological pathways not previously associated with neural tube defects. The study warrants replication in larger groups to validate findings and to inform targeted prevention strategies.

Arsenic modifies the effect of folic acid in spina bifida prevention, a large hospital-based case-control study in Bangladesh.

Background: Spina bifida, a developmental malformation of the spinal cord, is associated with high rates of mortality and disability. Although folic acid-based preventive strategies have been successful in reducing rates of spina bifida, some areas continue to be at higher risk because of chemical exposures. Bangladesh has high arsenic exposures through contaminated drinking water and high rates of spina bifida. Methods: We conducted a hospital-based case-control study at the National Institute of Neurosciences & Hospital (NINS&H) in Dhaka, Bangladesh, between December 2016 and December 2022. Cases were infants under age one year with spina bifida and further classified using data from observations by neurosurgeons and available imaging. Controls were drawn from children who presented to NINS&H or Dhaka Shishu Hospital (DSH) during the same study period. Mothers reported folic acid use during pregnancy, and we assessed folate status with serum assays. Arsenic exposure was estimated in drinking water using graphite furnace atomic absorption spectrophotometry (GF-AAS) and in toenails using inductively coupled plasma mass spectrometry (ICP-MS). Results: We evaluated data from 294 cases of spina bifida and 163 controls. We did not find a main effect of mother's arsenic exposure on spina bifida risk. However, in stratified analyses, folic acid use was associated with lower odds of spina bifida (adjusted odds ratio [OR]: 0.50, 95% confidence interval [CI]: 0.25-1.00, p = 0.05) among women with toenail arsenic concentrations below the median, and no association was seen among mothers with toenail arsenic concentrations higher than median (adjusted OR: 1.09, 95% CI: 0.52-2.29, p = 0.82). Conclusions: Mother's arsenic exposure modified the protective association of folic acid with spina bifida. Increased surveillance and additional preventive strategies, such as folic acid fortification and reduction of arsenic, are needed in areas of high arsenic exposure.

Neurological and Psychological Sequelae Associated With Multisystem Inflammatory Syndrome in Children.

Importance: Acute neurological involvement occurs in some patients with multisystem inflammatory syndrome in children (MIS-C), but few data report neurological and psychological sequelae, and no investigations include direct assessments of cognitive function 6 to 12 months after discharge. Objective: To characterize neurological, psychological, and quality of life sequelae after MIS-C. Design, Setting, and Participants: This cross-sectional cohort study was conducted in the US and Canada. Participants included children with MIS-C diagnosed from November 2020 through November 2021, 6 to 12 months after hospital discharge, and their sibling or community controls, when available. Data analysis was performed from August 2022 to May 2023. Exposure: Diagnosis of MIS-C. Main Outcomes and Measures: A central study site remotely administered a onetime neurological examination and in-depth neuropsychological assessment including measures of cognition, behavior, quality of life, and daily function. Generalized estimating equations, accounting for matching, assessed for group differences. Results: Sixty-four patients with MIS-C (mean [SD] age, 11.5 [3.9] years; 20 girls [31%]) and 44 control participants (mean [SD] age, 12.6 [3.7] years; 20 girls [45%]) were enrolled. The MIS-C group exhibited abnormalities on neurological examination more frequently than controls (15 of 61 children [25%] vs 3 of 43 children [7%]; odds ratio, 4.7; 95% CI, 1.3-16.7). Although the 2 groups performed similarly on most cognitive measures, the MIS-C group scored lower on the National Institutes of Health Cognition Toolbox List Sort Working Memory Test, a measure of executive functioning (mean [SD] scores, 96.1 [14.3] vs 103.1 [10.5]). Parents reported worse psychological outcomes in cases compared with controls, particularly higher scores for depression symptoms (mean [SD] scores, 52.6 [13.1] vs 47.8 [9.4]) and somatization (mean [SD] scores, 55.5 [15.5] vs 47.0 [7.6]). Self-reported (mean [SD] scores, 79.6 [13.1] vs 85.5 [12.3]) and parent-reported (mean [SD] scores, 80.3 [15.5] vs 88.6 [13.0]) quality of life scores were also lower in cases than controls. Conclusions and Relevance: In this cohort study, compared with contemporaneous sibling or community controls, patients with MIS-C had more abnormal neurologic examinations, worse working memory scores, more somatization and depression symptoms, and lower quality of life 6 to 12 months after hospital discharge. Although these findings need to be confirmed in larger studies, enhanced monitoring may be warranted for early identification and treatment of neurological and psychological symptoms.

