According to the World Health Organization (WHO), an estimated 303,000 neonates die within their first month of age every year globally as a result of a birth defect. Neural tube defects, serious birth defects of the brain and spine, are among the most common and severe of these birth defects. Since some low- and middle-income countries lack comprehensive, accurate data documenting the burden of these defects, providing technical assistance to help build birth defects surveillance programs can accelerate the collection of data needed to demonstrate this burden and advance prevention initiatives. We developed a birth defects surveillance toolkit, a technical assistance tool for country staff to help them implement birth defects surveillance. An evaluation of the toolkit with partners in Africa was conducted to assess perceptions of the usefulness, effectiveness, and policy impact of the surveillance toolkit and surveillance-related technical assistance provided to countries thus far. Overall, respondents provided very positive feedback about the toolkit components. Recommendations for improvement included customization to country contexts, such as photos reflective of African babies; surveillance examples from other countries; and consistent use of terms.

BACKGROUND: Folate-sensitive neural tube defects (NTDs) are an important, preventable cause of morbidity and mortality worldwide. There is a need to describe the current global burden of NTDs and identify gaps in available NTD data. METHODS AND FINDINGS: We conducted a systematic review and searched multiple databases for NTD prevalence estimates and abstracted data from peer-reviewed literature, birth defects surveillance registries, and reports published between January 1990 and July 2014 that had greater than 5,000 births and were not solely based on mortality data. We classified countries according to World Health Organization (WHO) regions and World Bank income classifications. The initial search yielded 11,614 results; after systematic review we identified 160 full text manuscripts and reports that met the inclusion criteria. Data came from 75 countries. Coverage by WHO region varied in completeness (i.e., % of countries reporting) as follows: African (17%), Eastern Mediterranean (57%), European (49%), Americas (43%), South-East Asian (36%), and Western Pacific (33%). The reported NTD prevalence ranges and medians for each region were: African (5.2-75.4; 11.7 per 10,000 births), Eastern Mediterranean (2.1-124.1; 21.9 per 10,000 births), European (1.3-35.9; 9.0 per 10,000 births), Americas (3.3-27.9; 11.5 per 10,000 births), South-East Asian (1.9-66.2; 15.8 per 10,000 births), and Western Pacific (0.3-199.4; 6.9 per 10,000 births). The presence of a registry or surveillance system for NTDs increased with country income level: low income (0%), lower-middle income (25%), upper-middle income (70%), and high income (91%). CONCLUSIONS: Many WHO member states (120/194) did not have any data on NTD prevalence. Where data are collected, prevalence estimates vary widely. These findings highlight the need for greater NTD surveillance efforts, especially in lower-income countries. NTDs are an important public health problem that can be prevented with folic acid supplementation and fortification of staple foods.

Our aim was to provide a descriptive overview of how the birth defects surveillance and folic acid fortification programs were implemented in Costa Rica-through the establishment of the Registry Center for Congenital Anomalies (Centro de Registro de Enfermedades Congénitas-CREC), and fortification legislation mandates. We estimated the overall prevalence of neural tube defects (i.e., spina bifida, anencephaly and encephalocele) before and after fortification captured by CREC. Prevalence was calculated by dividing the total number of infants born with neural tube defects by the total number of live births in the country (1987-2012).A total of 1,170 newborns with neural tube defects were identified from 1987 to 2012 (1992-1995 data excluded); 628 were identified during the baseline pre-fortification period (1987-1991; 1996-1998); 191 during the fortification period (1999-2002); and 351 during the post-fortification time period (2003-2012). The overall prevalence of neural tube defects decreased from 9.8 per 10,000 live-births (95 % CI 9.1-10.5) for the pre-fortification period to 4.8 per 10,000 live births (95 % CI 4.3-5.3) for the post-fortification period. Results indicate a statistically significant (P < 0.05) decrease of 51 % in the prevalence of neural tube defects from the pre-fortification period to the post-fortification period. Folic acid fortification via several basic food sources has shown to be a successful public health intervention for Costa Rica. Costa Rica's experience can serve as an example for other countries seeking to develop and strengthen both their birth defects surveillance and fortification programs.

