The effect of folic acid or multivitamin containing folic acid supplementation during pregnancy on enamel structure of deciduous teeth: an ultrastructural and microanalytical study

Focused Revision: Policy statement on folic acid and neural tube defects

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.

Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid–Sensitive Congenital Anomalies

Source: Wang D, Jin L, Zhang J, et al. Maternal periconceptional folic acid supplementation and risk for fetal congenital heart defects [published online ahead of print September 8, 2021]. J Pediatr. doi: 10.1016/j.jpeds.2021.09.004.Investigators from Peking University and Tongzhou Maternal and Child Health Hospital, both in Beijing, China, conducted a retrospective study to assess the effectiveness of periconceptional folic acid (FA) supplementation in preventing congenital heart defects (CHD). For the study, they reviewed data contained in the Prenatal Health Care System (PHCS) and Birth Defects Surveillance System (BDSS) databases on singleton deliveries (including live births, stillbirths, and terminated pregnancies) between 2013 and 2018 in the Tongzhou District, Beijing, China. PHCS is a registry that includes data on women during pregnancy and after delivery, including maternal age and educational level, delivery date, and periconceptional FA supplementation. Information about FA supplementation was based on maternal self-report and included type of FA supplementation and when it started (prior to or after conception). In China, women are provided FA in a daily dose of 0.4 mg by the central government. However, some women take micronutrient supplements containing FA (MMFA). The BDSS includes information on birth defects, beginning at 13 weeks of gestation, including CHD.Primary study outcomes were any CHD, ventricular septal defect (VSD), and critical CHD (defined using standardized criteria). Poisson regression was used to compare the risks of these outcomes in women with FA/MMFA supplementation and in those without supplementation. Risk of CHD also was compared in women taking FA vs MMFA, and with FA/MMFA supplementation beginning prior to or after conception. Regression models also included maternal age, education, and year of delivery.Data were analyzed on 63,969 women and their offspring. Women using FA/MMFA supplementation were significantly older and more educated than those who didn’t. There were 308 cases of CHD in the offspring of study women, including 152 live births and 156 stillbirths or terminated pregnancies; the most common CHD was VSD (125 cases). The use of periconceptional FA/MMFA was associated with a reduced risk of any CHD (adjusted risk ratio [ARR], 0.60; 95% CI, 0.44, 0.83), VSD (ARR, 0.47; 95% CI, 0.30, 0.74) and critical CHD (ARR, 0.41; 95% CI, 0.26, 0.67). There were no statistical differences between FA and MMFA supplementation for risk of any CHD (ARR, 0.84; 95% CI, 0.66, 1.09), VSD (ARR, 0.94; 95% CI, 0.63, 1.41) or critical CHD (ARR, 0.64; 95% CI, 0.44, 1.00). Initiation of FA/MMFA supplementation before conception, compared to post-conception, was associated with a reduced risk of any CHD (ARR, 0.68; 95% CI, 0.48, 0.95) and critical CHD (ARR, 0.26; 95% CI, 0.10, 0.71).The authors conclude that maternal periconceptional FA supplementation was associated with a decreased risk of CHD in off-spring, particularly when initiated prior to conception.Dr Doolittle has disclosed no financial relationship relevant to this commentary. This commentary does not contain a discussion of an unapproved/investigative use of a commercial product/device.FA, one of the B vitamins, is a micronutrient found in fresh fruit, vegetables, nuts, and eggs.1 FA deficiency has been associated with megaloblastic anemia and neural tube defects in infants, as well as heart disease and cancer in adults.1 Humans are unable to synthesize FA, and thus must rely on ingestion in the form of food or conversion of precursors in the gut microflora.1 FA is an important co-factor in DNA and RNA synthesis, and the formation of the heart neural crest cells are highly sensitive to FA.2 Since 1992, FA and other micronutrient deficiencies have been associated with CHD.3 However, the results of supplementation trials to prevent CHD have been equivocal.4 The results of the current investigation provide convincing evidence to support FA/MMFA supplementation to prevent CHD.The study design was robust, with a governmental registry of more than 63,000 women who were followed prospectively over 5 years. Of note, the investigators evaluated self-report of FA/MMFA supplementation. Although self-report may be imperfect, the study represents a real-world evaluation. Women who took FA/MMFA supplementation were older and better educated. As maternal age is a risk for CHD, and education usually confers better health outcomes, the investigators controlled for these variables.The results of the current study raises several provocative questions that merit future investigation. Pre-conception supplementation was associated with reduced CHD compared to peri-conception supplementation. This suggests that some independent maternal factors may influence CHD formation prior to conception. Also, despite the reduction of CHD due to supplementation, the continued prevalence of CHD suggests other factors such as genetic defects, exogenous toxin, or infection are at play.Maternal periconceptual supplementation with FA may be associated with a reduced risk of CHD, especially when initiated before conception. (See AAP Grand Rounds. 2020;44[6]:68.)5Perhaps the greater protective efficacy of preconceptual FA supplementation is related to the time it takes to achieve effective folate levels during the critical period of heart development.2

