Prevalence of Obesity Is Higher in Patients Admitted to an Acute Behavioral Hospital

Fruit, Vegetables, and Folate: Cultivating the Evidence for Cancer Prevention

Folate and Vitamin B6 Intake and Risk of Colon Cancer in Relation to p53 Expression

: Dietary folate, a water-soluble B vitamin found in a variety of fruits and vegetables, is of particular interest as a chemopreventive agent due to its role in DNA methylation and DNA synthesis and repair. We hypothesized that individuals with low folate intake would be at an increased risk for bladder cancer. Using an ongoing case-control study we assessed dietary folate in 409 incident bladder cancer patients and 451 healthy control subjects. A food-frequency questionnaire was used to estimate naturally occurring food folate (μg/kcal/day), dietary folate equivalents (DFE) from food sources (μg DFE/kcal/day), and DFE from all sources (μg DFE/kcal/day). Unconditional logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Bladder cancer patients reported a statistically significant lower intake of folate than control subjects for food folate and DFE from food sources (P < 0.001) but not for DFE from all sources (P = 0.061). In the highest quartile of food folate intake there was a 54% reduced risk for bladder cancer (OR = 0.46; 95% CI = 0.29-0.73) after adjusting for age, gender, ethnicity, smoking, and total energy intake. Similarly, the highest quartile of intake was associated with a 59% reduced risk for DFE from food sources (OR = 0.41; 95% CI = 0.26-0.65) and a 35% reduced risk for DFE from all sources (OR = 0.65; 95% CI = 0.42-1.00). In the joint-effects analyses using never smokers with high folate intake as the reference group (OR = 1.0), heavy smokers with low food folate intake had a 2.31-fold (95% CI = 1.11-4.82) increased risk, whereas heavy smokers with high folate intake had a reduced OR of 1.31 (95% CI = 0.53-3.26). Although the ORs were not statistically significant, light smokers and high folate intake exhibited a protective effect (OR = 0.62; 95% CI = 0.20-1.94), whereas an increased risk was observed for light smoking and low folate intake (OR = 1.41; 95% CI = 0.57-3.45). These patterns were consistent for the joint effects of smoking and DFE from food sources and DFE from all sources. In summary, high intake of dietary folate was associated with an overall decrease in bladder cancer risk. These data may have important implications for cancer prevention; however, large, hypothesis-driven, population-based clinical trials will be required to confirm these findings.

Background: High folate intake has been inversely associated with incident colorectal cancer risk. However, it is not clear whether folic acid, the synthetic folate added to foods and supplements, is as effective as natural folates. Vitamin B6, which is found in many of the same foods and participates in one-carbon metabolism with folate has also been inversely associated with colorectal cancer risk. Whether the associations between folate and vitamin B6 and risk of colorectal cancer are independent has not been investigated. Methods: The associations of folate and vitamin B6 intakes with colorectal cancer risk were investigated in the American Cancer Society Cancer Prevention Study II (CPS-II) Nutrition Cohort. Of the 43,512 men and 56,011 women who provided detailed dietary information in 1999, 526 men and 497 women were diagnosed with colorectal cancer between 1999 and 2007. Food frequency questionnaire (FFQ) responses, reported multivitamin and other supplement use, and composition values from the USDA were used to quantify intakes of natural folates (in food), dietary folate (natural food folates and folic acid from fortification), folic acid (in foods from fortification and from multivitamins and supplements), total folate (from all sources), dietary vitamin B6 (from food) and total vitamin B6 (from food, multivitamins and supplements). Cox proportional hazards modeling was used to calculate multivariate hazards ratios and 95% confidence intervals. Results: Higher intakes of natural folate (RRQ5vsQ1=0.82; 95% CI; 0.68, 1.01; p-trend=0.07), dietary folate (RRQ5vsQ1=0.83; 95% CI; 0.68, 1.02; p-trend=0.14), folic acid (RRQ5vsQ1=0.88; 95% CI; 0.72, 1.08; p-trend=0.09), and total folate (RRQ5vsQ1=0.79; 95% CI; 0.65, 0.97; p-trend=0.05) were associated with lower colorectal cancer risk, although not all results were statistically significant. Similarly, higher intakes of dietary B6 (RRQ5vsQ1=0.82; 95% CI; 0.67, 1.07; p-trend=0.07) and total vitamin B6 (RRQ5vsQ1=0.82; 95% CI; 0.67, 1.00; p-trend=0.12) also were associated with lower colorectal cancer risk. Exclusion of the first two years of follow-up strengthened the inverse associations with folate measures but attenuated associations with vitamin B6. Controlling for vitamin B6 intake did not substantively change risk estimates for measures of folate intake, although confidence intervals were widened. The associations of dietary and total vitamin B6 with colorectal cancer risk were somewhat attenuated but remained inverse when controlled for either dietary or total folate intake. Conclusions: Our findings add to the epidemiologic evidence which suggests that higher intakes of folate reduce colorectal cancer risk and indicate that synthetic folic acid is as effective as natural folates. The inverse association of vitamin B6 intake with colorectal cancer was somewhat weaker and may be due, at least in part, to the correlated intake of folate. While vitamin B6 intake did not appear to confound associations with folate, further studies with blood levels of these two nutrients might help to disentangle associations of folate and vitamin B6 with colorectal cancer risk. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A87.

