Effects of inositol supplementation in a cohort of mothers at risk of producing an NTD pregnancy

Neural tube defects (NTDs), most commonly spina bifida and anencephaly, can be prevented with periconceptional intake of folic acid in about 70% of cases. Recurrence of NTDs despite supplementation of high dose of folic acid further suggests that a proportion of NTD cases might be resistant to folic acid. Moreover, heterogeneity of NTDs has been suggested in animal studies, indicating that only some sub-type of NTDs should be considered sensitive to folate intake. Inositol isomers (particularly myo- and chiro-inositol) can prevent folate-resistant NTDs in the curly-tail mutant mouse, suggesting that some cases of human NTDs might benefit from inositol supplementation. In humans, lower inositol blood concentration was found in pregnant women carrying NTD fetuses, whereas a periconceptional combination therapy with folic acid associated with inositol has been linked to normal live births, despite high NTD recurrence risk. Fifteen pregnancies from 12 Caucasian women from different parts of Italy with at least one previous NTD-affected pregnancy underwent periconceptional combined myo-inositol and folic acid supplementation. Maternal serum α-feto-protein levels were found in the normal range, and normal results on ultrasound examination were found in all the pregnancies that followed. No collateral effects or intense uterine contractions were demonstrated in this pilot study in any of the pregnancies after inositol supplementation, and seventeen babies were born without any type of NTD.     

A case–control study of the effects of pregnancy planning on neural tube defects and its primary preventive measures

BACKGROUND: Measures for prevention of neural tube defects (NTDs) have been recommended for many years in China, but the compliance with these measures is unsatisfactory. This study aims to compare the effect differences between planned pregnancy and unplanned pregnancy in the compliance with these measures and analyze the interactions between pregnancy planning and these measures for NTD prevention. METHODS: A 1:1 matched case‐control study was conducted. We randomly selected 349 women who delivered or gestated babies/fetuses with NTDs in the last two years in two provinces and matched them with 349 women who delivered babies without obvious birth defects as controls. RESULTS: In the case group, 99 women reported that they had planned their pregnancies, accounting for 28.4%, and the proportion who received preconception examinations and took folic acid prior to conception was 13.8 and 8.6%, respectively. According to the multivariate analysis, health education (odds ratio [OR], 0.350), preconception examinations (OR, 0.497) and folic acid consumption prior to conception (OR, 0.257) all had preventative effects on NTDs (for all, p < 0.05). In both groups, the proportions of women who received preconception examinations and reported folic acid intake were much higher for those who reported planning their pregnancies compared to women with an unplanned pregnancy (for all, p < 0.01); and for NTD prevention, synergistic interactions existed between pregnancy planning and the other preventive measures. CONCLUSION: Folic acid consumption prior to conception, preconception examinations, and health education have preventive effects on NTDs. Pregnancy planning can significantly promote compliance with these preventive behaviors. In addition, there are synergistic interactions between pregnancy planning and these measures. Birth Defects Research (Part A), 2010. © 2010 Wiley‐Liss, Inc.     

Plasma vitamin values and antiepileptic therapy: case reports of pregnancy outcomes affected by a neural tube defect

BACKGROUND: Folic acid supplementation reduces the occurrence of neural tube defects (NTDs); however, it is not clear whether it protects against teratogenic effects of antiepileptic drugs. METHODS: We report the cases of four pregnant women receiving valproic acid therapy, who all had NTD-affected offspring, despite periconceptional 5 mg/day of folic acid supplementation (cases), and investigated homocysteine metabolism, linked with folate metabolism. Their plasma homocysteine, folates, and vitamin B6 and B12 results were compared with values of two other women, who were also receiving valproic acid and folic acid complement, but who had normal pregnancies (valproic acid controls), and values of 40 pregnant women who had normal pregnancies and were not receiving any therapy (controls without therapy). Because of the possible existence of a genetic susceptibility, polymorphisms in homocysteine metabolism were sought. RESULTS: Two cases showed a decreased phosphopyridoxal level, compared with levels in the controls not receiving therapy. The genotype TT (C677T) is an NTD genetic susceptibility, but it was observed in only one valproic acid control. Various polymorphisms were observed in the cases, but were also common in the controls. Several studies have reported that valproic acid therapy lowers vitamin B6 levels. Our case with the greatest decrease in plasma phosphopyridoxal, who was taking periconceptional folic acid plus pyridoxine therapy, had a normal second pregnancy outcome. CONCLUSIONS: In addition to folates, other vitamins, such as vitamin B6, may have played a role in NTDs in our patients taking an antiepileptic drug.     

