Recommendations For Folic Acid Supplementation Research Articles

Reaffirming Recommendations for Folic Acid Supplementation

Reaffirming Recommendations for Folic Acid Supplementation

Women Taking a Folic Acid Supplement in Countries with Mandatory Food Fortification Programs May Be Exceeding the Upper Tolerable Limit of Folic Acid: A Systematic Review.

Background: In preconception and pregnancy, women are encouraged to take folic acid-based supplements over and above food intake. The upper tolerable limit of folic acid is 1000 mcg per day; however, this level was determined to avoid masking a vitamin B12 deficiency and not based on folic acid bioavailability and metabolism. This review’s aim is to assess the total all-source intake of folate in women of childbearing age and in pregnancy in high-income countries with folate food fortification programs. Methods: A systematic search was conducted in five databases to find studies published since 1998 that reported folate and folic acid intake in countries with a mandatory fortification policy. Results: Women of childbearing age do not receive sufficient folate intake from food sources alone even when consuming fortified food products; however, almost all women taking a folic acid-based supplement exceed the upper tolerable limit of folic acid intake. Conclusions: Folic acid supplement recommendations and the upper tolerable limit of 1000 mcg set by policy makers warrant careful review in light of potential adverse effects of exceeding the upper tolerable limit on folic acid absorption and metabolism, and subsequent impacts on women’s health during their childbearing years.

Incidence and risk factors for neural tube defects in a Bosnian population

Introduction: Neural tube defects (NTDs) are multifactorial congenital anomalies of the central nervous system that results from failed neural tube closure between the 3rd and 4th weeks of embryonic development. Numerous clinical and experimental studies indicate that supplementation with folic acid before and during early pregnancy reduces the development of these anomalies. The present study examined the incidence and risk factors for NTDs and evaluated the effects of folic acid supplementation.Methods: This cross-sectional study included all children with NTDs who were hospitalized at the Pediatric Clinic, Clinical Centre University of Sarajevo during the period from January 01, 2008 to December 31, 2012. Data were collected retrospectively from the medical histories of hospitalized children. The study included children in pediatric clinics from four cantons (Sarajevo, Zenica–Doboj, Unsko–Sanski, and Central Bosnia) of the Federation of Bosnia and Herzegovina. The number of live births for the specified period in each of the four cantons was taken from a report by the Cantonal Ministry of Health.Results: Among the 69,096 live births recorded during the study period, 39 children had verified NTDs, with an overall incidence of 0.56:1,000 (or 5.6:10,000) in all four cantons. The most common NTDs were myelomeningocele with hydrocephalus (22/39, 56.4%), followed by isolated myelomeningocele (9/39, 23.1%), spina bifida occulta (7/39, 17.9%), and occipitocele (1/39, 2.6%). A total of 33.3% (13/39) of mothers took folic acid, but only one began supplementation prior to pregnancy, while 67.7% (26/39) of mothers did not take folic acid during pregnancy. NTDs were found more frequently in primiparas (53.8%), women with low education (basic school, 64.1%), and unemployed women (82.1%).Conclusion: It is important to make national recommendations for folic acid supplementation for women of reproductive age, but also change the public health policy that includes mandatory fortification of basic foods as this is the best measure for primary prevention of NTDs in the whole population regardless of employment and education status. Additional comprehensive studies are required to assess the incidence and risk factors throughout Bosnia and Herzegovina.

Periconceptional folic acid supplement use among women of reproductive age and its determinants in central rural Germany: Results from a cross sectional study

