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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., (© 2024 Wiley Periodicals LLC.)

Objectives: To determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000-2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour to be monitored., Design: Population-based, observational study using congenital anomaly (CA) registration data for England curated by the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS)., Setting: Regions of England with active registration in the time period., Participants: Babies that were liveborn or stillborn and pregnancies that resulted in a termination of pregnancy or a late miscarriage (20-23 weeks' gestation) with an NTD., Main Outcome Measures: Total birth prevalence of anencephaly, spina bifida and all NTDs in England. Poisson regression analysis was used to evaluate time trends with regional register as a random effect. The progress of national registration across England was assessed., Results: There were 4541 NTD pregnancies out of 3 637 842 births in England; 1982 anencephaly and 2127 spina bifida. NTD prevalence was 12.5 (95% CI 12.1 to 12.9) per 10 000 total births. NTD prevalence per 10 000 total births was significantly higher in 2015-2019 (13.6, 95% CI 12.9 to 14.4) compared with 2010-2014 (12.1, 95% CI 11.7 to 12.5). An increasing trend in NTDs overall was detected (incidence rate ratio (IRR) 1.01, 1.00 to 1.02), although further analysis determined this effect was confined to 2015-2019 (compared against 2000-2004, IRR 1.14, 1.04 to 1.24). The birth prevalence of anencephaly reflected this pattern. The prevalence of spina bifida remained relatively stable over time., Conclusions: Baseline NTD prevalence for England has been established. National and standardised CA registration is in place, facilitating the systematic and consistent monitoring of pre-fortification and post-fortification NTD trends and evaluating the impact of fortification on NTD prevalence., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Anencephaly, a fatal anomaly of the central nervous system, belongs to the group of defects of the neural tube (NTDs). It is considered the most common congenital NTD, characterized by concurrent absence of a significant portion of the brain and cranial vault. This deformity occurs between days 23 and 26 after fertilization due to improper closure of the neural tube at its cranial end. Many genetic, epigenetic, and non-genetic factors (nutritional, environmental and geographical factors, parental socioeconomic status) contribute to the etiology of this disease. Despite significant advances in treatment and preventive measures, NTDs continue to pose a significant health and financial burden on patients and society as a whole. This study aimed to examine the incidence of anencephaly in Slovakia compared to the Czech Republic between 2012 and 2020. The authors seek to elucidate the reasons behind the higher incidence of this disease in Slovakia as compared to the Czech Republic, explore the male predominance of anencephaly in Slovakia, and investigate whether the prevention standards used in Slovakia differ from those employed in other countries (Tab. 1, Fig. 2, Ref. 129). Keywords: neural tube defects, anencephaly, risk factors, folic acid, food fortification.

Background: Fetal deaths are a major source of information on the epidemiology of neural tube defects (NTDs; anencephaly and myelomeningocele). We analyzed NTDs prevalence and secular trend using fetal death records between 1994 and 2019 in Argentina., Materials and Methods: Data were obtained from the Department of Statistics and Information of the Ministry of Health (DEIS). Using the number of fetal deaths due to anencephaly and myelomeningocele, we estimated the proportion of all fetal deaths due to anencephaly, myelomeningocele, and NTDs (anencephaly + myelomeningocele) during pre- and post-fortification period in Argentina. We also estimated the ratio of fetal deaths due to anencephaly, myelomeningocele, and NTDs (anencephaly + myelomeningocele) to 10,000 live births. Secular trend in the outcomes was analyzed using a Poisson model and Joinpoint regression analysis., Results: In the entire period analyzed, the NTD proportion on fetal deaths was 1.32. In 1994, NTDs accounted for 34.7% of congenital malformations fetal deaths (CM) and 1.7% of all fetal deaths, whereas in 2019, these percentages were 9.4% and 0.5%, respectively. NTDs present a negative secular trend (p < .05). The risk of fetal death due to anencephaly and myelomeningocele decreases between 2005 and 2019 by 67% and 51% respectively (p < .05) in comparison to the period between 1994 and 2004 before the effective fortification of wheat flour used in the food industry destined for the domestic market., Discussion and Conclusion: We found a significant decrease in the risk of all fetal deaths due to NTDs, particularly anencephaly, in Argentina over the study period, with most reduction observed during the mandatory flour fortification era (introduced in Argentina in 2002). The inclusion of fetal deaths in NTD surveillance, coupled or uncoupled with other pregnancy outcomes, is essential for monitoring preventive supplementation measures., (© 2023 Wiley Periodicals LLC.)