The Centers for Disease Control and Prevention (CDC) conducted its first formal case-control study to better understand the causes of major birth defects in the early 1980s (Erickson et al., 1984). The primary purpose of the study was to evaluate the possible causal contribution of paternal experiences during military service in Vietnam, with particular emphasis on exposures to the herbicide known as “Agent Orange.” The cases and controls were drawn from births that occurred in the Atlanta, Georgia area, where CDC has operated a birth defects surveillance program since 1967. The case-control design permitted evaluation of a wide array of potential maternal exposures that might cause birth defects, as well as additional paternal influences (Erickson, 1991). For example, the study identified a neural tube defect preventive benefit of periconceptional multivitamin use which paved the way for folic acid intervention to prevent neural tube defects (Mulinare et al., 1988). | Building on this experience, the CDC launched the multicenter National Birth Defects Prevention Study (NBDPS) in 1997 to advance understanding of the causes of birth defects. Because the causes of most birth defects are unknown and might be preventable if risk factors are identified, the NBDPS focused on birth defects of unknown etiology (Holmes, 1989). These included neural tube defects, congenital heart defects, orofacial clefts, limb deficiencies, abdominal wall defects, intestinal atresias, and other major birth defects that can be reliably ascertained in early infancy. One unique aspect of the NBDPS addressed the variability of birth defects classification across previous epidemiologic studies. In an effort to increase homogeneity within analytic groups of defects, clinical geneticists collaborated to develop classification guidelines that were applied across the study sites (Rasmussen et al., 2003). This and other efforts to coordinate work and maintain consistent methodology across participating Centers in multiple states, improved the power of NBDPS to identify potential causes of specific birth defects despite the relatively low prevalence of each individual defect type. This is particularly important for studying the epidemiology of birth defects because to date, exposures identified as causing birth defects have a relatively specific impact on one or a few types of birth defects rather than increasing the risk of all birth defects (Tinker, Gilboa, et al., 2015). The NBDPS methods and final counts of data collected are summarized by Reefhuis et al. in this issue (Reefhuis et al., 2015), and the strengths and weaknesses of the NBDPS have been assessed (Dolk, 2015).

INTRODUCTION: Information on folate and vitamin B12 deficiency rates in Guatemala is essential to evaluate the current fortification program. The objectives of this study were to describe the prevalence of folate and vitamin B12 deficiencies among women of childbearing age (WCBA) in Guatemala and to identify vulnerable populations at greater risk for nutrient deficiency. METHODS: A multistage cluster probability study was designed with national and regional representation of nonpregnant WCBA (15-49 years of age). Primary data collection was carried out in 2009-2010. Demographic and health information was collected through face-to-face interviews. Blood samples were collected from 1473 WCBA for serum and red blood cell (RBC) folate and serum vitamin B12. Biochemical concentrations were normalized using geometric means. Prevalence rate ratios were estimated to assess relative differences among different socioeconomic and cultural groups including ethnicity, age, education level, wealth index and rural versus urban locality. RESULTS: National prevalence estimates for deficient serum [<10 nmol per liter (nmol/L)] and RBC folate (<340 nmol/L) concentrations were 5.1 % (95 % CI 3.8, 6.4) and 8.9 % (95 % CI 6.7, 11.7), respectively; for vitamin B12 deficiency (<148 pmol/L) 18.5 % (95 % CI 15.6, 21.3). Serum and RBC folate deficiency prevalences were higher for rural areas than for urban areas (8.0 vs. 2.0 % and 13.5 vs. 3.9 %, respectively). The prevalence of RBC folate deficiency showed wide variation by geographic region (3.2-24.9 %) and by wealth index (4.1-15.1 %). The prevalence of vitamin B12 deficiency also varied among regions (12.3-26.1 %). CONCLUSIONS: In Guatemala, folate deficiency was more prevalent among indigenous rural and urban poor populations. Vitamin B12 deficiency was widespread among WCBA. Our results suggest the ongoing need to monitor existing fortification programs, in particular regarding its reach to vulnerable populations.