Pregnancy pesticide exposure and child development in low- and middle-income countries: A prospective analysis of a birth cohort in rural Bangladesh and meta-analysis.

BACKGROUND: Despite considerable evidence on a negative association between pregnancy pesticide exposure and child development in high-income countries, evidence from low- and middle-income countries (LMICs) is limited. Therefore, we assessed associations between pregnancy pesticide exposure and child development in rural Bangladesh and summarised existing literature in a systematic review and meta-analysis. METHODS: We used data from 284 mother-child pairs participating in a birth cohort established in 2008. Eight urinary pesticide biomarkers were quantified in early pregnancy (mean gestational age 11.6±2.9 weeks) as an index of pesticide exposure. The Bayley Scales of Infant and Toddler Development, Third Edition were administered at 20-40 months of age. Associations between creatinine-adjusted urinary pesticide biomarker concentrations and child development scores were estimated using multivariable generalised linear models. We searched ten databases up to November 2021 to identify prospective studies on pregnancy pesticide exposure and child development conducted in LMICs. We used a random-effects model to pool similar studies, including our original analysis. The systematic review was pre-registered with PROSPERO: CRD42021292919. RESULTS: In the Bangladesh cohort, pregnancy 2-isopropyl-4-methyl-6-hydroxypyrimidine (IMPY) concentrations were inversely associated with motor development (-0.66 points [95% CI -1.23, -0.09]). Pregnancy 3,5,6-trichloro-2-pyridinol (TCPY) concentrations were inversely associated with cognitive development, but the association was small: -0.02 points (-0.04, 0.01). We observed no associations between 4-nitrophenol and 3-phenoxybenzoic acid (3-PBA) concentrations and child development. The systematic review included 13 studies from four LMICs. After pooling our results with one other study, we found consistent evidence that pregnancy 3-PBA concentrations were not associated with cognitive, language, or motor development. CONCLUSION: Evidence suggests that pregnancy exposure to some organophosphate pesticides is negatively associated with child development. Interventions to reduce in-utero pesticide exposure in LMICs may help protect child development.

Clinical characteristics of children with infantile epileptic spasms syndrome from a tertiary-care hospital in Dhaka, Bangladesh.

Background: We describe patient characteristics and response to initial treatment in a large case series of children presenting with infantile epileptic spasms syndrome to a tertiary-care hospital with a pediatric neurology service in Bangladesh. The purpose of the study was to add to the growing body of literature on infantile epileptic spasms syndrome in low- and middle-income countries. Methods: We enrolled 212 infants with new-onset infantile epileptic spasms syndrome (IESS) at the time of initial presentation to the National Institute of Neurosciences and Hospital (NINS) in Dhaka, Bangladesh, between January 2019 and August 2021. We collected data about seizure type and frequency, etiology, medication dosage, and available neuroimaging. Results: Median age at initial presentation to NINS was 9 months. Developmental delay and regression prior to presentation were found in 83% and 36%, respectively. Prior to their presentation at NINS, 197 (93%) patients had received anti-seizure medication to treat spasms, of whom only 8 (4%) had received standard therapy with ACTH, prednisolone, or vigabatrin. At NINS, 207 (98%) of patients received standard therapy, most frequently ACTH in 154 (73%). Median time between seizure onset to receipt of first-line therapy was 5 months. Of the 169 patients who were seen in follow-up at average of 5 weeks, 92 (54%) reported absence of clinical epileptic spasms. No serious adverse events requiring hospitalization were reported. Conclusions: This study highlights the long lead times to treatment for IESS in a low- and middle-income country, and the need for early referral of children with suspected epileptic spasms to epilepsy care centers.

Prepregnancy exposure to dietary arsenic and congenital heart defects.