Recommendations on the use of folic acid supplementation to prevent the recurrence of neural tube defects. Clinical Teratology Committee,Canadian College of Medical Geneticists.

OBJECTIVE: To prevent the recurrence of neural tube defects (NTDs) in families at increased risk of having offspring with NTDs with the use of periconceptional folic acid supplementation. OPTIONS: Genetic counselling and prenatal diagnosis of NTDs. OUTCOMES: NTDs cause stillbirth, neonatal death and severe disabilities. The cost for medical care and rehabilitation in the first 10 years of life of a child with spina bifida cystica was estimated to be $42,507 in 1987. EVIDENCE: The authors reviewed the medical literature, communicated with investigators from key studies, reviewed policy recommendations from other organizations and drew on their own expertise. A recent multicentre randomized controlled trial showed that among women at high risk of having a child with an NTD those who received 4 mg/d of folic acid had 72% fewer cases of NTD-affected offspring than nonsupplemented women. Two previous intervention studies also demonstrated that folic acid supplementation was effective in reducing the rate of NTD recurrence. Several retrospective studies support this conclusion. VALUES: Recommendations are the consensus of the Clinical Teratology Committee of the Canadian College of Medical Geneticists (CCMG) and have been approved by the CCMG Board. The committee believes that primary prevention of NTDs is preferable to treatment or to prenatal detection and abortion. BENEFITS, HARMS AND COSTS: Folic acid supplementation should result in fewer NTDs among infants in Canada and ancillary savings in medical costs. The recommended dosage of folic acid is not known to be associated with adverse effects. Higher dosages of folic acid may make vitamin B12 deficiency difficult to diagnose and may alter seizure frequency in patients with epilepsy due to drug interactions with anticonvulsants. RECOMMENDATIONS: A minimum dosage of folic acid of 0.8 mg/d, not to exceed 5.0 mg/d, is recommended along with a well-balanced, nutritious diet for all women who are at increased risk of having offspring with NTDs and who are planning a pregnancy or may become pregnant. Supplementation should begin before conception and continue for at least 10 to 12 weeks of pregnancy. VALIDATION: These guidelines are similar to those of the Society of Obstetricians and Gynaecologists of Canada, the US Centers for Disease Control and Prevention and the Department of Health in Britain. SPONSORS: These guidelines were developed by the CCMG Clinical Teratology Committee and endorsed by the Board of the CCMG. No funding for the development of these guidelines was obtained from any other sources.     

Prevention of developmental abnormalities with particular emphasis of primary prevention

The Hungarian total (birth + fetal) prevalences of different developmental abnormalities offer a possibility to estimate the proportion of preventable development abnormalities. The effectiveness of primary, secondary and tertiary preventive methods are evaluated with a particular emphasis of primary prevention based on periconceptional folic acid or folic acid-containing multivitamin supplementation. The total prevalence of informative offspring with developmental abnormalities is 66.83 per 1,000 in Hungary and within this major DAs have 27.01 per 1,000 rate. The latter can be reduced by 26.6% by primary preventive methods due to mainly periconceptional folic acid/multivitamin supplementation. Secondary prevention particularly neonatal orthopedic screening is very effective for deformities such as congenital dislocation of the hip. Antenatal diagnoses followed by termination of pregnancy can avoid the birth of malformed newborn infants in 8.7% of DAs, however, this figure is 20 and 27% among major and multiple developmental abnormalities, respectively. Early surgical intervention can achieve a complete recovery in 33.5% of cases with developmental abnormalities. Thus there are two major conclusions: at present the major part of developmental abnormalities are preventable, however, different developmental abnormalities do not represent a single pathological category therefore there is no single strategy for their prevention.     

Does prenatal screening for 5,10-methylenetetrahydrofolate reductase (MTHFR) mutations in high-risk neural tube defect pregnancies make sense?

