Folate absorption in women with a history of neural tube defect-affected pregnancy.

BACKGROUND: The risk of neural tube defects (NTDs) is significantly reduced by supplemental folic acid. NTD risk may be associated with impaired absorption of polyglutamyl folate, the primary form of naturally occurring food folate, and of folic acid in supplements or fortified food. Stable-isotope methods provide the specificity needed to test this hypothesis. OBJECTIVE: We determined whether women who had an NTD-affected pregnancy had a reduced ability compared with control women to absorb polyglutamyl folate relative to folic acid. DESIGN: Healthy, nonpregnant women with a history of an NTD-affected pregnancy (cases; n = 11) and control women (n = 11) were administered an oral dose containing a mixture of [(2)H]pteroylpentaglutamate ([(2)H(2)]PteGlu(5); 233 nmol) and [(13)C]pteroylmonoglutamate ([(13)C(5)]PteGlu(1); 567 nmol) after a 30-d saturation protocol (2 mg unlabeled folic acid/d). Relative extents of absorption were evaluated by urinary excretion of (2)H(2)- and (13)C(5)-labeled folates 48 h postdose. RESULTS: During the first 24 h postdose, cases excreted less (f1.gif" BORDER="0"> +/- SD) [(2)H(2)]PteGlu(5) (21 +/- 12% compared with 37 +/- 19%; P = 0.01) and [(13)C(5)]PteGlu(1) (17 +/- 8% compared with 31 +/- 14%; P = 0.007) than did controls. No significant differences between cases and controls were detected in the percentage of [(2)H(2)]PteGlu(5) or [(13)C(5)]PteGlu(1) excreted during the second 24 h postdose or when the data were averaged over 48 h. However, excretion of the [(2)H(2)]folates tended to be lower in cases than in controls over the 48-h period (33 +/- 13% compared with 45 +/- 26%; P = 0.21). A similar trend (P = 0.29) for lower excretion of [(13)C(5)]folates in cases was also observed (31 +/- 16% compared with 39 +/- 17%). The ratio of urinary [(2)H(2)]folates to [(13)C(5)]folates did not differ significantly between cases and controls. CONCLUSION: These data suggest the need for a larger-scale study using stable-isotope methods to further investigate this hypothesis.

Plasma homocyst(e)ine concentrations in pregnant and nonpregnant women with controlled folate intake.

OBJECTIVE: To assess the effects of folate intake and pregnancy on plasma total homocyst(e)ine concentrations in women during the second trimester of pregnancy compared with young, healthy nonpregnant women. METHODS: The diet provided either 450 or 850 microg of folate per day. These levels are approximately the current (400 microg/day) and previous (800 microg/day) Recommended Dietary Allowances for folate in pregnant women. Folate was provided as both food folate (120 microg/day) and supplemental folic acid (either 330 or 730 microg/day) for a period of 12 weeks. Plasma homocyst(e)ine (sum of free and protein-bound homocysteine), serum folate, and erythrocyte folate concentrations were determined weekly. RESULTS: Homocyst(e)ine concentrations were lower in pregnant women during the second trimester of normal pregnancy than in nonpregnant controls, independent of dietary folate intake. The overall mean (+/- standard deviation) homocyst(e)ine concentration of the pregnant subjects (5.4 +/- 1.4 micromol/L) was significantly lower than that observed in the nonpregnant control group (8.7 +/- 1.7 micromol/L) (P < .0001). This difference in homocyst(e)ine concentrations remained constant throughout the 12 weeks of the investigation. CONCLUSION: The folate intakes in this investigation were adequate to maintain constant homocyst(e)ine concentrations in pregnant and nonpregnant women. The lower homocyst(e)ine concentrations observed in pregnant subjects compared with nonpregnant controls may be a physiologic response to pregnancy.

Neural-tube defects are associated with low concentrations of cobalamin (vitamin B12) in amniotic fluid.

While folate supplementation reduces the risk of recurrent neural-tube defects (NTD), both folate and cobalamin deficiencies may be independent risk-factors for neural-tube defects. Folate-dependence and impaired remethylation of homocysteine are implicated as mechanisms for NTD. There are few references reported for folate, cobalamin, homocysteine and methionine in the fetal compartment. This case-controlled pilot study of amniotic fluid (AF) samples derived from 16 NTD pregnancies and 64 age-matched controls quantities total homocysteine (tHcy), total cysteine (tCys), folate, cobalamin (B12), and methionine. Only decreased AF B12 concentrations were found (150 pg/ml versus 540 pg/ml, P < 0.02). Since cobalamin, folate and homocysteine participate in the remethylation of homocysteine, via methyl transfer from 5-methyltetrahydrofolate to B12, to methionine, we compared ratios of these methionine synthase (EC 2.1.1.13)-related intermediates. The ratio of B12/folate for NTD versus controls was 48 (34-90) versus 126 (123-182), P < 0.001. The ratio of methionine/(folate x tHcy) was 1.4 (1.2-2.2) versus 2.7 (2.4-3.3), P < 0.001. We conclude that AF from pregnancies with NTD have lower B12 concentrations, and that ratios of product to substrate(s) of homocysteine remethylation suggest impaired methionine synthase in the fetal compartment through the early second trimester.

Cystathionine-beta-synthase deficiency: detection of heterozygotes by the ratios of homocysteine to cysteine and folate.

Elevated total plasma homocysteine (tHcy) is recognized as an independent risk factor for occlusive vascular disease. However, it is not known how much of the observed hyperhomocysteinemia in patients with vascular disease is due to heterozygosity for cystathionine-beta-synthase (CbetaS) deficiency, because a clinically useful screening method is unavailable. To determine this, parents of children who are homozygous for CbetaS deficiency (affected with homocystinuria) and a control population were compared for tHcy, total plasma cysteine (tCys), plasma folate, and plasma vitamin B12. The group of obligate heterozygotes had increased tHcy (P < or = .01), decreased tCys (P < or = .01), and decreased plasma folate (P < or = .01). The calculated ratios of tHcy/tCys (P = .01) and tHcy/plasma folate (P = .003) were the best metabolic discriminants for genotype. These ratios are likely to prove useful in heterozygote screening for CPS deficiency and in the development of rational treatment strategies for patients with increased tHcy.