Neural Tube Defects In Infants Research Articles

Dolutegravir and Folic Acid Interaction during Neural System Development in Zebrafish Embryos.

Dolutegravir (DTG) is one of the most prescribed antiretroviral drugs for treating people with HIV infection, including women of child-bearing potential or pregnant. Nonetheless, neuropsychiatric symptoms are frequently reported. Early reports suggested that, probably in relation to folic acid (FA) shortage, DTG may induce neural tube defects in infants born to women taking the drug during pregnancy. Subsequent reports did not definitively confirm these findings. Recent studies in animal models have highlighted the association between DTG exposure in utero and congenital anomalies, and an increased risk of neurologic abnormalities in children exposed during in utero life has been reported. Underlying mechanisms for DTG-related neurologic symptoms and congenital anomalies are not fully understood. We aimed to deepen our knowledge on the neurodevelopmental effects of DTG exposure and further explore the protective role of FA by the use of zebrafish embryos. We treated embryos at 4 and up to 144 h post fertilization (hpf) with a subtherapeutic DTG concentration (1 μM) and observed the disruption of the anterior-posterior axis and several morphological malformations in the developing brain that were both prevented by pre-exposure (2 hpf) and rescued by post-exposure (10 hpf) with FA. By whole-mount in situ hybridization with riboprobes for genes that are crucial during the early phases of neurodevelopment (ntl, pax2a, ngn1, neurod1) and by in vivo visualization of the transgenic Tg(ngn1:EGFP) zebrafish line, we found that DTG induced severe neurodevelopmental defects over time in most regions of the nervous system (notochord, midbrain-hindbrain boundary, eye, forebrain, midbrain, hindbrain, spinal cord) that were mostly but not completely rescued by FA supplementation. Of note, we observed the disruption of ngn1 expression in the dopaminergic regions of the developing forebrain, spinal cord neurons and spinal motor neuron projections, with the depletion of the tyrosine hydroxylase (TH)+ dopaminergic neurons of the dorsal diencephalon and the strong reduction in larvae locomotion. Our study further supports previous evidence that DTG can interfere with FA pathways in the developing brain but also provides new insights regarding the mechanisms involved in the increased risk of DTG-associated fetal neurodevelopmental defects and adverse neurologic outcomes in in utero exposed children, suggesting the impairment of dopaminergic pathways.

Low-dose daily folic acid (400 μg) supplementation does not affect regulation of folate transporters found present throughout the terminal ileum and colon of humans: a randomized clinical trial

BackgroundFolic acid supplementation during the periconceptional period reduces the risk of neural tube defects in infants, but concern over chronic folic acid exposure remains. An improved understanding of folate absorption may clarify potential risks. Folate transporters have been characterized in the small intestine, but less so in the colon of healthy, free-living humans. The impact of folic acid fortification or supplementation on regulation of these transporters along the intestinal tract is unknown. ObjectiveThe objective was to characterize expression of folate transporters/receptor (FT/R) and folate hydrolase, glutamate carboxypeptidase II (GCPII), from the terminal ileum and throughout the colon of adults and assess the impact of supplemental folic acid. MethodsIn this 16-wk open-labeled randomized clinical trial, adults consumed a low folic acid-containing diet, a folate-free multivitamin, and either a 400 μg folic acid supplement or no folic acid supplement. Dietary intakes and blood were assessed at baseline, 8 wk, and 16 wk (time of colonoscopy). Messenger RNA (mRNA) expression and protein expression of FT/R and GCPII were assessed in the terminal ileum, cecum, and ascending and descending colon. ResultsAmong 24 randomly assigned subjects, no differences in dietary folate intake or blood folate were observed at baseline. Mean ± SD red blood cell folate at 16 wk was 1765 ± 426 and 911 ± 242 nmol/L in the 400 and 0 μg folic acid group, respectively (P < 0.0001). Reduced folate carrier, proton-coupled folate transporter, and folate-receptor alpha expression were detected in the terminal ileum and colon, as were efflux transporters of breast cancer resistance protein and multidrug resistance protein-3. Other than a higher mRNA expression of FR-alpha and GCPII in the 400 μg supplement group in the ascending colon, no treatment differences were observed (P < 0.02). ConclusionsFolate transporters are present throughout the terminal ileum and colon; there is little evidence that a low dose of folic acid supplementation affects colonic absorption.This trial was registered at clinicaltrials.gov as NCT03421483.