Factors influencing folic acid, multivitamin, and calcium supplementation among pregnant women in China based on a national cross-sectional survey.

BackgroundEvidence suggests that folate deficiency may be causatively linked to depressive symptoms. However, little is known on the status of use of folic acid and vitamin supplements among people with mental disorders. This study examined the prevalence and the likelihood of use of folic acid or vitamin supplements among adults with depression and anxiety in comparison to those without these conditions.MethodsUsing data from 46, 119 participants (aged ≥ 18 years) in the 2006 Behavioral Risk Factor Surveillance System survey, we estimated the adjusted prevalence and odds ratios with 95% confidence intervals for taking folic acid and vitamin supplements among those with ever diagnosed depression (n = 8, 019), ever diagnosed anxiety (n = 5, 546) or elevated depressive symptoms (n = 3, 978, defined as having a depression severity score of ≥ 10 on the Patient Health Questionnaire-8 diagnostic algorithm).ResultsOverall, women were more likely than men to take folic acid supplements 1-4 times/day (50.2% versus 38.7%, P < 0.001) and vitamin supplements (62.5% versus 49.8%, P < 0.001). After multivariate adjustment, men with ever diagnosed depression or anxiety were 42% and 83%, respectively, more likely to take folic acid supplements < 1 time/day; 44% and 39%, respectively, more likely to take folic acid supplements 1-4 times/day; and 40% and 46%, respectively, more likely to take vitamin supplements compared to men without these conditions (P < 0.05 for all comparisons). Women with ever diagnosed depression were 13% more likely to take folic acid supplements 1-4 times/day and 15% more likely to take vitamin supplements than women without this condition (P < 0.05 for both comparisons). Use of folic acid and vitamin supplements did not differ significantly by elevated depressive symptoms in either sex.ConclusionThe prevalence and the likelihood of taking folic acid and vitamin supplements varied substantially by a history of diagnosed depression among both men and women and by a history of diagnosed anxiety among men, but not by presence of elevated depressive symptoms in either sex.