Despite the fact that neural tube defects (NTDs) are the most common congenital malformations of the central nervous system, investigators have yet to identify responsible gene(s). Research efforts have been productive in the identification of environmental factors, such as periconceptional folic acid supplementation, that modulate risk for the development of NTDs. Studies of the folic acid biosynthetic pathway led to the discovery of an association between elevated levels of homocysteine and NTD risk. Researchers subsequently identified single nucleotide polymorphisms in the gene coding for the enzyme 5,10-methylenetetrahydrofolate reductase (MTHFR). Association studies suggested it was a potential risk factor for NTDs, because the thermolabile form of the enzyme led to elevated homocysteine concentrations when folic acid intake is low. Numerous studies analyzing MTHFR variants have resulted in positive associations with increased NTD risk only in certain populations, suggesting that these variants are not large contributors to the etiology of NTDs. With our limited understanding of the genes involved in regulating NTD susceptibility, the paucity of data on how folic acid protects the developing embryo, as well as the observed decrease in birth prevalence of NTDs following folic acid supplementation and food fortification, it makes little sense for prospective parents to be tested for MTHFR variants, or for variants of other known folate pathway genes.     

Neural tube defects,folate, and immune modulation

Periconceptional supplementation with folic acid has led to a significant worldwide reduction in the incidence of neural tube defects (NTDs). However, despite increasing awareness of the benefits of folic acid supplementation and the implementation of food fortification programs in many countries, NTDs continue to be a leading cause of perinatal morbidity and mortality worldwide. Furthermore, there exists a significant subgroup of women who appear to be resistant to the protective effects of folic acid supplementation. The following review addresses emerging clinical and experimental evidence for a role of the immune system in the etiopathogenesis of NTDs, with the aim of developing novel preventative strategies to further reduce the incidence of NTD‐affected pregnancies. In particular, recent studies demonstrating novel roles and interactions between innate immune factors such as the complement cascade, neurulation, and folate metabolism are explored. Birth Defects Research (Part A) 97:602–609, 2013. © 2013 Wiley Periodicals, Inc.     

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Folic acid supplementation and neural tube defect recurrence prevention

BACKGROUND: It is well established that women who have had a pregnancy affected by a neural tube defect (NTD) have an elevated risk of a subsequent NTD-affected pregnancy and that a high dose (4 mg/day) of folic acid taken around the time of conception prevents most recurrences of NTDs. METHODS: We reviewed the literature to identify studies that quantify the reduction in risk if women with a prior-NTD affected pregnancy consistently take folic acid before and during a subsequent pregnancy and the effectiveness of NTD recurrence prevention programs in increasing the percentage of women who consistently consume folic acid supplements. RESULTS: A meta-analysis of randomized trials of folic acid for the prevention of recurrent NTDs indicates a 69% reduction in recurrence risk if analyzed on an intention-to-treat basis and an 87% reduction among those women who took supplements prior to the beginning of pregnancy. Observational studies report reductions in recurrence risk of 85% to 100% among women taking folic acid prior to subsequent pregnancies. The percentage of women who take folic acid prior to a subsequent pregnancy has been reported to vary from 33% to 85%, varying with the demographic background and the intensity of folic acid counseling efforts. CONCLUSIONS: Targeted folic acid information and counseling provided to women with an NTD-affected pregnancy has been demonstrated to substantially reduce the risk of recurrent NTDs and is feasible to implement on a public health basis.     

Decline in the prevalence of neural tube defects following folic acid fortification and its cost-benefit in South Africa