Dolutegravir-induced neural tube defects in mice are folate responsive.

In 2018, the Botswana Tsepamo Study reported a nine-fold increased risk of neural tube defects in infants whose mothers were treated with dolutegravir (DTG) from the time of conception. As maternal folate supplementation and status is a well known modifier of neural tube defect (NTD) risk, we sought to evaluate birth outcomes in mice fed normal and low folic acid diets treated with DTG during pregnancy. DTG was evaluated for developmental toxicity using pregnant mice fed normal or low folic acid diet. CD-1 mice were provided diet with normal (3 mg/kg) or low (0.3 mg/kg) folic acid. They were treated with water, a human therapeutic-equivalent dose, or supratherapeutic dose of DTG from mouse embryonic day E6.5 to E12.5. Pregnant dams were sacrificed at term (E18.5) and fetuses were inspected for gross, internal, and skeletal defects. Fetuses with exencephaly, an NTD, were present in both therapeutic human equivalent and supratherapeutic exposures in dams fed low folic acid diet. Cleft palates were also found under both folate conditions. Recommended dietary folic acid levels during mouse pregnancy ameliorate developmental defects that arise from DTG exposure. Since low folate status in mice exposed to DTG increases the risk for NTDs, it is possible that DTG exposures in people living with HIV with low folate status during pregnancy may explain, at least in part, the elevated NTD risk signal observed in Botswana. Based on these results, future studies should consider folate status as a modifier for DTG-associated NTD risk.

Contraception use and HIV outcomes among women initiating dolutegravir-containing antiretroviral therapy in Kenya: a retrospective cohort study.

The rollout of dolutegravir (DTG) in low- and middle-income countries was disrupted by a potential association reported with periconceptional DTG exposure among women living with HIV (WLHIV) and infant neural tube defects. This prompted countries to issue interim guidance limiting DTG use among women of reproductive potential to those on effective contraception. Data to understand the potential impact of such guidance on WLHIV are limited. We conducted a retrospective cohort analysis of WLHIV 15-49 years initiating DTG-containing antiretroviral treatment (ART) in Kenya from 2017 to 2020. We determined baseline effective (oral, injectable or lactational amenorrhea) and very effective (implant, intrauterine device or female sterilization) contraception use among women who initiated DTG before (Group 1) or during (Group 2) the interim guideline period. We defined incident contraception use in each group as the number of contraceptive methods initiated ≤180 days post-guideline (Group 1) or post-DTG initiation (Group 2). We determined the proportions of all women who switched from DTG- to non-nucleoside reverse transcriptase inhibitor (NNRTI)- (efavirenz or nevirapine) containing ART ≤12 months post-DTG initiation, compared their viral suppression (<1000 copies/ml) and conducted multivariable logistic regression to determine factors associated with switching from DTG to NNRTI-containing ART. Among 5155 WLHIV in the analysis (median age 43 years), 89% initiated DTG after transitioning from an NNRTI. Baseline effective and very effective contraception use, respectively, by the group were: Group 1 (12% and 13%) and Group 2 (41% and 35%). Incident contraception use in each group was <5%. Overall, 498 (10%) women switched from DTG to an NNRTI. Viral suppression among those remaining on DTG versus switched to NNRTI was 95% and 96%, respectively (p = 0.63). In multivariable analysis, incident effective and very effective contraception use was not associated with switching. Baseline, but not incident, effective contraception use was higher during the interim guideline period compared to before it, suggesting women already using effective contraception were preferentially selected to initiate DTG after the guideline was released. These findings reveal challenges in the implementation of policy which ties antiretroviral access to contraceptive use. Future guidance should capture nuances of contraception decision-making and support women's agency to make informed decisions.

Awareness of Vitamin and mineral supplements among college students.

