Miscarriage and Its Associations

Stephen Brown, M.D.


Semin Reprod Med. 2008;26(5):391-400. 

In This Article

Inherited Thrombophilia

Familial deficiency of protein S and protein C as well as polymorphisms of clotting cascade proteins (factor V Leiden [FVL] and factor II G20210A) are associated with increased risk of thromboembolism, leading to the term inherited thrombophilia. Several studies have also reported associations between inherited thrombophilia and adverse pregnancy outcomes, including early loss, late loss, and stillbirth. Before attempting to summarize this confusing literature, it is worth considering two basic observations that suggest that the magnitude of the effect of clotting factor polymorphisms on reproduction is likely to be small. First, FVL and factor II G20210A are found almost exclusively in the white population, and there is no evidence to suggest that adverse pregnancy outcome in whites is higher than in other ethnic groups. Second, heterozygosity for a polymorphism that confers a significant decrease in reproductive fitness will rapidly disappear from the gene pool, unless it also confers some major survival advantage. Whether or not FVL or other clotting cascade variants confer such an advantage is unknown but seems unlikely.

Rather than attempt a detailed review of studies, it is useful to consider a recent meta-analysis that attempted to evaluate the effects of various thrombophilias on various categories of pregnancy loss.[35a] In this report, homozygosity for FVL was associated with a 2-fold risk in early (< 19 weeks), nonrecurrent pregnancy loss, whereas heterozygosity for the same polymorphism was associated with a ∼1.7-fold increased risk that barely reached statistical significance. Heterozygosity for the factor II G20210A polymorphism was associated with a 2.4-fold increased risk, whereas homozygosity for methyl tetrahydrofolate reductase (MTHFR) polymorphisms was not associated with pregnancy loss. Further meta-analysis of the same data indicates that FVL heterozygosity is more strongly associated with second-trimester loss than with recurrent first-trimester loss (OR 4.12, 95% CI 1.93 to 8.81; and OR 1.91, 95% CI 1.01 to 3.61, respectively). The fact that the confidence interval for recurrent loss almost overlaps 1.0 reflects the heterogeneity among studies, with 3 of 8 actually showing a slight protective effect of FVL. Thus, the role of FVL heterozygosity in women with recurrent first-trimester loss remains unclear.

With respect to late pregnancy loss (19 to 24 weeks), meta-analysis suggests that both FVL and factor II G20210A are associated with an increased risk with OR of 2.06 (95% CI 1.10 to 3.86), and 2.66 (95% CI 1.28 to 5.53) respectively. Protein S deficiency was strongly associated with loss (OR 20.09, 95% CI 3.70 to 109.15), whereas protein C deficiency and MTHFR homozygosity did not show significant association.

In terms of treatment for inherited thrombophilia, aspirin and/or various types of heparin have been attempted. There is currently much debate about efficacy[36,37,38,39] and no consensus.[40] Some studies have shown a remarkable benefit to treatment (e.g., refs.[41,42]), whereas others have shown minimal or no effect.[43] In general, studies have had methodological flaws such as lack of untreated controls and inadequate matching of cases and controls. Given the ugly history of failed treatments for pregnancy loss (diethylstilbestrol, paternal lymphocyte injections, and others), it seems prudent to wait for adequately controlled prospective trials before drawing firm conclusions.

Attempting to draw clinically useful conclusions about testing for and treating inherited thrombophilia is challenging. It seems safe to say that the association between inherited thrombophilia and miscarriage is strongest in the second trimester, which also makes the most biological sense. Testing for inherited thrombophilia should probably be reserved for women with second-trimester losses. Treatment should be undertaken with the understanding that the evidence supporting its efficacy is questionable.


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