Previous Neural Tube Defect Research Articles

Inositols and female reproduction disorders: a consensus statement from the working group of the Club of the Italian Society of Endocrinology (SIE)-Women's Endocrinology.

To provide the latest scientific knowledge on the efficacy of inositols for improving reproductive disorders in women with and without polycystic ovary syndrome (PCOS) and to reach a consensus on their potential use through a Delphi-like process. A panel of 17 endocrinologists and 1 gynecologist discussed 4 key domains: menses irregularity and anovulation, fertility, pregnancy outcomes, and neonatal outcomes. A total of eight consensus statements were drafted. Myo-inositol (Myo) supplementation can be used to improve menses irregularities and anovulation in PCOS. Myo supplementation can be used in subfertile women with or without PCOS to reduce the dose of r-FSH for ovarian stimulation during IVF, but it should not be used to increase the clinical pregnancy rate or live birth rate. Myo supplementation can be used in the primary prevention of gestational diabetes mellitus (GDM), but should not be used to improve pregnancy outcomes in women with GDM. Myo can be preconceptionally added to folic acid in women with a previous neural tube defects (NTD)-complicated pregnancy to reduce the risk of NTDs in newborns. Myo can be used during pregnancy to reduce the risk of macrosomia and neonatal hypoglycemia in mothers at risk of GDM. This consensus statement provides recommendations aimed at guiding healthcare practitioners in the use of inositols for the treatment or prevention of female reproductive disorders. More evidence-based data are needed to definitively establish the usefulness of Myo, the appropriate dosage, and to support the use of D-chiro-inositol (DCI) or a definitive Myo/DCI ratio.

Periconceptional folic acid and risk for neural tube defects among higher risk pregnancies

Women with a previous neural tube defect (NTD)-affected pregnancy are recommended to consume 4,000 μg daily folic acid (FA) for prevention (10 times the general-population recommendation). Protection from doses between 400 and 4,000 μg for this and other higher risk groups is unclear. In the case-control Slone Birth Defects Study (1988-2015), we examined the associations between periconceptional FA doses and NTDs among four higher risk groups: NTD family history, periconceptional antiepileptic drug exposure (AED), pregestational diabetes, and prepregnancy obesity. Mothers completed standardized interviews about pregnancy events and exposures. FA categorizations were based on (a) supplements only and (b) supplements and diet ("total folate"). We estimated odds ratios (ORs) and 95% confidence intervals (CIs) (adjusted for age and study center) using logistic regression. Cases and controls included: 45 and 119 with family history, 25 and 108 with AED exposure, 12 and 63 with pregestational diabetes, 111 and 1,243 with obesity. Daily FA supplementation was associated with lower NTD risk compared to no supplementation (adjusted ORs were 0.33 [95% CI 0.13, 0.76] for family history, 0.31 [0.09, 0.95] for AED exposure, 0.25 [0.04, 1.05] for pregestational diabetes, 0.65 [0.40, 1.04] for obesity). Though estimates were imprecise, as total folate increased stronger point estimates were observed, notably among family history. No mothers with a prior NTD-affected pregnancy supplemented with 4,000 μg. Our findings reinforce that all women of childbearing potential should consume at least 400 μg FA/day to protect against NTDs. Higher risk groups may benefit from higher doses.

Neural Tube Defects: A case report

Neural tube defect is rare congenital defect of fetus. I have a case of 13 weeks period of gestation with meningomeyelocele came for termination of pregnancy. The diagnosis was confirmed by ultrasonography. History suggests that patient had previous neural tube defect baby, non-compliance to folic acid supplements. It is concluded that prenatal counseling, adherence to folic acid supplement and regular follow-up can prevent further complication.

Prenatal Diagnosis of Isolated Type 2 Diastematomyelia at 12 Weeks Using 2D Ultrasound with a Normal Intracranial Translucency

First-trimester ultrasound provides an opportunity to screen for various foetal abnormalities. Isolated Diastematomyelia is a rare spinal deformity which is infrequently diagnosed during the first-trimester ultrasound. Here, authors report a case of isolated Type 2 Diastematomyelia which was diagnosed in the 12-week ultrasound during a detailed survey of the foetal spine in view of previous neural tube defects.

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.

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).