Prevalence of neural tube defects (NTD) has not decreased in Germany despite longstanding recommendations for folic acid supplementation. To examine the prevalence of periconceptional folic acid supplement use and associated factors among German women of reproductive age. Cross-sectional survey was conducted in hospital-based maternity units in rural Germany. A sample of 1,004 women of reproductive age, either pregnant or in their early postpartum period, took interviewer/self-administered paper-based survey questionnaire. Prevalence of periconceptional folic acid supplement use was assessed, where periconception was defined as 1 month prior to and 3 months post-conception. Prevalence odds ratios (POR) and 95% confidence intervals (CI) using crude and adjusted logistic regression analysis were estimated to examine determinants of folic acid supplement use. Prevalence of folic acid supplement use was 41.5% (95% CI: 37.7%, 45.7%). Multivariable analysis showed lack of educational qualifications, unplanned pregnancy, later diagnosis of pregnancy, increased parity, and not having an awareness of importance of folic acid for optimal pregnancy outcomes were associated with not taking periconceptional folic acid supplements. Books, doctors, friends, media, were sources of information. Periconceptional folic acid is sub-optimal in rural Germany and thus failing to prevent NTDs. Targeted promotion of folic acid supplement use should be conducted periodically by gynecologists and primary care physicians during annual medical screenings. Mandatory folic acid fortification of staple foods is a complementary approach to overcome limitations of individual behaviors of folic acid supplement intake, and should be considered as it has been proven effective in multiple countries.

Moderately elevated first trimester fasting plasma total homocysteine is associated with increased probability of miscarriage. The Reus-Tarragona Birth Cohort Study

The association between elevated early pregnancy fasting plasma total homocysteine (tHcy) and miscarriage risk was investigated prospectively in participants (n = 544) from the Reus-Tarragona Birth Cohort study. Pregnancy was confirmed before 12 gestational weeks (GW) by ultrasound scan and a fasting blood sample collected. Pregnancies with complications other than miscarriages were excluded. Miscarriages were diagnosed by ultrasound scan and gestational age at the time of miscarriage estimated by embryo size, where possible. Cases in which blood samples were collected more than a week after the miscarriage, or the miscarriage was of known cause, were excluded.Fasting plasma folate, vitamin B12, tHcy, cotinine (biomarker of smoking), red blood cell (RBC) folate, MTHFR 677C > T (rs1801133) and SLC19A1 80G>A (rs1051266) genotypes were determined.The exposed group consisted of participants with first trimester tHcy ≥ P90 (7.1 μmol/L) (n = 57) and unexposed of those with tHcy < P90 (n = 487). Adherence to folic acid supplement recommendations, plasma folate, plasma vitamin B12, RBC folate and prevalence of optimal RBC folate status (≥ 906 μmol/L) were lower in the exposed compared to unexposed group. The prevalences of the MTHFR 677 TT genotype and miscarriage were higher in the exposed group. The relative risks (95% CI) of pregnancy ending in miscarriage were 2.5 (1.1, 5.7) and 2.1 (1.0, 4.5) for participants in the high tHcy and suboptimal RBC folate groups (compared to the reference groups) respectively. Adherence to folic acid supplement recommendations was positively associated, while the MTHFR 677 TT versus CC genotype and smoking versus non-smoking were negatively associated, with RBC folate status.

