Neural Tube Defects Pregnancies Research Articles

Global heterogeneity in folic acid fortification policies and implications for prevention of neural tube defects and stroke: a systematic review

Folic acid (pteroylmonoglutamic acid) supplements are highly effective for prevention of neural tube defects (NTD) prompting implementation of mandatory or voluntary folic acid fortification for prevention of NTDs. We used plasma folate levels in population studies by country and year to compare effects of folic acid fortification types (mandatory or voluntary folic acid fortification policies) on plasma folate levels, NTD prevalence and stroke mortality rates. We conducted systematic reviews of (i) implementation of folic acid fortification in 193 countries that were member states of the World Health Organization by country and year, and (ii) estimated population mean plasma folate levels by year and type of folic acid fortification. We identified relevant English language reports published between Jan 1, 1990 and July 31, 2023 using Google Scholar, Medline, Embase and Global Health. Eligibility criteria were observational or interventional studies with >1000 participants. Studies of pregnant women or children <15 years were excluded. Using an ecological study design, we examined the associations of folic acid fortification types with NTD prevalence (n=108 studies) and stroke mortality rates (n=3 countries). Among 193 countries examined up to 31 July 2023, 69 implemented mandatory folic acid fortification, 47 had voluntary fortification, but 77 had no fortification (accounting for 32%, 53% and 15% of worldwide population, respectively). Mean plasma folate levels were 36, 21 and 17nmol/L in populations with mandatory, voluntary and no fortification, respectively (and proportions with mean folate levels >25nmol/L were 100%, 15% and 7%, respectively). Among 75 countries with NTD prevalence, mean (95% CI) prevalence per 10,000 population were 4.19 (4.11-4.28), 7.61 (7.47-7.75) and 9.66 (9.52-9.81) with mandatory, voluntary and no folic acid fortification, respectively. However, age-standardised trends in stroke mortality rates were unaltered by the introduction of folic acid fortification. There is substantial heterogeneity in folic acid fortification policies worldwide where folic acid fortification are associated with 50-100% higher population mean plasma folate levels and 25-50% lower NTD prevalence compared with no fortification. Many thousand NTD pregnancies could be prevented yearly if all countries implemented mandatory folic acid fortification. Further trials of folic acid for stroke prevention are required in countries without effective folic acid fortification policies. Medical Research Council (UK) and British Heart Foundation.

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study

ObjectivesTo determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000–2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour...

The Relation of Vitamin D Deficiency with Neural Tube Defect Pregnancies

The Relation of Vitamin D Deficiency with Neural Tube Defect Pregnancies

Folate Receptor Alpha Autoantibodies in Autism Spectrum Disorders: Diagnosis, Treatment and Prevention.

Folate deficiency and folate receptor autoimmune disorder are major contributors to infertility, pregnancy related complications and abnormal fetal development including structural and functional abnormalities of the brain. Food fortification and prenatal folic acid supplementation has reduced the incidence of neural tube defect (NTD) pregnancies but is unlikely to prevent pregnancy-related complications in the presence of folate receptor autoantibodies (FRAb). In pregnancy, these autoantibodies can block folate transport to the fetus and in young children, folate transport to the brain. These antibodies are prevalent in neural tube defect pregnancies and in developmental disorders such as cerebral folate deficiency (CFD) syndrome and autism spectrum disorder (ASD). In the latter conditions, folinic acid treatment has shown clinical improvement in some of the core ASD deficits. Early testing for folate receptor autoantibodies and intervention is likely to result in a positive outcome. This review discusses the first identification of FRAb in women with a history of neural tube defect pregnancy and FRAb’s association with sub-fertility and preterm birth. Autoantibodies against folate receptor alpha (FRα) are present in about 70% of the children with a diagnosis of ASD, and a significant number of these children respond to oral folinic acid with overall improvements in speech, language and social interaction. The diagnosis of folate receptor autoimmune disorder by measuring autoantibodies against FRα in the serum provides a marker with the potential for treatment and perhaps preventing the pathologic consequences of folate receptor autoimmune disorder.

Prevention of Neural Tube Defects in Europe: A Public Health Failure.