INTRODUCTION: Arsenic crosses the placenta and accumulates in fetal tissues. In the United States, diet is the predominant route of arsenic exposure, but epidemiologic data are sparse regarding this exposure and development of birth defects. Using data from a large case-control study, we explored associations between maternal dietary arsenic exposure and congenital heart defects (CHDs), the most prevalent birth defects. METHODS: We used maternal self-reported dietary assessments and arsenic concentration estimates in food items to estimate average daily exposure to dietary arsenic during the year before pregnancy for mothers of 10,446 unaffected control children and 6,483 case children diagnosed with CHDs. Using tertiles of dietary exposure to total arsenic (all species) and inorganic arsenic, we applied logistic regression analysis to estimate associations for middle and high tertiles, compared with the low tertile. RESULTS: Positive associations (odds ratio [OR] ≥ 1.2) for total arsenic were observed in both tertiles for perimembranous ventricular septal defect (VSD) and high tertile only for double outlet right ventricle-transposition of the great arteries (DORV-TGA), partial anomalous pulmonary venous return (PAPVR), and tricuspid atresia. Positive associations were also observed in both tertiles (tricuspid atresia) and high tertile only (DORV-TGA, conoventricular VSD, PAPVR, and pulmonary atresia) for inorganic arsenic. Most remaining associations were near or below unity. DISCUSSION: Exploration of maternal dietary exposure to total and inorganic arsenic and CHDs produced few positive associations but was limited by available food item concentrations. Future research requires expanded collection of dietary data, improved estimates of concentrations, and consideration of nondietary sources of arsenic exposure.

A Cross-validated Ensemble Approach to Robust Hypothesis Testing of Continuous Nonlinear Interactions: Application to Nutrition-Environment Studies.

Gene-environment and nutrition-environment studies often involve testing of high-dimensional interactions between two sets of variables, each having potentially complex nonlinear main effects on an outcome. Construction of a valid and powerful hypothesis test for such an interaction is challenging, due to the difficulty in constructing an efficient and unbiased estimator for the complex, nonlinear main effects. In this work we address this problem by proposing a Cross-validated Ensemble of Kernels (CVEK) that learns the space of appropriate functions for the main effects using a cross-validated ensemble approach. With a carefully chosen library of base kernels, CVEK flexibly estimates the form of the main-effect functions from the data, and encourages test power by guarding against over-fitting under the alternative. The method is motivated by a study on the interaction between metal exposures in utero and maternal nutrition on children's neurodevelopment in rural Bangladesh. The proposed tests identified evidence of an interaction between minerals and vitamins intake and arsenic and manganese exposures. Results suggest that the detrimental effects of these metals are most pronounced at low intake levels of the nutrients, suggesting nutritional interventions in pregnant women could mitigate the adverse impacts of in utero metal exposures on children's neurodevelopment.

Identifying biomarkers for epilepsy after cerebral malaria in Zambian children: rationale and design of a prospective observational study.

INTRODUCTION: Malaria affecting the central nervous system (CM) is a major contributor to paediatric epilepsy in resource-poor settings, with 10%-16% of survivors developing epilepsy within 2 years of infection. Despite high risk for post-malaria epilepsy (PME), biomarkers indicating which CM survivors will develop epilepsy are absent. Such biomarkers are essential to identify those at highest risk who might benefit most from close surveillance and/or preventive treatments. Electroencephalography (EEG) contains signals (specifically gamma frequency activity), which are correlated with higher risk of PME and provide a biomarker for the development of epilepsy. We propose to study the sensitivity of quantitative and qualitative EEG metrics in predicting PME, and the potential increased sensitivity of this measure with additional clinical metrics. Our goal is to develop a predictive PME index composed of EEG and clinical history metrics that are highly feasible to obtain in low-resourced regions. METHODS AND ANALYSES: This prospective observational study being conducted in Eastern Zambia will recruit 250 children aged 6 months to 11 years presenting with acute CM and follow them for two years. Children with pre-existing epilepsy diagnoses will be excluded. Outcome measures will include qualitative and quantitative analysis of routine EEG recordings, as well as clinical metrics in the acute and subacute period, including histidine-rich protein 2 levels of parasite burden, depth and length of coma, presence and severity of acute seizures, presence of hypoglycaemia, maximum temperature and 1-month post-CM neurodevelopmental assessment scores. We will test the performance of these EEG and clinical metrics in predicting development of epilepsy through multivariate logistic regression analyses. ETHICS AND DISSEMINATION: This study has been approved by the Boston Children's Hospital Institutional Review Board, University of Zambia Biomedical Research Ethics Committee, and National Health Research Authority of Zambia. Results will be disseminated locally in Zambia followed by publication in international, open access, peer-reviewed journals when feasible.

Pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects.

OBJECTIVES: To explore associations between maternal pre-pregnancy exposure to arsenic in diet and non-cardiac birth defects. DESIGN: This is a population-based, case-control study using maternal responses to a dietary assessment and published arsenic concentration estimates in food items to calculate average daily total and inorganic arsenic exposure during the year before pregnancy. Assigning tertiles of total and inorganic arsenic exposure, logistic regression analysis was used to estimate OR for middle and high tertiles, compared to the low tertile. SETTING: US National Birth Defects Prevention Study, 1997-2011. PARTICIPANTS: Mothers of 10 446 children without birth defects and 14 408 children diagnosed with a non-cardiac birth defect. RESULTS: Maternal exposure to total dietary arsenic in the middle and high tertiles was associated with a threefold increase in cloacal exstrophy, with weak positive associations (1·2-1·5) observed either in both tertiles (intercalary limb deficiency) or the high tertile only (encephalocele, glaucoma/anterior chamber defects and bladder exstrophy). Maternal exposure to inorganic arsenic showed mostly weak, positive associations in both tertiles (colonic atresia/stenosis, oesophageal atresia, bilateral renal agenesis/hypoplasia, hypospadias, cloacal exstrophy and gastroschisis), or the high (glaucoma/anterior chamber defects, choanal atresia and intestinal atresia stenosis) or middle (encephalocele, intercalary limb deficiency and transverse limb deficiency) tertiles only. The remaining associations estimated were near the null or inverse. CONCLUSIONS: This exploration of arsenic in diet and non-cardiac birth defects produced several positive, but mostly weak associations. Limitations in exposure assessment may have resulted in exposure misclassification. Continued research with improved exposure assessment is recommended to identify if these associations are true signals or chance findings.

Household use of crop residues and fuelwood for cooking and newborn birth size in rural Bangladesh.

OBJECTIVES: We aimed to investigate the association between type of cooking biomass fuels (crop residues vs fuelwood) and newborn birth outcomes in Bangladeshi children. METHODS: In this birth cohort study, pregnant women who were 18 years or older with ultrasound confirmed singleton pregnancy of ≤16 weeks of gestation were enrolled from two Bangladesh clinics between January 2008 and June 2011. Exposure to cooking biomass fuels during pregnancy was assessed by an administered questionnaire. The newborn size metrics were measured at the time of delivery. We used multiple linear regression and logistic regression to assess the associations between the type of cooking biomass fuels and birth outcomes after adjusting for covariates. RESULTS: A total of 1137 participants were using biomass fuels, including crop residues (30.3%) and fuelwood (69.7%), respectively, for cooking. After adjusting for covariates, the use of crop residues for cooking was associated with a 0.13 SD decrease in birth length (95% CI 0.25 to -0.01), a 0.14 SD decrease in head circumference (95% CI -0.27 to -0.02), and increased risk of low birth weight (LBW, OR 1.52, 95% CI 1.07 to 2.15) compared with the use of fuelwood. CONCLUSION: The use of crop residues for cooking was associated with reduced birth size and increased risk for LBW in Bangladeshi children, implying that the use of crop residues during pregnancy may have a detrimental effect on fetal growth.

Neural tube defects prevalence does not increase after modification of the folic acid fortification program in Chile.