Folate Status of Young Canadian Women after Folic Acid Fortification of Grain Products

Association between folate and non-alcoholic fatty liver disease among US adults: a nationwide cross-sectional analysis.

The relationships between folic acid supplementation, folate intake, and GDM remain controversial. We conducted a preliminary investigation using a multimethod approach integrating a retrospective cohort study, Mendelian randomization, and dose-response analysis to explore this association. We examined the relationship between folic acid supplement use (including a combination preparation) and the GDM risk in a retrospective cohort of 10,479 pregnant women receiving care at Jiangsu Provincial People's Hospital using multivariable logistic regression analysis. MR analysis provides genetic support for a potential causal link between genetically predicted folic acid supplement use and GDM. A cross-sectional analysis of 3,680 pregnant women in the National Health and Nutrition Examination Survey (NHANES) evaluated total folate intake and dietary folate equivalents (DFEs) via 24-h dietary recall; multivariable logistic regression and restricted cubic spline models were used to characterize associations and generate dose-response curves. The models were adjusted for age, BMI, race or ethnic origin, education, and smoking history. Subgroup analyses were performed to assess potential effect modifications. In this retrospective cohort study, compared with non-users, folic acid supplement users had a 46.2% greater likelihood of having GDM (OR = 1.46, 95% CI: 1.339-1.595; p < 0.001). MR analysis supported a potential causal association between genetically predicted folic acid products and GDM risk (OR = 1.40, 95% CI 1.17-1.67, p < 0.001). In the NHANES cohort, higher total folate (OR = 1.42, 95% CI: 1.05-1.92, p = 0.02) and DFE intake (OR = 1.61, 95% CI: 1.23-2.10, p < 0.001) were linked to an increased GDM risk, with non-linear dose-response inflection points at approximately 445 μg/day and 582 μg/day, respectively. These associations were generally maintained after multivariable adjustment, and subgroup analyses revealed consistent trends toward an increased risk. This multimethod study indicates that both supplemental folic acid and dietary folate intake may be associated with an increased GDM risk. These observations support the need for additional research to better understand the potential impact of current recommendations on prenatal folate levels.