Maternal Vitamin B12 Status and Risk of Neural Tube Defects in a Population With High Neural Tube Defect Prevalence and No Folic Acid Fortification

Folic acid fortification has reduced neural tube defect prevalence by 50% to 70%. It is unlikely that fortification levels will be increased to reduce neural tube defect prevalence further. Therefore, it is important to identify other modifiable risk factors. Vitamin B(12) is metabolically related to folate; moreover, previous studies have found low B(12) status in mothers of children affected by neural tube defect. Our objective was to quantify the effect of low B(12) status on neural tube defect risk in a high-prevalence, unfortified population. We assessed pregnancy vitamin B(12) status concentrations in blood samples taken at an average of 15 weeks' gestation from 3 independent nested case-control groups of Irish women within population-based cohorts, at a time when vitamin supplementation or food fortification was rare. Group 1 blood samples were from 95 women during a neural tube defect-affected pregnancy and 265 control subjects. Group 2 included blood samples from 107 women who had a previous neural tube defect birth but whose current pregnancy was not affected and 414 control subjects. Group 3 samples were from 76 women during an affected pregnancy and 222 control subjects. Mothers of children affected by neural tube defect had significantly lower B(12) status. In all 3 groups those in the lowest B(12) quartiles, compared with the highest, had between two and threefold higher adjusted odds ratios for being the mother of a child affected by neural tube defect. Pregnancy blood B(12) concentrations of <250 ng/L were associated with the highest risks. Deficient or inadequate maternal vitamin B(12) status is associated with a significantly increased risk for neural tube defects. We suggest that women have vitamin B(12) levels of >300 ng/L (221 pmol/L) before becoming pregnant. Improving B(12) status beyond this level may afford a further reduction in risk, but this is uncertain.

Continuing low uptake of periconceptional folate warrants increased food fortification

Objective To assess whether the Health Education Authority’s recent promotion of periconceptional folic acid has been successful in increasing uptake sufficient to prevent neural tube defects. Design A retrospective questionnaire, completed by 162 patients in the early pregnancy clinic in Doncaster Royal Infirmary, an average-sized UK district general hospital. The study ran in February and March 1999. Methods and main outcome measures Data were collected on: supplementation and dietary intake of folic acid, both preconceptionally and after confirmation of pregnancy; awareness of the benefits of folic acid; source of information on folic acid; the reasons for not taking folic acid (if this was so); planned or unplanned pregnancy; previous pregnancies; previous neural tube defect in a pregnancy; smoking habit; and age. Results Eighty-one per cent of women were aware of the benefits of folic acid, but only 27% took it preconceptionally. Sixty-eight per cent took it after confirmation of pregnancy. A quarter of patients made an attempt to increase dietary folate. Unplanned pregnancy was a significant bar to uptake, with significant differences in awareness and consumption. Number of pregnancies had no effect. Older women were more likely to take postconceptional folate, but awareness and preconceptional use were the same as younger women. Conclusion Despite an extensive campaign commissioned by the Department of Health and run by the Health Education Authority, use of periconceptional folate will probably only prevent one-sixth of affected pregnancies. The adverse effects of fortification discussed in the body of this paper are small. It is now time for increased fortification of all cereal-grain products to be instituted in the UK in a similar manner to the United States.

Folate and neural tube defects

A protective effect of folate against the development of neural tube defects (NTDs), specifically, anencephaly and spina bifida, is now well recognized, having been established by a chain of clinical research studies over the past half century. This article summarizes the more important of these studies, which have led to the current situation in which all women capable of becoming pregnant are urged to ingest folic acid regularly. The recommended intakes are 4 mg/d for those at high risk (by virtue of a previous NTD pregnancy outcome) and 0.4 mg/d for all others. However, a reduction in NTD births did not follow promulgation of these recommendations, and so folic acid fortification was mandated in the United States and some other countries. Although some controversy remains about the adequacy of fortification levels, the process was followed by significant improvement in folate indexes and a reduction of 25–30% in NTD frequency (about one-half of the proportion of cases assumed to be responsive to folate). The folate-NTD relation represents the only instance in which a congenital malformation can be prevented simply and consistently. Nevertheless, several research gaps remain: identification of the mechanism by which the defect occurs and how folate ameliorates it; characterization of the relative efficacy of food folate, folic acid added to foods, and folic acid by itself; delineation of the dose-response relations of folate and NTD prevention; and more precise quantification of the dose needed to prevent recurrences.

