Maternal arsenic exposure modifies associations between arsenic, folate and arsenic metabolism gene variants, and spina bifida risk: A case‒control study in Bangladesh.

BACKGROUND: Spina bifida is a type of neural tube defect (NTD); NTDs are developmental malformations of the spinal cord that result from failure of neural tube closure during embryogenesis and are likely caused by interactions between genetic and environmental factors. Arsenic induces NTDs in animal models, and studies demonstrate that mice with genetic defects related to folate metabolism are more susceptible to arsenic's effects. We sought to determine whether 25 single-nucleotide polymorphisms (SNPs) in genes involved in folate and arsenic metabolism modified the associations between maternal arsenic exposure and risk of spina bifida (a common NTD) among a hospital-based case-control study population in Bangladesh. METHODS: We used data from 262 mothers and 220 infants who participated in a case‒control study at the National Institutes of Neurosciences & Hospital and Dhaka Shishu Hospital in Dhaka, Bangladesh. Neurosurgeons assessed infants using physical examinations, review of imaging, and we collected histories using questionnaires. We assessed arsenic from mothers' toenails using inductively coupled plasma mass spectrometry (ICP-MS), and we genotyped participants using the Illumina Global Screening Array v1.0. We chose candidate genes and SNPs through a review of the literature. We assessed SNP-environment interactions using interaction terms and stratified models, and we assessed gene-environment interactions using interaction sequence/SNP-set kernel association tests (iSKAT). RESULTS: The median toenail arsenic concentration was 0.42 µg/g (interquartile range [IQR]: 0.27-0.86) among mothers of cases and 0.47 µg/g (IQR: 0.30-0.97) among mothers of controls. We found an two SNPs in the infants' AS3MT gene (rs11191454 and rs7085104) and one SNP in mothers' DNMT1 gene (rs2228611) were associated with increased odds of spina bifida in the setting of high arsenic exposure (rs11191454, OR 3.01, 95% CI: 1.28-7.09; rs7085104, OR 2.33, 95% CI: 1.20-4.and rs2228611, OR 2.11, 95% CI: 1.11-4.01), along with significant SNP-arsenic interactions. iSKAT analyses revealed significant interactions between mothers' toenail concentrations and infants' AS3MT and MTR genes (p = 0.02), and mothers' CBS gene (p = 0.05). CONCLUSIONS: Our results support the hypothesis that arsenic increases spina bifida risk via interactions with folate and arsenic metabolic pathways and suggests that individuals in the population who have certain genetic polymorphisms in genes involved with arsenic and folate metabolism may be more susceptible than others to the arsenic teratogenicity.

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. This study examines the relationships between mother's arsenic exposure, folic acid, and spina bifida risk in Bangladesh. 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 by a neurosurgeon and imaging. Controls were drawn from children seen at NINS&H and nearby Dhaka Shishu Hospital. 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). We used logistic regression to examine the associations between arsenic and spina bifida. We used stratified models to examine the associations between folic acid and spina bifida at different levels of arsenic exposure. 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 value of 0.46 µg/g, and no association was seen among mothers with toenail arsenic concentrations higher than 0.46 µg/g (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.

Informing investment in health workforce in Bangladesh: a health labour market analysis.

BACKGROUND: As the 2016 Global Strategy on Human Resources for Health: Workforce 2030 (GSHRH) outlines, health systems can only function with health workforce (HWF). Bangladesh is committed to achieving universal health coverage (UHC) hence a comprehensive understanding of the existing HWF was deemed necessary informing policy and funding decisions to the health system. METHODS: The health labour market analysis (HLMA) framework for UHC cited in the GSHRH was adopted to analyse the supply, need and demand of all health workers in Bangladesh. Government's information systems provided data to document the public sector HWF. A national-level assessment (2019) based on a country representative sample of 133 geographical units, served to estimate the composition and distribution of the private sector HWF. Descriptive statistics served to characterize the formal and informal HWF. RESULTS: The density of doctors, nurses and midwives in Bangladesh was only 9.9 per 10 000 population, well below the indicative sustainable development goals index threshold of 44.5 outlined in the GSHRH. Considering all HWFs in Bangladesh, the estimated total density was 49 per 10 000 population. However, one-third of all HWFs did not hold recognized roles and their competencies were unknown, taking only qualified and recognized HWFs into account results in an estimated density 33.2. With an estimate 75 nurses per 100 doctors in Bangladesh, the second area, where policy attention appears to be warranted is on the competencies and skill-mix. Thirdly, an estimated 82% of all HWFs work in the private sector necessitates adequate oversight for patient safety. Finally, a high proportion of unfilled positions in the public sector, especially in rural areas where 67% of the population lives, account only 11% of doctors and nurses. CONCLUSION: Bangladesh is making progress on many of the milestones of the GSHRH, notably, the establishment of the HWF unit and reporting through the national health workforce accounts. However, particular investment on strengthening the intersectoral HWF coordination across sectors; regulation for assurance of patient safety and adequate oversight of the private sector; establishing accreditation mechanisms for training institutions; and halving inequalities in access to a qualified HWF are important towards advancing UHC in Bangladesh.

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.