Risk Assessment of Folic Acid in Food Supplements

Background: Higher folate intake has been reported to be associated with modestly lower risk of colorectal cancer, but the overall state of the evidence is inconclusive. Revisiting putative and established lifestyle-related risk factors from the perspective of intertumoral heterogeneity is warranted, as risk relationships for a molecular subtype may be attenuated toward the null when colorectal cancer is investigated as a single disease. Aim: To investigate folate and folic acid intakes in relation to the risk of molecular subtypes of colorectal cancer. Methods: We pooled individual-level observational data from 7542 colorectal cancer cases and 7066 controls within the collaborative framework of the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO) and the Colon Cancer Family Registry (CCFR). Odds ratios per sex- and study-specific quartile increase in dietary and total folate intake, and for folic acid supplement use (yes/no), were estimated using logistic regression for case-only analyses and multinomial models for case-control analyses. Minimally adjusted analyses included sex, age, study and total energy intake as covariates. Tumor marker variables included microsatellite instability (MSI) status, CpG island methylator phenotype (CIMP), and BRAF and KRAS mutations. Results: In case-only analyses, we observed no heterogeneity in associations between folate intake, with or without supplemental folic acid (taking into consideration folic acid fortification when relevant), or with folic acid supplement use, and the risk of any subtype of colorectal cancer based on individual molecular tumor markers (lowest p for heterogeneity 0.073). In case-control analyses, higher dietary and total folate intake and folic acid supplement use were associated with a lower risk of most molecular tumor subtypes (all odds ratios were below one, and most were statistically significant). Adjustment for a larger set of potential confounders had no material effect on risk estimates. Conclusion: In this large, pooled analysis, higher dietary and total folate intakes and folic acid supplement use were all associated with a lower risk of colorectal cancer, regardless of individual molecular tumor markers including MSI status, CIMP, and BRAF and KRAS mutations. Citation Format: Bethany Van Guelpen, Björn Gylling, Sophia Harlid, Anna Winkvist, Hermann Brenner, Daniel D. Buchanan, Peter T. Campbell, Andrew T. Chan, Jenny Chang-Claude, Steven J. Gallinger, Graham G. Giles, Marc J. Gunter, Michael Hoffmeister, Li Hsu, Mark A. Jenkins, Roger L. Milne, Polly A. Newcomb, Shuji Ogino, John D. Potter, Conghui Qu, Lori C. Sakoda, Robert E. Schoen, Martha L. Slattery, Mikael O. Woods, Tabitha A. Harrison, Ulrike Peters. Folate and folic acid intake in relation to molecular subtypes of colorectal cancer; a pooled analysis of 7542 cases [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2355.

Total folate and folic acid intake from foods and dietary supplements in the United States: 2003–2006

Folic Acid Intake and Spina Bifida in the Era of Dietary Folic Acid Fortification

In the United States, synthetic folic acid has become an important source of folate in the era of mandatory folic acid fortification. This study aimed to evaluate the associations between total folate, natural folate and synthetic folic acid intakes and depressive symptoms among US adults. Cross-sectional data was collected from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Dietary data were obtained through two 24-h dietary recall interviews. Depressive symptoms were detected by PHQ-9 (Patient Health Questionnaire-9), participants whose depression scores over 10 points were diagnosed as depressive symptoms. Weighted logistic regressions were used to analyze the associations between different forms of folate and depressive symptoms. Among 19244 participants included in this study, 9.2% of them met the definition of depressive symptoms. In fully adjusted models, total folate intake and natural folate intake were inversely associated with depressive symptoms respectively, while synthetic folic acid was not. The multivariate-adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of depressive symptoms were 0.69 (0.54-0.89), 0.51 (0.39-0.68) for the highest versus lowest quartile of total folate and natural folate intake, respectively. We also found two L-shaped dose-response curves among total folate intake, natural folate intake with depressive symptoms, respectively. Total folate intake, natural folate intake may be inversely associated with depressive symptoms among US adults, while the association was not significant between synthetic folic acid and depressive symptoms.