A Vitamin or mineral supplement is a kind of adjunct that aims to supplement the diet and it comprises a wide range of Vitamins, minerals, herbs, etc., that amplifies different nutrient levels. People intake such supplements for protection against health illnesses such as stress, cold, flu, osteoporosis, heart attacks, tooth decay, cancer, and neural tube defects in infants, etc. Anyhow, intake of large amounts without proper medical consideration can have severe negative consequences. This study aimed to assess the awareness on Vitamin and mineral supplements among College students. An online cross-sectional questionnaire was made using Google Forms and distributed among 100 College students. The data collected were analyzed using SPSS software. Descriptive analysis and Chi-square tests were done. Results showed that the majority of 63.43% of UG students and 21.64% of PG students believed that its consumption was beneficial and in general awareness was more among UG students. When asked about the Vitamin that should be avoided during pregnancy, a majority of 20.30% of UG students opted for Vitamin E and 7.52% of PG students opted for Vitamin A which shows that both were feasible options as they were fat-soluble vitamins capable of causing congenital defects. The most probable issue related with the use of dietary supplements is that the people who include them in their diet might see it as a substitute, in lieu of a supplement, thus, more people should be made aware of the proper consumption and side effects of Vitamin and mineral supplements.

Disparities in Dolutegravir Uptake Affecting Females of Reproductive Age With HIV in Low- and Middle-Income Countries After Initial Concerns About Teratogenicity : An Observational Study.

The transition to dolutegravir-containing antiretroviral therapy (ART) in low- and middle-income countries (LMICs) was complicated by an initial safety signal in May 2018 suggesting that exposure to dolutegravir at conception was possibly associated with infant neural tube defects. On the basis of additional evidence, in July 2019, the World Health Organization recommended dolutegravir for all adults and adolescents living with HIV. To describe dolutegravir uptake and disparities by sex and age group in LMICs. Observational cohort study. 87 sites that began using dolutegravir in 11 LMICs in the Asia-Pacific; Caribbean, Central and South America network for HIV epidemiology (CCASAnet); and sub-Saharan African regions of the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. 134672 patients aged 16 years or older who received HIV care from January 2017 through March 2020. Sex, age group, and dolutegravir uptake (that is, newly initiating ART with dolutegravir or switching to dolutegravir from another regimen). Differences in dolutegravir uptake among females of reproductive age (16 to 49 years) emerged after the safety signal. By the end of follow-up, the cumulative incidence of dolutegravir uptake among females 16 to 49 years old was 29.4% (95% CI, 29.0% to 29.7%) compared with 57.7% (CI, 57.2% to 58.3%) among males 16 to 49 years old. This disparity was greater in countries that began implementing dolutegravir before the safety signal and initially had highly restrictive policies versus countries with a later rollout. Dolutegravir uptake was similar among females and males aged 50 years or older. Follow-up was limited to 6 to 8 months after international guidelines recommended expanding access to dolutegravir. Substantial disparities in dolutegravir uptake affecting females of reproductive age through early 2020 are documented. Although this disparity was anticipated because of country-level restrictions on access, the results highlight its extent and initial persistence. National Institutes of Health.

MTHFR C677T and A1298C variants in Mexican Mestizo infants with neural tube defects from Western Mexico.

Our study investigated the role of MTHFR C677T and A1298C variants in infants with neural tube defects (NTDs) from western Mexico. Using TaqMan allelic discrimination assay, we genotyped 101 live-born patients with NTDs (cases) and 247 controls. Our findings do not support that homozygosity or heterozygosity for the variants C677T and A1298C in the MTHFR gene are associated with NTDs in infants. However, since we have the highest worldwide frequency of homozygotes for the MTHFR C677T variant, we cannot rule out that our propensity for NTDs may be related to how such gene variant interacts with other factors, mainly with our secular patterns of inappropriate folate intake.

