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1 From The Pennsylvania State University, University Park, and the Office of Dietary Supplements, National Institutes of Health, Bethesda, MD.
2 Address correspondence to MF Picciano, Office of Dietary Supplements, National Institutes of Health, 31 Center Drive, Room 1B29, Bethesda, MD 20892-2086. E-mail: piccianm{at}od.nih.gov.
See corresponding article on page 962.
Interest in the prognostic value of circulating homocysteine concentration continues to grow. There is already a large body of evidence indicating that elevated plasma total homocysteine (hyperhomocysteinemia) may be causally related to risk of coronary, cerebral, and peripheral arterial diseases (1). Currently, several randomized, placebo-controlled trials are ongoing and the results should make possible a meaningful assessment of whether lowering homocysteine concentration does indeed reduce the risk of cardiovascular diseases. In this issue of the Journal, Vollset et al (2) report their findings that hyperhomocysteinemia may also be an important biological marker for, and possibly even a cause of or a contributor to, complications and adverse outcomes of pregnancy. When comparing quartiles of homocysteine concentration measured in 1992–1993 with outcomes and complications of 14492 pregnancies that occurred between 1967 and 1996 in the same women, these authors noted an increased risk of preeclampsia, premature delivery, very low birth weight, neural tube defects, and clubfoot. How can derangements in the methionine-homocysteine pathway be implicated in the development of such a diverse array of disease processes and reproductive disorders?
Homocysteine is a sulfur-containing amino acid that is the demethylated derivative of methionine. Homocysteine is metabolized via 2 main pathways: remethylation to methionine or transsulfuration to cystathionine and to cysteine. A defect in either of these pathways leads to an accumulation of circulating homocysteine. The inborn error of cystathione ß-synthetase that was first reported by Mudd et al in 1964 (3) is a classic autosomal recessive disease. Patients with the cystathione ß-synthetase disorder have marked elevations of homocysteine in both plasma and urine, have mental retardation, and die prematurely from atherosclerosis. Additionally, untreated women with the classic disease experience a fetal loss of 50%. Mild forms of hyperhomocysteinemia also exist. Homozygosity for the C-to-T mutation of nucleotide 677 in the methylenetetrahydrofolate reductase (MTHFR) gene causes thermolability of MTHFR and hyperhomocystenemia due to 50% reduced enzymatic activity. The frequency of the 677 C-to-T mutation is 5–15% in the general population. Other reasons for mild hyperhomocysteinemia are nutrient related: deficiencies of folate, vitamin B-12, or vitamin B-6 cause homocysteine to accumulate because remethylation to methionine requires folate and vitamin B-12 and transsulfuration to cystathionine requires vitamin B-6.
Plasma homocysteine is normally lower in all 3 trimesters of pregnancy than in the nonpregnant state (4). Homocysteine concentrations are directly correlated with albumin concentrations, which decrease during pregnancy and decrease further in pregnant women taking folic acid supplements. Steegers-Theunissen et al (5) examined normal methionine metabolism in uncomplicated pregnancy. They measured methionine and homocysteine in samples of maternal serum and amniotic fluid collected from 23 women between 8 and 12 wk of gestation before elective surgical termination. Because concentrations of methionine were higher and those of homocysteine were lower in amniotic fluid than in maternal serum, these investigators suggested that methionine may be actively transported to the developing embryo. It is reasonable to assume that the developing embryo has a high requirement for methionine. As the precursor of S-adenosylmethionine, which is the universal methyl donor in many transmethylation reactions, including RNA and DNA synthesis, impaired production of methionine might be expected to have severe consequences in early pregnancy. In another study, Wenstrom et al (6) examined amniotic fluid from cases of neural tube defects diagnosed between 1988 and 1998 (n = 80) and from matched control pregnancies to assess the extent to which elevated amniotic fluid homocysteine, fetal MTHFR mutation, or both were related to fetal neural tube defect. Both elevated amniotic fluid homocysteine and the MTHFR mutation were significantly associated with neural tube defects, but the association with amniotic fluid homocysteine concentration was significant regardless of fetal MTHFR phenotype.
It is now well established that periconceptional folic acid supplementation reduces the occurrence of several human congenital malformations, including craniofacial and heart defects as well as neural tube defects. The underlying mechanism is unknown; however, it is speculated that there may be a defect in the maternal-to-fetal folate transport or an inherent fetal biochemical disorder that is corrected by folate supplementation. Although early supplementation studies used high amounts of folic acid for supplementation (800–4000 µg/d), recent evidence from China indicates that 400 µg/d, the current recommended dietary allowance for nonpregnant women, is just as effective (7). In this study of Chinese women, the baseline rate of neural tube defects was 4.8/1000 births in the northern regions and 1.0/1000 births in the southern regions, even though the rate of the MTHFR mutation was the same in both regions. These differences were attributed to the fact that dietary sources of folate were more plentiful and varied in southern China. Nonetheless, folic acid supplementation was effective in lowering neural tube defects in both regions of China and at about twice the rate in the northern region (80%) as in the southern. The folic acid intakes of women in the United States are projected to increase by 100 µg/d with the current Food and Drug Administration grain fortification policy in place. It will be interesting to view future national data on indexes of reproductive performance to ascertain whether such fortification affects measures of maternal and child health.
Results of a recent systematic review indicate that there is general agreement among several observational studies that folate deficiency, hyperhomocysteinemia, and homozygosity for the MTHFR thermolabile variant are probable risk factors for placenta-mediated diseases, such as preeclampsia, spontaneous abortion, and placental abruption (8). However, available data are not wholly satisfactory and prospective studies are needed to confirm these findings and to guide future research. The study of Vollest et al (2) raises many research questions that must be answered if these authors' findings are confirmed in prospective trials. The need for such research is evident when considering that in 1996, nearly 30000 US infants died before their first birthday and birth defects, preterm birth, low birth weight, and maternal and placental complications were among the leading causes.
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