Periconceptional Supplementation Research Articles

Awareness and use of folic acid, and blood folate concentrations among pregnant women in northern China—An area with a high prevalence of neural tube defects

Background The prevalence of neural tube defects (NTDs) in northern China remains high after 10 years since periconceptional supplementation with folic acid has been known to be effective in reducing the risk of NTDs. Objective The objectives of this study were to characterize folic acid awareness and use and to examine the association between folic acid supplementation with blood folate concentrations among early pregnant women in an area with a high prevalence of NTDs in northern China. Subject and method From December 2002 to February 2004, 693 early pregnant women were recruited and interviewed about folic acid awareness, knowledge and use. Four millilitres of venous blood was drawn and blood folate concentrations were measured. Results About 36% of women reported having ever heard of folic acid. Of these, 82.7% knew that folic acid can prevent NTDs, and 64.5% knew the best time to take it. Overall, 15% of women reported having ever taken folic acid. However, only 34.3% had begun to take it before the last menstrual period. Women with less education (21.1%), farmers (19.6%), rural dwellers (23.5%), and women who had a previous child (23.0%) were less likely to be aware of folic acid, and were less likely to take folic acid. Among women who had ever heard of folic acid, 37.5% took it during current pregnancy, compared with only 2.0% among those who had not. Women who were aware of folic acid were 25 times more likely to take it than women who were not. Overall, 44% of women had plasma folate deficiency, and 35% had red cell folate deficiency. Those who reported having ever taken folic acid had a lower rate of plasma folate deficiency (13.7%), compared with those who reported not taking folic acid (49.4%). The former group's mean plasma concentrations were twice as high as those of the latter group. Conclusion The levels of folic acid awareness, knowledge and use among Chinese women living in a high NTD prevalence area during early pregnancy were very low and folate deficiency was quite prevalent. Campaigns aimed at increasing the awareness, knowledge, and periconceptional use of folic acid should target to less educated, parous women and women living in rural areas.

Does long‐term supplementation with folic acid or (6S)‐5‐methyltetrahydrofolate have an impact on plasma vitamin B12 concentrations in healthy subjects?

Women with low vitamin B12 status have an increased risk of having an offspring with a neural tube defect (NTD). The objective of this investigation was to determine possible changes in vitamin B12 status after 24 weeks of supplementation with different forms and dosages of folate. Healthy female subjects (n = 144) aged 19 to 33 years with plasma vitamin B12 concentrations above 110pmol/L participated in this 24-week double blind, placebo-controlled intervention trial. Subjects were randomised to receive either 400μg/d folic acid, equimolar 416μg/d (6S)-5-methyltetrahydrofolate, 208μg/d (6S)-5-methyltetra-hydrofolate, or placebo. Fasting blood samples for plasma vitamin B12 determination were taken at baseline and at 8-week intervals. Dietary vitamin B12 intake was constant over the whole study period. Plasma vitamin B12 concentration did not change significantly in any of the four groups after 24 weeks of intervention. However, there was a mean non-significant decrease of between 4.7% and 11.5%. Women using oral contraceptives had significantly lower plasma vitamin B12 concentrations than non-users. In conclusion, plasma vitamin B12 concentrations tend to decrease after long-term folate administration in young, non-pregnant women. With respect to prevention of NTD by periconceptional supplementation and food fortification, the addition of vitamin B12 to folic acid should be considered.

Prevalence of periconceptional folic acid use and perceived barriers to the postgestation continuance of supplemental folic acid: Survey results from a Teratogen Information Service

Fewer than 40% of U.S. women are taking folic acid supplements periconceptionally at a time when the risk of neural tube defects (NTDs) can be reduced by supplementation. A better understanding of the vitamin-taking habits of childbearing-age women and effective methods for improving periconceptional supplement use are needed. A telephone survey conducted through the California Teratogen Information Service (TIS) between August 2003 and January 2004 assessed the prevalence and characteristics of pregnant callers who did not use folic acid supplements in the periconceptional period, and explored attitudes toward advice to continue vitamin use following pregnancy in order to be protected in a future pregnancy. A total of 327 pregnant women who called the TIS for information agreed to participate in the survey. More than half (53.2%) were not taking folic acid-containing supplements in the periconceptional period. Predictors of lack of use included a higher prepregnancy body mass index, younger maternal age, non-white race/ethnicity, lower education level, and unplanned pregnancy. One-quarter of the women said they would be willing to continue taking vitamins after the pregnancy if advised to do so by a physician. The remainder identified obstacles to following that advice--notably, not planning to become pregnant again and the belief that enough folate is derived from diet alone. More than half of the callers to the TIS were not compliant with recommendations regarding periconceptional folic acid supplementation. This represents an opportunity for TIS specialists and physicians to intervene in a current pregnancy to encourage maintenance of supplement use in the subsequent interpregnancy interval.

