ArticlesThrombophilic disorders and fetal loss: a meta-analysis
Introduction
Since 1965, substantial progress has been made in the identification and understanding of inherited hypercoagulable disorders that promote thrombosis, collectively termed inherited thrombophilia. These include the factor V Leiden, methylenetetrahydrofolate reductase (MTHFR), and prothrombin G20210A (PTm) mutations, and deficiencies of protein C, protein S, and antithrombin. The factor V Leiden mutation results from a guanine substitution for adenine at the 1691 position of the gene encoding factor V (1691G→A). This substitution renders factor V resistant to cleavage by activated protein C.1 The 677C→T mutation of the MTHFR encoding gene results in an alanine-to-valine aminoacid substitution in the enzyme MTHFR. By decreasing the conversion of homocysteine to methionine, this thermolabile variant of MTHFR can cause mild to moderate hyperhomocysteinaemia, which impairs endothelial cell function and promotes thrombosis.1 A 20210G→A mutation in the gene encoding prothrombin raises plasma concentrations of prothrombin and thereby increases the risk of thrombosis.1
Homozygous and heterozygous forms of factor V Leiden and PTm increase the risk of thrombosis, as does hyperhomocysteinaemia,1, 2 however, the association between homozygosity for the MTHFR mutation and thrombosis is controversial.1, 2 Activated protein C resistance (APCR) not due to factor V Leiden has also been identified as an independent risk factor for deep vein thrombosis.3
Hereditary deficiencies of the anticoagulant proteins antithrombin, protein C, and protein S are heterogeneous in nature and caused by several different genetic mutations.1 Although rarer than the genetic mutations described above, they are strongly associated with clinical thrombosis.1
Inherited thrombophilia could increase susceptibility to adverse pregnancy outcomes such as fetal loss.4 This potential association is important, since fetal loss is a common and significant problem: about 20% of women have at least one fetal loss and 5% have two or more spontaneous losses.5 Furthermore, 30–40% of recurrent fetal losses remain unexplained after standard gynaecological, hormonal, and karyotype investigations.5
Because of the conflicting results of studies with respect to the presence and magnitude of the associations between inherited thrombophilia and fetal loss, and because of the increasingly widespread availability of screening tests for thrombophilia, we undertook a meta-analysis to estimate the strength and precision of the association between individual inherited thrombophilic disorders and fetal loss, and to examine whether these associations vary according to the timing or definition of fetal loss.
Section snippets
Search strategy
We searched Medline and Current Contents for articles published between January, 1975, and May, 2002, with various combinations of the following terms: fetal loss, habitual abortion, recurrent abortion, spontaneous abortion, miscarriage, stillbirth, intrauterine fetal death, fetal death, abortion combined with thrombophilia, factor V, factor V Leiden, activated protein C resistance, factor II, factor II mutation, prothrombin, prothrombin G20210A mutation, MTHFR, methylenetetrahydrofolate
Results
The initial search strategy yielded 133 studies. Of these, 57 were abstracts, duplicate publications, case reports, letters, reviews, meta-analyses, or editorials. 40 studies were excluded because of unsuitable study population (n=14), inadequate outcomes (n=17), inadequate determination of exposure (n=4), or unsuitable controls (n=5). Of the remaining studies, five were unsuitable for our meta-analysis: two because of absence of thrombophilia in cases and controls, and three because recurrent
Discussion
Our findings indicate that some, but not all, of the thrmbophilias we examined are associated with fetal loss. First trimester recurrent fetal loss is associated with factor V Leiden, activated protein C resistance, and prothrombin G20210A mutation. The association between factor V Leiden and late recurrent fetal loss is stronger than for early recurrent fetal loss. The association between factor V Leiden and recurrent fetal loss is stronger if other potential causes of fetal loss are excluded.
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