12: Dietary and supplementary folate intake before and during pregnancy and the risk for spontaneous preterm delivery

After completing this article, readers should be able to:Birth defects are the leading cause of infant mortality and a major contributor to heightened morbidity in the United states. The basic definition of a birth defect is a structural abnormality present at birth. Infant mortality attributable to birth defects has not declined as rapidly as overall infant mortality; from 1968 to 1995, the proportion of infant mortality due to birth defects increased from 14.5% to 22.2%. It has been estimated that approximately 20% to 25% of all birth defects are due to gene mutations, 5% to 10% to chromosomal abnormalities, and another 5% to 10% to exposure to a known teratogenic agent (such as prescription drugs, chemicals, or radiation)or a maternal factor. Together, these percentages account for only 30% to 40% of birth defects, leaving the etiology of more than 50%unexplained. It has been speculated that environmental factors account for no more than 10% of all congenital anomalies. Genetic factors are responsible for 30% of pediatric hospital admissions.Birth defects rank somewhere between second and fifth among causes of death in children younger than 1 year of age; 3% to 4% of infants in their first year of life are diagnosed as having major birth defects. Of the 120,000 to 150,000 infants born with serious birth defects each year, approximately 6,000 die during their first 28 days of life and another 2,000 die before reaching their first birthdays.In an aggregate analysis of the expense of illness in the United States, congenital abnormalities as a group was estimated to cost$6.3 billion in 1980 or 1.4% of the total cost of illness. This estimate did not include nonmedical direct costs, such as special education and developmental services. Although recent advances in medical technology have increased the chances of survival for children who have birth defects and disabilities, the quality of life for most of these children remains compromised. The economic cost of medical conditions such as birth defects often is discussed without a full understanding of how these conditions affect the lives of infants and families.Because estimates of the cost per new case of birth defects represent the savings from preventing a case,an incidence-based approach enables assessment of the value of prevention strategies. This type of approach was used to estimate the cost of illness for some of the major, most clinically important structural birth defects in the United States. This report used data from a California birth defect monitoring program (adjusted to provide national estimates) and national data to estimate the costs of major structural birth defects occurring in the United States during 1992 (Table 1). The birth defects were selected based on their clinical significance and broad representation of the organ systemThese findings are subject to at least four limitations. First,California data used to estimate incidence rates and treatment costs may not be representative of the United States;total costs per case may vary from state to state. Second, the contribution of time and effort by family members to the provision of care were not estimated and may be substantial for some cases. Third, the psychological costs of these types of illness, which may exceed traditional human capital costs, were not included. For these and other reasons, the use of the human capital approach underestimates what the public is willing to pay to prevent these conditions. Finally, excess medical and educational costs probably were underestimated for some conditions because they could not be ascertained completely. If all of the approximately 120,000 to 150,000 infants born each year in the United States who have serious birth defects had been included in this analysis, the economic costs would have been higher.NTDs are among the most serious and common birth defects to cause infant mortality, morbidity, and disability in the United States. Each year, approximately 4,000 births that involve NTDs as well as other defects result in miscarriage or stillbirth. There are several forms of NTDs, and they vary widely in severity. The birth prevalence of these conditions has declined substantially over the past 60 years due to better medical care. NTDs are reported in 3.6 to 4.6/10,000 live births in the United States. These rates underestimate true incidence,however, because affected pregnancies may be spontaneously or electively aborted and because not all cases are detected and reported at birth. Population-based active surveillance programs that include prenatal diagnosis have reported NTD rates of 7.2 to 15.6/10,000 liveborn and stillborn infants. Women in the United States who have had a pregnancy resulting in an infant or fetus who has an NTD have a 2% to 3% risk for having another pregnancy resulting in a similarly