BACKGROUND: In 2000, Chile's Ministry of Health mandated fortification of wheat flour with folic acid at a concentration of 2.2 mg/kg to prevent neural tube defects (NTDs), resulting in a 50% reduction in NTD prevalence. Concerns about possible collateral effects of high folic acid intake led, in 2009, to decrease the folic acid fortification to 1.8 mg/kg of flour. Our study evaluated the impact of this modification on the prevalence of NTDs in Santiago. METHODS: This study measured the prevalence of NTDs in live births and stillbirths born in Santiago. We calculated prevalence ratios (PR) and 95% confidence intervals (CI) between pre-folic acid fortification (1999-2000), post-folic acid fortification (2001-2009), and post-modified folic acid fortification (2010-2015) periods for all NTDs and their specific types. We used chi-square tests to analyze proportions, and a Joinpoint regression to visualize prevalence time trends. RESULTS: The NTD prevalence for the period 2001-2015 was 8.9 per 10,000 births, which represents a 48% reduction (PR = 0.52; 95% CI = 0.45-0.61; p < .001) from the pre-folic acid fortification period. During 2010-2015, the NTD prevalence was 9.5/10,000 births, which was higher, but not statistically significantly different from 2001 to 2009 prevalence of 8.6/10,000 (PR = 1.11; 95% CI = 0.96-1.30, p = .17). CONCLUSIONS: Decreasing the concentration of folic acid fortification was not associated with a statistically significant change in the prevalence of NTDs. Mandatory folic acid fortification continues to be a safe and highly effective policy to prevent NTDs. Future studies should evaluate the prevalence of NTDs across Chile and adherence to folic acid fortification mandates.

Arsenic exposure during pregnancy and postpartum maternal glucose tolerance: evidence from Bangladesh.

BACKGROUND: Arsenic exposure has been associated with gestational diabetes mellitus. However, the extent to which arsenic exposure during pregnancy is associated with postpartum glucose intolerance is unknown. METHODS: We studied 323 women in Bangladesh. We assessed arsenic exposure in early pregnancy via toenail and water samples. We measured fasting glucose and insulin in serum at a mean (SD) of 4.0 (3.5) weeks post-delivery. We ran covariate-adjusted, linear regression models to examine associations of arsenic concentrations with HOMA-IR, a marker of insulin resistance, and HOMA-ß, a marker of beta cell function. RESULTS: Median (IQR) arsenic concentration was 0.45 (0.67) µg/g in toenails and 2.0 (6.5) µg/L in drinking water. Arsenic concentrations during pregnancy were not associated with insulin resistance or beta cell function postpartum. HOMA-IR was 0.07% (- 3.13, 3.37) higher and HOMA-ß was 0.96% (- 3.83, 1.99) lower per IQR increment in toenail arsenic, but effect estimates were small and confidence intervals crossed the null. CONCLUSIONS: Although arsenic exposure during pregnancy has been consistently associated with gestational diabetes mellitus, we found no clear evidence for an adverse effect on postpartum insulin resistance or beta cell function.

Bayesian kernel machine regression-causal mediation analysis.

Greater understanding of the pathways through which an environmental mixture operates is important to design effective interventions. We present new methodology to estimate natural direct and indirect effects and controlled direct effects of a complex mixture exposure on an outcome through a mediator variable. We implement Bayesian Kernel Machine Regression (BKMR) to allow for all possible interactions and nonlinear effects of (1) the co-exposures on the mediator, (2) the co-exposures and mediator on the outcome, and (3) selected covariates on the mediator and/or outcome. From the posterior predictive distributions of the mediator and outcome, we simulate counterfactuals to obtain posterior samples, estimates, and credible intervals of the mediation effects. Our simulation study demonstrates that when the exposure-mediator and exposure-mediator-outcome relationships are complex, BKMR-Causal Mediation Analysis performs better than current mediation methods. We applied our methodology to quantify the contribution of birth length as a mediator between in utero co-exposure to arsenic, manganese, and lead, and children's neurodevelopmental scores, in a prospective birth cohort in Bangladesh. Among younger children, we found a negative (adverse) association between the metal mixture and neurodevelopment. We also found evidence that birth length mediates the effect of exposure to the metal mixture on neurodevelopment for younger children. If birth length were fixed to its 75th percentile value, the harmful effect of the metal mixture on neurodevelopment is attenuated, suggesting nutritional interventions to help increase fetal growth, and thus birth length, could potentially block the harmful effect of the metal mixture on neurodevelopment.

Parental metal exposures as potential risk factors for spina bifida in Bangladesh.

