Folic Acid-Fortified Iodized Salt and Serum Folate Levels in Reproductive-Aged Women of Rural India: A Nonrandomized Controlled Trial.

Importance: India has a disproportionately high prevalence of neural tube defects, including spina bifida and anencephaly (SBA), causing a high number of stillbirths, elective pregnancy terminations, and child mortality; India contributes a large proportion of the global burden of SBA. Thirty years after folic acid was shown to be effective in reducing SBA prevalence, only about one-quarter of such births are prevented globally through cereal grain fortification. Objective: To determine the association of folic acid-fortified iodized salt with serum folate concentrations among nonpregnant and nonlactating women of reproductive age. Design, Setting, and Participants: This nonrandomized controlled trial using a preintervention and postintervention design was conducted in 4 rural villages in Southern India from July 1 to November 30, 2022. All households in the villages agreed to participate in the study. Preintervention and postintervention serum folate levels were analyzed among study participants at baseline and after 4 months, respectively. Intervention: Consumption of approximately 300 µg/d of folic acid using double fortified salt (folic acid plus iodine). Median serum folate concentrations were assessed at baseline and 4 months. Main Outcomes and Measures: Change in median serum folate levels between baseline and study end point as the primary outcome of the study. Results: A total of 83 nonpregnant nonlactating women aged 20 to 44 years (mean [SD] age, 30.9 [5.1] years) were eligible for the study and provided serum samples for analysis at baseline and the end point of the intervention. The median serum folate concentration increased from 14.6 (IQR, 11.2-20.6) nmol/L at baseline to 54.4 (IQR, 43.5-54.4) nmol/L at end of study, a 3.7-fold increase from baseline to study end point. Two-tailed Wilcoxon signed rank test showed the median difference in preintervention and postintervention serum folate concentrations to be highly significant (P < .001). The participants found the salt acceptable in color and taste. Conclusions and Relevance: Use of folic acid-fortified iodized salt was associated with increased serum folate concentrations in women of reproductive age. This novel evidence can inform public health policy to accelerate SBA prevention. Trial Registration: ClinicalTrials.gov Identifier: NCT06174883.

A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2020: 30-Year anniversary of gaining knowledge about folic acid's prevention potential for neural tube defects.

BACKGROUND: Spina bifida and anencephaly are major neural tube defects largely preventable through maternal periconceptional intake of folic acid. We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented through mandatory folic acid fortification of cereal grains, including wheat flour, maize flour, and rice, at the end of year 2020, a time point marking the 30th anniversary of the publication of landmark British Medical Research Council (MRC) study providing unequivocal knowledge on folic acid's FAP SBA prevention potential. METHODS: The Food Fortification Initiative database was used to identify countries with mandatory fortification policies with folic acid added to cereal grains. We examined the status of FAP SBA prevention assuming mandatory folic acid fortification at 200 mcg/day of folic acid protects against FAP SBA and reduces their prevalence to a minimum achievable rate of 0.5 cases/1000 live births. RESULTS: Our analysis showed that 61,680 FAP SBA cases were prevented in the year 2020 through mandatory folic acid fortification of cereal grains in 58 countries, translating to 22% prevention of total possible FAP SBA prevention globally. Many countries in Africa, Asia, and Europe are yet to implement fortification. In 2020, 30 years after the MRC study was published, 218,270 preventable FAP SBA cases still occurred globally. CONCLUSION: Global prevention efforts for FAP SBA are inadequate even after three decades of knowledge on their prevention. Universal mandatory fortification of staples should be urgently implemented to prevent thousands of FAP SBA and associated elective terminations, stillbirths, and child mortality.

Preventing birth defects, saving lives, and promoting health equity: an urgent call to action for universal mandatory food fortification with folic acid.

July 20, 2021 marked the 30th anniversary of the publication of the landmark trial by the British Medical Research Council showing unequivocally that maternal intake of folic acid (vitamin B9) starting before pregnancy prevents most cases of infant spina bifida and anencephaly-two major neural tube defects that are severe, disabling, and often fatal. Mandatory food fortification with folic acid is a safe, cost-effective, and sustainable intervention to prevent spina bifida and anencephaly. Yet few countries implement fortification with folic acid; only a quarter of all preventable spina bifida and anencephaly cases worldwide are currently avoided by food fortification. We summarise scientific evidence supporting immediate, mandatory fortification with folic acid to prevent the development of spina bifida and anencephaly. We make an urgent call to action for the World Health Assembly to pass a resolution for universal mandatory folic acid fortification. Such a resolution could accelerate the slow pace of spina bifida and anencephaly prevention globally, and will assist countries to reach their 2030 Sustainable Development Goals on child mortality and health equity. The cost of inaction is profound, and disproportionately impacts susceptible populations in low-income and middle-income countries.