BACKGROUND: In October 2003 South Africa embarked on a program of folic acid fortification of staple foods. We measured the change in prevalence of NTDs before and after fortification and assessed the cost benefit of this primary health care intervention. METHODS: Since the beginning of 2002 an ecological study was conducted among 12 public hospitals in four provinces of South Africa. NTDs as well as other birth defect rates were reported before and after fortification. Mortality data were also collected from two independent sources. RESULTS: This study shows a significant decline in the prevalence of NTDs following folic acid fortification in South Africa. A decline of 30.5% was observed, from 1.41 to 0.98 per 1,000 births (RR = 0.69; 95% CI: 0.49–0.98; p = .0379). The cost benefit ratio in averting NTDs was 46 to 1. Spina bifida showed a significant decline of 41.6% compared to 10.9% for anencephaly. Additionally, oro‐facial clefts showed no significant decline (5.7%). An independent perinatal mortality surveillance system also shows a significant decline (65.9%) in NTD perinatal deaths, and in NTD infant mortality (38.8%). CONCLUSIONS: The decrease in NTD rates postfortification is consistent with decreases observed in other countries that have fortified their food supplies. This is the first time this has been observed in a predominantly African population. The economic benefit flowing from the prevention of NTDs greatly exceeds the costs of implementing folic acid fortification. Birth Defects Research (Part A), 2008. © 2008 Wiley‐Liss, Inc.     

Awareness of folic acid for prevention of neural tube defects in a community with high prevalence of consanguineous marriages

Neural tube defects (NTDs) are severe congenital malformations and can be fatal. Intake of 0.4 mg folic in the periconceptional period reduces the risk of NTD by 50-70%. Consanguinity in the Arab population in Israel is a prevalent custom. The aim of this study was to assess the level of awareness regarding folic acid and its effect in the prevention of NTD among Arab Israeli women of childbearing age. We conducted a cross-sectional study. Of the 653 women (18-45 years) who were randomly selected for interview while visiting their family physician or well-baby clinic, 624 women completed the questionnaire. Fifty-three percent (n = 333) of the respondents had heard of folic acid; 14% (n = 89) were familiar with the protective effect of NTD and 3% (n = 18) had taken folic acid in the first months of pregnancy whereas none of them had used it in the preconception period. Highly educated women, women with one or two children, paramedics, and women of high socioeconomic status were more knowledgeable about the protective effects of folic acid (P < 0.001). Age and religion had no significant effect. An urgent need exists to improve the awareness of this population to the protective effect of folic acid. Daily supplementation and fertification of food with folic acid should be considered as the best way to improve the balance of folic acid in women of childbearing age of this special population (high prevalence of consanguinity).     

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

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.     

Prevention of congenital abnormalities by periconceptional multivitamin supplementation.

OBJECTIVE--To study the effect of periconceptional multivitamin supplementation on neural tube defects and other congenital abnormality entities. DESIGN--Randomised controlled trial of supplementation with multivitamins and trace elements. SETTING--Hungarian family planning programme. SUBJECTS--4156 pregnancies with known outcome and 3713 infants evaluated in the eighth month of life. INTERVENTIONS--A single tablet of a multivitamin including 0.8 mg of folic acid or trace elements supplement daily for at least one month before conception and at least two months after conception. MAIN OUTCOME MEASURES--Number of major and mild congenital abnormalities. RESULTS--The rate of all major congenital abnormalities was significantly lower in the group given vitamins than in the group given trace elements and this difference cannot be explained totally by the significant reduction of neural tube defects. The rate of major congenital abnormalities other than neural tube defects and genetic syndromes was 9.0/1000 in pregnancies with known outcome in the vitamin group and 16.6/1000 in the trace element group; relative risk 1.85 (95% confidence interval 1.02 to 3.38); difference, 7.6/1000. The rate of all major congenital abnormalities other than neural tube defects and genetic syndromes diagnosed up to the eighth month of life was 14.7/1000 informative pregnancies in the vitamin group and 28.3/1000 in the trace element group; relative risk 1.95 (1.23 to 3.09); difference, 13.6/1000. The rate of some congenital abnormalities was lower in the vitamin group than in the trace element group but the differences for each group of abnormalities were not significant. CONCLUSIONS--Periconceptional multivitamin supplementation can reduce not only the rate of neural tube defects but also the rate of other major non-genetic syndromatic congenital abnormalities. Further studies are needed to differentiate the chance effect and vitamin dependent effect.     