Open spina bifida (OSB) is a common neural tube defect. Medical and surgical care involves addressing the baseline orthopedic, urologic, and neurological dysfunction as well as the changes or declines that may occur as the patient ages. Given the complexity of this disease, coordinated, multidisciplinary care involving specialists in neurosurgery, orthopedics, urology, rehabilitation and physical medicine, pediatrics, and psychology is necessary to establish and optimize baseline function. Traditionally in the US, pediatric multispecialty spina bifida clinics have provided the patient with a coordinated medical support system. Unfortunately, this coordinated, medical home has been difficult to establish during the transition from pediatric to adult care. Medical professionals must have a strong understanding of OSB to properly manage the disease and detect and prevent associated complications. In this manuscript, we (1) describe the changing needs and challenges of people living with OSB over a lifespan, (2) delineate current practices in the transition of care for people with OSB from childhood to adulthood, and (3) provide recommendations for best practices in navigating the transition process for clinicians who provide care for those afflicted with this most complex congenital abnormality of the nervous system compatible with long term survival., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Congenital anomalies are the fifth most common cause of neonatal mortality in Nicaragua, and neural tube defects (NTDs) are the most common of all cases of lethality associated with a birth defect. Prevalence and mortality estimates are needed to propose effective intervention strategies that prevent NTDs over time., Methods: A cross-sectional study was carried out in northwestern Nicaragua from January 2006 to December 2018. All cases of NTDs (anencephaly, spina bifida, and encephalocele) were registered in hospital surveillance systems, and the medical histories of the mothers and newborns were reviewed. Prevalence was calculated by considering the number of live births and stillbirths older than 20 weeks of gestation with NTDs, divided by the total number of live births and stillbirths in each study year. Neonatal mortality rate (NMR) for NTD, and case fatality for spina bifida was calculated., Results: Two hundred fifty cases of NTDs were identified from 178,498 deliveries (177,316 live births and 1,182 stillbirths). The prevalence of NTDs during this time period was 14.01 (95% CI: 12.27-15.74) per 10,000 births. The prevalence of spina bifida (n = 140), anencephaly (n = 97), and encephalocele (n = 13) was 7.84, (95% CI: 6.54-9.14), 5.43 (95% CI: 4.30-6.45), and 0.73 (95% CI: 0.33-1.12) per 10,000 births, respectively. Mothers with fetus or newborns affected with NTDs did not use folic acid prior to conception, and 11% experienced periods of hyperthermia during the first trimester of pregnancy. NMR for NTDs was 0.55 per 1.000 livebirths. Case fatality for all NTDs and for spina bifida were 55% and 18%, respectively., Conclusion: The prevalence and mortality of NTDs in the northwestern region of Nicaragua present peaks and troughs during the study period. Spina bifida was the most frequent type of NTD. We believe that these findings could be of use by health policy makers to strengthen the primary prevention of NTDs in the region through the monitoring of the food fortification policy and folic acid supplementation to women of childbearing age. Additional etiologic studies of NTDs should be considered to identify additional prevention measures., (© 2023 Wiley Periodicals LLC.)

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., (© 2022 Wiley Periodicals LLC.)

Objective: The global neurosurgery movement arose at the crossroads of unmet neurosurgical needs and public health to address the global burden of neurosurgical disease. The case of folic acid fortification (FAF) of staple foods for the prevention of spina bifida and anencephaly (SBA) represents an example of a new neurosurgical paradigm focused on public health intervention in addition to the treatment of individual cases. The Global Alliance for the Prevention of Spina Bifida-F (GAPSBiF), a multidisciplinary coalition of neurosurgeons, pediatricians, geneticists, epidemiologists, food scientists, and fortification policy experts, was formed to advocate for FAF of staple foods worldwide. This paper serves as a review of the work of GAPSBiF thus far in advocating for universal FAF of commonly consumed staple foods to equitably prevent SBA caused by folic acid insufficiency., Methods: A narrative review was performed using the PubMed and Google Scholar databases., Results: In this review, the authors describe the impact of SBA on patients, caregivers, and health systems, as well as characterize the multifaceted requirements for proper spina bifida care, including multidisciplinary clinics and the transition of care, while highlighting the role of neurosurgeons. Then they discuss prevention policy approaches, including supplementation, fortification, and hybrid efforts with folic acid. Next, they use the example of FAF of staple foods as a model for neurosurgeons' involvement in global public health through clinical practice, research, education and training, and advocacy. Last, they describe mechanisms for involvement in the above initiatives as a potential academic tenure track, including institutional partnerships, organized neurosurgery, neurosurgical expert groups, nongovernmental organizations, national or international governments, and multidisciplinary coalitions., Conclusions: The role of neurosurgeons in caring for children with spina bifida extends beyond treating patients in clinical practice and includes research, education and training, and advocacy initiatives to promote context-specific, evidence-based initiatives to public health problems. Promoting and championing FAF serves as an example of the far-reaching, impactful role that neurosurgeons worldwide may play at the intersection of neurosurgery and public health.

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 B 9 ) 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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Neural tube defects (NTDs) encompass a variety of distinct types. We assessed if the preventive effect of folic acid (FA) varied by NTD type and infant sex., Methods: We examined all pregnancies with NTD status confirmation from a pregnancy-monitoring system in selected locations in northern and southern regions of China between 1993 and 1996. Women who took 400 μg of FA daily during 42 days after last menstrual period were considered FA users. We analyzed NTD prevalence by FA use status, NTD type, geographic region, and infant sex., Results: Among 626,042 pregnancies, 700 were affected by an NTD. Among FA nonusers, 65 pregnancies (8.8 per 10,000) in the north and 51 pregnancies (1.2 per 10,000) in the south were affected by one of the two rare NTDs, that is, craniorachischisis, iniencephaly. FA use prevented occurrence of these two rare NTDs and reduced the prevalence of spina bifida (SB) by 78% (from 17.9 to 3.9 per 10,000) in the north and 51% (from 2.4 to 1.2 per 10,000) in the south. Among FA users, SB prevalence, including SB with high lesion level, was significantly reduced in both geographic regions. FA use reduced prevalence of anencephaly and encephalocele by 85% and 50%, respectively in the north, while it did not reduce the prevalence of these two NTDs in the south. There was a greater reduction in NTD prevalence in female than in male infants and fetuses., Conclusions: This is the first study to show that FA prevents the entire spectrum of NTD types., (© 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

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., (©The Author(s) 2021. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health.)