affected infant or fetus.Spina bifida is an inclusive name for various conditions characterized by incomplete fusion of the vertebral arches with a protruding sac that contains meninges, spinal cord, or nerve roots that cause permanent damage to the spinal cord and spinal nerves. It is a complicated and common birth defect that can affect pregnancy without warning. Results of prenatal examinations suggest that affected fetuses exhibit leg movement until the third trimester but become paralyzed later in pregnancy, several months after the initial spinal cord defect occurs. The Centers for Disease Control and Prevention (CDC) estimates that 300,000 to 400,000 infants are born each year with spina bifida worldwide. In the United States,approximately 2,500 infants are born annually with spina bifida and anencephaly, and an estimated 1,500 fetuses affected by these birth defects are aborted.Based on 1992 cohort data, the estimated lifetime cost of spinal bifida is $294,000 per case. Spina bifida can range from mild (spina bifida occulta) to severe(myelomeningocele). Depending on the pattern and level of spinal cord involvement, the resultant deficit can include a lifelong handicap due to infectious complications, motor and sensory paraplegia, bladder and bowel incontinence, Arnold-Chiari malformations, and hydrocephalous.Unlike spina bifada, in which 80%to 90% of infants survive into adulthood, anencephaly is a lethal malformation characterized by the absence of the cranial vault and the cerebral hemisphere that usually results in stillbirth or death within hours or days. Fifty percent of anencephalic fetuses are aborted spontaneously, but if pregnancy goes to term, the infants quickly succumb,showing only slow, stereotyped movements and frequent decerebrate posturing. The incidence of anencephaly is 1/1,000 live births and is responsible for about 50% of all NTDs.Encephalocele is a rare congenital defect of the skull that results in herniation of meninges and brain tissue. It is seen most commonly in the occipital region, where it may be associated with other anomalies,such as brainstem and skull base deformities and hydrocephalous. The incidence of occipital encephalocele is 1/10,000 live births. Most encephaloceles are detected in children shortly after birth, and the outcome relates to the position of the defect and to the associated anomalies. The primitive nervous system begins as a flat neural plate 2 weeks after conception, which becomes indented by a longitudinal groove at 20 days,with neural folds on the flanks. These folds begin to fuse in the midline, forming a cylinder in the middle of the plate. In a zipper fashion, this dorsal closure is promulgated rostally and caudally, resulting in a tubular structure with an open anterior and posterior aperture. At 26 days, the anterior aperture closes,followed at 29 days by the posterior aperture. Factors necessary for formation of the neural tube are intrinsic in the neural ectoderm and adjacent mesoderm. A teratologic insult in embryogenesis timed to interfere with the closure of the anterior aperture will result in anencephalus. Failure of the posterior aperture to close results in an exposed spinal cord, which is recognized later as spina bifida. In broad terms, NTDs result from incomplete neurulation and refer to a wide spectrum of congenital malformations in which separations of the midline vertebral and cranial elements are the common feature,but they usually are taken to mean anencephalus, spina bifida, and encephalocele.Despite considerable progress having been made in understanding NTDs, they remain the most common serious birth defect, and the etiology of most cases still is unknown. It is accepted that there is a genetic-environmental interaction in the causation of NTDs. Genetic and epidemiologic studies have suggested high-risk groups: those who have a past history of NTDs; a maternal age of less than 20 or more than 35 years; parity (primipara and grand multipara); and low socioeconomic status with gross nutritional deficiency and inadequate antenatal care.Several clinical and epidemiologic studies have reported various teratogens that produce NTDs in offspring, including radiation;maternal hyperthermia such as prolonged high fever; exposure to heat and hot-tub use; hypo- and hypervitaminosis A; maternal viral infections such as rubella, toxoplasma, and cytomegalovirus; and drugs such as aminopterin, pyrimethamine,trimethoprim, triamterane,sulfasalazine, methotrexate, anticonvulsants(eg, valproic acid and carbamazepine),aliphatic nitrites, phenothiazines, cyclophosphamide,and cyanide. Teratogens cause NTDs by acting as folic acid antagonists or by being associated with inadequate folic acid availability to the embryo.A number of environmental agents also have been hypothesized as etiologic, particularly dietary agents such as soft water, blighted potatoes, nitrite-cured corn beef,canned peas treated with magnesium salts, effluent