Case for mandatory fortification of food with folate in Australia, for the prevention of neural tube defects

BACKGROUND: Since the publication of randomized controlled trials demonstrating the prevention of neural tube defects (NTDs) with periconceptional folate, several Australian states have promoted an increase in periconceptional use of folic acid supplements. Since 1996, voluntary fortification of food with folate has been allowed in Australia and New Zealand for the purpose of preventing NTDs. METHODS: For this report, we synthesized published and unpublished data on folic acid supplement use, voluntary fortification, and trends in NTDs. RESULTS: There has been an increase in the proportion of women (up to 30-40%) taking periconceptional folic acid supplements in Australia, and many foods (mainly breakfast cereals) are fortified. Supplement use is strongly correlated with educational and socioeconomic status; consumption of voluntarily fortified foods is not. There has been a fall in NTDs of about 30% in the non-Aboriginal population, but no change has been seen in the Aboriginal population. CONCLUSIONS: These data support mandatory fortification of food as a more equitable approach to achieving sufficient folate intake in the periconceptional period for all women in Australia and New Zealand to prevent the majority of NTDs in their offspring. In May 2004, based on these and other considerations, the Australia and New Zealand Food Regulation Ministerial Council agreed that mandatory fortification of food with folate should be considered as a priority.     

Preconceptional folic acid‐containing supplement use in the national birth defects prevention study

Background: Despite public health campaigns encouraging women to take a daily folic acid supplement, the proportion of reproductive age women, in the United States, who comply with this recommendation is less than optimal. The objective of this analysis was to identify predictors of preconceptional folic acid‐containing supplement use to define subgroups of women who may benefit from targeted folic acid campaigns. Methods: This study included 6570 mothers of live born infants from the control population of National Birth Defects Prevention Study (1997–2005). Logistic regression analyses were used to identify predictors of preconceptional folic acid supplementation. A classification and regression tree (CART) analysis was used to define subgroups of women with different patterns of preconceptional folic acid supplementation. Results: Race/ethnicity, education, age at delivery, nativity, employment, income, number of dependents, smoking, and birth control use were significantly associated with preconceptional folic acid‐containing supplement use. Based on a CART analysis, education, race/ethnicity, and age were the most distinguishing factors between women with different preconceptional supplementation patterns. Non‐white women with <4 years of a college education were the least likely to use folic acid‐containing supplements (11%). However, even in the most compliant subgroup (women with ≥4 years of college), only 60% of women supplemented with folic acid. Conclusion: These results demonstrate the need for continued efforts to increase folic acid supplementation among all reproductive aged women. However, the success of such efforts may be improved if maternal characteristics such as education, race/ethnicity, and age, are considered in the development of future interventions. Birth Defects Research (Part A) 100:472–482, 2014. © 2014 Wiley Periodicals, Inc.     

Extremely high prevalence of neural tube defects in a 4-county area in Shanxi Province, China

BACKGROUND: In the past, northern China's Shanxi Province has reported the highest incidence of neural tube defects (NTDs) in the world. However, little is known about the epidemiology of NTDs in this area in recent years. METHODS: Data were collected from a population-based birth defects surveillance system in 4 counties that captures information on all live births, stillbirths of at least 20 weeks' gestation, and pregnancy terminations at any gestational age resulting from prenatal diagnosis of a birth defect. We also surveyed mothers of NTD case patients to determine their use of folic acid before and during early pregnancy. RESULTS: During 2003, 160 NTD cases were identified among 11,534 births (NTD birth prevalence = 138.7/10,000 births). The rates of anencephaly, spina bifida and encephalocele were 65.9, 58.1, and 14.7 per 10,000, respectively, and a female predominance was observed among anencephaly cases (male-to-female relative risk [RR], 0.49; 95% confidence interval [CI], 0.30-0.79), but not among spina bifida (RR, 0.90; 95% CI, 0.55-1.45) and encephalocele (RR, 1.03; 95% CI, 0.40-2.69) cases. The percentages of pregnancy termination following prenatal diagnosis of anencephaly, spina bifida, and encephalocele were 50%, 41.8%, and 35.3%, respectively. NTD birth prevalence tended to be higher among mothers aged <20 or > or =30 years (P = .06) and was markedly associated with lower levels of maternal education (P < .001). Among 143 NTD mothers, only 6 (4.2%) used folic acid supplements during the periconceptional period. CONCLUSIONS: The NTD birth prevalence rate in the study area is among the highest worldwide. Folic acid deficiency may be one important risk factor.     