Surveillance data have highlighted continued disparities in neural tube defects (NTDs) by race-ethnicity in the United States. Starting in 2016, the Food and Drug Administration (FDA) authorized voluntary folic acid fortification of corn masa flour to reduce the risk of neural tube defects (NTDs) among infants of Hispanic women of reproductive age. To assess the impact of voluntary corn masa fortification, cross-sectional data from the National Health and Nutrition Examination Survey (NHANES) 2011-2018 for Hispanic women of reproductive age with available red blood cell (RBC) folate concentrations were analyzed, with additional analyses conducted among Hispanic women whose sole source of folic acid intake was fortified foods (enriched cereal grain products (ECGP) only), excluding ready-to-eat cereals and supplements. RBC folate concentration (adjusted geometric mean) among Hispanic women of reproductive age did not differ between 2011-2016 and 2017-2018, though RBC folate concentration increased significantly among lesser acculturated Hispanic women consuming ECGP only. Concentrations of RBC folate for those born outside the U.S and residing in the U.S <15 years increased from 894 nmol/L (95% CI: 844-946) in 2011-2016 to 1018 nmol/L (95% CI: 982-1162; p < 0.001) in 2017-2018. Primarily Spanish-speaking Hispanic women of reproductive age who only consumed ECGP saw an increase from 941 nmol/L (95% CI: 895-990) in 2011-2016 to 1034 nmol/L (95% CI: 966-1107; p = 0.03) in 2017-2018. By subpopulation, we observed no significant changes in the proportion at risk of NTDs (<748 nmol/L) and no changes in the model-based estimated NTD rates following voluntary corn masa fortification. This analysis suggests that there is a remaining risk among Hispanics for folate sensitive NTDs, though continued monitoring of folate status in future NHANES data cycles will help inform the long-term efficacy of voluntary fortification of corn masa flour.

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., (© 2020 Wiley Periodicals LLC.)

In 2009, the Australian government mandated the addition of folic acid to bread flour to reduce the incidence of neural tube defects (NTD)-affected pregnancies. In 2011-2012, the Australian Health Measures Survey (AHMS) reported a mean red blood cell (RBC) folate in women of reproductive age (16-44 y) of 1647 nmol/L. Over 99% of women had an RBC folate ≥ 906 nmol/L, a concentration consistent with a very low risk of NTDs if a woman became pregnant. However, RBC folate was measured using an immunoassay, which is not a recommended method due to questionable accuracy. The microbiological assay is the preferred method for RBC folate measurement. To determine whether the immunoassay method may have led to spurious conclusions about the folate status of Australian women, we collected fasting blood samples from 74 healthy non-pregnant, non-lactating women (18-44 y) and measured RBC folate using both the immunoassay and microbiological methods. Mean RBC folate (95% confidence interval) concentration measured with the immunoassay method was 1735 (1666, 1804) nmol/L compared with 942 (887, 1012) nmol/L using the microbiological method. No woman had an RBC folate < 906 nmol/L using the immunoassay method, whereas 46% of women had an RBC folate < 906 nmol/L using the microbiological method. The NTD risk was estimated to be 0.06% using the immunoassay method and 0.14% using the microbiological method. RBC folate using AHMS survey may have underestimated NTD risk in Australian women., Competing Interests: M.M. reports grants from National Health and Medical Research Council during the conduct of the study; she has also received honoraria from Nestle and Fonterra for memberships of Scientific Advisory Board, which have been paid to her institution, outside the submitted work. B.S.M. has received honoraria for serving on the Nestle Nutrition Institute Advisory board and for giving presentations for BASF, which have been paid to her institution, outside the submitted work. T.J.G. reports grants from the International Development Research Centre, Nutrition International, and the Nestle Nutrition Institute; he has also received honoraria from Fonterra for membership on a Scientific Advisory Board that has been paid to his institution, outside the submitted work.

Background: Neural tube defects (NTD)s are common birth defects with a multifactorial etiology. Findings from human studies examining environmental (non-inherited) exposures tend to be inconclusive. In particular, although animal studies of alcohol exposure and NTDs support its teratogenic potential, human studies are equivocal. Using data from the National Birth Defects Prevention Study (NBDPS), associations between maternal periconceptional (1 month before through 1 month after conception) alcohol consumption and NTDs in offspring were examined., Methods: NTD cases and unaffected live born singleton controls with expected dates of delivery from October 1997-December 2011 were enrolled in the NBDPS. Interview reports of alcohol consumption (quantity, frequency, variability, type) from 1,922 case and 11,251 control mothers were analyzed. Crude and adjusted odds ratios (aOR)s and 95% confidence intervals (CI)s for alcohol consumption and all NTDs combined and selected subtypes (spina bifida, anencephaly, encephalocele) were estimated using unconditional logistic regression analysis., Results: Among mothers in the NBDPS, 28% of NTD case and 35% of control mothers reported any periconceptional alcohol consumption. For each measure of alcohol consumption, inverse associations were observed for all NTDs combined (aORs = 0.6-1.0). Results for NTD subtypes tended to be similar, but CIs for spina bifida and encephalocele were more likely to include the null., Conclusions: These findings suggest a lack of positive associations between maternal periconceptional alcohol consumption and NTDs. Future studies should continue to evaluate the association between maternal alcohol consumption and NTDs in offspring accounting for methodological limitations such as potential misclassification from self-reported alcohol consumption., (© 2020 Wiley Periodicals, Inc.)

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., (© 2019 Wiley Periodicals, Inc.)

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., (© 2018 Wiley Periodicals, Inc.)

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., (© 2019 Wiley Periodicals, Inc.)