Objective: Thirty years ago it was demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). Despite Public Health Initiatives across Europe recommending that women take 0.4 mg folic acid before becoming pregnant and during the first trimester, the prevalence of NTD pregnancies has not materially decreased in the EU since 1998, in contrast to the dramatic fall observed in the USA. This study aimed to estimate the number of NTD pregnancies that would have been prevented if flour had been fortified with folic acid in Europe from 1998 as it had been in the USA.Design and Setting: The number of NTD pregnancies from 1998 to 2017 that would have been prevented if folic acid fortification had been implemented in the 28 countries who were members of the European Union in 2019 was predicted was predicted using data on NTD prevalence from 35 EUROCAT congenital anomaly registries and literature searches for population serum folate levels and folic acid supplementation.Results: From 1998 to 2017 an estimated 95,213 NTD pregnancies occurred amongst 104 million births in the 28 countries in the EU, a prevalence of 0.92 per 1,000 births. The median serum folate level in Europe over this time period was estimated to be 14.1 μg/L. There is a lack of information about women taking folic acid supplements before becoming pregnant and during the first trimester of pregnancy, with one meta-analysis indicating that around 25% of women did so. An estimated 14,600 NTD pregnancies may have been prevented if the European countries had implemented fortification at the level adopted by the USA in 1998 and 25% of women took folic acid supplements. An estimated 19,500 NTD pregnancies would have been prevented if no women took folic acid supplements.Conclusions: This study suggests that failure to implement mandatory folic acid fortification in the 28 European countries has caused, and continues to cause, neural tube defects to occur in almost 1,000 pregnancies every year.

Maternal ethnicity and the prevalence of British pregnancies affected by neural tube defects.

BackgroundFew data are available on the prevalence of neural tube defects (NTDs) within different ethnic communities of the UK. This study aimed to calculate prevalence estimates for NTD-affected pregnancies, classified by maternal ethnicity, and to explore why variations in prevalence might exist.MethodsA cross-sectional study was performed with data from regional congenital anomaly registers in England and Wales, for NTD-affected pregnancies between 2006 and 2011. Using binomial regression models, we examined NTD-affected pregnancy prevalence estimates and rate ratios (PRRs), by maternal ethnicity.ResultsThe prevalence of NTDs was 12.14 per 10,000 births, with no differences between study years. Anencephaly, encephalocele and spina bifida occurred at 4.98, 1.37 and 5.80 per 10,000 births respectively. Mothers of Indian ethnicity were 1.84 times more likely (95% CI: 1.24, 2.73) and Bangladeshi mothers 2.86 times more likely (95% CI: 1.48, 5.53) than White mothers to have an NTD-affected pregnancy, after adjusting for maternal deprivation and maternal age. The excess prevalence in Indian mothers was specifically for anencephaly (PRR 2.57; 95% CI: 1.52, 4.34), and in Bangladeshi mothers the trend was for increased spina bifida (PRR 3.86; 95% CI: 0.72, 8.69). Anencephaly in Indian mothers was especially associated with other congenital anomalies (non-isolated NTDs).ConclusionsDifferent British ethnic groups vary in NTD prevalence. The excess prevalence of anencephaly as a non-isolated NTD in pregnancies of Indian mothers could indicate involvement of genetic or other unmeasured behavioral factors. Future work is needed to seek etiological explanations for the ethnicity differences and to develop improved methods for primary prevention.

Maternal biomarkers for early prediction of the neural tube defects pregnancies.

Neural tube defects (NTD) are one of the most common congenital birth defects. The reason for the NTD cause is still not completely known, but it is believed that some genetic and environmental factors might play a role in its etiology. Among the genetic factors the polymorphism in the folate gene pathway is crucial. Numerous studies have suggested the possible role of maternal higher plasma concentration of homocysteine and low concentration of folate and cobalamin in the development of NTD but some negative studies are also published. Aim of the present was to find out the exact relation between NTD and maternal biomarkers like folate, cobalamin and homocysteine by conducting a meta-analysis. Different electronic databases were searched for the eligible studies. Standardized mean difference (SMD) with 95% confidence interval (CI) was used to determine association between maternal markers as risk for NTD pregnancy. The p value <0.05 was considered statistically significant in all tests. All the statistical analyses were done in the Open Meta-Analyst program. The homocysteine is significantly associated with the increased risk of NTD (SMD = 0.57; 95% CI: 0.35-0.80, p = <0.001; I2 = 93.01%), s-folate showed protective role in NTD (SMD = -0.48; 95% CI: -0.77 to -0.19, p = 0.001; I2 = 95.73%), similarly cobalamin is also having protective role (SMD = -0.28; 95% CI: -0.43 to -0.13, p = <0.001; I2 = 80.40%). In conclusion this study suggest that different maternal biomarkers may be used for the early prediction of the NTDs.