周産期の医薬品使用の安全性に関する研究

We have been conducting research with the aim of generating evidence for the safety of perinatal drugs. As a result of reviewing the records of inquiries to the Drug Information Office of our hospital, we found a large discrepancy between the description of perinatal drugs in package inserts in Japan and the description of the Pregnancy Risk Category according to the U.S. Food and Drug Administration. In the Japan Environment and Children's Study (JECS), we determined the proportion of drug and supplement use among 97464 pregnant women. We clarified that prescriptions of antihypertensive drugs for pregnant women increased during the second half of pregnancy, while prescriptions of anti-epileptic and anti-anxiety drugs decreased after pregnancy using a claims database. A survey of pharmacists and pharmacy students revealed a lack of awareness of effective folic acid intake to reduce the risk of neural tube defects in infants. The percentage of pre-pregnancy folic acid supplementation among pregnant women participating in the Babies and their Parents' Longitudinal Observation in Suzuki Memorial Hospital on Intrauterine Period (BOSHI) study, the JECS, and the Tohoku Medical Megabank (TMM) Birth and Three-Generation (BirThree) cohort study was 6.3-18.0%. As a result of close examination of the records of inquiries to the Drug Information Office of our hospital, and of cases in which our lactation plan sheet was applied, it was found that there were discrepancies between the information on the drug package insert and the information on Medications & Mother's Milk, etc. in Japan. The results obtained have been clinically applied in daily practice and we are continuing our research while taking measures.

Validity of diagnosis and procedure codes for identifying neural tube defects in infants.

The use of validated criteria to identify birth defects in electronic healthcare databases can avoid the cost and time-intensive efforts required to conduct chart reviews to confirm outcomes. This study evaluated the validity of various case-finding methodologies to identify neural tube defects (NTDs) in infants using an electronic healthcare database. This analysis used data generated from a study whose primary aim was to evaluate the association between first-trimester maternal prescription opioid use and NTDs. The study was conducted within the Medication Exposure in Pregnancy Risk Evaluation Program. A broad approach was used to identify potential NTDs including diagnosis and procedure codes from inpatient and outpatient settings, death certificates and birth defect flags in birth certificates. Potential NTD cases were chart abstracted and confirmed by clinical experts. Positive predictive values (PPVs) and 95% confidence intervals (95% CI) are reported. The cohort included 113 168 singleton live-born infants: 55 960 infants with opioid exposure in pregnancy and 57 208 infants unexposed in pregnancy. Seventy-three potential NTD cases were available for the validation analysis. The overall PPV was 41% using all diagnosis and procedure codes plus birth certificates. Restricting approaches to codes recorded in the infants' medical record or to birth certificate flags increased the PPVs (72% and 80%, respectively) but missed a substantial proportion of confirmed NTDs. Codes in electronic healthcare data did not accurately identify confirmed NTDs. These results indicate that chart review with adjudication of outcomes is important when conducting observational studies of NTDs using electronic healthcare data.

Mutational landscape screening of methylene tetrahydrofolate reductase to predict homocystinuria associated variants: An integrative computational approach

Methylene tetrahydrofolate reductase (MTHFR) is a flavoprotein, involved in one-carbon pathway and is responsible for folate and homocysteine metabolism. Regulation of MTHFR is pivotal for maintaining the cellular concentrations of methionine and SAM (S-adenosyl methionine) which are essential for the synthesis of nucleotides and amino acids, respectively. Therefore, mutations in MTHFR leads to its dysfunction resulting in conditions like homocystinuria, cardiovascular diseases, and neural tube defects in infants. Among these conditions, homocystinuria has been highly explored, as it manifests ocular disorders, cognitive disorders and skeletal abnormalities. Hence, in this study, we intend to explore the mutational landscape of human MTHFR isoform-1 (h.MTHFR-1) to decipher the most pathogenic variants pertaining to homocystinuria. Thus, a multilevel stringent prioritization of non-synonymous mutations in h.MTHFR-1 by integrative machine learning approaches was implemented to delineate highly deleterious variants based on its pathogenicity, impact on structural stability and functionality. Subsequently, extended molecular dynamics simulations and molecular docking studies were also integrated in order to prioritize the mutations that perturbs structural stability and functionality of h.MTHFR-1. In addition, displacement of Loop (Arg157-Tyr174) and helix α9 (His263-Ser272) involved in open/closed conformation of substrate binding domain were also probed to confirm the functional loss. On juxtaposed analysis, it was inferred that among 126 missense mutations screened, along with known pathogenic mutations (H127 T, A222 V, T227 M, F257 V and G387D) predicted that W500C, P254S and D585 N variants could be potentially driving homocystinuria. Thus, uncovering the prospects for inclusion of these mutations in diagnostic panels based on further experimental validations.