84 Folate-methionine cycle and folate transport in developing buffalo embryos

Periconceptional folic acid is known to have a major role in the prevention of neural tube defects, leading to global recommendations for folic acid supplementation before and in early pregnancy. Maternal folate throughout pregnancy may have other roles in offspring health, including neurodevelopment and cognitive performance in childhood. Folate and folic acid (vitamin B9) act as a co-enzyme essential for single carbon metabolism, a network of pathways involved in several biological processes including nucleotide synthesis, DNA repair, and methylation reactions. In general, rapidly growing and multiplying cells require an adequate supply of folate. A primary deficiency of natural folate resulting in an increase of the total homocysteine concentration may be detrimental to the quality of the oocyte, subsequent fertilisation, embryogenesis, implantation, and fetal development. However, to date, folate-methionine metabolism and folate transport have not been studied in developing buffalo embryos. The present study details transcript expression for genes encoding key enzymes in the linked folate-methionine cycles in the ovary tissue, cumulus cells, immature oocytes, IVM oocytes, and pre-implantation embryos and also estimates the folate concentration in follicular fluid (FF) of buffalo. The FF was pooled and collected by aspiration of different sizes of surface follicles (2-8mm diameter). The total number of analysed samples was three, with different dilutions and estimation of folate in FF of buffalo done by chemiluminescence assay. Total RNA was extracted from oocytes, cumulus cells, ovarian tissue, and embryos produced from IVF. RT-PCR was performed to analyse the expression of folate-methionine cycle enzymes and folate transporters. Transcripts for all the enzymes of the folate-methionine cycle (i.e. SHMT, MTR, MTRR, MAT1A, MAT2B, GNMT, AHCY, CBS, and DHFR) and folate transporters (FOLR1, FOLR2) and reduced folate carrier (SLC19A1) were expressed in ovarian tissue, cumulus cells, oocytes, and pre-implantation embryos. Immunocytochemical analysis revealed FOLR2 and SLC19A1 protein expression on the plasma membrane and/or cytoplasm of the oocytes and embryos, and FOLR1 in the nucleus of pre-implantation embryos. The folate concentration in FF was 24ngmL−1. This is the first report to examine the concentration of folate in FF and revealed the identification of transcripts in different samples of buffalo species. The presence of these enzymes could have a profound effect on single-carbon metabolism within the ovary and pre-implantation embryo, therefore indicating that folate from FF is being disseminated through folate receptors within oocytes and embryos to participate in the folate pathway. This study advocates the necessity for examination of the result of folate supplementation throughout invitro embryo production for improving the quality and quantity of transferable blastocysts and subsequently live calf births in buffalo.

Modelling the impact of mandatory folic acid fortification of bread or flour in Ireland on the risk of occurrence of NTD-affected pregnancies in women of childbearing age and on risk of masking vitamin B12 deficiency in older adults

The rate of neural tube defects (NTDs) in Europe has remained similar since the 1990s despite folic acid supplement recommendations (400µg/day) for women of childbearing age. Mandatory folic acid fortification of staple foods has proved effective for reducing the prevalence of NTDs in over 80 countries. This study estimated the impact of addition of folic acid to bread or flour in the Republic of Ireland on reducing the risk of occurrence of NTD-affected pregnancies and the possible risk of masking (undiagnosed) vitamin B12 deficiency in older adults. Analyses were based on the Irish National Adult Nutrition Survey (2008-2010). Folic acid fortification was modelled using DaDiet© software. Estimates were made of the increase in average daily folic acid intake in women (18-50years) and the risk of exceeding the tolerable upper intake level (UL) of 1000µg for folic acid in adults over 50years of age. The fortification scenarios examined would reduce the risk of NTD-affected pregnancies by 8-32%, corresponding to an increase of 39-152μg in the mean daily folic acid intake of WCBA. The risk of masking anaemia associated with vitamin B12 deficiency in older adults would be negligible as the probability of exceeding the UL for folic acid, even by a small amount, is very low (≤ 0.2%). These levels of addition of folic acid to bread or flour would effectively reduce the risk of NTDs while allowing safe consumption of folic acid at current levels from other fortified foods and supplements.

The Importance of Maternal Folate Status for Brain Development and Function of Offspring

The importance of an adequate periconceptional maternal folate status to prevent fetal neural tube defects has been well demonstrated and resulted in the recommendation for women to use folic acid supplements during the periconception period. The importance of maternal folate status for offspring neurodevelopment and brain health is less well described. We reviewed the current evidence linking maternal folate status before conception and during pregnancy with neurodevelopment and cognition of the offspring. We discuss both animal and human studies. Preclinical research revealed the importance of maternal folate status for several key processes required for normal neurodevelopment and brain functioning in the offspring, including DNA synthesis, regulation of gene expression, synthesis of phospholipids and neurotransmitters, and maintenance of healthy plasma homocysteine concentrations. Human observational studies are inconclusive; about half have shown a positive association between maternal folate status and cognitive performance of offspring. Whereas some studies suggest a positive association between maternal folate intake and cognition of offspring during childhood, data from interventional studies are too limited to conclude that there is a direct effect. Future preclinical studies are needed to help us characterize the behavioral effects, understand the underlying mechanisms, and to establish an optimal dosage and time window of folate supplementation. Moreover, more conclusive data from well-designed human observational studies and randomized controlled trials are needed to determine whether current recommendations for folic acid supplementation during pregnancy cover the needs for normal cognitive development in the offspring.