Background: We examined the relationship between timing and duration of folic acid (FA) supplementation in achieving red blood cell (RBC) folate levels in early pregnancy which are optimal (>906 nmol/l) for the prevention of neural tube defects (NTDs)., Methods: Clinical, FA supplementation and dietary folate details were computerized at the first antenatal visit. Maternal blood samples were analysed for RBC and serum folate., Results: Of the 502 women, 98.2% (n = 493) reported taking FA. There was a positive correlation between duration of supplementation and both RBC folate (r = 0.43, P < 0.001) and serum folate (rho = 0.29, P < 0.001). The optimal RBC folate level was achieved in 80.4% (n = 46) of women who started FA 400 μg 4-8 weeks before their LMP compared with only 53.6% (n = 153) in women who started 4-8 weeks after their LMP (P < 0.001)., Conclusions: This study provides, for the first time, information on both the timing and duration of FA that will achieve the optimum RBC folate levels associated with the prevention of NTDs. Women who are taking FA (400 μg) need to start before they conceive.

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., (© 2018 Wiley Periodicals, Inc.)

Objectives: Mandatory fortification of flour with folic acid has been proven to be a highly effective way to prevent spina bifida and anencephaly. Yet, over 100 countries worldwide do not implement this intervention. Our objectives were to identify countries with an immediate potential for mandatory fortification of wheat flour with folic acid and to estimate the number of preventable cases of spina bifida and anencephaly that would be averted each year through the intervention., Methods: We examined folic acid fortification characteristics in countries as of September 2017. Country selection criteria included current fortification status, existing industrial capacity for flour production, fortification coverage, and daily grams of per capita wheat flour available for human consumption. We estimated the country-specific number of preventable cases of spina bifida and anencephaly by calculating the difference between the observed prevalence (prefortification) and expected prevalence that can be achieved postfortification (0.5 per 1,000 live births)., Results: We identified 71 countries with an immediate potential for mandatory fortification of 145 million metric tons of wheat flour with folic acid. Fortification in identified countries would avert approximately 57,000 live births associated with folic acid-preventable spina bifida and anencephaly annually and increase global prevention from the current rate of 13% to a new rate of 34%., Conclusions: Fortification can be achieved immediately in many countries with existing industrial milling infrastructure. Effective fortification interventions can accelerate global primary prevention efforts of folic acid-preventable spina bifida and anencephaly, especially in developing countries with a high prevalence of neural tube defects and associated morbidity and mortality., (© 2018 Wiley Periodicals, Inc.)

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., (© 2017 Wiley Periodicals, Inc.)

Neural tube defects (NTD) are potentially preventable in two-thirds of cases by periconceptional maternal Folic Acid (FA) supplementation. A national audit for the years 2009-11 showed no decline in NTD rates over twenty years. The aim of this national audit was to determine trends/rates and inform revision of national FA supplementation and food fortification strategies. Of 274,732 live and stillbirths there were 121(42.0%) cases of anencephaly, 136(47.2%) cases of spina bifida and 31(10.8%) cases of encephalocoele giving a total of 288 and overall rate of 1.05/1000 compared with 1.04/1000 in 2009-11(NS). In the 184 women where the information was available, only 29.9%(n=55) reported starting FA before pregnancy. The number of cases diagnosed antenatally was 91%(n=262) and 53%(n=154) were live-born. This audit confirms that over a generation, healthcare interventions have not succeeded in decreasing the number of pregnancies in Ireland complicated by NTD, and that revised strategies need to be developed and implemented.

Background: The United States Public Health Service recommends that all women of reproductive age consume 400 μg of folic acid daily to prevent major neural tube defects. Hispanics have the highest prevalence of neural tube defects compared with other race/ethnic groups. We studied prevalence of preconception folic acid supplement use, and its association with race/ethnicity among pregnant women in Georgia., Methods: Using state-wide population-based data from 2009 to 2011 Georgia Pregnancy Risk Assessment Monitoring System, we examined the prevalence of preconception folic acid supplement use among pregnant women aged 18 to 45 years. We conducted multivariable logistic regression and estimated adjusted odds ratios and 95% confidence intervals to examine the association between race/ethnicity and supplemental folic acid use among study participants., Results: Overall, 25% of all participants reported taking folic acid supplements daily before conception. Only 21% of Hispanic women reported preconception folic acid supplement use. Hispanic women were twice as likely to not take folic acid supplements (adjusted odds ratio = 2.15; 95% confidence interval, 1.35-3.40) compared with non-Hispanic whites, after controlling for maternal age, parity, pregnancy intention, knowledge that folic acid prevents birth defects, and preconception smoking and exercise., Conclusion: Hispanics are a growing population in the United States with an expected 14 million women of child-bearing age by 2020, and the prevalence of preconception folic acid supplement use is low in this group with a high risk of neural tube defects. Promotion of voluntarily fortified corn masa flour can lower neural tube defects in Hispanics. Mandatory corn masa fortification will be a more effective public health policy.Birth Defects Research 109:38-48, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Neural tube defects (NTDs) are a group of severe congenital malformations, induced by the combined effects of genes and the environment. The most valuable finding so far has been the protective effect of folic acid supplementation against NTDs. However, many women do not take folic acid supplements until they are pregnant, which is too late to prevent NTDs effectively. Long-term intake of folic acid-fortified food is a good choice to solve this problem, and mandatory folic acid fortification should be further promoted, especially in Europe, Asia and Africa. Vitamin B2, vitamin B-6, vitamin B-12, choline, betaine and n -3 polyunsaturated fatty acids (PUFAs) can also reduce the NTD risk by interacting with the one-carbon metabolism pathway. This suggest that multivitamin B combined with choline, betaine and n -3 PUFAs supplementation may have a better protective effect against NTDs than folic acid alone. Genetic polymorphisms involved in one-carbon metabolism are associated with NTD risk, and gene screening for women of childbearing age prior to pregnancy may help prevent NTDs induced by the risk allele. In addition, the consumption of alcohol, tea and coffee, and low intakes of fruit and vegetable are also associated with the increased risk of NTDs, and should be avoided by women of childbearing age., Competing Interests: The authors declare no conflict of interest.