Neural Tube Defects in Pregnancies Among Women With Diagnosed HIV Infection - 15 Jurisdictions, 2013-2017.

In May 2018, a study of birth defects in infants born to women with diagnosed human immunodeficiency virus (HIV) infection in Botswana reported an eightfold increased risk for neural tube defects (NTDs) among births with periconceptional exposure to antiretroviral therapy (ART) that included the integrase inhibitor dolutegravir (DTG) compared with other ART regimens (1). The World Health Organization* (WHO) and the U.S. Department of Health and Human Services† (HHS) promptly issued interim guidance limiting the initiation of DTG during early pregnancy and in women of childbearing age with HIV who desire pregnancy or are sexually active and not using effective contraception. On the basis of additional data, WHO now recommends DTG as a preferred treatment option for all populations, including women of childbearing age and pregnant women. Similarly, the U.S. recommendations currently state that DTG is a preferred antiretroviral drug throughout pregnancy (with provider-patient counseling) and as an alternative antiretroviral drug in women who are trying to conceive.§ Since 1981 and 1994, CDC has supported separate surveillance programs for HIV/acquired immunodeficiency syndrome (AIDS) (2) and birth defects (3) in state health departments. These two surveillance programs can inform public health programs and policy, linkage to care, and research activities. Because birth defects surveillance programs do not collect HIV status, and HIV surveillance programs do not routinely collect data on occurrence of birth defects, the related data have not been used by CDC to characterize birth defects in births to women with HIV. Data from these two programs were linked to estimate overall prevalence of NTDs and prevalence of NTDs in HIV-exposed pregnancies during 2013-2017 for 15 participating jurisdictions. Prevalence of NTDs in pregnancies among women with diagnosed HIV infection was 7.0 per 10,000 live births, similar to that among the general population in these 15 jurisdictions, and the U.S. estimate based on data from 24 states. Successful linking of data from birth defects and HIV/AIDS surveillance programs for pregnancies among women with diagnosed HIV infection suggests that similar data linkages might be used to characterize possible associations between maternal diseases or maternal use of medications, such as integrase strand transfer inhibitors used to manage HIV, and pregnancy outcomes. Although no difference in NTD prevalence in HIV-exposed pregnancies was found, data on the use of integrase strand transfer inhibitors in pregnancy are needed to understand the safety and risks of these drugs during pregnancy.

Inositol Deficiency Increases Neural Tube Defect Susceptibility by PI3K/AKT Signaling Pathway (P11-009-19)

Abstract Objectives To explore the possible mechanisms of inositol deficiency in neural tube defects (NTDs). Methods The gas chromatography–mass spectrometry (GC-MS) analysis was used to detect the plasma inositol levels of NTD pregnancies and non-NTD controls from a high-prevalence area of Shanxi Province in northern China. A maternal MI deficient mouse model was established by using intraperitoneal injection of Li2CO3, which act as an inhibitor of inositol 1-phosphatase (IMPase) and a key enzyme for the synthesis and recycling of inositol in vivo. Using the phospho-protein array to find the possible differential phosphorylated proteins between the NTD and control group in MI deficiency human and mouse respectively. We performed pathway analysis on the differential phosphorylated proteins using KEGG databases of human NTDs with MI deficiency. Results We found that maternal MI deficiency was associated with an increased risk of NTDs (Pearson correlation coefficient r = –0.19, P &lt; 0.05). The MI levels of the pregnant mouse decreased significantly after Li2CO3 injection and reach to the lowest level at 8h after the injection (23.72mg/L vs 44.15 mg/L P &lt; 0.05). Repeat trials showed that the average incidence of NTDs was 26.7%. The NTD phenotypes included encephalocele (85.8%), anencephaly (5.7%) and spina bifida (8.5%). The result of phospho-protein array displayed that PI3K-Akt signaling pathway (hsa04151) was the most enriching pathway. We then validated the proteins involved in the PI3K-Akt signaling pathway using a mouse phospho-protein array. A total of 21 proteins were found to be differentially phosphorylated (Fold change &gt; 1.5), and 14 of them were differentially phosphorylated in both the human and mouse, including YWHAZ, AKT1, AKT2, BCL2, CCND1, NOS3, PTK2, IRS1, MTOR (mTOR), TP53, RPS6KB1 (p70S6K), PDPK1, PPP2CA and PTEN. Further pathway analysis on the 14 common differentially phosphorylated protein found that PI3K/Akt/mTOR/p70S6K pathway was the most disturbed signaling pathway induced by MI deficiency. Conclusions Our study indicated that PI3K-Akt signaling pathway might be one of the important regulatory mechanisms of inositol deficiency-induced NTDs. Funding Sources This study was supported by The National Key Basic Research Program (2018YFC1002500), National Nature Science Foundation of China (81571443 to JW, 81801451 to JG).