Folate is found naturally in foods or as synthetic folic acid in dietary supplements and fortified foods. Adequate periconceptional folic acid intake can prevent neural tube defects. Folate intake impacts blood folate concentration; however, the dose-response between natural food folate and blood folate concentrations has not been well described. We estimated this association among healthy females. A systematic literature review identified studies (1 1992-3 2014) with both natural food folate intake alone and blood folate concentration among females aged 12-49 years. Bayesian methods were used to estimate regression model parameters describing the association between natural food folate intake and subsequent blood folate concentration. Seven controlled trials and 29 observational studies met the inclusion criteria. For the six studies using microbiologic assay (MA) included in the meta-analysis, we estimate that a 6% (95% Credible Interval (CrI): 4%, 9%) increase in red blood cell (RBC) folate concentration and a 7% (95% CrI: 1%, 12%) increase in serum/plasma folate concentration can occur for every 10% increase in natural food folate intake. Using modeled results, we estimate that a natural food folate intake of ≥450 mug dietary folate equivalents (DFE)/day could achieve the lower bound of an RBC folate concentration (~1050 nmol/L) associated with the lowest risk of a neural tube defect. Natural food folate intake affects blood folate concentration and adequate intakes could help women achieve a RBC folate concentration associated with a risk of 6 neural tube defects/10,000 live births.

BACKGROUND: The methylenetetrahydrofolate reductase (MTHFR) 677C>T polymorphism is a risk factor for neural tube defects. The T allele produces an enzyme with reduced folate-processing capacity, which has been associated with lower blood folate concentrations. OBJECTIVE: We assessed the association between MTHFR C677T genotypes and blood folate concentrations among healthy women aged 12-49 y. DESIGN: We conducted a systematic review of the literature published from January 1992 to March 2014 to identify trials and observational studies that reported serum, plasma, or red blood cell (RBC) folate concentrations and MTHFR C677T genotype. We conducted a meta-analysis for estimates of percentage differences in blood folate concentrations between genotypes. RESULTS: Forty studies met the inclusion criteria. Of the 6 studies that used the microbiologic assay (MA) to measure serum or plasma (S/P) and RBC folate concentrations, the percentage difference between genotypes showed a clear pattern of CC > CT > TT. The percentage difference was greatest for CC > TT [S/P: 13%; 95% credible interval (CrI): 7%, 18%; RBC: 16%; 95% CrI: 12%, 20%] followed by CC > CT (S/P: 7%; 95% CrI: 1%, 12%; RBC: 8%; 95% CrI: 4%, 12%) and CT > TT (S/P: 6%; 95% CrI: 1%, 11%; RBC: 9%; 95% CrI: 5%, 13%). S/P folate concentrations measured by using protein-binding assays (PBAs) also showed this pattern but to a greater extent (e.g., CC > TT: 20%; 95% CrI: 17%, 22%). In contrast, RBC folate concentrations measured by using PBAs did not show the same pattern and are presented in the Supplemental Material only. CONCLUSIONS: Meta-analysis results (limited to the MA, the recommended population assessment method) indicated a consistent percentage difference in S/P and RBC folate concentrations across MTHFR C677T genotypes. Lower blood folate concentrations associated with this polymorphism could have implications for a population-level risk of neural tube defects.

In 1992, the U.S. Public Health Service recommended that all women capable of becoming pregnant consume 400 microg 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 microg 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.

BACKGROUND: Childhood asthma has become a critical public health problem because of its high morbidity and increasing prevalence. The impact of nutrition and other exposures during pregnancy on long-term health and development of children has been of increasing interest. OBJECTIVE: We performed a systematic review and meta-analysis of the association of folate and folic acid intake during pregnancy and risk of asthma and other allergic outcomes in children. DESIGN: We performed a systematic search of 8 electronic databases for articles that examined the association between prenatal folate or folic acid exposure and risk of asthma and other allergic outcomes (eg, allergy, eczema, and atopic dermatitis) in childhood. We performed a meta-analysis by using a random-effects model to derive a summary risk estimate of studies with similar exposure timing, exposure assessment, and outcomes. RESULTS: Our meta-analysis provided no evidence of an association between maternal folic acid supplement use (compared with no use) in the prepregnancy period through the first trimester and asthma in childhood (summary risk estimate: 1.01; 95% CI: 0.78, 1.30). Because of substantial heterogeneity in exposures and outcomes, it was not possible to generate summary measures for other folate indicators (eg, blood folate concentrations) and asthma or allergy-related outcomes; however, the preponderance of primary risk estimates was not elevated. CONCLUSIONS: Our findings do not support an association between periconceptional folic acid supplementation and increased risk of asthma in children. However, because of the limited number and types of studies in the literature, additional research is needed.