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., (© 2016 Wiley Periodicals, Inc.)

During the last decade critical new information has been published pertaining to folic acid supplementation in the prevention of neural tube defects (NTDs) and other folic acid-sensitive congenital malformations. These new data have important implications for women, their families, and health care professionals. We performed a review looking for the optimal dosage of folic acid that should be given to women of reproductive age who are planning or not avoiding conception to propose updated guidelines and thus help health care providers and patients. In addition to fortification of dietary staples with folic acid, women of reproductive age should supplement before conception with 0.4-1.0 mg of folic acid daily as part of their multivitamins. In the United States all enriched rice is also fortified with folic acid at 0.7 mg per pound of raw rice. However, this is not the case in many countries, and it has been estimated that only 1% of industrially milled rice is fortified with folic acid. In countries where rice is the main staple (eg, China), this does not allow effective folate fortification. Whereas the incidence of NTDs is around 1/1000 in the United States, it is 3- to 5-fold higher in Northern China and 3-fold higher in India. A recent population-based US study estimated that the reduction in NTD rates by folic acid is more modest than previously predicted. The potential of NTD prevention by folic acid is underutilized due to low adherence with folic acid supplementation, and calls for revising the policy of supplementation have been raised. We identified groups of women of reproductive age who may benefit from higher daily doses of folic acid, and this should be considered in current practice. These include women who have had previous pregnancies with NTDs, those who did not plan their pregnancy and hence did not supplement, and women with low intake or impaired adherence to daily folic acid supplementation. In addition, women with known genetic variations in the folate metabolic cycle, those exposed to medications with antifolate effects, smokers, diabetics, and the obese may benefit from higher doses of folic acid daily during the first trimester., (© 2015 The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.)

Periconceptional folic acid (FA) reduces neural tube defect (NTD) risk, but seems to have a varying effect per NTD subtype. We aimed to study the effect of FA supplementation on NTD subtype distribution using data from EUROCAT Northern Netherlands. We included all birth types with non-syndromal NTDs born in 1997-2012. By Fisher's exact test we analyzed possible differences in NTD subtype distribution between a correct FA supplementation group and incorrect FA supplementation group. We found proportionally fewer cervical/thoracic spina bifida cases and more lumbar/sacral spina bifida cases in the correct FA supplementation group, irrespective of the presence of the main NTD risk factors. The effect on NTD subtype distribution was only seen when FA supplementation was started before conception. We conclude that FA not only prevents the occurrence of a significant proportion of NTDs, but might also decrease the severity of NTDs, as long as supplementation is started before conception., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Periconceptional intake of folic acid has demonstrated to be effective to reduce the frequency of neural tube defects, and food fortification has been one of the strategies implemented to increase it. An update is herein presented on the reduced prevalence of neural tube defect cases in the post-fortification period in Argentina and an estimation of cases averted in the 2005-2013 period as a result of this intervention. When comparing the prevalence observed in the post-fortification period to that reported in the pre-fortification period, anencephaly and encephalocele decreased by 66%, and spina bifida, by 47%, which were significant reductions. The estimated number of cases averted was higher for anencephaly, followed by spina bifida; encephalocele showed the lowest number of cases averted given that the prevalence of this defect was smaller. The decrease observed in the prevalence supports findings from previous studies on the impact of fortification.

Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence., (© 2015 Wiley Periodicals, Inc.)

Aim: In gynecology, the importance of an adequate folate intake in the periconceptional period and during pregnancy is widely accepted. Its purpose is to decrease the risk of maternal and fetal diseases, such as neural tube defects (NTD), so that Italy strongly recommends that women who are pregnant or are planning to become pregnant receive folate supplementation (i.e. 0.4 or 4-5 mg per day, as needed). Despite that, recent studies show women's low awareness of the importance of folate supplementation, above all during the periconceptional period. Basing on these considerations, we surveyed pregnant women to investigate their awareness and the real use of folate., Methods: From January to October 2014 we surveyed 650 pregnant women. We used a questionnaire with closed and semi-closed questions., Results: The mean age of the enrolled women was 32.8 (±2.9). The survey showed that a significant proportion of women knew folate benefits in pregnancy (about 70%) and they used it during gestational period (89.8%), whereas folate supplementation during periconceptional period was inadequate, used by only the 16.9% of women and often at a lower than recommended amount., Conclusion: Awareness and use of folate can be promoted through informational campaigns among general practitioners and obstetricians/gynecologists, through preconceptional and prenatal counseling, and through a risk assessment addressed to choose the appropriate folate type and dosage.

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., (© 2015 Wiley Periodicals, Inc.)

