Objective: To estimate the relative risk of recurrent early pregnancy loss for different total plasma homocysteine and serum folate concentrations.
Methods: In a case-control study, we measured homocysteine (fasting and afterload), folate (serum and red cells), pyridoxal 5′-phosphate, and cobalamin concentrations in 123 women who had at least two consecutive spontaneous early pregnancy losses each and compared concentrations with those of 104 healthy controls.
Results: Women with recurrent early pregnancy losses had significantly lower serum folate concentrations than controls, whereas the other measurements were similar to those of controls. Elevated homocysteine, fasting greater than 18.3 μmol/L and afterload greater than 61.5 μmol/L, was a risk factor for recurrent early pregnancy loss, with odds ratios (ORs) and 95% confidence intervals (95% CIs) of 3.6 (1.2, 12.7) and 2.7 (0.9, 8.8) in the group with recurrent miscarriages: 6.4 (1.9, 24.3) and 4.3 (1.2, 17.3) in primary aborters, and 4.2 (1.3, 15.4) and 3.4 (1.0, 12.8) in those with three or more miscarriages. The ORs (95% CIs) in the same study populations for serum folate concentrations less than 8.4 nmol/L were 2.1 (0.9, 4.8), 2.7 (1.0, 7.8), and 3.2 (1.3, 8.1), respectively. A significant dose-response relationship between serum folate concentrations and risk of recurrent early pregnancy loss suggested a protective effect by high serum folate concentrations.
Conclusion: Elevated homocysteine and reduced serum folate concentrations were risk factors for recurrent spontaneous early pregnancy losses. Folic acid supplementation might be beneficial in women with histories of early pregnancy loss.
After observing the induction of fetal death by the folic acid antagonist 4-aminopteroylglutamic acid in 1952, Thiersch1 suggested that spontaneous abortions might be caused by folic acid deficiency. The first studies that investigated the relationship between folate deficiency and early pregnancy loss were published in the following decades.2-6 The consistent conclusion was that disturbed formino glutamic acid excretion tests or low folate concentrations might identify women predisposed to spontaneous abortion. More recent reports did not find lower folate concentrations,7,8 but they investigated folate concentrations in those women after, not during, their pregnancies. In several reports, other sensitive markers of dysfunctional folate metabolism appeared to be related to recurrent early pregnancy loss, one of which was elevated plasma total homocysteine concentration.7,9-11
Homocysteine is a demethylated derivative of methionine, and B vitamins are needed for its efficient metabolism. Folate and cobalamin (vitamin B12) are involved in homocysteine remethylation, and pyridoxal 5′-phosphate (the active form of vitamin B6) in homocysteine transsulfuration. Elevated homocysteine can occur in cases of dietary or genetic vitamin deficiency, or reduced enzyme activities. In a preliminary study in 1992, Steegers-Theunissen et al9 first suggested the relationship between recurrent early pregnancy loss and elevated homocysteine concentrations. Recently, others7,10,11 have confirmed that association.
The definition of hyperhomocysteinemia, whether or not fasting or afterload homocysteine concentrations were incorporated, influenced the percentage of hyperhomocysteinemia in cases and controls. A dose-response effect for homocysteine concentrations was noted in cardiovascular disease,12,13 so it would be more appropriate to estimate the relative risk (RR) for recurrent early pregnancy loss at different cutoff levels, and for fasting and afterload homocysteine, separately. Therefore, we did a case-control study to estimate the RR of recurrent early pregnancy loss for different homocysteine and folate concentrations.