Food Fortification With Folic Acid for Prevention of Spina Bifida and Anencephaly: The Need for a Paradigm Shift in Evidence Evaluation for Policy-Making.

Context-specific evidence evaluation is advocated in modern epidemiology to support public health policy decisions, avoiding excessive reliance on experimental study designs. Here we present the rationale for a paradigm shift in evaluation of the evidence derived from independent studies, as well as systematic reviews and meta-analyses of observational studies, applying Hill's criteria (including coherence, plausibility, temporality, consistency, magnitude of effect, and dose-response) to evaluate food fortification as an effective public health intervention against folic acid-preventable (FAP) spina bifida and anencephaly (SBA). A critical appraisal of evidence published between 1983 and 2020 supports the conclusion that food fortification with folic acid prevents FAP SBA. Policy-makers should be confident that with mandatory legislation, effective implementation, and periodic evaluation, food fortification assures that women of reproductive age will safely receive daily folic acid to significantly reduce the risk of FAP SBA. Current evidence should suffice to generate the political will to implement programs that will save thousands of lives each year in over 100 countries.

A 2019 global update on folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Mandatory folic acid fortification of staples is a proven intervention to prevent spina bifida and anencephaly, two life-threatening and disabling neural tube defects. We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented through mandatory folic acid fortification of wheat and/or maize flour in 2019. METHODS: Using data from the Global Fortification Data Exchange, we identified countries with mandatory fortification policies that required at least 1.0 ppm folic acid be added to wheat and/or maize flour and had information on percentage of industrially milled flour that is fortified. We built FAP SBA prevention models assuming mandatory folic acid fortification at 200 µg/day of folic acid fully protects against FAP SBA and would lower the prevalence neural tube defects to 0.5 per 1,000 live births. RESULTS: In 2019, 56 countries met our criteria for mandatory folic acid fortification of wheat (n = 56 countries) and/or maize (n = 15 countries) flour and with complete data for our modeling. Overall, our prevention model estimated that 65,380 FAP SBA cases were prevented in 2019 through folic acid fortification of wheat and/or maize flour. We estimated the current global prevention proportion of all preventable FAP SBA cases worldwide to be at 23% of total possible prevention. CONCLUSION: Global prevention efforts for FAP SBA are slow and have stalled. Mandatory fortification should be urgently implemented in all countries to prevent epidemics of FAP SBA, and to achieve health-related Sustainable Development Goals for year 2030 by reducing child mortality due to preventable FAP SBA.

Modeling shows high potential of folic acid-fortified salt to accelerate global prevention of major neural tube defects.

BACKGROUND: We estimated the global proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) potentially prevented through mandatory double fortification of iodized salt with folic acid. METHODS: Using United Nations Children's Fund (UNICEF) and Global Fortification Data Exchange (GFDx) data sets, we modeled country-specific number of FAP SBA cases prevented annually using (a) current coverage of the salt in households worldwide and (b) expected daily amount of folic acid intake from folic acid-fortified iodized salt. Our evidence-based modeling strategy assumed mandatory folic acid fortification of salt at 20 ppm, and that at 200 µg/day intake of folic acid through fortified salt, should achieve 100% prevention of all FAP SBA in countries. RESULTS: One hundred countries that have data on percent of households consuming iodized salt globally were examined; 55 of them have ≥80% households consuming iodized salt. Our model estimated approximately 180,000 cases of FAP SBA could be prevented in these 100 countries through folic acid-fortified iodized salt, and 150,000 of them would be in countries where ≥80% households consuming iodized salt that can be potentially fortified with folic acid. Salt fortification with folic acid could contribute to the prevention of about 65% global FAP SBA cases annually. CONCLUSIONS: Our evidence-based model shows that there is high potential to prevent FAP SBA using folic acid-fortified iodized salt. Prevention will reach countries where there is a limited reach of centrally processed folic acid-fortified wheat or maize flour. If this intervention is made feasible by the salt industry, it can accelerate the prevention of FAP SBA significantly.

The Fallacy of Using Administrative Data in Assessing the Effectiveness of Food Fortification. Comment on: "Folic Acid Fortification and Neural Tube Defect Risk: Analysis of the Food Fortification Initiative Dataset. Nutrients 2020, 12, 247".