Folic Acid to Prevent Neural Tube Defects: A Potential Pharmacy Initiative with Public Health Implications

PurposeThis study (1) reviewed available data and recommendations regarding the prevention of neural tube defects (NTDs) through folic acid supplementation for the general population, women with previous NTD pregnancies, and women with epilepsy and (2) examined the potential role of pharmacy in the prevention of NTDs.MethodsPublished clinical literature was identified through a review of articles abstracted from MEDLINE and International Pharmaceutical Abstracts. Search terms were folic acid, neural tube defect, spina bifida, myelomeningocele, anencephaly, epilepsy, clinical guidelines, and pregnancy. Clinically relevant information consistent with current guidelines was extracted.ResultsAdministration of 0.4 mg/day of folic acid to women of childbearing age decreases rates of NTDs. In the general population, two types of NTD-reduction strategies have been employed: educational campaigns and food supply supplementation. Continued surveillance of NTD rates is needed to fully assess the effect of food supply supplementation in the US. Women with previous NTD pregnancies should consume 4 mg/day of folic acid during the month before and the month after conception. Public health interventions, including targeted educational materials and a national database to track subsequent pregnancies in women with previous NTD pregnancies, are needed. No evidence-based information about the effectiveness or dosing of folic acid supplements in women with epilepsy is available.ConclusionsPharmacists have an important role to play in the education of other health care professionals and patients about periconceptual folic acid supplementation. However, pharmacists must first be prepared to fulfill this role. Significant research in special populations — to determine the best folic acid dose and the most effective educational strategies — should be undertaken in the future.

Continuing low uptake of periconceptional folate warrants increased food fortification

Objective To assess whether the Health Education Authority’s recent promotion of periconceptional folic acid has been successful in increasing uptake sufficient to prevent neural tube defects. Design A retrospective questionnaire, completed by 162 patients in the early pregnancy clinic in Doncaster Royal Infirmary, an average-sized UK district general hospital. The study ran in February and March 1999. Methods and main outcome measures Data were collected on: supplementation and dietary intake of folic acid, both preconceptionally and after confirmation of pregnancy; awareness of the benefits of folic acid; source of information on folic acid; the reasons for not taking folic acid (if this was so); planned or unplanned pregnancy; previous pregnancies; previous neural tube defect in a pregnancy; smoking habit; and age. Results Eighty-one per cent of women were aware of the benefits of folic acid, but only 27% took it preconceptionally. Sixty-eight per cent took it after confirmation of pregnancy. A quarter of patients made an attempt to increase dietary folate. Unplanned pregnancy was a significant bar to uptake, with significant differences in awareness and consumption. Number of pregnancies had no effect. Older women were more likely to take postconceptional folate, but awareness and preconceptional use were the same as younger women. Conclusion Despite an extensive campaign commissioned by the Department of Health and run by the Health Education Authority, use of periconceptional folate will probably only prevent one-sixth of affected pregnancies. The adverse effects of fortification discussed in the body of this paper are small. It is now time for increased fortification of all cereal-grain products to be instituted in the UK in a similar manner to the United States.

Deficiencia de folatos y su asociación con defectos de cierre del tubo neural en el norte de México

To evaluate folic acid deficiency and other risk factors and their relationship with the occurrence of neural tube defects (NTD), in the rural population of northern Mexico (Chihuahua, Durango and Zacatecas).A multicentric case-control study was performed. Cases were both live and stillborn with NTD, and controls were healthy newborns without congenital malformations. Exposure to known risk factors was determined, establishing its association with NTD using multiple logistic regression analysis.Risk factors associated to NTD were: folic acid deficiency (OR 11.1; CI 95% 1.2-106.2, p = 0.04); the antecedents of previous NTD pregnancies (OR 3.3; CI 95% 1.1-18.8, p = 0.05) and stillbirths (OR 7.1; CI 95% 1.1-46.3, p = 0.04).Folic acid deficiency is one of the major risk factors associated to NTD among the rural population of northern Medico. Further investigations are necessary to determine the role of involved risk factors and implement adequate preventive measures.

Risk of Neural Tube Defect-Affected Pregnancy Is Associated with a Block in Maternal One-Carbon Metabolism at the Level ofN-5-Methyltetrahydrofolate:Homocysteine Methyltransferase