Objective: To provide updated information on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies. This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy., Evidence: Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies. Costs, risks, and benefits: The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy. These associations may require consideration before initiating folic acid supplementation. The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications., Values: The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1). Summary Statement In Canada multivitamin tablets with folic acid are usually available in 3 formats: regular over-the-counter multivitamins with 0.4 to 0.6 mg folic acid, prenatal over-the-counter multivitamins with 1.0 mg folic acid, and prescription multivitamins with 5.0 mg folic acid. (III) Recommendations 1. Women should be advised to maintain a healthy folate-rich diet; however, folic acid/multivitamin supplementation is needed to achieve the red blood cell folate levels associated with maximal protection against neural tube defect. (III-A) 2. All women in the reproductive age group (12-45 years of age) who have preserved fertility (a pregnancy is possible) should be advised about the benefits of folic acid in a multivitamin supplementation during medical wellness visits (birth control renewal, Pap testing, yearly gynaecological examination) whether or not a pregnancy is contemplated. Because so many pregnancies are unplanned, this applies to all women who may become pregnant. (III-A) 3. Folic acid supplementation is unlikely to mask vitamin B12 deficiency (pernicious anemia). Investigations (examination or laboratory) are not required prior to initiating folic acid supplementation for women with a risk for primary or recurrent neural tube or other folic acid-sensitive congenital anomalies who are considering a pregnancy. It is recommended that folic acid be taken in a multivitamin including 2.6 ug/day of vitamin B12 to mitigate even theoretical concerns. (II-2A) 4. Women at HIGH RISK, for whom a folic acid dose greater than 1 mg is indicated, taking a multivitamin tablet containing folic acid, should be advised to follow the product label and not to take more than 1 daily dose of the multivitamin supplement. Additional tablets containing only folic acid should be taken to achieve the desired dose. (II-2A) 5. Women with a LOW RISK for a neural tube defect or other folic acid-sensitive congenital anomaly and a male partner with low risk require a diet of folate-rich foods and a daily oral multivitamin supplement containing 0.4 mg folic acid for at least 2 to 3 months before conception, throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues. (II-2A) 6. Women with a MODERATE RISK for a neural tube defect or other folic acid-sensitive congenital anomaly or a male partner with moderate risk require a diet of folate-rich foods and daily oral supplementation with a multivitamin containing 1.0 mg folic acid, beginning at least 3 months before conception. Women should continue this regime until 12 weeks' gestational age. (1-A) From 12 weeks' gestational age, continuing through the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (II-2A) 7. Women with an increased or HIGH RISK for a neural tube defect, a male partner with a personal history of neural tube defect, or history of a previous neural tube defect pregnancy in either partner require a diet of folate-rich foods and a daily oral supplement with 4.0 mg folic acid for at least 3 months before conception and until 12 weeks' gestational age. From 12 weeks' gestational age, continuing throughout the pregnancy, and for 4 to 6 weeks postpartum or as long as breast-feeding continues, continued daily supplementation should consist of a multivitamin with 0.4 to 1.0 mg folic acid. (I-A). The same dietary and supplementation regime should be followed if either partner has had a previous pregnancy with a neural tube defect. (II-2A).

Objective: To test the hypothesis that a concise intervention to promote the preconception use of folic acid (FA) supplements among mothers who visit a well-baby clinic (WBC) for the 6-month check-up of their youngest child is effective. Effectiveness was measured as intention to use or actual use of FA supplements before a next pregnancy among women who expected to be pregnant within 0-12 months., Design: Controlled intervention study with independent samples of intervention and control mothers. The intervention took place at the 6-month visit. A post-intervention measurement was done in the intervention group and a comparable measurement in the control group at the 11-month check-up visit., Setting: The intervention, verbal and in writing, was implemented in four Dutch WBC and given by the WBC physician to the mothers who visited the WBC., Subjects: All mothers visiting the WBC were eligible for inclusion, unless they were unable to complete a questionnaire. The intervention group consisted of 198 (68 %) mothers recruited from 291 6-month intervention visits and the control group of 215 (84%) mothers recruited from 255 11-month normal visits., Results: In mothers who expected to be pregnant within 0-12 months, the proportion using or intending to use FA was 65% in the intervention group (n 49) v. 42% in the control group (n 43; difference 23%, 95% CI 4, 43%, P<0·05)., Conclusions: Health education intervention at the 6-month WBC visit is an effective means to promote the use of FA supplements or the intention to do so.

In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 µg of folic acid daily to prevent neural tube defects (NTDs). NTDs are major birth defects of the brain and spine that occur early in pregnancy as a result of improper closure of the embryonic neural tube, which can lead to death or varying degrees of disability. The two most common NTDs are anencephaly and spina bifida. Beginning in 1998, the United States mandated fortification of enriched cereal grain products with 140 µg of folic acid per 100 g. Immediately after mandatory fortification, the birth prevalence of NTD cases declined. Fortification was estimated to avert approximately 1,000 NTD-affected pregnancies annually. To provide updated estimates of the birth prevalence of NTDs in the period after introduction of mandatory folic acid fortification (i.e., the post-fortification period), data from 19 population-based birth defects surveillance programs in the United States, covering the years 1999-2011, were examined. After the initial decrease, NTD birth prevalence during the post-fortification period has remained relatively stable. The number of births occurring annually without NTDs that would otherwise have been affected is approximately 1,326 (95% confidence interval = 1,122-1,531). Mandatory folic acid fortification remains an effective public health intervention. There remain opportunities for prevention among women with lower folic acid intakes, especially among Hispanic women, to further reduce the prevalence of NTDs in the United States.

Lipopolysaccharide (LPS) has been associated with adverse pregnant outcomes, including fetal demise, intra-uterine growth restriction (IUGR), neural tube defects (NTDs) and preterm delivery in rodent animals. Previous studies demonstrated that melatonin protected against LPS-induced fetal demise, IUGR and preterm delivery. The aim of the present study was to investigate the effects of melatonin on LPS-induced NTDs. All pregnant mice except controls were intraperitoneally injected with LPS (25 µg/kg) daily from gestational day (GD)8 to GD12. Some pregnant mice were orally administered with melatonin (MT, 50 mg/kg) before each LPS injection. A five-day LPS injection resulted in 27.5% of fetuses with anencephaly, exencephaly or encephalomeningocele. Additional experiment showed that maternal LPS exposure significantly down-regulated placental proton-coupled folate transporter (pcft) and disturbed folate transport from maternal circulation through the placentas into the fetus. Interestingly, melatonin significantly attenuated LPS-induced down-regulation of placental pcft. Moreover, melatonin markedly improved the transport of folate from maternal circulation through the placentas into the fetus. Correspondingly, orally administered melatonin reduced the incidence of LPS-induced anencephaly, exencephaly or encephalomeningocele. Taken together, these results suggest that orally administered melatonin prevents LPS-induced NTDs through alleviating LPS-induced disturbance of folate transport from maternal circulation through the placenta into the fetus.