Decreased placental folate transporter expression and activity in first and second trimester in obese mothers

Obese women have an approximately twofold higher risk to deliver an infant with neural tube defects (NTDs) despite folate supplementation. Placental transfer of folate is mediated by folate receptor alpha (FR-α), proton coupled folate transporter (PCFT), and reduced folate carrier (RFC). Decreased placental transport may contribute to NTDs in obese women. Serum folate levels were measured and placental tissue was collected from 13 women with normal BMI (21.9±1.9) and 11 obese women (BMI 33.1±2.8) undergoing elective termination at 8–22 weeks of gestation. The syncytiotrophoblast microvillous plasma membranes (MVM) were isolated using homogenization, magnesium precipitation, and differential centrifugation. MVM expression of FR-α, PCFT and RFC was determined by western blot. Folate transport capacity was assessed using radiolabeled methyl-tetrahydrofolate and rapid filtration techniques. Differences in expression and transport capacity were adjusted for gestational age and maternal age in multivariable regression models. P<.05 was considered statistically significant. Serum folate levels were not significantly different between groups. Placental MVM folate transporter expression did not change with gestational age. MVM RFC (−19%) and FR-α (−17%) expression was significantly reduced in placentas from obese women (P<.05). MVM folate transporter activity was reduced by−52% (P<.05) in obese women. These differences remained after adjustment for gestational age. There was no difference in mTOR signaling between groups. In conclusion, RFC and FR alpha expression and transporter activity in the placental MVM are significantly reduced in obese women in early pregnancy. These results may explain the higher incidence of NTDs in infants of obese women with adequate serum folate.

Congenital anomalies following antenatal exposure to dolutegravir: a Canadian surveillance study.

Dolutegravir is recommended worldwide as a first-line antiretroviral therapy (ART) for individuals living with HIV. A recent study reported increased rates of neural tube defects in infants of dolutegravir-treated women. This study examined rates of congenital anomalies in infants born to women living with HIV (WLWH) in Canada. The Canadian Perinatal HIV Surveillance Programme captures surveillance data on pregnant WLWH and their babies and was analysed to examine the incidence of congenital anomalies. Paediatric HIV clinics. Live-born infants born in Canada to WLWH between 2007 and 2017. Data on mother-infant pairs, including maternal ART use at conception and during pregnancy, are collected by participating sites. Congenital anomalies. Of the 2423 WLWH, 85 (3.5%, 95% CI 2.85-4.36%) had non-chromosomal congenital anomalies. There was no evidence of a significant difference in rates of congenital anomalies between women who were on ART in their first trimester (3.9%, CI 1.7-7.6%) or later in the pregnancy (3.9%, 95% CI 2.6-5.6%). Four of the 80 (5.0%, 95% CI 1.4-12.3%) neonates born to WLWH on dolutegravir during the first trimester had congenital anomalies, none were neural tube defects (95% CI 0.00-3.10%). Despite recent evidence raising a safety concern, this analysis found no signal for increased congenital anomalies. Five percent of the infants of Canadian women living with HIV on dolutegravir at conception had congenital anomalies; none had neural tube defects.