Improving Folic Acid Supplementation Rates in Women of Childbearing Age With Epilepsy

BackgroundThis study aims to improve the rate of folic acid supplementation to adolescent women with epilepsy on an antiepileptic drug (AED) regimen seen by the pediatric neurology providers at the Children's Hospital at Montefiore, in compliance with the 2009 American Academy of Neurology and American Epilepsy Society practice parameter. MethodsWe designed a quality improvement study with implementation of a series of interventions and compared folic acid supplementation rates before and after intervention. We made additional comparisons based on specific age groups (12 to 15 years and 16 to 21 years) and a diagnosis with or without developmental impairment. ResultsA review of 1850 charts from 2004 to 2015 showed an average folic acid prescription rate of 41%. Supplementation rates gradually increased to 52.2%, 58.5%, 60.3%, and finally up to 81.6% after this respective intervention: initial email reminder, provider education, posting signs in examination rooms, and implementation of an electronic medical record best practice advisory. There was improvement across all categories, in both age groups (12 to 15 years and 16 to 21 years) and in those with or without developmental impairment. There was a trend for higher compliance rates in adolescents without developmental impairment. ConclusionsOur interventions resulted in an increase in folic acid supplementation rates of adolescent women with epilepsy. These results are encouraging. We plan to extend education about the recommendations for folic acid supplementation to non-neurology providers, as well as expand to apply our interventions and assess adherence to other defined epilepsy quality measures.

In memoriam: Dr. Andrew Czeizel.

In memoriam: Dr. Andrew Czeizel.

Long term trends in prevalence of neural tube defects in Europe: population based study

Study question What are the long term trends in the total (live births, fetal deaths, and terminations of pregnancy for fetal anomaly) and live birth prevalence of neural tube defects...

A cohort study of a tailored web intervention for preconception care.

BackgroundPreconception care may be an efficacious tool to reduce risk factors for adverse pregnancy outcomes that are associated with lifestyles and health status before pregnancy. We conducted a web-based cohort study in Italian women planning a pregnancy to assess whether a tailored web intervention may change knowledge and behaviours associated with risks for adverse pregnancy outcomes.MethodsThe study was entirely conducted on the web on a cohort of Italian women of childbearing age. Data collected at baseline on health status, lifestyles and knowledge of risk factors for adverse pregnancy outcomes were used for generating a tailored document including recommendations for folic acid supplementation, obesity and underweight, smoking, alcohol consumption, vaccinations, chronic and genetic diseases, exposure to medications. Prevalence of risk factors and knowledge was assessed 6 months after the intervention. Logistic regression models were used to explore the factors associated with risk factors after the intervention.ResultsOf the 508 enrolled women, 282 (55.5%) completed the study after 6 months since the delivery of tailored recommendations. At baseline, 48% of the participants took folic acid supplementation (95% CI 43.2; 51.9) and 69% consumed alcohol (95% CI 64.7; 72.9). At the follow up 71% of the participants had a preconception visit with a physician. Moreover we observed a decrease of alcohol consumption (−46.5% 95% CI −53.28; −38.75) and of the proportion of women not taking folic acid supplementation (−23.4% 95% CI −31.0; 15.36). We observed an improvement in knowledge of the information about the preconception behaviours to prevent adverse pregnancy outcomes (20.9% 95% CI 14.6%; 27.1%). Having a preconception visit during follow up was significally associated to an increase in folic acid supplementation (OR 2.53 95% CI 1.40; 4.60).ConclusionsOur results suggest that a tailored web intervention may improve general preconception health in women planning a pregnancy. A web preconception intervention may be integrated with classic preconception care by health professionals. Clinical trials should be conducted to confirm these findings.

