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.

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.

Scorecard for spina bifida research, prevention, and policy - A development process.

Spina bifida is a serious and largely preventable neural tube birth defect and an important cause of mortality and lifelong disability. The People and Organizations United for Spina Bifida and Hydrocephalus (PUSH!) Global Alliance was formed in 2014 to provide a common platform for various organizations worldwide to raise the visibility of spina bifida and hydrocephalus. In its formative phase, the alliance recognized that in order to accelerate surveillance, prevention, and care for these conditions, there was a need to provide an evidence-based assessment of how nations are performing in specific areas. In this paper, we describe the impetus for, and the process of, developing country-level scorecards for spina bifida surveillance, prevention and care. The PUSH! Executive Committee formulated a comprehensive list of six actionable indicators measuring availability of published studies on population-based folate studies; surveillance of prevalence and mortality; prevention-based policies; access to care; and quality of life associated with spina bifida. Rubrics were developed to score each country on the aforementioned indicators. Country scores were pooled across each indicator and the composite scores ranged between zero and three if there was a need for improvement, four and five if they were in good standing, or six for an excellent status. The scorecard included country-specific recommendations assimilated from the literature and published guidelines to aid policy makers in accelerating surveillance and prevention, and improving the care and quality of life indicators. For comparison, country-level scorecards were grouped by WHO-regions. Score cards were made available publicly through the website "www.pu-sh.org".

A 2015 global update on folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Spina bifida and anencephaly are two major neural tube defects. They contribute substantially to perinatal, neonatal, infant, and under-five mortality and life-long disability. To monitor the progress toward the total prevention of folic acid-preventable spina bifida and anencephaly (FAP SBA), we examined their global status in 2015. METHODS: Based on existing data, we modeled the proportion of FAP SBA that are prevented in the year 2015 through mandatory folic acid fortification globally. We included only those countries with mandatory fortification that added at least 1.0 ppm folic acid as a fortificant to wheat and maize flour, and had complete information on coverage. Our model assumed mandatory folic acid fortification at 200 µg/day is fully protective against FAP SBA, and reduces the rate of spina bifida and anencephaly to a minimum of 0.5 per 1000 births. RESULTS: Our estimates show that, in 2015, 13.2% (35,500 of approximately 268,700 global cases) of FAP SBA were prevented in 58 countries through mandatory folic acid fortification of wheat and maize flour. Most countries in Europe, Africa, and Asia were not implementing mandatory fortification with folic acid. CONCLUSION: Knowledge that folic acid prevents spina bifida and anencephaly has existed for 25 years, yet only a small fraction of FAP SBA is being prevented worldwide. Several countries still have 5- to 20-fold epidemics of FAP SBA. Implementation of mandatory fortification with folic acid offers governments a proven and rapid way to prevent FAP SBA-associated disability and mortality, and to help achieve health-related Sustainable Development Goals. Birth Defects Research (Part A) 106:520-529, 2016. © 2016 Wiley Periodicals, Inc.

Preventable spina bifida and anencephaly in Europe.

BACKGROUND: Promotion of voluntary folic acid supplement use among women of reproductive age has been proven to be ineffective in lowering the risk of neural tube defects in Europe. METHODS: Using surveillance data from all births covered by the full member countries of the European Surveillance of Congenital Anomalies (EUROCAT), we estimated the total prevalence of spina bifida and anencephaly per 10,000 births between 2000 and 2010. We also estimated additional lifetime direct medical costs among individuals with spina bifida, compared with those without, in Germany for the year 2009. RESULTS: During the study period, there were 7478 documented cases of spina bifida and anencephaly among the 9,161,189 births, with an estimated average combined prevalence of 8.16 per 10,000 births (95% confidence interval, 7.98 - 8.35). For the 241 spina bifida-affected live births in 2009 in Germany, the estimated additional lifetime direct medical costs compared with non-spina bifida affected births were €65.5 million. Assuming a 50% reduction in the prevalence if folic acid has been provided to all women before pregnancy, 293 spina bifida cases could have been prevented in Germany in 2009. The estimated lifetime direct medical cost saving for the live births in 2009 was €32.9 million assuming a 50% reduction, or €26.1 million assuming a 40% risk reduction. CONCLUSION: Europe has an epidemic of spina bifida and anencephaly compared with countries with mandatory folic acid fortification policy. Primary prevention through mandatory folic acid fortification would considerably reduce the number of affected pregnancies, and associated additional costs.

Population-based study to determine mortality in spina bifida: New York State Congenital Malformations Registry, 1983 to 2006.