Our objective in this comment is to highlight several limitations in an ecological research study that was published in Nutrients by Murphy and Westmark (2020) in January 2020. The study used data from the Food Fortification Initiative (FFI) website, and applying an ecological study design, made an error of "ecologic fallacy" in concluding that "national fortification with folic acid is not associated with a significant decrease in the prevalence of neural tube defects (NTDs) at the population level". We list study limitations that led to their erroneous conclusions, stemming from incorrect considerations regarding NTD prevalence, the average grain availability for a country, the fortification coverage in a country, the population reach of fortified foods within a country, and the absence of the consideration of fortification type (voluntary vs. mandatory), country-specific policies on elective terminations for NTD-affected pregnancies, stillbirth proportions among those with NTDs, and fortification implementation. FFI data are derived from many sources and intended for fortification advocacy, not for hypothesis testing. The flawed study by Murphy & Westmark (2020) in Nutrients promotes a confusing and incorrect message to stakeholders, misguides policy makers, and hinders progress in global NTD prevention through a cost-effective, safe, and effective intervention: the mandatory large-scale folic acid fortification of staple foods.

High potential for reducing folic acid-preventable spina bifida and anencephaly, and related stillbirth and child mortality, in Ethiopia.

BACKGROUND: Recent surveillance studies in Ethiopia show an epidemic of spina bifida and anencephaly, two major neural tube birth defects that are severe and life-threatening. Our objective was to estimate proportional reductions in current stillbirth and child mortality rates in Ethiopia through folic acid-based interventions to prevent spina bifida and anencephaly. METHODS: Using secondary data from multiple sources, we estimated percent reductions in stillbirth, neonatal, infant, and under-five child mortality rates that would have occurred in Ethiopia in the year 2016 had all folic acid-preventable spina bifida and anencephaly been prevented; and the contributions of these reductions toward Ethiopia's Year 2030 Every Newborn Action Plan (ENAP) goal on stillbirth, and sustainable development goal (SDG) on child mortality rates. The 2016 prevalence of spina bifida and anencephaly in Ethiopia was assumed as 13 per 1,000 total births, with the prevention goal reaching 0.5 per 1,000 total births. RESULTS: Folic acid interventions in Ethiopia would have prevented about 41,610 cases of folic acid-preventable spina bifida and anencephaly-affected pregnancies during the year 2016. We estimate that this prevention is associated with reduction of 31,830 stillbirths and 7,335 under-five child deaths annually. The proportional contribution of this prevention toward achieving Ethiopia's ENAP goal is 54% for stillbirth, and toward SDG is 4.5% for neonatal- and 6.8% for under-five mortality. CONCLUSIONS: Spina bifida and anencephaly contribute to substantial stillbirths and child death in Ethiopia. Large-scale fortification of foods like wheat flour and salt can help achieve Ethiopia's ENAP and SDG targets addressing preventable stillbirth, neonatal, and under-five mortality.

Nation-wide failure of voluntary folic acid fortification of corn masa flour and tortillas with folic acid.

BACKGROUND: The United States Food and Drug Administration (FDA) required all enriched cereal grains to be fortified with folic acid in 1998. In April 2016, the FDA published regulations allowing voluntary fortification of corn masa flour with folic acid to address the high prevalence of folic acid-preventable spina bifida and anencephaly among Hispanics. Our objective was to survey folic acid-fortified corn masa and corn tortilla products in the country using a national social media campaign. METHODS: In January 2019, we conducted a social media campaign (#FindFolicAcid) engaging citizens nationwide to survey local stores for folic acid in corn masa flour and corn tortilla products. Photos of products and nutrition labels were shared with the researchers on various social media portals (e.g., Twitter, Facebook, and Instagram). The posts were summarized for a descriptive analysis. RESULTS: People from 28 states shared photos of 132 products, including 43 unique corn masa flour or corn tortilla products. Of those, only three corn masa flour products included folic acid: (a) Maseca Instant White (4.4 lb bag); (b) Masa Brosa Instant; and (c) Masa Brosa Instant Blue. None of the corn tortilla products were fortified. CONCLUSION: There is a failure of voluntary folic acid fortification of corn masa flour and products nationally. Until folic acid fortification of corn masa products is implemented fully in the country, Hispanic women of reproductive age should take a daily vitamin supplement which includes at least 400 mcg of folic acid to prevent spina bifida and anencephaly.

Reductions in child mortality by preventing spina bifida and anencephaly: Implications in achieving Target 3.2 of the Sustainable Development Goals in developing countries.