CARACTERÍSTICAS EPIDEMIOLÓGICAS DAS ANOMALIAS CONGÊNITAS DO TUBO NEURAL EM MENORES DE 5 ANOS DE IDADE E POSSÍVEIS FATORES DE RISCO PARA A SUA OCORRÊNCIA EM CAMPOS DOS GOYTACAZES-RJ

As anomalias congênitas, possuem etiologia multifatorial, envolvendo aspectos genéticos e ambientais. Entre diversos fatos geradores, é evidente a importância do ácido fólico na redução ou mesmo prevenção de malformações. Esta vitamina relaciona-se com a síntese de DNA e RNA, portanto, com o desenvolvimento fetal. Foi implementada no País a fortificação compulsória das farinhas de trigo e milho com ferro e ácido fólico resultando em redução de anomalias em 35%. Já níveis diários de suplementação medicamentosa superiores a 5mg de ácido fólico reduz entre 75% e 91%. Tal fato demonstra a relevância e benefícios do folato no pré-natal. O período ideal de administração seria o periconcepcional, de 1 a 3 meses antes da gestação e até 4 meses após a concepção. Este estudo objetiva avaliar a prevalência de Anomalias Congênitas do tubo neural de menores de 5 anos de idade no município de Campos dos Goytacazes-RJ, através de um estudo de caso controle para serem analisados possíveis fatores de risco para ocorrência de tais anormalidades. Para análise da distribuição de defeitos do tubo neural foram usadas as variáveis: nível socioeconômico e educacional, idade materna, utilização ou não do ácido fólico, realização de pré-natal, número de consultas, entre outras. A amostra coletada é do tipo probabilística aleatória simples, período de realização, 1º de março de 2016 à 30 de maio de 2017. Este projeto atenderá a resolução 196/96 versão 2012 do CNS relativas ás questões da ética em pesquisa com humanos.&#x0D;

The occurrence and co-occurrence of aflatoxin and fumonisin along the maize value chain in southwest Nigeria

Aflatoxin and fumonisin are two major foodborne mycotoxins: toxic chemicals produced by fungi that contaminate food commodities including maize, a staple food in sub-Saharan Africa. Aflatoxin causes liver cancer, and is associated with acute liver toxicity and immunotoxicity; while fumonisin is associated with neural tube defects in infants and esophageal cancer. Both mycotoxins have been associated with child growth impairment. Previous studies suggest that co-occurrence of these mycotoxins may have potentially synergistic toxicological effects. Despite health risks associated with co-occurrence of these mycotoxins, no study has examined their co-occurrence along key food supply chains in Africa. This study is the first report that examines the occurrence and co-occurrence of aflatoxins and fumonisins along the maize value chain in Nigeria. All samples were analyzed using LC-MS/MS. About 52% and 21% of the samples had aflatoxin levels above the Nigerian and US standards for human food, respectively. Though no regulatory limits exist for fumonisin in Nigeria, 13% of the samples contained fumonisin levels higher than the US regulatory limit. Aflatoxin levels can become dangerously high in maize stored four months or longer. Adequately addressing mycotoxin risk requires consideration of the entire maize value chain and associated value chains for food production.

Outcome of Choroid Plexus Cauterization with Endoscopic 3&amp;lt;sup&amp;gt;rd&amp;lt;/sup&amp;gt; Ventriculostomy vs Ventricular Shunting in Management of Hydrocephalus Secondary to Neural Tube Defect

Background: Different surgical management of infants suffering neural tube defects (NTD) associated hydrocephalus were reported in the literature. Great debate whether combining endoscopic third ventriculostomy (ETV) with choroid plexus cauterization (CPC) is more effective than ventriculoperitoneal (VP) shuntfor management of congenital hydrocephalus secondary to neural tube defects ininfants younger than 1 year of age. Purpose: To evaluate and compare the therapeutic efficacy of ETV combined with CPC versus VP shunts in infants with infantile hydrocephalus associated with NTD. Methods: Thirty infants with infantile NTD associated hydrocephalus (de novo), were equally divided and randomly allocated to each intervention group either ETV/CPC or VP shunts). They were monitored for at least 6 months for any sign of raised intracranial pressure (rICP) and/or hydrocephalic metrics (fontanelle quality, HC, and ventricular size) were also documented and compared between two groups. Statistical Analysis: The association between intervention group and outcome was tested with Chi-square test and P=0.05 or less was considered statistically significant. Results: Of the total thirty patients included in the study, thirteen patients (43.3%) were male and seventeen were female (56.7%) with mean age of 80.3±11.5 days. Twenty patients (66%) were under 6 months of age. The overall success rate in 1-year follow-up was 54% and 60% for VP shunt and ETV/CPC, respectively; with the difference being not statistically significant. Conclusion: Combined ETV-CPC is considered a successful surgical option for treatment of infantile hydrocephalus associated with NTD; achieving success rate better than VPS implantation.