Promotion of folate for the prevention of neural tube defects: who benefits?

Since the publication of randomised trials showing firm evidence of prevention of neural tube defects with periconceptional folic acid, there have been population health promotion programmes to encourage women to take folic acid supplements, and the introduction of voluntary fortification of some foods with folic acid in Australia. In order to evaluate these two strategies, we collected data by self-administered questionnaire from a random sample of recently pregnant women in Western Australia between September 1997 and March 2000. Response to health promotion was measured in three ways: (1) knowledge of the association between periconceptional folate and prevention of spina bifida (the 'correct message'); (2) use of periconceptional vitamin supplements of folic acid daily in the periconceptional period; and (3) daily folate intake from fortified foods in the 6 months before pregnancy. We examined the relationship of maternal demographic and behavioural characteristics with these three measures. Overall, 62.3% of women were aware of the correct message before pregnancy, 28.5% reported taking 200 microg or more of folic acid from supplements daily in the periconceptional period and 56.6% of women obtained 100 microg or more of folic acid from fortified foods. Women who first became aware of the correct message during pregnancy or who were unaware of the correct message before or during pregnancy were more likely than women aware before pregnancy to be younger, having their first pregnancy, be single or in a de facto relationship, have no tertiary education, and be a public patient. Similar associations were seen for women taking either no folic acid or < 200 microg of folic acid in supplements daily in the periconceptional period. There were no significant associations between these demographic variables and amount of folate obtained from fortified foods. Women who were unaware of the correct message and did not take folic acid supplements were more likely to have smoked, not to have engaged in exercise, and not to have planned their pregnancy, whereas there was no association with these behavioural characteristics and intake of folate from fortified foods. These results indicate that health promotion strategies have not reached all segments of the target population equally, but there is no such disparity with folate-fortified foods, and they suggest that mandatory fortification of a staple food is likely to reach all women regardless of demographic and behavioural characteristics, and hence provide improved opportunity for prevention of neural tube defects in Australia.

Spontaneous neural tube defects in splotch mice supplemented with selected micronutrients

Splotch (Sp/Sp) mice homozygous for a mutation in the Pax3 gene inevitably present with neural tube defects (NTDs), along with other associated congenital anomalies. The affected mutant embryos usually die by gestation days (E) 12-13. In the present study, the effect of modifier genes from a new genetic background (CXL-Sp) and periconceptional supplementation with selected micronutrients (folic acid, 5-formyltetrahydrofolate, 5-methyltetrahydrofolate, methionine, myoinositol, thiamine, thymidine, and alpha-tocopherol) was determined with respect to the incidence of NTDs. In order to explore how different exposure parameters (time, dose, and route of compound administration) modulate the beneficial effects of micronutrient supplementation, female mice received either short- or long-term nutrient supplements via enteral or parenteral routes. Embryos were collected on E12.5 and examined for the presence of anterior or posterior NTDs. Additionally, whole mount in situ hybridization studies were conducted in order to reveal/confirm normal expression patterns of the Pax3 gene during neurulation in the wild-type and Sp/Sp homozygous mutant mouse embryos utilized in this study. A strong Pax3 signal was demonstrated in CXL-Sp embryos during neural tube closure (E9.5 to E10.5). The intensity and spatial pattern of expression were similar to other Splotch mutant mice. Of all the micronutrients tested, only supplementation with folic acid or 5-methyltetrahydrofolate rescued the normal phenotype in Sp/Sp embryos. When the folate supplementation dose was increased to 200 mg/kg in the diet, the incidence of rescued splotch homozygotes reached 30%; however, this was accompanied by six-fold increased resorption rate.