from factories, and zinc deficiency. However, none of these factors has been proved scientifically to be linked with NTDs.Certain occupations such as male painters, female agricultural workers, and male welders have been associated with an increased risk of NTDs in offspring. Also, several studies suggested that compared with women of normal weight,women who are extremely obese before pregnancy have a significantly increased risk of having an infant who has NTDs and several other malformations, such as central nervous system, great vessel, ventral wall, or other intestinal defects.Mildly elevated maternal plasma homocysteine (Hcy) levels recently have been observed in some pregnancies that resulted in NTDs and other birth defects. In the past 2 decades, research has shown mild hyperhomocysteinemia to be linked to an increased risk of premature atherosclerosis, pregnancies complicated by NTDs, early pregnancy loss, and venous thrombosis. Plasma Hcy is governed by both genetic and nutritional factors. A lack of B vitamins (folic acid), mutation of the 5,10-methylenetetrahydrofolate reductase genes, or a combination of the two can explain elevated Hcy levels in blood plasma. Genetic mutations were found on the first chromosome (677 C T and 1298 A–C) and can explain up to 50% of the protective effect of folic acid against NTDs. A personal or family history of a pregnancy affected by an NTD is associated with an increased risk of having an affected pregnancy, as is maternal type 1 diabetes, but about 90% to 95% of cases occur in the absence of any positive history. Infants of women who have type 1 diabetes have a 1% to 2% risk of NTDs. NTDs are seen more frequently in certain racial/ethnic groups, particularly Hispanics and Caucasians of European extraction,and are less common among Ashkenazi Jews, most Asians, and African-Americans. NTDs also appear to occur more frequently in association with fetal alcohol syndrome. Folic acid supplementation is not known to prevent NTDs or other teratogenic effects of alcohol on the embryo and fetuses of alcoholic women. The primary goal for such women is to avoid excessive alcohol ingestion during pregnancy. Women who have a folic acid deficiency because of intestinal disorders (such as celiac disease,small intestine malabsorption, or intestinal bypass) and those who have epilepsy and are using certain anticonvulsants may be at greater risk for having offspring who have NTDs. Infants of women treated with valproic acid and carbamazepine during pregnancy have an estimated 1% to 2% and 1% risk for spina bifida in offspring,respectively. It seems prudent to determine whether women who have epilepsy and are planning a pregnancy have a folic acid deficiency. It is not known, however, whether folic acid supplementation would decrease the risk of NTDs in the offspring of these women.Thirty years ago, it was suggested that maternal intake of certain vitamins during pregnancy affected the incidence of serious fetal malformations. Subsequent research has revealed that folate (folic acid), a B vitamin, plays a crucial role in the development of the central nervous system during the early weeks of gestation, which generally is before pregnancy is confirmed. In a significant number of embryos, an inadequate supply of folate at this time leads to failure of the primitive neural tube to close and differentiate normally, resulting in NTDs. Numerous studies have confirmed the importance of an adequate intake of folate during the weeks just before and after conception. Randomized placebo-controlled trials and nonrandomized controlled trials in pregnant women who had a prior pregnancy affected by an NTD have demonstrated that folic acid supplements substantially reduce the risk of recurrent NTDs.It has been suspected that diet has a role in the causation of NTDs. The possibility that folic acid might be involved was raised in 1964 by Hibbard. In 1980 and 1981, the results of two other interventional studies were published in which vitamin supplementation was instituted around the time of conception among women who already had had a child who had an NTD. In the first study, which was not randomized,participating women were given a mixture of eight vitamins that included folic acid (0.36 mg/d), with women who already were pregnant or who had declined to take part in the study serving as controls. The risk of recurrence in the supplemented group was about one-seventh that of the group who received no supplements. The second study was a small randomized trial of folic acid supplementation alone (4 mg/d). It yielded inconclusive results when analyzed according to randomly allocated treatment group (so avoiding bias), but when analyzed after transferring to the control group those women in the folic acid group who did not take their capsules (ie, ignoring the randomization and so introducing the possibility of bias), the supplemented women had a significantly lower risk.To avoid