Clinical Background of Early Miscarriage
The term miscarriage is used to emphasize the spontaneous interruption of pregnancy. For clinical and scientific reasons, it is important to avoid the international confusion on the duration of pregnancy when the term abortion is used because the range of pregnancy duration can be as wide as from 0 to 28 wk. Another reason for this distinction is that the causes for embryonic loss are quite different from those of fetal loss. We therefore tried to unravel literature reports in embryonic loss (up to 10 wk of menstrual age, or 8 wk postconceptional age) and fetal loss (from 10-8 wk up to the 16-24-wk period).
The prevalence of neural tube defects in miscarriages is 10-fold higher compared to the prevalence at birth (52,53).
Despite all research efforts, not much can be offered to a couple that experiences repeated recurrent early pregnancy loss. In only 5% of cases are factors associated with miscarriage found. Among the maternal factors, uterine malformations and positive coagulation factors are the most frequent. Even when these associated factors are found, there is, up to now, no evidence-based proposal for treatment of such disorders.
When early embryonic loss is found, chromosomal abnormalities are reported in more than 50% of cases. This does not include that one always has to accept "the filter of nature" as an unavoidable consequence of genetic deviations residing in the germ cells and/or the processes that govern mei-otic divisions and the fertilization process.
Women Who Experience Repeated Unexplained Early Pregnancy Loss Have a Twofold to Threefold Increased Risk for Recurrence as a Result Low Folate Status, Hyperhomocysteinemia, and a Higher Prevalence of the C677T Mutation
With the start of the homocysteine research in relation to neural tube defects and the genetic mutations found, it was logical to also explore this fascinating field of early embryonic development.
Hibbard et al. (54) was the first to suggest a possible relationship between miscarriage and folate deficiency. An increased FIGLU excretion was found after histidine loading in 32% of women with an isolated unexplained "abortion" and in 60.5% of women with two or more recurrent events.
Sutterlin et al. (55) did not find significant differences in serum concentrations of folate and cobalamin in 29 patients with a history of 3 or more consecutive early losses. Patients with at least four previous events showed a significant negative correlation with the number of miscarriages and serum folate concentration.
Mild hyperhomocysteinemia was suggested in patients with recurrent early pregnancy loss (56).
In later studies, mild homocysteinemia was confirmed (57-59). The pooled odds ratio (OR) of these studies was 2.7 (95% confidence interval [CI]: 1.4-5.2) for fasting homocysteine and 4.2 (95% CI: 2.0-8.6) for homocysteine after methionine loading.
The common mutation C677T was found (60) in 16% of 185 Dutch women with unexplained recurrent early loss and in 5% of 113 case controls (OR: 3.3; 95% CI: 1.3-10.1) and 1250 population controls (OR: 2.0; 95% CI: 1.2-3.2). This was confirmed in a small French retrospective study (61).
Ray and Laskin (62) calculated a pooled odds ratio of 3.4 (95% CI: 1.29.9) for folate deficiency, 3.7 (CI: 0.96-16.5) for hyperhomocysteinemia following methionine loading, and 3.3 (CI: 1.2-9.2) for the MTHFR mutation.
One of the factors recently found for early miscarriage is a defect in the vascularization of the chorionic villi. Nelen et al. (63) found that women with elevated homocysteine concentrations also after methionine loading showed significant smaller vascular areas and perimeters. This suggests that the vascular influence of homocysteine is also apparent in the vessels of the early placenta.
The higher prevalence of the C677T mutation in women with recurrent early pregnancy loss was confirmed by Guttormsen et al. (64) in the Norwegian Hordaland study.
Homozygotes for the mutant gene of thermolabile MTHFR were sensitive to 0.5 mg of folic acid per day and normalized their plasma homocysteine concentrations (65).
It is important to realize that the possibly preventive effect of folic acid on the recurrence of early pregnancy loss cannot be investigated any longer in a placebo-randomized fashion because of the evidence-based prevention of neural tube defects with folic acid (66), a preventive approach that has to start around conception. Therefore, more in-depth research into the mechanisms that interfere with embryonic development is necessary.
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