The NAT1 C1095A polymorphism, maternal multivitamin use and smoking, and the risk of spina bifida

The risk of having a child with a neural tube defect (NTD) can be reduced by maternal, periconceptional supplementation with folic acid, but the underlying folate-dependent protective mechanism remains unclear. N-acetyltransferase 1 is involved in acetylation of aromatic and heterocyclic amines and the catabolism of folates. Hence, functional polymorphisms in NAT1, the gene encoding N-acetyltransferase 1, are plausible risk factors for NTDs. Such variants could exert an influence on the risk of NTDs via their role in acetylation or folate catabolism and could act through the maternal or the embryonic genotype. NAT1 C1095A genotypes and information on maternal, periconceptional multivitamin use and smoking were obtained as part of a family-based study of spina bifida. Associations between spina bifida and the embryonic and maternal NAT1 C1095A genotypes, and potential NAT1 C1095A genotype-exposure interactions were evaluated using log-linear modeling. The analyses provided no evidence that the embryonic or maternal NAT1 C1095 genotypes influence the risk of spina bifida independently, or through interactions with maternal use of multivitamins. There was evidence that the embryonic, and possibly the maternal, NAT1 C1095A genotype influence the risk of spina bifida via interactions with maternal smoking status. The genotype for the NAT1 C1095A polymorphism does not appear to be an independent risk factor for spina bifida. However, the results of these analyses provide preliminary evidence that this polymorphism may be associated with the risk of spina bifida in the offspring of women who smoke during early pregnancy.

Periconceptional vitamin use and leukemia risk in children with Down syndrome

Periconceptional vitamin supplementation reduces the risk of neural tube defects, and possibly may reduce the risk of certain childhood malignancies, including acute lymphoblastic leukemia (ALL). Because children with Down syndrome (DS) experience a 20-fold higher risk of leukemia than the general population, the authors evaluated whether periconceptional vitamin supplementation reduced the risk of leukemia in children with DS. From 1997 to 2002, 158 children ages birth-18 years with DS and acute leukemia (n = 61 children with acute myeloid leukemia [AML] and n = 97 children with ALL) were enrolled through the Children's Oncology Group in North America. Children with DS alone (n = 173) were identified through the cases' pediatric clinics and frequency matched to cases on age. Mothers of cases and controls completed a telephone interview that included questions regarding vitamin supplement use in the periconceptional period and after knowledge of pregnancy. A decreased risk of leukemia was observed with vitamin supplementation in the periconceptional period (odds ratio [OR] = 0.63; 95% confidence interval [95% CI], 0.39-1.00). When stratified by leukemia type, the reduced risk was observed for ALL (OR = 0.51; 95% CI, 0.30-0.89), but not for AML (OR = 0.92; 95% CI, 0.48-1.76). Compared with vitamin use in the periconceptional period, use only after knowledge of pregnancy was associated with an increased risk of leukemia (OR = 1.61; 95% CI, 1.00-2.58). This was observed for both ALL and AML. These data added to a growing body of evidence that suggests that periconceptional vitamin use may be protective in the development of certain childhood cancers.

Reduced folate carrier gene is a risk factor for neural tube defects in a Chinese population

There is a considerable body of data demonstrating that periconceptional supplementation of folic acid can prevent a significant proportion of neural tube defects (NTDs). At present, the mechanism by which folic acid exerts its beneficial effect remains unknown. Folate transporter genes, including the reduced folate carrier gene (RFC1), have been proposed as NTD risk factors. The study population included 104 nuclear families with NTDs and 100 nonmalformed control families. We investigated the possible association between a common RFC1 polymorphism (A80G) and NTD risk among offspring, as well as potential gene-environment interactions between the infant RFC1 genotype and maternal periconceptional use of folic acid through a population-based case-control study. We observed that the infants of the GG genotype were associated with a 2.56-fold increased risk of NTDs when compared to the AA genotype (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.04-6.36) in our study population. Among mothers who did not utilize folic acid supplements, the risk for having a child with an NTD was 3.30 (95% CI, 1.15-9.65) for offspring with the GG genotype, compared to the reference (AA) genotype. Children who had the GG genotype and whose mothers did not take folic acid had an elevated risk for NTDs (OR, 8.80; 95% CI, 2.83-28.69), compared to offspring with the AA and GA genotypes whose mothers utilized folic acid supplements. Our findings suggest that the RFC1 G allele is likely to be an important genetic factor in determining folate transport and subsequently may be a risk factor for NTDs in this Chinese population.