bias, an international multicenter, double-blind,randomized British Medical Research Council (MRC) prevention trial was initiated in July 1983. Conducted at 33 centers (17 in the United Kingdom and 16 in six other countries), it was designed to determine whether supplementation with 4 mg folic acid(one of the vitamins in the B group)or a mixture of seven other vitamins(A, D, B1, B2, B6, C, and nicotinamide) around the time of conception could prevent NTDs. A total of 1,817 women who had previous pregnancies affected by an NTD that was not associated with the autosomal recessive disorder were eligible for the study if they were planning another pregnancy and were not already taking vitamin supplements. Women who had epilepsy were excluded in case the folic acid supplementation adversely affected their treatment. The effect of both forms of supplementation was investigated by use of a factorial study design.The women were allocated randomly to one of four groups—folic acid, other vitamins, both, or neither. The four groups were similar with respect to age and the occurrence of previous pregnancies. Women were asked to take a single capsule each day from the date of randomization until 12 weeks of pregnancy (estimated from the first day of the last menstrual period). Of 1,817 women, 1,195 had a completed pregnancy in which the fetus or infant was known to have or not have an NTD. A total of 27 infants had known NTDs, with 6 in the folic acid groups and 21 in the two other groups. Sequential analysis showed a 72% protective effect(relative risk, 0.28; 95% confidence interval [CI], 0.12 to 0.71). The other vitamins showed no significant protective effect (relative risk, 0.80;95% CI, 0.32 to 1.72). There was no demonstrable harm from the folic acid supplementation, although the ability of the study to detect rare or slight adverse effects was limited. The study result is unlikely to be due to chance, and the randomized double-blind design excluded bias as an explanation. The results also demonstrate that folic acid, rather than any other vitamins, is responsible for the preventive effect.Another significant study was a randomized, double-blind, controlled trial from Hungary that enrolled 4,753 women planning pregnancy. Results documented that the first occurrences of NTDs could be prevented significantly by administering periconceptional multivitamin supplements daily that included 0.8 mg of folic acid. This study was extended to examine the effect of supplementation on other congenital abnormalities. Periconceptional administration of multivitamin supplements reduced NTDs by 50% and the incidence of other major genetic congenital abnormalities, such as cardiovascular anomalies, defects of the urinary tract, congenital hypertrophic pyloric stenosis, and congenital limb defects.Six observational studies of dietary folate or the use of folic acid and other vitamin supplements and NTDs and one nonrandomized folic acid supplementation study have been published. All but one showed an association, but all may have suffered from selection bias, and none could identify folic acid specifically as the responsible vitamin.Results of the British MRC randomized, controlled trial proved that folic acid can prevent spina bifida and anencephaly and provided critical scientific data on which to base public health policy for preventing these birth defects. Within weeks of publication of this study, the CDC developed and issued guidelines for women who had had a pregnancy affected by spina bifida or anencephaly. In September 1992, the United States Public Health Service(USPHS) issued the recommendation that all women of child-bearing age who are capable of becoming pregnant should be offered treatment with 0.4 mg of folic acid daily to reduce their risk of having an NTD-affected pregnancy. For women who already have had an NTD-affected pregnancy, the USPHS also administration of of folic acid day 1 to months prior to the conception and the first months of during the past years it that who not take folic acid supplements are at increased risk for folate which has been to cause spina bifida and anencephaly and has been associated with an increased risk for cardiovascular The that of folic acid during the periconceptional can reduce the number of NTDs has been for several data are from randomized control nonrandomized interventional and observational studies (Table Research on adverse effects from folic acid supplementation is limited. that folic acid supplements in daily of 1 to mg can the of vitamin diagnosis and treatment and leading to permanent is to interventional studies and case in also has been reported in some folic acid of less than 1 but the is not particularly at lower this has been as one to avoid supplementation or with folic acid. However, it also has been that it is to and the deficiency diagnosis at the risk of an NTD. of folate and levels and high Hcy levels with NTDs, that a for these defects may be an