BACKGROUND: The Institute of Medicine set a tolerable upper intake level (UL) for usual daily total folic acid intake (1,000 microg). Less than 3% of US adults currently exceed the UL. OBJECTIVE: The objective of this study was to determine if folic acid fortification of corn masa flour would increase the percentage of the US population who exceed the UL. DESIGN: We used dietary intake data from NHANES 2001-2008 to estimate the percentage of adults and children who would exceed the UL if corn masa flour were fortified at 140 microg of folic acid/100 g. RESULTS: In 2001-2008, 2.5% of the US adult population (aged≥19 years) exceeded the UL, which could increase to 2.6% if fortification of corn masa flour occurred. With corn masa flour fortification, percentage point increases were small and not statistically significant for US adults exceeding the UL regardless of supplement use, sex, race/ethnicity, or age. Children aged 1-8 years, specifically supplement users, were the most likely to exceed their age-specific UL. With fortification of corn masa flour, there were no statistically significant increases in the percentage of US children who were exceeding their age-specific UL, and the percentage point increases were small. CONCLUSIONS: Our results suggest that fortification of corn masa flour would not significantly increase the percentage of individuals who would exceed the UL. Supplement use was the main factor related to exceeding the UL with or without fortification of corn masa flour and within all strata of sex, race/ethnicity, and age group.

OBJECTIVE: Hispanics with lower acculturation may be at higher risk for neural tube defects compared with those with higher acculturation due to lower total folic acid intake or other undetermined factors. Modelling has indicated that fortification of corn masa flour with folic acid could selectively target Mexican Americans more than other race/ethnicities. We assessed whether fortification of corn masa flour with folic acid could selectively increase folic acid intake among Mexican-American women with lower acculturation, as indicated by specific factors (language preference, country of origin, time living in the USA). DESIGN: We used dietary intake and dietary supplement data from the National Health and Nutrition Examination Survey 2001-2008, to estimate the amount of additional total folic acid that could be consumed if products considered to contain corn masa flour were fortified at 140 mcg of folic acid per 100 g of corn masa flour. SETTING: USA. SUBJECTS: Non-pregnant women aged 15-44 years (n 5369). RESULTS: Mexican-American women who reported speaking Spanish had a relative percentage change in usual daily total folic acid intake of 30.5 (95 % CI 27.8, 33.4) %, compared with 8.3 (95 % CI 7.3, 9.4) % for Mexican-American women who reported speaking English. We observed similar results for other acculturation factors. An increase of 6.0 percentage points in the number of Mexican-American women who would achieve the recommended intake of ≥400 mcg folic acid/d occurred with fortification of corn masa flour; compared with increases of 1.1 percentage points for non-Hispanic whites and 1.3 percentage points for non-Hispanic blacks. An even greater percentage point increase was observed among Mexican-American women who reported speaking Spanish (8.2). CONCLUSIONS: Fortification of corn masa flour could selectively increase total folic acid intake among Mexican-American women, especially targeting Mexican-American women with lower acculturation, and result in a decrease in the number of pregnancies affected by neural tube defects.

