Controversies in OB/GYN: Does heparin prevent adverse pregnancy outcomes associated with inherited thrombophilia?

Key Points

Yes. LMWH is a reasonable option for certain women with FVL or PGM.

The FVL mutation results from a substitution of adenine for guan ine, causing an amino acid substitution, (glutamine for arginine) in the DNA structure. As a con sequence, factor V then becomes resistant to cleavage by activated protein C. The PGM is a promoter mu tation that is associated with increased (150% to 200%) circulating levels of prothrombin.

What the Gris trial and LIVE-ENOX studies tell us

According to a recent Cochrane review, based upon an extensive literature search between 1966 and 2004, among women with a history of two or more spontaneous losses or one fetal demise with no apparent cause other than inherited thrombophilia, only one trial using heparin in the setting of thrombophilia was conducted (the so-called Gris trial).³ In that study, Gris and colleagues carried out a prospective randomized trial that compared 40 mg/day of the LMWH enoxaparin with 100 mg/day of low-dose aspirin in 160 women with one unexplained fetal loss (8E10th week of gestation) and either FVL, PGM, or a protein S deficiency.⁴ Treatments were started at 8 weeks' gestation. The live birthrate was 86% in the enoxaparin-treated women versus 29% in the aspirin-treated group (OR for live birth with LMWH 15.5; 95% CI, 7–34). While this study has been criticized because of its lack of therapeutic concealment and high loss rate in the aspirin group, the magnitude of the resulting odds ratio is indisputable.

IN A MULTICENTER randomized trial to evaluate the efficacy and safety of two doses of enoxaparin (40 mg once a day or 40 mg twice a day) in 183 women with recurrent pregnancy loss and an inherited thrombophilia (LIVE-ENOX Study), Brenner and colleagues found that enoxaparin significantly increased the live birthrate and lowered rates of other pregnancy complications, compared with the patient's prior history.⁵ Recurrent pregnancy loss was defined as three or more losses before the end of the first trimester, two or more in the second trimester, or one intrauterine fetal death in the third trimester.

Of the 166 women who completed the study, 135 gestations resulted in live births: 70 (84.3%) in the 40-mg/day group and 65 (78.3%) in the 80-mg/day group. There was no significant difference in pregnancy outcome between the 40-mg/day and 80-mg/day dosages. The live birthrate following prophylaxis with enoxaparin ranged from 76.9% to 84.3%, compared with a live birthrate of 28% in previous pregnancies. This study has been criticized because patients were used as their own controls; however, the resultant live birth rate is substantially higher than would have been expected given the patients horrific obstetric histories.