Markers of macromolecular oxidative damage in maternal serum and risk of neural tube defects in offspring

Neural tube defects (NTDs) are among the most common and severe congenital malformations. To examine the association between markers of macromolecular oxidative damage and risk of NTDs, we measured levels of 8-hydroxy-2′-deoxyguanosine (8-OHdG), protein carbonyl (PC), and 8-iso-prostaglandin F2α (8-iso-PGF2α) in maternal serum samples of 117 women with NTD-affected pregnancies and 121 women with healthy term newborns. We found higher levels of 8-OHdG and PC in the NTD group than in the control group; however, we did not observe a statistically significant difference in 8-iso-PGF2α levels between the NTD and the control groups. NTD risk increased with increasing quartiles of 8-OHdG [odds ratio (OR)=1.17; 95% confidence interval (CI) 0.39–3.51; OR=2.19; 95% CI, 0.68–7.01; OR=3.70; 95% CI, 1.30–10.51, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.009], and with increasing quartiles of PC (OR=2.26; 95% CI, 0.66–7.69; OR=3.86; 95% CI, 1.17–12.80; OR=5.98; 95% CI, 1.82–19.66, for the second, third, and fourth quartile relative to the lowest quartile, respectively; P=0.002]. Serum levels of 8-OHdG were higher in women who did not take folic acid supplements during the periconceptional period. These results suggest that oxidative stress is present in women carrying pregnancies affected by NTDs.     

Effects of folate supplementation on the risk of spontaneous and induced neural tube defects in Splotch mice

BACKGROUND: Neural tube defects (NTDs) are among the most common human congenital malformations. Although clinical investigations have reported that periconceptional folic acid supplementation can reduce the occurrence of these defects, its mechanism remains unknown. Therefore, the murine mutant Splotch, which has a high incidence of spontaneous NTDs, along with the inbred strains SWV and LM/Bc, were used to investigate the relationship between folate and NTDs. METHODS: To investigate whether folates could reduce spontaneous NTDs, heterozygous Splotch dams (+/Sp) were treated with either folate or folinic acid throughout neurulation, gestational day (GD) 6.5 to 10.5. On GD 18.5 the dams were sacrificed and the fetuses examined for any neural tube defects. Subsequently, Sp/+ dams were treated with arsenic while receiving either a folate or folinic acid supplementation. Similar experiments were performed in the LM/Bc and SWV strains. RESULTS: Neither folate nor folinic acid supplements reduced the frequency of spontaneous NTDs in the embryos from Splotch heterozygote crosses. Arsenic increased the frequency of NTDs and embryonic death in the Splotch, LM/Bc and SWV litters and folinic acid failed to ameliorate the teratogenic effect of this metal. A folate supplement given to arsenic-treated dams proved to be maternally lethal in all three strains. CONCLUSIONS: Splotch embryos were not protected from either spontaneous or arsenic-induced NTDs by folinic or folic acid supplementation. Furthermore, folinic acid supplements did not reduce the incidence of arsenic-induced NTDs in either the LM/Bc or SWV litters.     

Trends of selected malformations in relation to folic acid recommendations and fortification: an international assessment

BACKGROUND: Two crucial issues relative to the benefits and impact of folic acid in the prevention of birth defects are whether supplementation recommendations alone, without fortification, are effective in reducing the population-wide rates of neural tube defects (NTDs), and whether such policies can reduce the occurrence of other birth defects. Using data from 15 registries, we assessed rates and trends of 14 major defects, including NTDs, in areas with official recommendations or fortification to assess the effectiveness of recommendations and fortification on a wide range of major birth defects. METHODS: We evaluated surveillance data through 2003 on major birth defects from population-based registries from Europe, North America, and Australia. All included ascertainment of pregnancy terminations (where legal). Trends before and after policies or fortification were assessed via Poisson regression and were compared via rate ratios. RESULTS: Significant changes in trends were seen for NTDs in areas with fortification but not in areas with supplementation recommendations alone. For other major birth defects, there was an overall lack of major trend changes after recommendations or fortification. However, some significant declines were observed for select birth defects in individual areas. CONCLUSIONS: Recommendations alone remain an ineffective approach in translating the known protective effect of folic acid in population-wide decline in NTD rates. Fortification appears to be effective in reducing NTDs. The effect on other birth defects remains unclear.