Risks and benefits of dolutegravir-based antiretroviral drug regimens in sub-Saharan Africa: a modelling study

SummaryBackgroundThe integrase inhibitor dolutegravir could have a major role in future antiretroviral therapy (ART) regimens in sub-Saharan Africa because of its high potency and barrier to resistance, good tolerability, and low cost, but there is uncertainty over appropriate policies for use relating to the potential for drug resistance spread and a possible increased risk of neural tube defects in infants if used in women at the time of conception. We used an existing individual-based model of HIV transmission, progression, and the effect of ART with the aim of informing policy makers on approaches to the use of dolutegravir that are likely to lead to the highest population health gains.MethodsWe used an existing individual-based model of HIV transmission and progression in adults, which takes into account the effects of drug resistance and differential drug potency in determining viral suppression and clinical outcomes to compare predicted outcomes of alternative ART regimen policies. We calculated disability adjusted life-years (DALYs) for each policy, assuming that a woman having a child with a neural tube defect incurs an extra DALY per year for the remainder of the time horizon and accounting for mother-to-child transmission. We used a 20 year time horizon, a 3% discount rate, and a cost-effectiveness threshold of US$500 per DALY averted.FindingsThe greatest number of DALYs is predicted to be averted with use of a policy in which tenofovir, lamivudine, and dolutegravir is used in all people on ART, including switching to tenofovir, lamivudine, and dolutegravir in those currently on ART, regardless of current viral load suppression and intention to have (more) children. This result was consistent in several sensitivity analyses. We predict that this policy would be cost-saving.InterpretationUsing a standard DALY framework to compare health outcomes from a public health perspective, the benefits of transition to tenofovir, lamivudine, and dolutegravir for all substantially outweighed the risks.FundingBill & Melinda Gates Foundation.

Effects of maternal folic acid supplementation on airway remodeling and allergic airway disease development

Objective: Maternal folic acid supplementation has been recommended prior to and during the first trimester of pregnancy to reduce the risk of infant neural tube defects. However, an uncertain relationship between folic acid supplementation during pregnancy and development of childhood asthma exists. Recent data show a methyl donor-rich diet could increase the risk of developing allergic airway disease through DNA methylation and aberrant gene transcription. This study evaluated the effect of folic acid supplementation during pregnancy on airway remodeling and allergic airway disease vulnerability in a mouse asthma model.Methods: BALB/c mice were divided into four groups according to gestational folic acid supplementation and postnatal ovalbumin (OVA) exposure: Group 1 (whole pregnancy folic acid supplementation + OVA-exposed group), Group 2 (first gestational week folic acid supplementation + OVA-exposed group), Group 3 (no folic acid supplementation + OVA-exposed group), and Group 4 (control group). Offspring were sacrificed on day 45 for immunohistological and ultrastructural tests.Results: In OVA challenged groups, folic acid supplementation led to a thicker epithelial and subepithelial smooth muscle layer than in the unsupplemented group. Moreover, folic acid supplementation during whole pregnancy (Group 1) was associated with a thicker epithelial and subepithelial smooth muscle layer than folic acid supplementation during the first week of pregnancy (Group 2), suggesting a duration–response relationship. Electron microscopic imaging revealed that structural changes including the loss of epithelial integrity, thickening of basement membrane, and subepithelial fibrosis were more prominent in the folic acid supplementation groups.Conclusions: This study suggested that maternal folic acid supplementation during pregnancy affects airway remodeling and increases the allergic responses induced by ovalbumin challenge in offspring. In addition, the effect size increased as the duration and cumulative dose increased.

Improving maternal folate status to prevent infant neural tube defects: working group conclusions and a framework for action.