Vitamin B-12 and liver activity and expression of methionine synthase are decreased in fetuses with neural tube defects

The risk of neural tube defects (NTDs) is influenced by nutritional factors and genetic determinants of one-carbon metabolism. A key pathway of this metabolism is the vitamin B-12- and folate-dependent remethylation of homocysteine, which depends on methionine synthase (MS, encoded by MTR), methionine synthase reductase, and methylenetetrahydrofolate reductase. Methionine, the product of this pathway, is the direct precursor of S-adenosylmethionine (SAM), the universal methyl donor needed for epigenetic mechanisms. This study aimed to evaluate whether the availability of vitamin B-12 and folate and the expression or activity of the target enzymes of the remethylation pathway are involved in NTD risk. We studied folate and vitamin B-12 concentrations and activity, expression, and gene variants of the 3 enzymes in liver from 14 NTD and 16 non-NTD fetuses. We replicated the main findings in cord blood from pregnancies of 41 NTD fetuses compared with 21 fetuses with polymalformations (metabolic and genetic findings) and 375 control pregnancies (genetic findings). The tissue concentration of vitamin B-12 (P=0.003), but not folate, and the activity (P=0.001), transcriptional level (P=0.016), and protein expression (P=0.003) of MS were decreased and the truncated inactive isoforms of MS were increased in NTD livers. SAM was significantly correlated with MS activity and vitamin B-12. A gene variant in exon 1 of GIF (Gastric Intrinsic Factor gene) was associated with a dramatic decrease of liver vitamin B-12 in 2 cases. We confirmed the decreased vitamin B-12 in cord blood from NTD pregnancies. A gene variant of GIF exon 3 was associated with NTD risk. The decreased vitamin B-12 in liver and cord blood and decreased expression and activity of MS in liver point out the impaired remethylation pathway as hallmarks associated with NTD risk. We suggest evaluating vitamin B-12 in the nutritional recommendations for prevention of NTD risk beside folate fortification or supplementation.

Exposure to Folate Receptor Alpha Antibodies during Gestation and Weaning Leads to Severe Behavioral Deficits in Rats: A Pilot Study.

The central nervous system continues to develop during gestation and after birth, and folate is an essential nutrient in this process. Folate deficiency and folate receptor alpha autoantibodies (FRα-AuAb) have been associated with pregnancy-related complications and neurodevelopmental disorders. In this pilot study, we investigated the effect of exposure to FRα antibodies (Ab) during gestation (GST), the pre-weaning (PRW), and the post weaning (POW) periods on learning and behavior in adulthood in a rat model. In the open field test and novel object recognition task, which examine locomotor activity and anxiety-like behavior, deficits in rats exposed to Ab during gestation and pre-weaning (GST+PRW) included more time spent in the periphery or corner areas, less time in the central area, frequent self-grooming akin to stereotypy, and longer time to explore a novel object compared to a control group; these are all indicative of increased levels of anxiety. In the place avoidance tasks that assess learning and spatial memory formation, only 30% of GST+PRW rats were able to learn the passive place avoidance task. None of these rats learned the active place avoidance task indicating severe learning deficits and cognitive impairment. Similar but less severe deficits were observed in rats exposed to Ab during GST alone or only during the PRW period, suggesting the extreme sensitivity of the fetal as well as the neonatal rat brain to the deleterious effects of exposure to Ab during this period. Behavioral deficits were not seen in rats exposed to antibody post weaning. These observations have implications in the pathology of FRα-AuAb associated with neural tube defect pregnancy, preterm birth and neurodevelopmental disorders including autism.