Examining the folate status of Canadians: An analysis of the Canadian Health Measures Survey to assess and guide folate policies

Canada fortifies certain products with folic acid and has periconceptional supplementation guidelines [Formula: see text] policies designed to improve folate status and reduce the incidence of poor birth outcomes. Though optimal folate concentrations have been linked to health benefits, concerns have been raised regarding potential associations with adverse health outcomes. Direct biochemical assessment of the folate status of Canadians based on a nationally representative sample has not been done in more than 40 years. The overall purpose of this research was to investigate the folate status of the Canadian population. All analyses used the nationally representative 2007–2009 Canadian Health Measures Survey (CHMS). Red blood cell (RBC) folate was measured by Immulite 2000 immunoassay. Key findings indicate that folate deficiency (&lt;305 nmol/L) was virtually nonexistent in the Canadian population (6–79 years old). Still, one-fifth of women of childbearing age (WCBA; 15–45 years old) had suboptimal concentrations for the prevention of neural tube defects (&lt;906 nmol/L). Folic acid supplement intake was a primary determinant of WCBA, achieving a RBC folate concentration of ≥906 nmol/L. A distinct shift towards elevated RBC folate concentrations emerged. Three hypothetical cut-offs (1450 nmol/L, 1800 nmol/L and 2150 nmol/L) were examined to create a dialogue since a universal definition of high RBC folate concentration does not exist. Females, participants aged 60–79 years, and those who were overweight or obese had the greatest prevalence of having high RBC folate at each cut-off. We conducted the first national-level comparison of RBC folate concentrations between the United States and Canada. Two different folate assay methods [Formula: see text] microbiologic assay (NHANES) and Immulite 2000 immunoassay (CHMS) [Formula: see text] necessitated the application of a conversion equation. Median Canadian RBC folate concentrations (adjusted to microbiologic assay) were lower than those of Americans but unadjusted Canadian median RBC folate values were higher. Canadian WCBA were less likely than American WCBA to have RBC folate ≥906 nmol/L, though Canadian WCBA with unadjusted RBC folate values were more likely to achieve this cut-off. These results indicate a need for strategies targeting WCBA to improve compliance with folic acid supplement recommendations. The strength and necessity of supplements for the general population should be re-assessed. Further, harmonization of folate measurement procedures in future surveillance efforts would support comparisons and inform policy directions.

Folate and Asthma

Findings from experimental studies and animal models led to the hypothesis that folic acid supplementation during pregnancy confers an increased risk of asthma. This review provides a critical examination of current experimental and epidemiologic evidence of a causal association between folate status and asthma. In industrialized nations, the prevalence of asthma was rising before widespread fortification of foodstuffs with folic acid or folate supplementation before or during pregnancy, thus suggesting that changes in folate status are an unlikely explanation for "the asthma epidemic." Consistent with this ecologic observation, evidence from human studies does not support moderate or strong effects of folate status on asthma. Given known protective effects against neural tube and cardiac defects, there is no reason to alter current recommendations for folic acid supplementation during conception or pregnancy based on findings for folate and asthma. Although we believe that there are inadequate data to exclude a weak effect of maternal folate status on asthma or asthma symptoms, such effects could be examined within the context of very large (and ongoing) birth cohort studies. At this time, there is no justification for funding new studies of folate and asthma.

Recent Decrease in the Prevalence of Congenital Heart Defects in Europe

To examine trends in the prevalence of congenital heart defects (CHDs) in Europe and to compare these trends with the recent decrease in the prevalence of CHDs in Canada (Quebec) that was attributed to the policy of mandatory folic acid fortification. We used data for the period 1990-2007 for 47 508 cases of CHD not associated with a chromosomal anomaly from 29 population-based European Surveillance of Congenital Anomalies registries in 16 countries covering 7.3 million births. We estimated trends for all CHDs combined and separately for 3 severity groups using random-effects Poisson regression models with splines. We found that the total prevalence of CHDs increased during the 1990s and the early 2000s until 2004 and decreased thereafter. We found essentially no trend in total prevalence of the most severe group (group I), whereas the prevalence of severity group II increased until about 2000 and decreased thereafter. Trends for severity group III (the most prevalent group) paralleled those for all CHDs combined. The prevalence of CHDs decreased in recent years in Europe in the absence of a policy for mandatory folic acid fortification. One possible explanation for this decrease may be an as-yet-undocumented increase in folic acid intake of women in Europe following recommendations for folic acid supplementation and/or voluntary fortification. However, alternative hypotheses, including reductions in risk factors of CHDs (eg, maternal smoking) and improved management of maternal chronic health conditions (eg, diabetes), must also be considered for explaining the observed decrease in the prevalence of CHDs in Europe or elsewhere.

