Maternal B12 Research Articles

Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.

Amelioration of sodium valproate-induced neural tube defects in mouse fetuses by maternal folic acid supplementation during gestation.

Infants of epileptic women treated with valproic acid (VPA) during pregnancy have a higher risk of developing spina bifida than those of the general population. VPA induces exencephaly in experimental animal embryos. But the pathogenetic mechanism remains rather elusive. Antiepileptic drugs (AED) in general accentuate pregnancy-imposed fall in maternal folate levels. Periconceptional folic acid supplementation is reported to protect embryos from developing neural tube defects (NTD). Conflicting results have been reported by experimental studies that attempted to alleviate VPA-induced NTD by folic acid. Our objectives were to determine the critical developmental stages and an effective dose of folic acid for the prevention of VPA-induced exencephaly in mouse fetuses. A single teratogenic dose of 400 mg/kg of VPA was administered to TO mice on gestation day (GD) 7 or 8. It was followed by (1) a single dose of 12 mg/kg of FA (folinic acid) or (2) 3 doses of FA 4 mg/kg each. In experiment (3), FA (4 mg/kg) was administered thrice daily starting on GD 5 and continued through GD 10. These animals received VPA on GD 7 or 8. VPA and B12 concentrations were determined by radioimmunoassay. The single heavy dose of FA had no rescue effect on NTD. Three divided doses of FA on GD 7 and continuous dosing of FA from GD 5 through GD 10 substantially reduced the VPA-induced exencephaly in the fetuses. In the later experiments, the neural folds elevated faster than the non-supplemented group. VPA considerably reduced maternal plasma folate and B12 concentrations. The heavy dose of FA only moderately improved vitamin levels. Three divided doses of FA elevated the vitamin levels slightly better but it was the prolonged dosing of FA that was associated with sustained elevation of plasma levels higher than the control levels and acceleration of neural tube closure thus accounting for the pronounced protection against VPA-induced NTD development. These data suggest that plasma levels of FA and B12 have to be kept substantially elevated and maintained high throughout organogenesis period to protect embryos against VPA-induced NTD in this mouse model.

Maternal Serum B12 Levels and Risk for Neural Tube Defects in a Texas-Mexico Border Population

Neural tube defects (NTDs) are common birth defects that can be prevented with folate fortification and supplementation. Studies suggest that other nutrients may also be essential to neural tube closure and have a potential role in risk reduction, with vitamin B(12) mentioned most often. We determined the effect of maternal serum B(12) levels, measured postpartum, on the risk of NTDs among a high risk Mexican American population. The case-control study included 157 Mexican American women with NTD-affected pregnancies and 186 Mexican American women with normal pregnancies, who were residents of Texas-Mexico border counties and delivered during 1995 to 2000. Compared with women in the highest vitamin B(12) quintile, women in the lowest quintile showed a strong risk effect (odds ratio (OR) = 3.0, confidence interval (CI): 1.4, 6.3); while those in the 2nd and 3rd quintiles showed moderate risk effects (OR = 1.6, CI = 0.7, 3.6 and OR = 1.7, CI = 0.8, 3.8, respectively). Adjusting for obesity, vitamin supplements, dietary folate, dietary B(12), red blood cell folate, and other covariates did not materially change these estimates. Insufficient levels of serum B(12), which are not normally indicative of a classical vitamin B(12) deficiency nor stem from an inadequate diet, may be an important etiologic factor for NTDs in this population.

Association between maternal and infant class I and II HLA alleles and of their concordance with the risk of perinatal HIV type 1 transmission.