Corn masa flour, used to make products such as corn tortillas, is a staple food for Hispanic populations residing in the United States, particularly among Mexican Americans and Central Americans. Research has indicated that Hispanic women in the United States continue to be at a higher risk of having a neural tube defect-affected pregnancy than women of other races/ethnicities, even after the introduction of folic acid fortification of cereal grain products labeled as "enriched." Corn masa flour has, therefore, been suggested as a potential food vehicle for folic acid in the United States. This paper explores the potential impact that folic acid fortification of corn masa flour could have on the Hispanic population in the United States., (© 2014 New York Academy of Sciences.)

Malaria remains the leading cause of mortality and morbidity in children under the age of 5 years and pregnant women. To counterbalance the malaria burden in pregnancy, an intermittent preventive treatment strategy has been developed. This is based on the use of the antifolate sulfadoxine/pyrimethamine, taken at specified intervals during pregnancy, and reports show that this approach reduces the malaria burden in pregnancy. Pregnancy is also associated with the risk of neural tube defects (NTDs), especially in women with low folate status, and folic acid supplementation is recommended in pregnancy to lower the risk of NTDs. Thus, in malaria-endemic areas, pregnant women have to take both antifolate medication to prevent malaria and folic acid to lower the risk of NTDs. However, the concomitant use of folate and antifolate is associated with a decrease in antifolate efficacy, exposing pregnant women to malaria. Thus, there is genuine concern that this strategy may not be appropriate. We have reviewed work carried out on malaria folate metabolism and antifolate efficacy in the context of folate supplementation. This review shows that: (i) the folate supplementation effect on antifolate efficacy is dose-dependent, and folic acid doses required to protect pregnant women from NTDs will not decrease antifolate activity; and (ii) 5-methyl-tetrahydrofolate, the predominant form of folate in the blood circulation, could be administered (even at high dose) concomitantly with antifolate without affecting antifolate efficacy. Thus, strategies exist to protect pregnant women from malaria while maintaining adequate folate levels in the body to reduce the occurrence of NTDs.

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., (Copyright © 2013 Wiley Periodicals, Inc.)

Background: Hispanics in the US have a higher prevalence of neural tube defect (NTD) -affected pregnancies than non-Hispanic whites, and lower median total folic acid (FA) intake. FA fortification of corn masa flour (CMF) is a policy-level intervention for NTD prevention; however, the impact on NTD prevalence has not been estimated., Methods: We developed a model to estimate the percentage reduction in prevalence of spina bifida and anencephaly (NTDs) that could occur with FA fortification of CMF. Model inputs included estimates of the percentage reduction in United States NTD prevalence attributed to FA fortification of enriched cereal grain products (1995-1996 vs. 1998-2002), the increase in median FA intake after enriched cereal grain product fortification, and the estimated increase in median FA intake that could occur with CMF fortification at the same level as enriched cereal grain products (140 μg/100 g). We used Monte Carlo simulation to quantify uncertainty. We stratified analyses by racial/ethnic group and rounded results to the nearest 10., Results: We estimated CMF fortification could prevent 30 Hispanic infants from having spina bifida (95% uncertainty interval: 0, 80) and 10 infants from having anencephaly (95% uncertainty interval: 0, 40) annually. The estimated impact among non-Hispanic whites and blacks was smaller., Conclusion: CMF fortification with FA could prevent from 0 to 120 infants, with the most likely value of approximately 40, from having spina bifida or anencephaly among Hispanics, the population most likely to benefit from the proposed intervention. While this estimated reduction is unlikely to be discernible using current birth defect surveillance methods, it still suggests an important benefit to the target population., (Copyright © 2013 Wiley Periodicals, Inc.)

Study Question: Can reproductive life plan (RLP)-based information in contraceptive counselling before pregnancy increase women's knowledge of reproduction, and of the importance of folic acid intake in particular?, Summary Answer: The RLP-based information increased women's knowledge of reproduction including knowledge of folic acid intake., What Is Known Already: Many women have insufficient knowledge of reproduction, including a health-promoting lifestyle prior to conception, and highly educated women in particular postpone childbearing until an age when their fertile capacity has started to decrease., Study Design, Size, Duration: The study was an randomized controlled trial with one intervention group (IG) and two control groups (CG1, CG2). A sample size calculation indicated that 82 women per group would be adequate. Recruitment took place during 3 months in 2012 and 299 women were included. The women were randomized in blocks of three. All groups received standard care (contraceptive counselling, Chlamydia testing, cervical screening). In addition, women in the IG were given oral and written RLP-based information about reproduction., Participants/materials, Setting, Methods: A total of 299 out of 338 (88%) Swedish-speaking women visiting a Student Health Centre were included (mean age 23 years); response rate was 88%. Before the counselling, women in the IG and the CG1 completed a baseline questionnaire, including questions about lifestyle changes in connection to pregnancy planning, family planning intentions and knowledge of reproduction (e.g. the fecundity of an ovum). At follow-up 2 months after inclusion, a structured telephone interview was performed in all groups (n = 262, 88% participation rate)., Main Results and the Role of Chance: There was no difference between the groups regarding the mean knowledge score at baseline. The IG scored higher at follow-up than at baseline (P < 0.001); the mean increased from 6.4 to 9.0 out of a maximum 20 points. The women in the CG1 scored no differently at follow-up than at baseline. The difference in the knowledge score between the IG and the two CGs was significant (P < 0.001), whereas no difference was shown between the two CGs. There was no difference between the groups at baseline regarding how many women could mention folic acid intake among the things to do when planning to get pregnant. At follow-up, 22% in the IG, 3% in CG1 and 1% in CG2 mentioned folic acid intake (P < 0.001). At follow-up, more women in the IG also wished to have their last child earlier in life (P < 0.001) than at baseline, while there was no difference in the CG1., Limitations, Reasons for Caution: As the study sample consisted of university students, it is possible that the effect of the intervention was connected to a high level of education and conclusions for all women of reproductive age should be drawn with caution., Wider Implications of the Findings: The provision of RLP-based information seems to be a feasible tool for promoting reproductive health., Study Funding/competing Interest(s): Study funding was received from the Faculty of Medicine, Uppsala University, Sweden. There are no conflicts of interest., Trial Registration Number: ClinicalTrial.gov Identifier NCT01739101.