Inositol for the prevention of neural tube defects: a pilot randomised controlled trial.

Although peri-conceptional folic acid (FA) supplementation can prevent a proportion of neural tube defects (NTD), there is increasing evidence that many NTD are FA non-responsive. The vitamin-like molecule inositol may offer a novel approach to preventing FA-non-responsive NTD. Inositol prevented NTD in a genetic mouse model, and was well tolerated by women in a small study of NTD recurrence. In the present study, we report the Prevention of Neural Tube Defects by Inositol (PONTI) pilot study designed to gain further experience of inositol usage in human pregnancy as a preliminary trial to a future large-scale controlled trial to evaluate efficacy of inositol in NTD prevention. Study subjects were UK women with a previous NTD pregnancy who planned to become pregnant again. Of 117 women who made contact, ninety-nine proved eligible and forty-seven agreed to be randomised (double-blind) to peri-conceptional supplementation with inositol plus FA or placebo plus FA. In total, thirty-three randomised pregnancies produced one NTD recurrence in the placebo plus FA group (n 19) and no recurrences in the inositol plus FA group (n 14). Of fifty-two women who declined randomisation, the peri-conceptional supplementation regimen and outcomes of twenty-two further pregnancies were documented. Two NTD recurred, both in women who took only FA in their next pregnancy. No adverse pregnancy events were associated with inositol supplementation. The findings of the PONTI pilot study encourage a large-scale controlled trial of inositol for NTD prevention, but indicate the need for a careful study design in view of the unwillingness of many high-risk women to be randomised.

Evaluation of proton-coupled folate transporter (SLC46A1) polymorphisms as risk factors for neural tube defects and oral clefts.

Many folate-related genes have been investigated for possible causal roles in neural tube defects (NTDs) and oral clefts. However, no previous reports have examined the major gene responsible for folate uptake, the proton-coupled folate transporter (SLC46A1). We tested for association between these birth defects and single nucleotide polymorphisms in the SLC46A1 gene. The NTD study population included 549 complete and incomplete case-family triads, and 999 controls from Ireland. The oral clefts study population comprised a sample from Utah (495 complete and incomplete case-family triads and 551 controls) and 221 Filipino multiplex cleft families. There was suggestive evidence of increased NTD case risk with the rs17719944 minor allele (odds ratio (OR): 1.29; 95% confidence intervals (CI): [1.00-1.67]), and decreased maternal risk of an NTD pregnancy with the rs4795436 minor allele (OR: 0.62; [0.39-0.99]). In the Utah sample, the rs739439 minor allele was associated with decreased case risk for cleft lip with cleft palate (genotype relative risk (GRR): 0.56 [0.32-0.98]). Additionally, the rs2239907 minor allele was associated with decreased case risk for cleft lip with cleft palate in several models, and with cleft palate only in a recessive model (OR: 0.41; [0.20-0.85]). These associations did not remain statistically significant after correcting for multiple hypothesis testing. Nominal associations between SLC46A1 polymorphisms and both Irish NTDs and oral clefts in the Utah population suggest some role in the etiology of these birth defects, but further investigation in other populations is needed.

Prevention of neural tube defects in the UK: a missed opportunity

ObjectiveIn 1991, the Medical Research Council (MRC) Vitamin Study demonstrated that folic acid taken before pregnancy and in early pregnancy reduced the risk of a neural tube defect (NTD). We...

Identification of PCSK9 as a novel serum biomarker for the prenatal diagnosis of neural tube defects using iTRAQ quantitative proteomics.

