Clinical Review

Inherited thrombophilia and adverse pregnancy outcomes: What the evidence shows

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Placental abruption and infarct. Hyperhomocysteinemia, folate deficiency, and MTHFR polymorphisms may also contribute to abruption and placental infarct. Hyperhomocysteinemia is 3 times more common in study patients versus controls (31% versus 9%), with fasting levels more significantly increased than postmethionine levels.19 Likewise, MTHFR polymorphisms have been significantly associated with abruption and fetal growth restriction. The combination of heterozygosity for 2 MTHFR polymorphisms, C677T and A1298C, occurs in almost a quarter of placental abruptions.20

FIGURE Factor V Leiden among women with habitual pregnancy loss



TABLE 1

Meta-analysis of the association between preeclampsia and selected metabolic defects6

METABOLIC DEFECTODDS RATIO95% CI
Folate deficiency1.20.5–2.7
Hyperhomocysteinemia20.93.6–121.6
Methylene tetrahydrofolate reductase polymorphisms2.61.4–5.1

Other contributors to placental thrombosis

Several factors reflecting normal physiologic changes of pregnancy also contribute to the increased thrombotic risk when thrombophilia polymorphisms are present during pregnancy. The low vascular resistance of the placenta, key to the adequate perfusion of the fetus, conversely sets the stage for fibrin deposition and clot formation. The normal increase in the levels of fibrinogen and clotting proteins during pregnancy also contribute to clot formation. These physiologic changes of pregnancy may be modulated by diverse environmental changes. When the most common polymorphism of MTHFR is present, the rate of this enzyme’s functioning is further impaired by low folate, a condition often present due to physiologic decreases of folate during pregnancy. Suppression of available folate associated with cigarette smoking may further compound the deleterious effects of the MTHFR polymorphism on homocysteine levels.

Multiple thrombophilias increase risk

In a similar additive fashion, an individual with multiple thrombophilia polymorphisms faces even greater increases in thrombotic risk. For example, factor V Leiden working concomitantly with protein C or protein S deficiency, or factor V Leiden or prothrombin 20210A paired with hyperhomocysteinemia carry relative risks of venous thrombosis greater than any of these elements alone. For patients with a history of thrombotic disease from the European Prospective Cohort on Thrombophilia (EPCOT) study, the highest odds for a stillbirth (odds ratio [OR], 14.3; 95% CI, 2.4–86.0) occurred in women with combined thrombophilia abnormalities.8

Multiple inherited thrombophilias also may interact at the maternal-fetal interface. Consistent with Mendelian inheritance, the fetus will inherit 1 of the maternal alleles at each gene of the clotting-cascade proteins. Chronologically, the fetal arterial supply is established as maternal spiral arteries perfuse the intervillous spaces, with the maternal and fetal blood supply of the placenta present 3 to 4 weeks after conception. Histologically, evidence of placental ischemia can be found on either the maternal or fetal side. It is unknown whether the risk of placental compromise is greater in the presence of maternal or fetal thrombophilia, alone or in combination. Initial study of factor V Leiden from spontaneous miscarriages suggests a slight skewing toward increased fetal inheritance of the maternal polymorphism, suggesting a further contributory role of the fetus to overall risk.21 Interestingly, MTHFR polymorphisms in combination (C677T and A1298C) occur significantly more often among spontaneous losses than in fetal bloods at delivery, suggesting a decreased potential for viability among such fetuses.22 In populations with no association between preeclampsia and maternal factor V Leiden, the MTHFR polymorphism or prothrombin polymorphism fetal studies are likewise unrevealing.23

Promising results of enoxaparin, folate studies

Inherited thrombophilias may be amenable to treatment with baby aspirin, heparin, folic acid, intravenous immunoglobulin G (IgG), or factor concentrates. Currently, no randomized, controlled intervention trials have been conducted. Further, since initial adverse pregnancy outcomes in inherited thrombophilia patients are relatively rare, it will be difficult to identify a sufficiently sizable population at risk.

For inherited thrombophilia carriers with recurrent adverse pregnancy outcomes, 2 areas for intervention deserve greater attention: enoxaparin treatment for women experiencing habitual late fetal loss24 and folic acid treatment for severe preeclampsia.30

Enoxaparin and recurrent fetal loss. The Brenner enoxaparin trial examined 96 women who had experienced recurrent pregnancy loss (3 or more in the first trimester [7-12 weeks], 2 or more in the second trimester, or 1 in the third trimester). Only losses with a fetal pole previously documented by ultrasound were counted. Approximately 66.6% of the participants had a thrombophilia polymorphism identified.

Subsequent pregnancies among these women were treated with 40 mg enoxaparin daily (80 mg daily for women with combined abnormalities). A significant difference in pregnancy outcome was noted when these patients were compared with their historical outcomes, although no differential in risk for solitary versus combined defects (83% versus 69%, P=.37) could be determined. Results appeared equally efficacious with either 40 mg or 80 mg enoxaparin a day.

Although these findings are encouraging, the use of historical controls for pregnancy outcome studies is notorious for overestimating the benefit of any single intervention. More complete analysis of the benefits of enoxaparin must await randomized controlled trials.

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