The disposition of whole blood mono- to hexaglutamyl methylfolate and plasma homocysteine (HCY) was used to evaluate potential lesion sites in one-carbon metabolism which could be responsible for neural tube defect(NTD)-affected pregnancies. An isocratic high-performance liquid chromatographic system (HPLC) with photodiode array detection was used to quantify and speciate whole-blood methylfolate into mono-, di-, tri-, tetra-, penta-, and hexaglutamate forms. This technique was also used with off-line radioassay to identify nonmethyl whole-blood folates. Isocratic HPLC with fluorescence detection was used to quantify SBDF derivatized homocysteine in plasma. The study investigated blood from 11 women who had experienced a previous NTD- affected pregnancy and 11 controls of similar age and social class. No subjects were pregnant. HCY levels were significantly higher in NTD subjects (P= 0.0486, 95% CI −2.799,0.001 using the Mann–Whitney test), as was the ratio of known intracellular (tri- to hexaglutamyl) methylfolate compared to extracellular (mono- and diglutamyl) methylfolate (P= 0.0062 95% CI −0.543, 3.862 using the Mann–Whitney test). Vitamin B12, red cell folate, circulating total methylfolate, and circulating mono- to hexaglutamyl methylfolates showed no difference between population groups. The disposition between individual and cumulative glutamate chain lengths of methylfolate showed significant trends which differed between population groups: (i) total blood methylfolate (Glu1–6) appears to be utilized byN-5-methyltetrahydrofolate:homocysteine methyltransferase (MS) in control blood but not NTD blood, where it appears to accumulate following a 45-min incubation; (ii) whole-blood hexaglutamyl methylfolate (5CH3-H4PteGlu6) becomes a larger proportion of the total blood methylfolate in NTD than in control populations; and (iii) the intermediate glutamate chains of methylfolate (Glu1–5) remain relatively constant as 5CH3-H4PteGlu6accumulates in NTD but appear to increase linearly with 5CH3-H4PteGlu6in controls. The significant elevation of HCY in the NTD population is associated with the increasing proportion of 5CH3-H4PteGlu6relative to the total methylfolate, since, when corrected for HCY level, the proportion of 5CH3-H4PteGlu6to total methylfolate is similar in NTD and control populations. These trends are consistent with a defect at the level of vitamin B12dependent MS which “traps” folate at the 5CH3-H4PteGlu6level.

The Methylfolate Axis in Neural Tube Defects: In Vitro Characterization and Clinical Investigation

We have investigated various micronutrients important to folate metabolism in women with two previous neural tube defect (NTD)-affected pregnancies. Results suggest the disposition of plasma 5-methyltetrahydrofolate (5CH3-H4PteGlu) with respect to dietary intake may differ from that of the control population. It appears that to achieve a given plasma level of 5CH3-H4PteGlu, the population with a history of NTD pregnancies needs to take in more dietary folate than controls. We discuss this in the context of a potential lesion at or upstream from 5,10-methylenetetrahydrofolate reductase (MTHFR). This metabolic axis, which is responsible for the multienzymic conversion of PteGlu to 5CH3-H4PteGlu, has been investigated in a rat model using liver homogenate. The anticonvulsant drug (ACD) carbamazepine was found to inhibit the reaction in terms of a reduced Vmax and increased Km. Inhibition approaching maximal was found to occur at therapeutic levels of ACD. Various potential inhibitory sites along the methylfolate axis are considered and possible relationships to congenital malformations discussed. We describe folate and one carbon metabolism in relation to potential NTD lesion sites, not only in the light of present findings, but with respect to the published findings of other workers. Based on our hypothesis that an NTD lesion exists upstream from MTHFR, we expound how pteroylmonoglutamate supplementation may protect against NTD (i) by reducing endotoxic homocysteine and (ii) through inhibiting MTHFR (as do dihydrofolates) and thus diverting one carbon units into DNA thymine.

Antenatal detection of neural tube defects: Comparison of biochemical and immunofluorescence methods

The aim of this study was to determine whether identification of glial cells in amniotic fluid samples could form a useful supplementary test in the antenatal diagnosis of neural tube defects (NTDs). In a 5-year study, 1452 samples of middle trimester amniotic fluid were examined blind to the results of other antenatal diagnostic tests and to the outcome of pregnancy. Reason of amniocentesis included raised serum alpha-fetoprotein (329), previous NTD (73), and a family history of NTDs (71). Duplicate cytospin preparations were stained with Giemsa and an antibody to glial fibrillary acidic protein (GFAP), and on this basis a prediction of fetal NTD status was made which was not communicated to clinicians. Subsequent management of pregnancies was influenced only by the results of routine antenatal testing for NTDs. Twenty cases of NTDs occurred among the 1406 cases in which the outcome was subsequently known. Of these 20 cases, only five (four anencephalic, one spina bifida) were correctly predicated by immunofluorescent identification of GFAP-positive cells in the amniotic fluid. The remaining 15 cases (two anencephalic, 13 spina bifida) were not so identified. In a further 18 cases, apparently GFAP-positive cells were identified in the absence of NTDs. We conclude that GFAP immunofluorescence examination of routine amniocentesis samples of amniotic fluid is not a useful predictive test for NTDs.