We aimed to investigate the influence of class I and class II HLA specificities and of the concordance between maternal and infant HLA on vertical HIV-1 transmission. HLA typing of samples from mothers and infants enrolled in the Ariel study, a perinatal HIV-1 transmission cohort including 203 mother-infant pairs, was performed by serological and molecular methods. HLA effects were evaluated alone and by multivariate modeling considering also other known predictors of perinatal HIV-1 transmission (maternal viral load, antiretroviral therapy, duration of rupture of membranes, and histological chorioamnionitis). Modest associations were seen with specific HLA markers (increased risk with infant B67 and B58 and maternal DR1; decreased risk with maternal B12), but these were not statistically significant after adjusting for multiple comparisons. Mother-infant concordance at any class I locus was a strong predictor of transmission (odds ratio [OR], 4.16; p = 0.028). Transmission was not associated with class II concordance. Class I HLA concordance retained its importance after adjusting for maternal viral load, antiretroviral therapy, duration of rupture of membranes or histological chorioamnionitis. In multivariate modeling, only class I concordance (OR, 3.59; p = 0.069) and chorioamnionitis (OR, 3.79; p = 0.030) were retained as independent predictors of transmission. HLA alleles, and in particular the class I concordance between maternal and neonatal HLA, may regulate the risk of perinatal HIV-1 transmission.

Relationship between total homocysteine and folate levels in pregnant women and their newborn babies according to maternal serum levels of vitamin B12.

To determine total homocysteine and folate levels in pregnant women according to vitamin B12 (B12) levels, and to analyse the impact of maternal B12 levels on the nutritional status of their newborn babies. Cross sectional observational study. Two public hospitals in Jundiai City, São Paulo, Brazil. Sixty-nine pregnant women and their respective newborn babies at the time of delivery. Maternal blood was collected up to 8 hours before delivery. Umbilical cord blood was collected after the expulsion of the placenta. Total homocysteine was measured by high perfomance liquid chromatography, folate by ion capture methodology and B12 by enzyme immunoassay. Relationship between low maternal vitamin B12 levels and total homocysteine and folate levels in pregnant women and newborn babies. There was a significant correlation between maternal and neonatal B12 levels, but not between maternal B12 and neonatal red blood cell (RBC) folate. There was a weak correlation between maternal B12 levels and neonatal serum folate. However, there were significant correlations between maternal and neonatal total homocysteine levels and between neonatal B12 and neonatal total homocysteine levels. Mean (+/- SD) umbilical cord blood B12, RBC folate, serum folate and total homocysteine levels were 1.7 +/- 0.8, 1.8 +/- 0.8, 2.2 +/- 0.8 and 0.9 +/- 0.3 times higher than maternal B12, RBC folate, serum folate and total homocysteine values, respectively. These data suggest that pregnant women with low B12 levels are unable to provide the necessary amount of B12 to their fetuses. The clinical consequences could be the presence of neurological abnormalities as well as the lack of utilisation of homocysteine for methionine transformation.

Influence of Vitamin B12 Status on the Inactivation of Methionine Synthase by Nitrous Oxide

We have studied the influence of maternal serum B12 concentration on the inactivation of placental methionine synthase activity by nitrous oxide in an obstetric population. This group was known to include patients with a wide range of B12 values. Over 70% of patients were given nitrous oxide either for analgesia during labour or for delivery by Caesarean section, for periods ranging from a few minutes to 11 h. Patients undergoing normal delivery and Caesarean section under extradural anaesthesia served as controls. There was a highly significant relation between placenta methionine synthase activity and duration of exposure to nitrous oxide. Inactivation was slower than that described for the liver, which may reflect the intermittent use. There was also a significant relation between maternal B12 and placenta methionine synthase activity, but there was a wide scatter of results and the data were not thought to be predictive. There was evidence that inactivation by nitrous oxide was more rapid in patiens with small concentrations of B12. We conclude that some patients with reduced serum concentrations of B12 may be at a disadvantage with nitrous oxide anaesthesia.