Risk Assessment of Folic Acid in Food Supplements

Background: Previous reviews explored the association between maternal use of folic acid and multivitamin supplements and risk of neural tube defect (NTD) in children, with no definitive conclusion. These reviews had produced contradictory results, and there had been no umbrella review. Therefore, the objective of this umbrella review is to combine the inconsistent data on the effect of prenatal folic acid and/or multivitamin supplementation for the prevention of NTD in offspring. Methods: Using the PRISMA guideline, PubMed, Embase, Scopus, Web of Sciences, Cochrane Database of Systematic Reviews, Scopus, and Google Scholar reported that the effects of folic acid and/or multivitamin supplementation for the prevention of NTD in offspring were searched. The quality of the included studies was assessed using Assessment of Multiple Systematic Reviews (AMSTAR). A weighted inverse variance random-effects model was applied to find the pooled estimates. The subgroup analysis, heterogeneity, publication bias, and sensitivity analysis were also assessed. Result: Ten SRM with 296,816 study participants were included. The random-effects model analysis from 10 included systematic review and meta-analysis revealed that the pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD globally is found to be 0.43 (95% CI: 0.29, 0.58) (I2 = 93.50%; p ≤0.001). In the subgroup analysis, the pooled effect was found to be 0.23 (0.09, 0.37) in folic acid group, while this estimate is 0.63 (0.53, 0.72) and 0.61 (0.46, 0.75) in groups who took multivitamin. The pooled effect of prevention of NTD was found to be 0.50 (0.34, 0.66) in SRMs aimed at occurrence prevention (primary prevention) group, while this estimate is 0.20 (−0.01, 0.41) among SRMs, which aimed at reoccurrence (secondary) prevention, and 0.61 (0.46, 0.75) among those SRMs aimed to assess the effect folic acid or multivitamin for the prevention of both occurrence and reoccurrence. The pooled effect of either folic acid or multivitamin supplementation for the prevention of NTD was found to be 0.45 (0.03, 0.87) in SRMs of observational studies, while this estimate is 0.43 (0.32, 0.54) among SRMs of randomized controlled trials. Conclusion: This umbrella review of systematic review and meta-analysis found that prenatal folic acid and/or multivitamin supplementation was associated with a 57% reduction in NTD. Participants who took folic acid supplementation were associated with a slightly higher (77%) percentage of reduction in NTD compared with those who took multivitamin (37%). Reductions of 80% and 50% were observed for reoccurrence and occurrence prevention of NTD. Reductions of 57% and 55% of NTD have been found in SRM of RCTs and observational studies. This umbrella review revealed that both folic acid and multivitamin were associated with significantly lower levels of NTD in children. Considering the incorporation of those supplements in NTD prevention strategies during the preconception period is recommended. More large-scale prospective cohort and RCTs are needed to understand the protective effect of multivitamins and/or folic acid on NTD risk addressing the molecular mechanisms and to determine the optimal dose, duration, and timing of maternal multivitamin and folic acid intake for best child NTD risk reduction.

It is well established from randomized controlled trials and other studies that periconceptional folic acid supplements reduce the risk of neural tube defects (NTDs). It has been suggested that prenatal administration of folic acid supplements may have beneficial effects on aspects of neurodevelopment after birth. No follow-up trials have investigated whether prenatal exposure to folic acid affects child neurodevelopment. This prospective observational study used data from the Norwegian Mother and Child Cohort Study to investigate whether maternal use of folic acid supplements was associated with a reduced risk of severe language delay in children at age 3 years. The cohort comprised pregnant women from Norway recruited between 1999 and 2008 who received folic acid supplements and/or other supplements from 4 weeks before to 8 weeks after conception. The questionnaire was sent to the participants at 17 weeks of gestation and periodically up to age 3 years. All children included in the study were born before 2008. Multiple logistic regression analysis was used to compare the effect of exposure and no exposure to folic acid on severe language delay and to adjust for potential confounders. The primary study outcome measure was children's language competency at age 3 years assessed by maternal report on a 6-point ordinal language grammar scale; ratings ranged from no word production to complete sentences. Children rated as having severe language delay used minimal expressive language (only 1 word or unintelligible utterances). Severe language delay was evaluated in 4 categories based on exposure or no exposure to folic acid during the specified interval: (1) reference group (no folic acid or other supplements); (2) supplements and no folic acid; (3) only folic acid; and (4) folic acid plus supplements. Of the 38,954 children in the cohort, 204 (0.5%) had severe language delay. Compared with no use of dietary supplements, the adjusted odds ratio were 1.04 (95% confidence interval [CI], 0.62–1.74) for the other supplements and no folic acid group; 0.55 (95% CI, 0.35–0.86) for the folic acid only group; and 0.55 (95% CI, 0.39–0.78) for the folic acid plus other supplements group. These findings suggest that maternal use of supplements containing folic acid within the period from 4 weeks before to 8 weeks after conception is associated with a reduced risk of severe language delay in children at age 3 years in a cohort of Norwegian women.