Detection of hydatidiform mole in maternal serum screening programmes for Down's syndrome.

To determine how frequently hydatidiform mole will be detected in a maternal serum Down's syndrome screening programme. Affected pregnancies were identified using a national register. Unconjugated oestriol (uE3) and human chorionic gonadotrophin (hCG) were measured in stored serum samples and alphafetoprotein (AFP) levels were available from previous neural tube defect screening at 15-20 weeks gestation. Ten pregnancies with a complete mole (i.e., hydropic placenta without a fetus), nine with stored serum samples and one with an AFP level only. The median values were 0.08, 0.13 and 1.83 multiples of the normal median for AFP, uE3 and hCG respectively. Six out of nine (67%) tested for all three markers had a high risk of Down's syndrome given maternal age and the marker levels. Many molar pregnancies that have not presented clinically before 15 weeks will be detected through Down's syndrome screening.

Primary prevention of neural tube defects with folic acid supplementation: Cuban experience

Folic acid (5 mg) was given daily, for not less than one menstrual period before conception and until the tenth week of pregnancy, to 81 women (FS) with a history of a previous neural tube defect (NTD) birth. There was no NTD recurrence among this group or among the offspring of a further 20 women (PS) whose folic acid supplementation fell short of the full regime. In another 114 women who became pregnant without folic acid supplementation (US), there were four NTD recurrences (3.5 per cent). Our results suggest that folic acid supplementation might be an effective method of primary prevention of neural tube defects.

Neural tube defect recurrence after 'partial' vitamin supplementation.

A total of 227 mothers enrolled for periconceptional multivitamin supplementation because of previous neural tube defect (NTD) births took vitamins for less than the recommended minimum period (at least 28 days before conception until two menstrual periods have been missed). Of 213 examined infants/fetuses born to these partially supplemented mothers, two had NTD, one of whom followed four previous NTDs. The observed NTD recurrence rate is similar to that observed in fully supplemented mothers. A further 14 mothers started supplements before the second missed period but after the normal time of neural tube closure. Three of their offspring had NTD. The significance of this apparently high recurrence rate is discussed.

Amniotic fluid folate, vitamin B12 and transcobalamins in neural tube defects

Levels of folate, vitamin B12, the vitamin B12 binding proteins, apotranscobalamin I, II and III (TC I, II and III) and the unsaturated vitamin B12 binding capacity (UBBC) were measured in mid-trimester amniotic fluids from normal pregnancies, and from those where the fetus had open spina bifida, anencephaly or omphalocoele, and where the fetus was normal but the mother had had a previous neural tube defect pregnancy. At 15-19 weeks' gestation, vitamin B12 levels were low in the fluids of all the types of abnormal fetuses, and also of normal fetuses where there had been a previous NTD sib. In contradistinction, TC I, II and III and UBBC levels were generally abnormally high in all these groups. Low vitamin B12 levels in the face of high carrier protein levels suggest deranged vitamin B12 production or transport. Since these abnormalities are present in fluids from normal sibs of NTD individuals as well as from those with midline lesions, an inherited defect is implied. We propose that at least part of the genetic predisposition to NTD, and possibly other midline defects, could reside in an abnormality connected with vitamin B12 production, transport or metabolism, and a mechanism is suggested.

Increased levels of apo‐transcobalamins I and II in amniotic fluid from pregnant women with previous neural tube defect offspring

In an attempt to identify biochemical components of the genetic predisposition to neural tube defects (NTDs), levels of folate, cobalamin, apo-transcobalamins I and II and alpha-fetoprotein were studied in midtrimester amniotic fluid from 24 pregnant women who had previously had a child with NTD. The control group consisted of 76 mothers, subjected to amniocentesis for reasons other than risk of NTD in offspring. Only pregnancies with normal outcome were included. No differences were found between groups for levels of folate, cobalamin or alpha-fetoprotein. Folate intake or metabolism did not appear to differ between groups. In contrast, the level of apo-transcobalamin I was doubled and the level of apo-transcobalamin II tripled in amniotic fluid from women who had had a child with NTD compared with the control group. Since the variation in apo-transcobalamin II in adults is to a high degree genetically determined, the present results may suggest that the genetic predisposition to NTD is associated with variation in this protein. Further studies are needed to substantiate or reject this possibility.