Folic acid supplement use is the most significant predictor of folate concentrations in Canadian women of childbearing age

One-fifth of Canadian women of childbearing age (WCBA) have red blood cell (RBC) folate concentrations below those considered optimal for neural tube defect risk reduction (≥906 nmol·L(-1)). Determinants of optimal concentrations have not been examined in a nationally representative sample of Canadian WCBA since food fortification with folic acid was implemented. This study explored correlates of optimal RBC folate concentrations and characteristics of folic acid supplement users in a sample of Canadian WCBA. RBC folate concentrations from the 2007-2009 Canadian Health Measures Survey were assessed in women aged 15 to 45 years (n = 1162). Sociodemographic, behavioural, and clinical determinants of RBC folate ≥906 nmol·L(-1) were examined using univariate and separate multiple logistic regression models that controlled for age and household income. t tests were used to study differences between folic acid supplement users and nonusers. WCBA not taking folic acid supplements were less likely to achieve a RBC folate concentration ≥906 nmol·L(-1) compared with folic acid supplement users (odds ratio, 0.47; 95% confidence interval, 0.24, 0.92). Twenty-five percent of WCBA reported folic acid supplement use, and there was a higher percentage of folic acid supplement users in the highest income group. Folic acid supplement users were also more frequent consumers of supplemental vitamin B(12) and of fruit and vegetables (>3 times per day). Folic acid supplement use was the most significant predictor of WCBA achieving optimal RBC folate concentrations. These results indicate a need for targeted strategies to improve compliance with folic acid supplement recommendations among WCBA.

Inadequate compliance with periconceptional folic acid supplementation in South Australia

Despite recommendations for women to take folic acid supplements, there has been little reduction in the number of neural tube defect cases occurring each year. To assess the level of compliance of pregnant women to recommendations for folic acid supplementation in South Australia, and audit the labelled content in reported supplements used. A survey was conducted from May to September 2005 with 304 pregnant women recruited from antenatal clinics at the Lyell McEwin Health Service, the Women's and Children's Hospital and the Modbury Hospital in Adelaide. Full compliance with supplementation recommendations for both timing and dose was achieved by 30% of women. Partial compliance was achieved by 43%, while 27% took no folic acid supplements. There is currently poor compliance with folic acid supplementation around conception. Additional food fortification may better achieve an adequate daily level of folic acid.

Folic acid and the prevention of neural tube defects: A position paper of the national society of genetic counselors

Considerable scientific evidence demonstrates the reduction in risk for neural tube defects (NTDs) associated with maternal preconceptional folic acid supplementation. The National Society of Genetic Counselors (NSGC) endorses the U.S. Public Health Service recommendations for folic acid supplementation at the 0.4 mg level for women in the general population and at the 4.0 mg level for women at high or increased risk for NTD pregnancies for at least 4 weeks prior to active pursuit of conception. We encourage targeted educational efforts and surveillance to assess results of this dietary supplementation. The NSGC further urges the Food and Drug Administration to fortify staple foodstuffs with folic acid for a population-based approach to minimize the number of NTD births.

Periconceptional supplementation with folic acid: Does it prevent neural tube defects?

There has been considerable controversy in recent years concerning the benefit of periconceptional vitamin supplementation in the prevention of neural tube defects. Recent reports of a successful randomized clinical trial have prompted official recommendations for folic acid supplementation in women with a history of an affected pregnancy. Periconceptional supplementation of low-risk women remains controversial.

Interim CDC Recommendations for Folic Acid Supplementation for Women—August 1991

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