BACKGROUND: Neural tube defects are a pressing public health concern despite advances in prevention from folic acid-based strategies. Numerous chemicals, in particular arsenic, have been associated with neural tube defects in animal models and could influence risk in humans. OBJECTIVES: We investigated the relationship between parental exposure to arsenic and 17 metals and risk of neural tube defects (myelomeningocele and meningocele) in a case control study in Bangladesh. METHODS: Exposure assessment included analysis of maternal and paternal toenail samples using inductively coupled plasma mass spectrometry (ICP-MS). A total of 278 participants (155 cases and 123 controls) with data collected from 2016 to 2020 were included in the analysis. RESULTS: In the paternal models, a one-unit increase in the natural logarithm of paternal toenail arsenic was associated with a 74% (odds ratio: 1.74, 95% confidence interval: 1.26-2.42) greater odds of having a child with spina bifida, after adjusting for relevant covariates. Additionally, paternal exposure to aluminum, cobalt, chromium, iron, selenium, and vanadium was associated with increased odds of having a child with spina bifida in the adjusted models. In the maternal models, a one-unit increase in the natural logarithm of maternal toenail selenium and zinc levels was related to a 382% greater (odds ratio: 4.82, 95% confidence interval: 1.32-17.60) and 89% lower (odds ratio: 0.11, 95% confidence interval: 0.03-0.42) odds of having a child with spina bifida in the adjusted models, respectively. Results did not suggest an interaction between parental toenail metals and maternal serum folate. DISCUSSION: Parental toenail levels of numerous metals were associated with increased risk of spina bifida in Bangladeshi infants. Paternal arsenic exposure was positively associated with neural tube defects in children and is of particular concern given the widespread arsenic poisoning of groundwater resources in Bangladesh and the lack of nutritional interventions aimed to mitigate paternal arsenic exposure. The findings add to the growing body of literature of the impact of metals, especially paternal environmental factors, on child health.

Umbilical Cord Blood Metal Mixtures and Birth Size in Bangladeshi Children.

BACKGROUND: Studies have evaluated environmental exposure to toxic metals such as arsenic (As), cadmium (Cd), manganese (Mn), or lead (Pb) on birth size; however, information on potential effects of exposures to metal mixtures is limited. OBJECTIVES: We assessed the association between metal mixtures (As, Cd, Mn, Pb) in umbilical cord blood and neonate size in Bangladeshi children. METHODS: In this birth cohort study, pregnant women who were ≥18 years of age with an ultrasound-confirmed singleton pregnancy of ≤16wk gestation were recruited from two Bangladesh clinics between 2008 and 2011. Neonate size metrics were measured at the time of delivery. Metals in cord blood were measured using inductively coupled plasma mass spectrometry. We employed multivariable linear regression and Bayesian kernel machine regression (BKMR) to estimate associations of individual metals and metal mixtures with birth size parameters. RESULTS: Data from 1,088 participants was assessed. We found a significant negative association between metal mixture and birth length and head circumference when all metal concentrations were above the 60th and 55th percentiles, respectively, compared with the median. An interquartile range (IQR) increase in log Cd concentration {log[Cd (in micrograms per deciliter)] IQR=2.51} was associated with a 0.13-standard deviation (SD) decrease in mean birth length (95% CI: -0.25, -0.02) and a 0.17-SD decrease in mean head circumference (95% CI: -0.28, -0.05), based on linear regression models adjusted for covariates and the other metals. An IQR increase in log Mn concentration {log[Mn (in micrograms per deciliter)] IQR=0.69} was associated with a 0.07-SD decrease in mean birth weight (95% CI: -0.15, 0.002). DISCUSSION: Metal mixtures in cord blood were associated with reduced birth size in Bangladeshi children. Results from linear regression models adjusted and the BKMR mixtures analyses suggest adverse effects of Cd and Mn, as individual metal exposures, on birth size outcomes. https://doi.org/10.1289/EHP7502.

Feasibility of Lead Exposure Assessment in Blood Spots using Energy-Dispersive X-ray Fluorescence.

Collecting blood spots from newborns is a common procedure used to diagnose multiple health conditions. Fingerstick blood samples are routinely collected from children to diagnose elevated blood lead levels. In our study, we wanted to test the feasibility of using a high-power energy-dispersive X-ray fluorescence (EDXRF) device to accurately measure the concentration of lead in blood spots. We created spotted standards of a known concentration of lead on a filter paper at different volumes and concentrations. We determined the detection limit for lead through repeated measurements of our standards and calibration line slopes. We also tested the variability of the measured lead concentration across procedures and spotted blood volumes and found no significant additions to uncertainty in measurements. Finally, we compared blood lead concentrations measured by EDXRF and atomic absorption spectroscopy (AAS) and found EDXRF to be a significant predictor of blood lead (n = 22, R = 0.98, p value <0.001) with an average detection limit of 1.7 µg/dL of blood lead. This detection limit is similar to that of the AAS technique, which is commonly used in clinical testing laboratories for blood lead surveillance. These findings provide a proof of concept that blood spots measured by EDXRF may be used as a surveillance tool for lead exposure, even at elevated blood lead levels of 2-3 µg/dL.