BACKGROUND: The lifetime risk of death among individuals with spina bifida is 10-times higher compared with the general population. A population-based analysis on cause-specific mortality among individuals spina bifida is lacking. METHODS: Using statewide, population-based New York Congenital Malformations Registry, we examined all births between years 1983 and 2006, and identified 1988 births with spina bifida and 10,951 births with congenital hypertrophic pyloric stenosis (CHPS). We linked registry records to birth and death files from vital records, and determined age- and cause-specific mortality for isolated and multiple spina bifida, and compared the findings with the less fatal CHPS. RESULTS: Mortality in spina bifida is significantly high compared with CHPS (16.9% vs. 0.96%, respectively). The probability of survival in spina bifida was lower compared with CHPS. A majority of the deaths in spina bifida occurred in infants within the first year of birth; however, an increased risk of death persisted in young adulthood for both isolated and multiple cases of spina bifida. The common causes of death in children with spina bifida were hydrocephalus, infections, cardiac anomalies, pneumonia, and pulmonary embolism; while infections, heart or kidney failure, injuries and neoplasms contributed to deaths in adults. CONCLUSION: We conclude that mortality in spina bifida is a large concern, and individuals living with the defect require improved clinical care for lethal medical complications. Primary prevention of spina bifida through mandatory folic acid fortification remains as the best strategy to reduce both disability and mortality associated with this defect across the world.

A global update on the status of prevention of folic acid-preventable spina bifida and anencephaly in year 2022.

BACKGROUND: Mandatory fortification of staple foods with folic acid is an effective public health strategy to prevent folic acid-preventable spina bifida and anencephaly (FAP SBA). We estimated the global proportion of FAP SBA prevented through mandatory folic acid fortification of cereal grains (i.e., wheat flour, maize flour, and rice). METHODS: We used year 2022 data from the Food Fortification Initiative to identify countries (n = 69) with mandatory fortification of grains that includes folic acid. Sixty-eight countries were eligible for analysis with complete data. Proportion of FAP SBA prevention was modeled assuming >150 mcg/day of folic acid fortification protects against FAP SBA, reducing post-fortification prevalence to a lowest achievable level of 0.5 cases per 1000 births. RESULTS: Our analysis found that a total of 63,520 cases of FAP SBA were prevented in the year 2022 in 68 countries implementing mandatory folic acid fortification of grains with folic acid. This translated to a 23.7% prevention of all possible FAP SBA prevention globally. An excess of 204,430 cases of FAPSBA still occurred in over 100 countries where mandatory staple food fortification with folic acid is not implemented. CONCLUSION: Our study showed that only a quarter of all FAP SBA cases were averted through mandatory folic acid fortification in the year 2022; many countries are not implementing the policy, resulting in a large proportion of FAP SBA cases that can be prevented. Fortification will help countries with achieving 2030 Sustainable Development Goals on neonatal- and under-five mortality, disability, stillbirths, and elective terminations prevention, from FAP SBA.

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.

2012 Update on global prevention of folic acid-preventable spina bifida and anencephaly.

BACKGROUND: Folic acid was proven in 1991 to prevent most cases of spina bifida and anencephaly. In 2008, less than 10% of folic acid-preventable spina bifida and anencephaly (FAPSBA) was prevented through folic acid fortification programs. This study updates the global estimates of the proportion of FAPSBA prevented with various types of folic acid fortification as of 2012. METHODS: For each country, we estimated the annual birth prevalence of FAPSBA and the daily amount of folic acid consumed from mandatory folic acid fortification programs. Assuming in Model I (our original Bell and Oakley model) that it required 400 µg, and in Model II (a new model), 200 µg of folic acid daily for total prevention of FAPSBA, we estimated the percentage of FAPSBA being prevented in each country by fortification. RESULTS: Using the original model, we estimate that 15% of FAPSBA is being prevented in 2012, compared with 2006 (6.8%) and 2008 (9.1%). We estimate in our new model that 25% of FAPSBA is being prevented. CONCLUSION: We estimate an increasing prevention of FAPSBA in the world through folic acid fortification, yet the pace is slow. Our new model estimates that only 25% prevention and reminds us that there remains a lot of work to do in countries that do not implement mandatory fortification, which is key to achieving global and total prevention. If we are to prevent all FAPSBA, there is an urgent need to build the global political will to find sufficient resources to aid in this effort.

Valproate prescriptions for nonepilepsy disorders in reproductive-age women.

BACKGROUND: Scientific evidence has consistently shown taking valproate during pregnancy increases risks of congenital malformations and cognitive impairment. As such, elimination of its use would be an important step in birth defects prevention. There are guidelines discouraging its use among women with epilepsy, but none exists for women without epilepsy, nor is the prevalence of valproate for nonepilepsy indications known. METHODS: Using de-identified data from the National Hospital and Ambulatory Medical Care Surveys (1996-2007), we examined individual prescriptions for reproductive-age adolescent girls and adult women ages 15 to 44 years in the United States, and estimated the number of antiepileptic drug and valproate prescriptions in the aggregate. We classified our study population using International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis codes, as women with epilepsy and women without epilepsy. The prevalence of antiepileptic drug and valproate prescriptions among women without epilepsy was estimated as prescriptions per 1000 patient visits for every 3-year time interval and the overall study period. RESULTS: We found 83% of valproate prescriptions were issued to women without epilepsy and 74% of these were for psychiatric diagnoses. The prevalence of antiepileptic drug prescriptions among women without epilepsy tripled during the study period (10.3 [1996-1998] vs. 34.9 [2005-2007] per 1000 patient visits), whereas valproate prescriptions remained relatively stable (3.1 [1996-1998] vs. 3.7 [2005-2007] per 1000 patient visits). CONCLUSION: Most women of reproductive age who receive a valproate prescription do not have epilepsy. Valproate prescriptions did not decline, despite increasing knowledge of its teratogenicity. Reducing valproate use among women of reproductive age, especially among those who use the drug for psychiatric indications, would prevent birth defects and cognitive deficits.