Whole genomewide linkage screen for neural tube defects reveals regions of interest on chromosomes 7 and 10

Neural tube defects (NTDs) are the second most common birth defects (1 in 1000 live births) in the world. Periconceptional maternal folate supplementation reduces NTD risk by 50–70%; however, studies...

Epidemiology of neural tube defects

The epidemiological investigation of the common open neural tube defects (NTDs), anencephaly, and spina bifida, has a long history. The most significant finding from these past studies of NTDs was the identification of the protective effect of maternal, periconceptional supplementation with folic acid. Fortuitously, the association between folic acid and NTDs became widely accepted in the early 1990s, at a time when genetic association studies of complex traits were becoming increasingly feasible. The confluence of these events has had a major impact on the direction of epidemiological, NTD research. Association studies to evaluate genes that may influence the risk of NTDs through their role in folate-related processes, or through other metabolic or developmental pathways are now commonplace. Moreover, the study of genetic as well as non-genetic, factors that may influence NTD risk through effects on the nutrient status of the mother or embryo has emerged as a major research focus. Research efforts over the past decade indicate that gene-gene, gene-environment, and higher-order interactions, as well as maternal genetic effects influence NTD risk, highlighting the complexity of the factors that underlie these conditions. The challenge for the future is to design studies that address these complexities, and are adequately powered to detect the factors or combination of factors that influence the development of NTDs.

Neurosurgical Management of Myelomeningocele (Spina Bifida)

1. Mark S. Dias, MD, FAAP* 1. *Associate Professor of Neurosurgery, Pennsylvania State University College of Medicine and Milton S. Hershey Medical Center, Hershey, Pa After completing this article, readers should be able to: 1. Understand the outcomes regarding survival, cognitive abilities, ambulation capacities, and urologic functions for the child who has a myelomeningocele. 2. Appreciate the importance of folate in the pathogenesis of myelomeningoceles and the rationale for periconceptional folate supplementation in the prevention of neural tube defects. 3. Describe the initial neurosurgical care and rationale for neurosurgical treatment for the child who has a myelomeningocele. 4. Discuss the common presenting features of a shunt malfunction in the child who has a myelomeningocele. 5. Understand the significance and describe the management of the child who has signs or symptoms of shunt malfunction and no change in ventricular size on imaging studies. 6. Discuss the importance of considering shunt malfunction before initiating other neurosurgical treatments for the deteriorating child who has a myelomeningocele. 7. Describe the common signs and symptoms of spinal cord tethering, Chiari malformation, and syringomyelia, and the surgical options for each. Myelomeningocele (spina bifida) is the most common congenital neurologic malformation compatible with life. Therefore, every busy pediatric practice includes at least a few children who have spina bifida, and it is important for the primary care clinician to have a practical working knowledge about the unique and important problems that face this group of children. The incidence of myelomeningocele in the United States is between 0.41 and 1.43 per 1,000 live births (1) and is lower among African-Americans than Caucasians. Native Africans have a very low incidence of 0.1 per 1,000 live births. (2) The incidence of myelomeningocele in the United States and worldwide has declined significantly over the past 3 decades. (2) This decline has been attributed, in part, to improved maternal nutrition and periconceptional vitamin supplementation and to wider availability of prenatal diagnostic tests with a corresponding increase in the number of elective terminations. However, these …

Hungarian cohort‐controlled trial of periconceptional multivitamin supplementation shows a reduction in certain congenital abnormalities

The 1984-1991 Hungarian randomized controlled trial (RCT) of periconceptional multivitamin supplementation containing folic acid (0.8 mg) showed a significant reduction in the first occurrence of neural tube defects (NTDs), and of urinary tract and cardiovascular abnormalities, but no reduction in orofacial clefts. A controlled cohort trial was designed to confirm or deny these results. Supplemented women were recruited from the Hungarian Periconceptional Service using the same multivitamin as the Hungarian RCT. Unsupplemented pregnant women were recruited in the standard regional antenatal care clinics and were matched to each supplemented pregnant woman on the basis of age, socioeconomic status, place of residence, and year of pregnancy. A total of 3056 informative offspring were evaluated in each cohort. The occurrence of congenital cardiovascular malformations (31 vs. 50) was reduced (odds ratio [OR], 0.60; 95% confidence interval [CI], 0.38-0.96) in the supplemented cohort, accounted for mainly by ventricular septal defects (5 vs. 19; OR, 0.26; 95% CI, 0.09-0.72). There was no significant difference (14 vs. 19) in the occurrence of urinary tract defects between the two cohorts, but stenosis/atresia of pelvic-ureteric junction (2 vs. 13) showed a significant reduction (OR, 0.19; 95% CI, 0.04-0.86). The protective effect of the folic acid-containing multivitamin for NTDs (one offspring in the supplemented vs. nine in the unsupplemented cohort) was confirmed (OR, 0.11; 95% CI, 0.01-0.91). There was, however, no protective effect on orofacial clefts or on multiple congenital abnormalities. The results of this cohort-controlled trial support the findings of the previous Hungarian RCT. The primary prevention of some major structural birth defects by multivitamins containing folic acid or by folic acid has great public health importance.