Long Term Maintenance of Neural Tube Defects Prevention in a High Prevalence State

Methotrexate is a folic acid antagonist widely used for the treatment of inflammatory disorders for more than 50 years. Methotrexate is a standard systemic therapy for severe psoriasis and rheumatoid arthritis. Folic acid supplementation has been advocated to limit the toxicity of methotrexate on blood cells, gastrointestinal tract and liver. However, there is still controversy regarding the usefulness of folic acid supplementation. We sought to assess the evidence for the efficacy of folic acid supplementation in patients treated with methotrexate for inflammatory diseases. We also investigated whether folic acid supplementation may decrease the efficacy of methotrexate. Cochrane and MEDLINE databases were systematically searched. Randomized controlled trials in patients treated with methotrexate for rheumatoid arthritis or psoriasis with or without arthritis were included. Study selection, assessment of methodological quality, data extraction and analysis were carried out by two independent researchers. We selected double-blind randomized placebo-controlled trials. Analysis was performed for each subgroup of side-effects: gastrointestinal, mucocutaneous, haematological and hepatic. Six randomized controlled trials met the inclusion criteria, with a total sample of 648 patients. There were 257 patients in the placebo group, 198 patients treated with folic acid, and 193 patients treated with folinic acid. The statistical analysis showed a significant reduction of 35.8% of hepatic side-effects induced by methotrexate for patients with supplementation with folic or folinic acid (95% confidence interval -0.467 to -0.248). There was no statistical difference for mucocutaneous and gastrointestinal side-effects although there was a trend in favour of supplementation. The effect of supplementation on haematological side-effects could not be assessed accurately due to a low incidence of these events in the population studied. We were unable to analyse the effect of supplementation on the effectiveness of methotrexate, as markers of activity used in each study were not comparable. Supplementation with folic acid is an effective measure to reduce hepatic adverse effects associated with methotrexate treatment. There is no difference between folinic acid and folic acid, but the lower cost of the latter promotes its use.

Prenatal Micronutrient Supplementation Is Not Associated with Intellectual Development of Young School-Aged Children1–3

BackgroundMethotrexate (MTX) is the disease-modifying anti-rheumatic drug (DMARD) most commonly used in the treatment of rheumatoid arthritis (RA), and folic acid (FA) supplementation is usually employed to prevent MTX-related adverse...

It has been proven that periconceptional folic acid (FA) supplementation could prevent neural tube defects. However, FA supplementation during different stages of pregnancy and its association with the neurobehavioral development of offspring remains unclear, particularly the effects of continued FA supplementation during the second and third trimesters. This study aimed to investigate the relationship between maternal FA supplementation at various stages of pregnancy and infant neurobehavioral development. In a prospective birth cohort study involving 3246 parent-child pairs, 2905 infants completed neurobehavioral development assessments at 6 months and 3005 infants at 18 months. Information regarding micronutrient supplementation at various stages of pregnancy was recorded. Multivariable logistic regression was used to evaluate the association between FA supplementation and infant neurobehavioral developmental delays. In addition, propensity score analysis was performed to correct the potential imbalances in the distribution of related factors between the groups. During the periconceptional period, maternal standardized FA supplementation (taking 0.4 mg FA daily before and in early pregnancy, as officially recommended) was associated with a reduced risk of possible development delays in 18-month-old infants in the communication domain (RR = 0.48, 95% CI: 0.26-0.86; P = 0.015). After the 12th gestational week, maternal continuous FA supplementation in the second and third trimesters was significantly associated with a decreased risk of possible neurobehavioral development delay in 6-month-old infants in fine motor domain (RR = 0.31, 95% CI: 0.12-0.82; P = 0.019) and the problem-solving domain (RR = 0.20, 95% CI: 0.05-0.79; P = 0.022). These associations remained significant after adjusting for confounders and propensity scores. FA supplementation at different stages of pregnancy may enhance neurobehavioral development in offspring. To confirm these findings, additional investigations or trials with larger sample sizes and consistent tracking of folate status throughout pregnancy are recommended.

The effect of maternal protein and folic acid intake on the developmental programming of adulthood diseases