Through the early 20th century, the human uterus was thought to protect the developing fetus from maternal infections and environmental exposures. However, in the 1940s the first case reports of maternal rubella infection being linked to birth defects appeared in the literature, and, in the early 1960s, it was understood that maternal use of thalidomide caused an epidemic of limb deficiencies. These sentinel events led to the realization that maternal infections and other environmental factors could cause birth defects. This realization, in turn, led to the establishment of birth defects surveillance systems in the United States and other countries. | Public health surveillance is defined as the ongoing, systematic collection, analysis, interpretation, and dissemination of data regarding a health-related event for use in public health action to reduce morbidity and mortality and to improve health in the population (Thacker and Berkelman, 1992; CDC, 2001). Birth defects surveillance data have been used for public health action, program planning and evaluation, and formulating research hypotheses. Some examples of the types of public health action for which birth defects surveillance data have been used include the following: | Guiding action for issues of public health importance or concern. Birth defects surveillance data have been useful in evaluating community concerns about specific environmental exposures (e.g., water fluoridation, airport noise, air pollution) and birth defects (Erickson et al., 1976; Edmonds et al., 1979; Strickland et al., 2009), as well as for addressing concerns about clusters of birth defects possibly associated with less well-defined environmental factors (Calvert et al., 2007; Kucik et al., 2008). | Quantifying the burden of disease. Birth defects surveillance data have been useful in documenting the prevalence of major birth defects in the population (Correa et al., 2007; Rynn et al., 2008), the birth prevalence for specific defects such as Down syndrome, neural tube defects, and heart defects (Siffel et al., 2004; Canfield et al., 2006; Reller et al., 2008), as well as the prevalence of spina bifida and Down syndrome among children and adolescents (Shin et al., 2008; Shin et al., 2009). | Identifying populations at risk and/or health disparities. Birth defects surveillance data have been useful in identifying a higher prevalence of neural tube defects among Hispanics as compared to non-Hispanic whites in the United States (Kirby et al., 2000; Canfield et al., 2006). Similarly, linkages of birth defects surveillance data with vital status data have been useful in identifying race/ethnic disparities in survival for several defects (Dott et al., 2003; Rasmussen et al., 2006; Yang et al., 2006). Such studies have stimulated more research into possible determinants of such disparities in prevalence and survival. | Monitoring trends in the prevalence of birth defects. Birth defects surveillance data have been important in documenting decreasing trends in the prevalence of congenital rubella in relation to declining prevalence of maternal rubella infections (Cochi et al., 1989), trends in prevalence of selected birth defects before and after folic acid fortification (Canfield et al., 2005; Botto et al., 2006), and trends in the prevalence of gastroschisis (Williams et al., 2005; Loane et al., 2007), hypospadias (Carmichael et al., 2003; Dolk et al., 2004; Nassar et al., 2007), and congenital heart defects (Botto et al., 2001). | Evaluating outcomes among children with birth defects. Birth defects surveillance data have been useful in population-based evaluations of whether children with birth defects have an increased prevalence of developmental disorders (Decoufle et al., 2001; Yazdy et al., 2008) and the survival experience of children with birth defects (Nembhard et al., 2001; Wong and Paulozzi, 2001; Cleves et al., 2003; Rasmussen et al., 2006; Copeland and Kirby, 2007; Fixler et al., 2010). | Guiding the planning, implementation, and evaluation of programs to prevent birth defects and adverse exposures. Birth defects surveillance data on the prevalence of neural tube defects and in the variation of such prevalence by race/ethnic groups in the population have been instrumental in the development, implementation, and evaluation of policies for folic acid fortification for the prevention of neural tube defects (Canfield et al., 2005; Botto et al., 2006; Bower, 2006). | Serving as case registries for epidemiologic research. Several birth defects surveillance systems have served as cases registries for epidemiologic studies, including studies of possible associations of birth defects with paternal Vietnam Veteran status (Erickson et al., 1984), maternal vitamin supplement use (Mulinare et al., 1988), diabetes (Correa et al., 2008), obesity (Watkins et al., 2003; Waller et al., 2007; Gilboa et al., 2010), smoking (Honein et al., 2007; Malik et al., 2008), assisted reproductive technologies (Bower and Hansen, 2005; Reefhuis et al., 2009), and certain medications (Reefhuis et al., 2006; Caton et al., 2009; Alwan et al., 2010).

BACKGROUND: The recurrence risk for neural tube defects (NTDs) in subsequent pregnancies is approximately 3%, or 40 times the background risk. Prevention projects target these high-risk women to increase their folic acid consumption during the periconceptional period, a behavior which decreases their recurrence risk by at least 85%. This study surveyed birth defect surveillance programs to assess their NTD recurrence prevention activities and to identify components of intervention projects that might be implemented in states with limited resources. METHODS: In 2005, the National Birth Defects Prevention Network developed and distributed an online survey to primary state birth defects surveillance contacts for the purpose of gathering information on NTD recurrence prevention activities in the United States. RESULTS: Responses came from 37 contacts in 34 states and Puerto Rico. There were 13 active NTD recurrence prevention projects, four past projects, and three planned projects. Fifteen past and present projects recommended that women with a prior NTD-affected birth take 4.0 mg of folic acid daily, and four projects provided folic acid to the women. Reasons given for not having an NTD recurrence prevention project included staffing limitations (53%), lack of funds (47%), lack of priority (18%), and confidentiality/privacy concerns (6%). CONCLUSIONS: Only 15 states and Puerto Rico had or were planning NTD recurrence prevention projects. An NTD recurrence prevention project using minimal resources should consist of timely case ascertainment, educational materials, and mechanisms for disseminating these materials.