Periconceptional multivitamin intake during early pregnancy, genetic variation of acetyl‐N‐transferase 1 (NAT1), and risk for orofacial clefts

Periconceptional supplementation of multivitamins that include folic acid have been shown to prevent several birth defects, including neural tube defects and orofacial clefts. We investigated whether polymorphic variants of fetal acetyl-N-transferase 1 (NAT1), an enzyme involved in the catabolism of folates, differentially interacted with maternal multivitamin use during early pregnancy to alter the risk of delivering an infant with an orofacial cleft malformation. Using a large population-based case-control study, we genotyped 421 California infants born with an isolated cleft and 299 controls for two NAT1 polymorphisms. Compared to the homozygous wild-type genotypes, odds ratios for isolated cleft lip with/without cleft palate were slightly increased among infants who were homozygous for the variant alleles of NAT1 1088 and 1095. For isolated cleft palate, no similar associations with these two NAT1 variants were observed. For NAT1 1088 genotypes, we did not observe any differential risks for clefts related to maternal multivitamin intake. For NAT1 1095 genotypes, however, we found a two-fold higher risk for isolated cleft lip with/without cleft palate among infants who were homozygous for the variant allele and whose mothers did not take multivitamins during early pregnancy. We found evidence suggestive of an interaction between the NAT1 1095 polymorphism and lack of maternal multivitamin use that increased risks of isolated cleft lip with/without cleft palate.

Homocysteine and Folate in Pregnancy

The importance of folate during pregnancy was addressed 40 years ago by Bryan Hibbard (1) in his study of folate status in 1484 low-income obstetric patients from Liverpool. He assessed folate status as urinary excretion of formiminoglutamic acid. Abnormal formiminoglutamic acid excretion was related not only to placental abruption and spontaneous abortion but also to adverse outcomes in previous pregnancies, including prematurity, congenital defects, and perinatal mortality. Shortly thereafter, Hibbard and Smithells (2) suggested that folate deficiency in pregnancy may be related to central nervous system malformations, and Smithells started a series of observational and intervention studies demonstrating that adequate folate status reduced the risk of neural tube defects (NTDs), observations that eventually in the early 1990s were confirmed in large, randomized intervention trials (3)(4). It is now established that periconceptional folate supplementation reduces the occurrence and recurrence of NTDs (3)(4). The results obtained in many observational studies suggest that low folate intake or low circulating folate increases the risk of preterm delivery and low birth weight (5). However, a recent Dutch study on several B vitamins measured before and during pregnancy in healthy, well-nourished women demonstrated no association between the vitamin concentrations and birth weight or risk of early pregnancy loss (6). The results from randomized intervention trials with folic acid have been equivocal (5). Thus, the link between maternal folate status and birth weight is uncertain. The conclusions of the observational studies on vitamins and adverse pregnancy outcomes have been questioned because of methodologic weaknesses. These include inaccurate assessment of vitamin intake, measurement errors attributable to variable plasma-volume expansion during pregnancy, and confounders such as drug use and stress, intake of other micronutrients, …

Evidence for suboptimal use of periconceptional folic acid supplements globally.