To identify candidate serum molecule biomarkers for the non-invasive early prenatal diagnosis of neural tube defects (NTDs), we employed an iTRAQ-based quantitative proteomic approach to analyze the proteomic changes in serum samples from embryonic day (E) 11 and E13 pregnant rats with spina bifida aperta (SBA) induced by all-trans retinoic acid. Among the 390 proteins identified, 40 proteins at E11 and 26 proteins at E13 displayed significant differential expression in the SBA groups. We confirmed 5 candidate proteins by ELISA. We observed the space-time expression changes of proprotein convertase subtilisin/kexin type 9 (PCSK9) at different stages of fetal development, including a marked decrease in the sera of NTD pregnancies and gradual increase in the sera of normal pregnancies with embryonic development. PCSK9 demonstrated the diagnostic efficacy of potential NTD biomarkers [with an area under the receiver operating characteristic curve of 0.763, 95% CI: 065–0.88]. Additionally, PCSK9 expression in the spinal cords and placentas of SBA rat fetuses was markedly decreased. PCSK9 could serve as a novel molecular biomarker for the non-invasive prenatal screening of NTDs and may be involved in the pathogenesis of NTDs at critical periods of fetal development.

Association of maternal homocysteine and vitamins status with the risk of neural tube defects in Tunisia: A case-control study.

This study was conducted to determine whether low folate and vitamin B12 levels, as well as high homocysteine levels in pregnant women are associated with neural tube defects (NTDs) in Tunisia. A total of 75 NTDs pregnancies and 75 matched controls were included in the study. Their vitamin B12, folate, and red blood cell folate concentrations were measured using a radio-immunoassay kit and total homocysteine concentrations were determined using a fluorescent polarization immunoassay. Vitamin B12 and folate concentrations were lower in NTD-affected pregnant women than in controls (respectively, p = 0.009 and p < 0.001). Total homocysteine concentration was significantly higher in the NTDs group than in controls (p = 0.008). In the case group, the folate levels were positively related with vitamin B12 levels (r = 0.54; p < 0.001) and negatively correlated with total homocysteine levels (r = -0.19; p = 0.04). Besides, red blood cell folate levels were positively correlated with folate levels (r = 0.24; p = 0.02) and negatively correlated with total homocysteine levels (r = -0.37; p = 0.001). Lower concentrations of folate and vitamin B12 are related to the increased risk of NTDs. Both folate and vitamin B12 intake insufficiency could contribute to the increased risk of NTDs. A dietary supplement, combining folate and vitamin B12, might be an effective measure to decrease the NTDs incidence in Tunisia.

When folic acid fails: Insights from 20 years of neural tube defect surveillance in South Carolina.

Neural tube defects (NTDs) are the most common of the severe malformations of the brain and spinal cord. Increased maternal intake of folic acid (FA) during the periconceptional period is known to reduce NTD risk. Data from 1046 NTD cases in South Carolina were gathered over 20 years of surveillance. It was possible to determine maternal periconceptional FA use in 615 NTD-affected pregnancies. In 163 occurrent (26.9%) and two recurrent (22%) NTD cases, the mothers reported periconceptional FA use. These women were older and more likely to be white. Maternal periconceptional FA usage was reported in 40.4% of cases of spina bifida with other anomalies but in only 25.2% of isolated spina bifida cases (P = 0.02). This enrichment for associated anomalies was not noted among cases of anencephaly or of encephalocele. Among the 563 subsequent pregnancies to mothers with previous NTD-affected pregnancies, those taking FA had a 0.4% NTD recurrence rate, but the recurrence without FA was 8.5%. NTDs with other associated findings were less likely to be prevented by FA, suggesting there is a background NTD rate that cannot be further reduced by FA. Nonetheless, the majority (73.9%) of NTDs in pregnancies in which the mothers reported periconceptional FA use were isolated NTDs of usual types. Cases in which FA failed in prevention of NTDs provide potential areas for further study into the causation of NTDs. The measures and techniques implemented in South Carolina can serve as an effective and successful model for prevention of NTD occurrence and recurrence.

Pre-conception Folic Acid and Multivitamin Supplementation for the Primary and Secondary Prevention of Neural Tube Defects and Other Folic Acid-Sensitive Congenital Anomalies.