BACKGROUND: There is an opportunity to reduce child mortality by preventing folic acid-preventable spina bifida and anencephaly (FAP SBA) in developing countries. We estimated reductions in FAP SBA-associated child mortality in 69 countries with an immediate potential for mandatory fortification of wheat flour. METHODS: Using data from multiple sources, we estimated the percent reductions in neonatal, infant, and under-five mortality that would have occurred by preventing FAP SBA; and the contributions of these reductions toward each country's Sustainable Development Goals (SDG) for child mortality reduction. We used the combined prevalence of spina bifida and anencephaly in selected countries before fortification, and estimated preventable child mortality associated with FAP SBA, assuming 0.5 per 1,000 live births as minimum achievable prevalence from mandatory fortification. RESULTS: Annually, 56,785 live births with FAP SBA occurred in the 69 countries examined. Of these, about 49,680 (87%) would have resulted in deaths under age 5 years, and are preventable through mandatory folic acid fortification. On average, compared to current rates, prevention of FAP SBA would have reduced the neonatal, infant, and under-five mortality by 19% (95% uncertainty interval [UI]: 16-24%), 15% (UI: 13-17%), and 14%, (95% UI: 13-17%), respectively. Prevention of FAP SBA seemed to contribute toward achieving SDG on neonatal and under-five mortality in developing countries. CONCLUSIONS: Prevention of FAP SBA will lead to notable and immediate reductions in child mortality. Many countries have an opportunity to effectively move toward child mortality-related SDG targets with existing milling infrastructure for food fortification.

A 2017 global update on folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Spina bifida and anencephaly are largely preventable birth defects through mandatory folic acid fortification. Our objective was to estimate the proportion of folic acid-preventable spina bifida and anencephaly (FAP SBA) prevented worldwide through mandatory fortification of wheat and/or maize flour with folic acid during the year 2017. METHODS: Using existing data, we identified countries with mandatory fortification policies that added at least 1.0 ppm folic acid to wheat and/or maize flour and had information on percentage of industrially milled flour that is fortified. We assumed mandatory folic acid fortification at 200 µg/day of folic acid fully protects against FAP SBA, reducing the prevalence of spina bifida and anencephaly to 0.5 per 1,000 live births. RESULTS: Overall, 59 countries met our criteria for implementing mandatory folic acid fortification of wheat and/or maize flour in 2017. These countries prevented about 50,270 out of 280,500 FAP SBA births in 2017. Thus, we have only achieved 18% prevention of FAP SBA worldwide. Several countries in Africa and Asia with a high number of FAP SBA-affected births do not have mandatory fortification. CONCLUSION: About 230,000 children unnecessarily developed FAP SBA globally in 2017. There is an urgent need for all countries to implement mandatory folic acid fortification, a proven, safe public health intervention that saves money and prevents infant mortality and disability. Prevention of FAP SBA can play an important role in helping countries to achieve their Sustainable Development Goals for health.

Total prevention of folic acid-preventable spina bifida and anencephaly would reduce child mortality in India: Implications in achieving Target 3.2 of the Sustainable Development Goals.

BACKGROUND: The potential to reduce child mortality by preventing folic acid-preventable spina bifida and anencephaly (FAP SBA) is inadequately appreciated. To quantify possible reduction in FAP SBA-associated child mortality in low- and middle-income countries, we conducted an analysis to demonstrate in India, a country with more than 25 million births and 1.2 million under-five deaths each year, the decrease in neonatal, infant, and under-five mortality that would occur through total prevention of FAP SBA. METHODS: We estimated the percent reductions in neonatal, infant, and under-five mortality that would have occurred in India in 2015 had all of FAP SBA been prevented. We also estimated the contributions of these reductions toward India's Sustainable Development Goals on child mortality indicators. We considered the overall prevalence of spina bifida and anencephaly in India as 5 per 1,000 live births, of which 90% were preventable with effective folic acid intervention. RESULTS: In the year 2015, folic acid interventions would have prevented about 116,070 cases of FAP SBA and 101,565 under-five deaths associated with FAP SBA. Prevention of FAP SBA would have reduced annually, neonatal, infant, and under-five mortality by 10.2%, 8.9%, and 8.3%, respectively. These reductions would have contributed 18.5% and 17.2% to the reductions in neonatal and under-five mortality, respectively, needed by India to achieve its 2030 Sustainable Developmental Goal Target 3.2 addressing preventable child mortality. CONCLUSIONS: Total prevention of FAP SBA clearly has a significant potential for immediate reductions in neonatal, infant, and under-five mortality in India, and similarly other countries.

Thomas H. Shepard, M.D., pioneer in embryology and teratology.

Dr. Thomas H. Shepard died on October 3, 2016 at the age of 93. He was a major figure in the fields of teratology, embryonic and fetal pathology, and pediatrics. He was beloved by his colleagues as he was by the many students and fellows whom he taught, mentored and befriended. His contributions to teratology are extraordinary and he is greatly missed. © 2017 Wiley Periodicals, Inc.