To systematically summarise the available evidence concerning the rate of folic acid supplement use pre- and periconceptionally, to identify those characteristics associated with low rates of use and to assess whether folic acid public awareness campaigns are associated with higher folic acid use. Systematic overview. Survey studies. Women of reproductive age, most of whom were currently or recently pregnant. Two investigators searched MEDLINE, Embase and Nutriotiongate databases between 1990 and 2003. Bibliographies of retrieved references were scanned for other relevant publications, and authors were contacted if necessary. Studies were included that evaluated the rate of folic acid supplement use either before conception or in early pregnancy. Rate of preconceptional and/or periconceptional folic acid use, rate of planned pregnancy in each study, as well as significant characteristics differentiating non-users from users of folic acid, including the effect of folic acid awareness campaigns. A total of 52 studies were included. In 34 studies, reported preconceptional folic acid use varied from 0.9% to 50%. In 49 studies, the reported rate of periconceptional supplement use ranged from 0.5% to 52%. Significant predictors of reduced periconceptional folic acid use were a low level of formal education, immigrant status, young maternal age, lack of a partner and an unplanned pregnancy. Four studies examined the effect of mass media campaigns on periconceptional folic acid use; the reported rates increased significantly, by a factor of 1.7 to 7.2, but in no study was the post-campaign rate above 50%. In many countries, fewer than 50% of women take periconceptional folic acid supplements. Consideration should be given to the practical advantages of folic acid fortification of centrally processed foods, such as wheat, corn and rice flour, while further promoting vitamin tablet supplement use and planned pregnancy.

Supplementation with [6S]-5-methyltetrahydrofolate or folic acid equally reduces plasma total homocysteine concentrations in healthy women

Increased plasma total homocysteine (tHcy) is a risk factor for vascular disease and adverse pregnancy outcomes. Health authorities recommend periconceptional supplementation with 400 micro g folic acid to prevent neural tube defects. Several countries have implemented food fortification with folic acid. However, excessive intake of folic acid could mask an undiagnosed vitamin B-12 deficiency. The biologically active [6S]-5-methyltetrahydrofolate ([6S]-5-MTHF) may be an alternative to folic acid because it is unlikely to mask vitamin B-12 deficiency symptoms. We compared the tHcy-lowering potential of 2 dosages of [6S]-5-MTHF with that of 400 micro g folic acid during 24 wk of supplementation. In this double-blind, randomized, controlled intervention trial, 144 female participants were supplemented daily with 400 micro g folic acid, 416 micro g [6S]-5-MTHF, 208 micro g [6S]-5-MTHF, or placebo. Concentrations of tHcy and plasma folate were measured at baseline and at 4-wk intervals. After supplementation, there was a significant interaction between time and treatment with respect to changes in tHcy and plasma folate (both P < 0.001 by two-factor repeated-measures analysis of variance). The decrease in tHcy did not differ significantly between the 3 supplemented groups (P > 0.05; Tukey's post hoc test). The increase in plasma folate in the group receiving 208 micro g [6S]-5-MTHF was significantly lower than that in the groups receiving 400 micro g folic acid (P < 0.001) or 416 micro g [6S]-5-MTHF (P < 0.05). [6S]-5-MTHF was shown to be an adequate alternative to folic acid in reducing tHcy concentrations. Supplementation with 416 micro g [6S]-5-MTHF was no more effective than that with 208 micro g [6S]-5-MTHF.

Autoantibodies against folate receptors in women with a pregnancy complicated by a neural-tube defect.

In the absence of clinical folate deficiency, periconceptional supplementation with folic acid reduces a woman's risk of having an infant with a neural-tube defect. Since antiserum to folate receptors induces embryo resorption and malformations in rats, we hypothesized that autoantibodies against folate receptors in women may be associated with pregnancy complicated by a neural-tube defect. Serum from 12 women who were or had been pregnant with a fetus with a neural-tube defect and from 24 control women (20 with current or prior normal pregnancies and 4 who were nulligravid) was analyzed for autoantibodies by incubation with human placental folate receptors radiolabeled with [3H]folic acid. The properties of these autoantibodies were characterized by incubating serum and the autoantibodies isolated from serum with placental membranes, ED27 cells, and KB cells, which express the folate receptors. Serum from 9 of 12 women with a current or previous affected pregnancy (index subjects) and 2 of 20 control subjects contained autoantibodies against folate receptors (P<0.001). The autoantibodies blocked the binding of [3H]folic acid to folate receptors on placental membranes and on ED27 and KB cells incubated at 4 degrees C and blocked the uptake of [3H]folic acid by KB cells when incubated at 37 degrees C. Serum from women with a pregnancy complicated by a neural-tube defect contains autoantibodies that bind to folate receptors and can block the cellular uptake of folate. Further study is warranted to assess whether the observed association between maternal autoantibodies against folate receptors and neural-tube defects reflects a causal relation.