Abstract Objective To provide updated information on the pre- and post-conception use of oral folic acid with or without a multivitamin/micronutrient supplement for the prevention of neural tube defects and other congenital anomalies This will help physicians, midwives, nurses, and other health care workers to assist in the education of women about the proper use and dosage of folic acid/multivitamin supplementation before and during pregnancy. Evidence Published literature was retrieved through searches of PubMed, Medline, CINAHL, and the Cochrane Library in January 2011 using appropriate controlled vocabulary and key words (e.g., folic acid, prenatal multivitamins, folate sensitive birth defects, congenital anomaly risk reduction, pre-conception counselling). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies published in English from 1985 and June 2014. Searches were updated on a regular basis and incorporated in the guideline to June 2014 Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology-related agencies, clinical practice guideline collections, clinical trial registries, and national and international medical specialty societies Costs, risks, and benefits The financial costs are those of daily vitamin supplementation and eating a healthy folate-enriched diet. The risks are of a reported association of dietary folic acid supplementation with fetal epigenetic modifications and with an increased likelihood of a twin pregnancy These associations may require consideration before initiating folic acid supplementation The benefit of folic acid oral supplementation or dietary folate intake combined with a multivitamin/micronutrient supplement is an associated decrease in neural tube defects and perhaps in other specific birth defects and obstetrical complications. Values The quality of evidence in the document was rated using the criteria described in the Report of the Canadian Task Force on Preventative Health Care (Table 1).

Brief report pregnancy outcome in women assigned an ICD-9/ICD-9-CM 655.0 code "central nervous system malformation in fetus affecting management of pregnancy": can these codes aid in surveillance for central nervous system defects?

The difficulty many birth defects registries have in identifying early pregnancy terminations can lead to significant underreporting of certain types of malformations. This study was designed to determine the potential benefit of using maternal ICD-9 codes relating to management of pregnancy due to fetal anomaly in surveillance of central nervous system (CNS) defects (655.0). Women assigned the ICD-9/ICD-9-CM (henceforth termed ICD-9) code 655.0 between 1990 and 2000 were ascertained from two administrative health databases in Manitoba, Canada, one relating to maternal serum screening and one based on hospital discharges. Information was collected on the type of CNS defect identified and whether it was isolated or associated with other anomalies. The relationship of these variables to pregnancy outcome and its potential impact on surveillance for these types of defects was explored. Neural tube defects were the most common finding (67%) identified in the fetuses/infants of women assigned code 655.0, followed by hydrocephaly (20%) and Dandy-Walker anomaly (6%), but the proportion of neural tube defect cases declined after food fortification with folic acid. Termination of pregnancy occurred in ∼50% of neural tube defect cases, 18% before 20 weeks of gestation, but was rare for other CNS defects. The maternal ICD-9 code 655.0 had a very high (97%) positive predictive value for identifying fetuses with a CNS defect; 655.00 was particularly effective in identifying neural tube defects pregnancies terminated before 20 weeks gestation that would be difficult to ascertain, especially by passive surveillance systems using infant related data alone.

SELDI-TOF-MS proteomic profiling of serum, urine, and amniotic fluid in neural tube defects.

Neural tube defects (NTDs) are common birth defects, whose specific biomarkers are needed. The purpose of this pilot study is to determine whether protein profiling in NTD-mothers differ from normal controls using SELDI-TOF-MS. ProteinChip Biomarker System was used to evaluate 82 maternal serum samples, 78 urine samples and 76 amniotic fluid samples. The validity of classification tree was then challenged with a blind test set including another 20 NTD-mothers and 18 controls in serum samples, and another 19 NTD-mothers and 17 controls in urine samples, and another 20 NTD-mothers and 17 controls in amniotic fluid samples. Eight proteins detected in serum samples were up-regulated and four proteins were down-regulated in the NTD group. Four proteins detected in urine samples were up-regulated and one protein was down-regulated in the NTD group. Six proteins detected in amniotic fluid samples were up-regulated and one protein was down-regulated in the NTD group. The classification tree for serum samples separated NTDs from healthy individuals, achieving a sensitivity of 91% and a specificity of 97% in the training set, and achieving a sensitivity of 90% and a specificity of 97% and a positive predictive value of 95% in the test set. The classification tree for urine samples separated NTDs from controls, achieving a sensitivity of 95% and a specificity of 94% in the training set, and achieving a sensitivity of 89% and a specificity of 82% and a positive predictive value of 85% in the test set. The classification tree for amniotic fluid samples separated NTDs from controls, achieving a sensitivity of 93% and a specificity of 89% in the training set, and achieving a sensitivity of 90% and a specificity of 88% and a positive predictive value of 90% in the test set. These suggest that SELDI-TOF-MS is an additional method for NTDs pregnancies detection.