As infectious disease control programs achieve increasing success, further reductions in child mortality in low- and middle-income countries (LMICs) will require focused prevention strategies for birth defects and other noninfectious diseases. Neural tube defects (NTDs) can cause early death or lifelong disability. Preventing NTDs provides a feasible, significant opportunity to decrease the toll of birth defects and contribute to further reducing child mortality globally. The Micronutrient Forum convened a technical consultation on Folate Status in Women and Neural Tube Defects Prevention to develop a roadmap to inform and prioritize investments in NTD prevention in LMICs; help guide implementation efforts in terms of the feasibility of interventions and the potential for acceleration; and identify research and knowledge gaps. Here, we describe the impetus for and approach to the consultation and present the conclusions and a framework for developing a roadmap for action to accelerate NTD prevention in LMICs. The framework (1) provides options for action on folate status assessment; (2) outlines a way forward to develop and implement a time-bound global action plan for NTD prevention; and (3) identifies common impediments to NTD prevention, broad strategies to overcome or minimize these impediments, and basic building blocks necessary to accelerate action.

Risk factors associated with neural tube defects in infants referred to western Iranian obstetrical centers; 2013-2014.

BackgroundNeural tubes defects (NTDs) are known to be the second most prevalent congenital disorder worldwide whose risk factors have not been explicitly addressed yet.AimTo determine the risk factors affecting NTDs among infants who referred to obstetrical centers in Kurdistan, a western province of Iran.MethodsThis prospective case-control study was conducted in the form of prospective case-control. Sample population included all women (27,153 cases) who referred to obstetrical centers in Kurdistan for either delivery or abortion during 2013 and 2014. Inclusion criterion was the presence of a known NTD in infants, and exclusion criterion was the reluctance of patients to participate in the study. Accordingly, 46 cases participated in the study as the case group, and 138 cases (three times higher than case group) were selected to be the control group. Case and control groups were matched in terms of the number of pregnancies and place of birth. The variables investigated in the present study were as follows: age, occupation, BMI, abortion history, family relation with husband, fetus’ sex, number of twins, history of previous children with NTD, receiving prenatal surveillance, consumption of folic acid and multivitamins, smoking, alcohol drinking, passive smoking, and suffering from such diseases as epilepsy and diabetes. Data were analyzed using various statistical tests, including chi-square, Fishers’ exact test, multiple logistic regression analysis using SPSS version 20. In the study group, inclusion criteria included all women who had an infant with tube defects that their total number was 46 individuals. In the control group inclusion criteria included mothers with healthy infants who were similar to the study group in terms of birth place and frequency of pregnancy.ResultsThe results of the present study demonstrated that prenatal surveillance (p<0.002), multivitamin consumption (p<0.001), history of having a child with NTD (p<0.001), alcohol drinking (p<0.014), and passive smoking were related to NTDs (p<0.001).ConclusionBefore fertilization and during pregnancy, mothers should be examined in terms of exposure to harmful agents, diet, and nutritional status in order to identify possible risk factors and find opportunities to prevent NTDs in infants.

MaternalFolicAcidSupplementationduring PregnancyandChildhoodAllergicDisease Outcomes:AQuestionofTiming?

Since the early 1990s, maternal folic acid supplementation has been recommended prior to and during the first trimester of pregnancy, to reduce the risk of infant neural tube defects. In addition, many countries have also implemented the folic acid fortification of staple foods, in order to promote sufficient intakes amongst women of a childbearing age, based on concerns surrounding variable dietary and supplementation practices. As many women continue to take folic acid supplements beyond the recommended first trimester, there has been an overall increase in folate intakes, particularly in countries with mandatory fortification. This has raised questions on the consequences for the developing fetus, given that folic acid, a methyl donor, has the potential to epigenetically modify gene expression. In animal studies, folic acid has been shown to promote an allergic phenotype in the offspring, through changes in DNA methylation. Human population studies have also described associations between folate status in pregnancy and the risk of subsequent childhood allergic disease. In this review, we address the question of whether ongoing maternal folic acid supplementation after neural tube closure, could be contributing to the rise in early life allergic diseases.