abnormality in a and If these results are supplementation with both folic acid and may be to prevent NTDs. This could reduce the for adverse effects of folate supplementation in in of the trials of pregnant women reported serious adverse effects associated with folic acid In the infants born to women who received a with folic acid did not in mortality, and and total serious or disorders at to 21 of age from those born to women only The of and was significantly increased among those received but more affected infants in the supplemented group also had a family history of these This also may be a effect due to the number of A group of children born to women who had taken daily mg of folic acid to prevent NTD revealed no adverse effects on developmental status at age to years compared with the There were significant in but whether this was attributable to folic acid or to other causes to having had a affected is of the randomized and nonrandomized controlled trials showed that among women at high risk of having a child who had an who received 4 of folic acid had approximately cases of NTD-affected offspring than those who received no supplements. interventional and studies also this the of this is 30% of NTDs appear to folic acid with the a of The administration of to the can such defects, but this not occur in The by which this is is to be by the of the acid in the which a folate did not reduce NTDs, but The has been to determine the agents that prevent NTDs in Prevention has been found with acid, C, vitamin C, and vitamin prevention was seen with folic acid, acid, vitamin B6, vitamin or of of folic acid still is being suggested that there may be a rather than a deficiency have found that the Hcy level is significantly for of infants who have NTDs during pregnancy than for vitamin controls. is a and a defect in it would to increased levels of an abnormality in Hcy particularly an abnormality of by folic acid is is in to produce basic and for of which may be the responsible for incidence of NTDs is the the of and of maternal and The two are as and should not be as part of the of women at risk of NTDs. is used both as a and as a after positive results on All cases of anencephaly and approximately of cases of spinal bifida could be by of and in the rates of NTDs in the United States before the availability of prenatal the of a substantial environmental in the etiology of these defects data that folic acid can to NTDs when at of 4 to women who already have had an NTD-affected pregnancy. Results of the British MRC study suggest that the of other vitamins to the folic acid no in of NTDs. on the findings from several folic acid supplementation at a of 4 1 to months prior to conception and the first trimester is for women planning pregnancy who have had a pregnancy affected by an results of controlled trials that folic acid supplementation will not prevent all NTDs. The protective effect demonstrated in studies of folic by the of NTD from none to it is to estimate that administration of folic acid supplementation to all women capable of pregnancy would reduce the incidence of NTDs in the United use of periconceptional folic acid supplements not for the of such is to be reduced if there is a lower risk of The possibility of the number of cases of NTDs in the United States by with the of of folic acid per day an important in public should be made to that all women capable of becoming pregnant 0.4 mg of folic acid daily to this of this recommendation a because 50% of the pregnancies in the United States are it is if not to a daily intake of 0.4 mg of folate diet the protective of vitamin supplementation, women begin to take supplements before conception a less if pregnancy of is a health that can intake of folic acid during the critical of In the USPHS that folic acid of and corn would become as of is to the daily intake of folic acid among women of age by about would prevent about spina bifida and anencephaly birth defects each year and as as premature each year from most commonly risk of is the of that often is associated with vitamin might the diagnosis and treatment of this the for should be of this possibility and that vitamin although occurring most commonly in the can occur at any Also, care should be taken to total folate to less than 1 the of a intake of folate in the periconceptional may be by women who could become pregnant to a diet with a daily vitamin with folic or these should be to other health and the public about the value of folic acid supplementation in preventing NTDs. surveillance programs should the prevalence of NTDs in fetuses and and clinical research into the by which folic acid NTDs should be In more clinical trials are to determine the of folic acid in preventing the occurrence and recurrence of NTDs.

High folate and low vitamin B-12 intakes during pregnancy are associated with small-for-gestational age infants in South Indian women: a prospective observational cohort study