Background and Objective: The study of congenital defects (CD) must include termination of pregnancy (TOP) for CD and evaluate risk factors that modify their frequency., Patients and Methods: Consecutive series of 517 newborn and 202 TOP with CD among 38,191 childbirths, between 1982-2009 years., Results: The mean frequency for newborns with CD is 13.54‰ and for newborn and TOP with CD is 18.73‰. Single CD are 61.12% in newborns and 52.17% in TOP. The 18.37% of CD in newborn and 40.58% of TOP are syndromic. Mean gestational age for TOP is 17.92 weeks. Overall frequency of anencephaly is 2.62‰ for newborns and 6.77 for 10,000 for newborns and TOP. Spina bifida is 3.14 for 10,000 newborns and 5.99 for 10,000 newborns and TOP. Overall frequency of Down syndrome (DS) is 10.74 for 10,000 newborns and 22.14 for 10,000 newborns and TOP. The percentage of foreign mothers was 35.9% in 2009 and the mean maternal age significantly increased in this period., Conclusion: We observe a significant decrease of CD in newborns but not in their conception. We have not detected primary prevention for neural tube defects. The decrease in DS in newborns is not statistically relevant but ethnic diversity and maternal aging may be modifying the frequency. The 53% of CD were TOP in the period 2007-2009. It is mandatory a complete study for CD in TOP in order to offer serious reproductive counselling., (Copyright © 2012 Elsevier España, S.L. All rights reserved.)

Background: Congenital malformations (CMF) have an important role in infant mortality. Neural tube defects (NTD) have great relevance from both social and public health points of view. The ECLAMC (Collaborative Latin American Study of Congenital Malformations) maintains in Chile an epidemiological surveillance of CMF prevalence rate at birth since 1969., Aim: To assess the effect of wheat flour folic acid fortification on the prevalence of NTD., Patients and Methods: Only Anencephaly, Spina bifida and Cephalocele were considered as NTD. All children born in the maternities incorporated to ECLAMC between 1969 and 1999 were considered as belonging to the pre folic acid fortification period and those who were born from 2001 to 2010 were considered as belonging to the post fortification period., Results: The NTD prevalence rate at birth in the pre fortification period was 17.03/10,000. In the second period, there were 291,996 births and among them, 280 newborns were affected by a form of NTD (9.59 in 10,000 births). This represents a 44% decrease (p < 0.01). Anencephaly rate fell from 7.16/10,000 to 3.67/10,000, representing a 49% lower rate (p < 0.01). Spina bifida rate decreased from 8.61/10,000 to 4.49/10,000, representing a 48% lower rate (p < 0.01). Cephalocele had a 20% non-significant reduction., Conclusions: Wheat flour fortification with folic acid reduced by 44% the prevalence rate of NTD at birth. This means that NTDs were prevented in 185 Chilean newborns each year.

This cross-sectional study analyzed the prevalence and spatial distribution of neural tube defects before and after folic acid flour fortification. The study used the Information System on Live Births (SINASC) and presented prevalence rates according to maternal characteristics with odds ratios (OR) and 95% confidence intervals (95%CI). Polynomial regression was used in time trend analysis and empirical Bayesian smoothed maps for spatial analysis. Total prevalence of neural tube defects decreased by 35%, from 0.57/1,000 to 0.37/1,000 live births after fortification (OR = 0.65; 95%CI: 0.59-0.72). There was a reduction among newborns of mothers with the following characteristics: all age groups (except < 15 years), more than three years of schooling, and seven or more prenatal visits. There was a reduction over time and in most of São Paulo State, except in a few municipalities (counties) located in the western region of the State. Other factors may have contributed to the observed decline, but the results corroborate flour fortification as an important measure to prevent neural tube defects. Further research is needed to elucidate the lack of a decline in neural tube defects in the western part of São Paulo State.

Objective: Dietary intake of methyl donors such as folic acid prevents neural tube defects (NTD), but recent studies showed that it might also favor the development of asthma. In this work a possible ecological association between NTD and asthma was explored., Material and Methods: Data bases from Mexico and the United States (US) were reviewed to obtain information about geographical distribution (by state) and temporal trends (by year) of NTD and asthma., Results: Those states with the lowest frequency of NTD had the highest frequency of asthma, both in Mexico (rS=-0.48, p=0.005) and US (rS=-0.39, p=0.005). Temporal trends also showed an inverse correlation in Mexico (1997-2007, rS=-0.73, p=0.01) and US (1979-1998, rS=-0.91, p<0.001)., Conclusions: In both countries the frequency of asthma inversely correlated with the frequency of NTD, both in geographical distribution and annual trends, giving support to the possibility that methyl donors intake in diet or supplements is influencing the asthma frequency.