Stunting and lead: using causal mediation analysis to better understand how environmental lead exposure affects cognitive outcomes in children.

BACKGROUND: Many children in Bangladesh experience poor nutritional status and environmental lead exposure, both of which are associated with lower scores on neurodevelopmental assessments. Recent studies have suggested that part of lead's adverse effects on neurodevelopment are caused in part by lead's effect on growth. New statistical methods are now available to evaluate potential causal pathways in observational studies. This study used a novel statistical method to test the hypothesis that stunting, a measure of linear growth related to poor nutrition, is a mediator and/or an effect modifier of the lead exposure's adverse effect on cognitive development. METHODS: Participants were 734 children from a longitudinal birth cohort established in rural Bangladesh to study the health effects of prenatal and early childhood environmental metal exposures. Lead exposure was estimated using umbilical cord blood samples obtained at birth and blood obtained via venipuncture at age 20-40 months. Stunting was determined using the World Health Organization's standards. Neurodevelopment was assessed at age 20-40 months years using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). We evaluated the effect of lead on stunting and whether the effect of lead on cognitive scores is modified by stunting status in multivariable regression analyses. We then conducted a novel 4-way mediation analysis that allows for exposure-mediator interaction to assess how much of the effect of lead on cognitive scores is explained by the pathway through stunting (mediation) and how much is explained by the interaction between lead and stunt (effect modification). RESULTS: Stunting was not a mediator of the effect of lead in our analyses. Results suggested effect modification by stunting. In an area of Bangladesh with lower lead exposures (median umbilical cord blood lead concentration, 1.7 µg/dL), stunting modified the relationship between prenatal blood lead concentrations and cognitive score at age 2-3 years. A 1-unit increase in natural log cord blood lead concentration in the presence of stunting was associated with a 2.1-unit decrease in cognitive scores (ß = - 2.10, SE = 0.71, P = 0.003). This interaction was not found in a second study site where lead exposures were higher (median umbilical cord blood lead concentration, 6.1 µg/dL, ß = - 0.45, SE = 0.49, P = 0.360). CONCLUSIONS: We used a novel method of mediation analysis to test whether stunting mediated the adverse effect of prenatal lead exposure on cognitive outcomes in Bangladesh. While we did not find that stunting acted as mediator of lead's effect on cognitive development, we found significant effect modification by stunting. Our results suggest that children with stunting are more vulnerable to the adverse effects of low-level lead exposure.

Development and Evaluation of a Pediatric Epilepsy Training Program for First Level Providers in Zambia.

Introduction. The developing world continues to face challenges in closing the large treatment gap for epilepsy, due to a high burden of disease and few experienced providers to manage the condition. Children with epilepsy are susceptible to higher rates of developmental impairments and refractory disease due to delays or absence of appropriate management as a result. We demonstrated that a structured education intervention on pediatric epilepsy can improve knowledge, confidence, and impact clinical practice of first level providers in Zambia. Methods. Three first-level facilities across Zambia were included. After initial pilot versions and revisions, the final course was implemented at each site. Pre- and post-intervention knowledge and confidence assessments were performed. Additionally, chart reviews were conducted prior to intervention and 4 months after completion of training at each site to assess change on management. Results. Twenty-three of the original 24 participants from all 3 sites completed the training; 48% clinical officers, 43% nurses, 9% other expertise. Of the 15 concepts tested by knowledge assessment, 12 showed trends in improvement, 7 of which were significant (P < .05). Chart reviews demonstrated significant improvement in documentation of seizure description (P = .008), seizure frequency (P = .00), and possible causes of seizures/epilepsy (P = .034). Discussion. Key elements of success to this program included hands on clinical skills building and case-based teaching, development of a program with direct and ongoing input from the target audience, and inclusion of assessments to monitor impact on clinical practice. Future studies looking at health outcomes are necessary to determine sustained impact.