Pregnancy termination following prenatal diagnosis of anencephaly or spina bifida: a systematic review of the literature.

BACKGROUND: In regions where prenatal screening for anencephaly and spina bifida is widespread, many cases of these defects are diagnosed prenatally. The purpose of this study was to estimate the frequency of termination of pregnancy (TOP) following prenatal diagnosis of anencephaly or spina bifida and to investigate factors associated with TOP that might lead to selection bias in epidemiologic studies. METHODS: We included articles indexed in Medline or Embase between 1990 and May 2012 reporting the frequency of TOP following prenatal diagnosis of anencephaly or spina bifida with English-language abstracts, 20 or more prenatally diagnosed cases, and at least half of the study years in 1990 or later. We summarized the frequency of TOP across studies using random-effects metaanalysis and stratified results by fetal and study characteristics. RESULTS: Among the 17 studies identified, 9 included anencephaly and 15 included spina bifida. Nine were from Europe, six were from North America, and one each was from South America and Asia. The overall frequency of TOP following prenatal diagnosis was 83% for anencephaly (range, 59-100%) and 63% for spina bifida (range, 31-97%). There were insufficient data to stratify the results for anencephaly; TOP for spina bifida was more common when the prenatal diagnosis occurred at less than 24 weeks' gestation, with defects of greater severity, and in Europe versus North America. CONCLUSIONS: Because underascertainment of birth defects might be more likely when the pregnancy ends in TOP and TOP is associated with fetal characteristics, selection bias is possible in epidemiologic studies of anencephaly or spina bifida.

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.

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.

Association between vitamin B12-containing supplement consumption and prevalence of biochemically defined B12 deficiency in adults in NHANES III (third national health and nutrition examination survey).

OBJECTIVE: To explore the association between vitamin B(12) (B(12))-containing supplement use, low B(12) concentrations and biochemically defined B(12) deficiency in US adults. DESIGN: A cross-sectional study with adjustment for survey design. Prevalence ratios for two age groups (18-50 and >50 years) were estimated using unconditional logistic models. Outcome measures included prevalence of low serum B(12) concentration (<148 pmol/l) and biochemical B(12) deficiency (serum B(12)< 148 pmol/l with concomitant homocysteine > 10 mumol/l). SETTING: A population survey of health and nutritional measures. SUBJECTS: Subjects were non-institutionalized adults, aged 18 years and older, who participated in Phase 2 of NHANES III (Third National Health and Nutrition Examination Survey). RESULTS: Low B(12) concentrations were less prevalent among persons consuming B(12)-containing supplements (P = 0.001) with an adjusted prevalence ratio of 0.6 (95 % CI 0.3, 1.0). Biochemical B(12) deficiency showed a similar trend (P = 0.0002), with an adjusted prevalence ratio of 0.3 (95 % CI 0.1, 0.8). Prevalence ratios were similar in adults >50 years of age, although the prevalence of low B(12) and biochemical deficiency was proportionally higher. CONCLUSIONS: Consumption of B(12)-containing supplements was associated with at least 50 % lower prevalence of both low serum B(12) and biochemical B12 deficiency in a nationally representative sample of US adults, suggesting increased consumption of B(12) from supplements or from fortified foods may reduce the prevalence of B(12) deficiency. Additionally, the current Recommended Daily Allowance for B(12) of 2.4 microg may be insufficient for those aged >50 years.

Considering the case for vitamin B12 fortification of flour.

Reasons to fortify flour with vitamin B12 are considered, including the high prevalence of depletion and deficiency of this vitamin that occurs in persons of all ages in resource-poor countries and in the elderly in wealthier countries, and the adverse functional consequences of poor vitamin B12 status. From a global perspective, the main cause of inadequate intake and status is a low intake of animal-source foods; even lacto-ovo vegetarians have lower serum vitamin B12 concentrations than omnivores, and for various reasons many populations have limited consumption of animal-source foods. Infants are vitamin B12-depleted from early infancy if their mothers' vitamin B12 status and intake are poor during pregnancy and lactation. Even in the United States, more than 20% of the elderly have serum vitamin B12 concentrations that indicate depletion, and an additional 6% have deficiency, primarily due to gastric atrophy, which impairs the absorption of the vitamin from food but usually not from supplements or fortified foods. Although the evidence is limited, it shows that fortified flour, consumed as bread, can improve vitamin B12 status. Where vitamin B12 fortification is implemented, the recommendation is to add 20 microg/kg flour, assuming consumption of 75 to 100 g flour per day, to provide 75% to 100% of the Estimated Average Requirement; the amount of the vitamin that can be added is limited by its cost. The effectiveness of this level of addition for improving vitamin B12 status in programs needs to be determined and monitored. In addition, further research should evaluate the bioavailability of the vitamin from fortified flour by elderly people with food cobalamin malabsorption and gastric atrophy.

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.