The primary prevention of birth defects: Multivitamins or folic acid?

Periconceptional use of folic acid alone or in multivitamin supplements is effective for the primary prevention of neural-tube defects. The Hungarian randomized and two-cohort controlled trials showed that periconceptional multivitamin supplementation can reduce the occurrence of some other structural birth defects, i.e. congenital abnormalities. These findings were supported by many, but not all observational studies. Recently there have been two main debated questions. The first one is whether the use of folic acid alone or folic acid-containing multivitamins is better. The second one is connected with the dilemma of whether high dose of folic acid (e.g. 5 mg) might be better than a daily multivitamin with 0.4 - 0.8 mg of folic acid. Comparison of the pooled data of two Hungarian trials using a multivitamin containing 0.8 mg folic acid and the data of the Hungarian Case-Control Surveillance of Congenital Abnormalities using high dose of folic acid seemed to be appropriate to answer these questions. Multivitamins containing 0.4 - 0.8 mg of folic acid were more effective for the reduction of neural-tube defects than high dose of folic acid. Both multivitamins and folic acid can prevent some part of congenital cardiovascular malformations. Only multivitamins were able to reduce the prevalence at birth of obstructive defects of urinary tract, limb deficiencies and congenital pyloric stenosis. However, folic acid was effective in preventing some part of rectal/anal stenosis/atresia, and high dose of folic acid had effect in preventing some orofacial clefts. The findings are consistent that periconceptional multivitamin and folic acid supplementation reduce the overall occurrence of congenital abnormalities in addition to the demonstrated effect on neural-tube defects.

Methylenetetrahydrofolate reductase and transcobalamin genetic polymorphisms in human spontaneous abortion: biological and clinical implications

The pathogenesis of human spontaneous abortion involves a complex interaction of several genetic and environmental factors. The firm association between increased homocysteine concentration and neural tube defects (NTD) has led to the hypothesis that high concentrations of homocysteine might be embryotoxic and lead to decreased fetal viability. There are several genetic polymorphisms that are associated with defects in folate- and vitamin B12-dependent homocysteine metabolism. The methylenetetrahydrofolate reductase (MTHFR) 677C>T and 1298A>C polymorphisms cause elevated homocysteine concentration and are associated with an increased risk of NTD. Additionally, low concentration of vitamin B12 (cobalamin) or transcobalamin that delivers vitamin B12 to the cells of the body leads to hyperhomocysteinemia and is associated with NTD. This effect involves the transcobalamin (TC) 776C>G polymorphism. Importantly, the biochemical consequences of these polymorphisms can be modified by folate and vitamin B12 supplementation. In this review, I focus on recent studies on the role of hyperhomocysteinemia-associated polymorphisms in the pathogenesis of human spontaneous abortion and discuss the possibility that periconceptional supplementation with folate and vitamin B12 might lower the incidence of miscarriage in women planning a pregnancy.

Phenotype of the neural tube defect mouse model bent tail is not sensitive to maternal folinic acid, myo-inositol, or zinc supplementation.

Bent tail is a mouse model for X-linked neural tube defects (NTDs) that is characterized by the presence of exencephaly, a delayed posterior neuropore closure, and a tail phenotype. In addition, Bent tail shows laterality defects and increased prenatal mortality. The congenital malformations of this mouse are caused by a submicroscopic deletion that completely encompasses the gene coding for the zinc finger transcription factor Zic3. In this study we investigated the sensitivity of the phenotype of Bent tail to the nutrients folinic acid, myo-inositol, and zinc. These nutrients are thought to be involved in the etiology of NTDs, in combination with a genetic predisposition. The most penetrant phenotype of the Bent tail mouse, the tail malformation, was used as a marker for the nutrient sensitivity of the neural phenotype. The size of the litters and the survival of the offspring, subdivided according to genotype, were analyzed as markers for the nutrient sensitivity of other phenotypic features of Bent tail. In confirmation of earlier studies, we observed the prenatal loss of a number of homozygous females and hemizygous males, as well as the effect of genotype on the tail phenotype of Bent tail. However, periconceptional supplementation of the maternal diet with folinic acid, myo-inositol, or zinc produced no significant effects on either the tail phenotype of the offspring or the size and genotypic composition of the litters. Bent tail appears to be a folinic acid-, myo-inositol-, and zinc-insensitive mouse model for NTDs.