INFLUENCE OF VITAMIN B12 STATUS ON THE INACTIVATION OF METHIONINE SYNTHASE BY NITROUS OXIDE

We have studied the influence of maternal serum B12 concentration on the inactivation of placental methionine synthase activity by nitrous oxide in an obstetric population. This group was known to include patients with a wide range of B12 values. Over 70% of patients were given nitrous oxide either for analgesia during labour or for delivery by Caesarean section, for periods ranging from a few minutes to 11 h. Patients undergoing normal delivery and Caesarean section under extradural anaesthesia served as controls. There was a highly significant relation between placental methionine synthase activity and duration of exposure to nitrous oxide. Inactivation was slower than that described for the liver, which may reflect the intermittent use. There was also a significant relation between maternal B12 and placental methionine synthase activity, but there was a wide scatter of results and the data were not thought to be predictive. There was evidence that inactivation by nitrous oxide was more rapid in patients with small concentrations of B12. We conclude that some patients with reduced serum concentrations of B12 may be at a disadvantage with nitrous oxide anaesthesia.

Serum vitamin B12 content and UBBC in gravid and fetal rabbits.

It is well known that human serum vitamin B12 decreases progressively during pregnancy (1-3) with lowest levels present at term. Within 4-6 weeks post partum, the maternal serum B12 level returns to normal or higher (4-5). In general, fetal cord blood contains more vitamin B12 than comparable maternal blood (3). The unsaturated vitamin B12 binding capacity (UBBC) of the mother increases during pregnancy and returns to normal within a month of parturition (6, 7). Similar phenomenon have also been found in rats (1). Although pregnant women and gravid experimental rats appear to follow the same pattern with regard to serum vitamin B12, no definitive rationale has as yet been offered to explain these effects. Rabbits are known to contain the highest serum vitamin B12 content and UBBC of all laboratory mammals so far tested (8). Because rabbits are often used as models for fetal development, it was of interest to determine the serum B12 and UBBC during gravidity and in the fetus. Materials. Samples. Sera of gravid New Zealand rabbits, fetuses near term and sera of both sexes during growth and development were obtained commercially.1 Sera from New Zealand strain rabbits that were maintained in the laboratory were used for comparative purposes. Sera of normal pregnant women were obtained a few hours prior to parturition and cord blood was obtained from their normal healthy infants. All sera were maintained frozen at −20° until analyzed. Vitamin B12 assay. Vitamin B12 was determined by a competitive binding assay using porcine intrinsic factor (IF)2 as the binding protein, high specific activity 57Co labelled cyanocobalamin (15 μCi/μg B12-60 μCi/μg B12)3 and equilibrium dialysis briefly described as follows:

IN UTERO TREATMENT OF METHYLMALONIC ACIDEMIA (MMA-EMIA) WITH VITAMIN B12

The question of whether Vitamin B12 can prevent fetal accumulation of methylmalonic acid (MMA) in the vitamin-responsive form of the disease was investigated for the first time. During the second pregnancy of a woman who had previously lost a child with presumed MMA-emia, sonicated amniotic fluid cells initially showed no activity of MM-CoA Mutase and no accumulation of the coenzyme 5'-deoxyadenosylcobalamin. Full activity of the enzyme was restored with the addition of this cofactor. Vitamin B12 in large doses was given to the mother from 32 wks. gestation to term. Maternal serum B12 levels reached 3,000-6,000 pg/ml (normal < 900) in the last 6 weeks. Cord blood B12 was over 19,000 pg/ml; maternal serum B12 taken simultaneously measured over 18,000. Instead of the anticipated progressive increase in maternal urinary MMA during the last 2 months of pregnancy, there was a decrease. Following birth, the infant's urinary MMA content was 67/μm/mg creatinine (normal < 5.0), and has remained essentially the same for the first 5 weeks of life on a diet containing 1.5 gm protein/Kg/day; thus far supplemental B12 has not been necessary. Skin biopsy studies to confirm B12 responsiveness are nearing completion. It seems likely that administration of large doses of Vitamin B12 to mothers carrying fetuses with the B12 responsive form of MMA-emia can slow prenatal accumulation of MMA.