Adverse pregnancy outcomes associated with thrombophilias [Classics Series]

1. The incidence of genetic thrombophilias was found to be higher in women with adverse pregnancy outcomes.

Original Date of Publication: January 1999

Study Rundown: Inadequate placental perfusion is associated with numerous adverse pregnancy outcomes including placental abruption, growth restriction and stillbirth. Certain thrombophilic mutations, including mutations of Factor V Leiden, prothrombin and methylenetetrahydrofolate reductase (MTHFR), are associated with an increased risk of thromboembolic complications. Other thrombophilias including deficiences of Protein C, Protein S and antithrombin III as well as the presence of anticardiolipin antibodies and lupus anticoagulant also increase a woman’s clot risk. Further, risk of thrombosis is increased in pregnancy and the postpartum period due to elevated levels of estrogen and progesterone-mediated venous stasis. Inadequate perfusion of the fetal-placental unit may arise from thrombosis of the maternal vessels supplying the placenta (e.g. intervillous and spiral artery thrombosis) such that researchers have postulated whether women at risk for thrombosis might be at higher risk for adverse pregnancy outcomes. In the present work, researchers investigate whether the adverse obstetric outcomes of severe pre-eclampsia, placental abruption, fetal growth retardation and stillbirth are related to thrombophilias by comparing the incidence of thrombophilias among women who experienced adverse obstetric outcomes and among women who had uncomplicated deliveries.

This landmark study demonstrated that women who experienced adverse pregnancy outcomes were significantly more likely to be carriers of genetic thrombophilias. Notably, however, more recent investigations have failed to substantiate the association identified herein. The diagnostic criteria for obstetric diagnoses, such as severe preeclampsia, has changed over the years but this is unlikely to result in systemic directional bias since it is not plausibly related to the incidence of genetic thrombophilias. Following this landmark investigation, additional investigations have explored the benefit of prophylactic anticoagulation in pregnancy for high-risk thrombophilias.

Click to study in NEJM

Dr. Alan Peaceman, MD, talks to 2 Minute Medicine: Northwestern University School of Medicine; Chief, Division of Obstetrics and Gynecology-Maternal Fetal Medicine.

“This investigation was the first to identify a high prevalence of thrombogenic mutations among women who experienced severe obstetric complications. Findings imply that women with genetic thrombophilias are at increased risk for adverse pregnancy outcomes including severe preeclampsia, placental abruption or stillbirth.”

In-Depth [case-control study]: A total of 220 women were tested for genetic thrombophilias in the postpartum period and incidence of thrombophilias was compared among women who experienced uncomplicated normal pregnancies (n = 110) and those who experienced obstetric complications including placental abruption, severe preeclampsia, fetal growth restriction and stillbirth (n=110). Exposures of interest were the Factor V Leiden mutation, methylenetetrahydrofolate reductase (MTHFR) mutation, prothrombin mutations, Protein C deficiency, Protein S deficiency, Antithrombin III deficiency and the presence of anticardiolipin antibodies. Outcomes of interest were obstetrical complications including severe pre-eclampsia, placental abruption, fetal growth restriction, stillbirth and placental thromboses or underperfusion.

Women who experienced adverse obstetric outcomes in pregnancy were more likely to have a thrombophilic mutation (52% vs 17%, p < 0.001). Specifically, more women with adverse pregnancy outcomes were found to be carriers of the Factor V Leiden mutation (20 vs. 6 %, p = 0.003), MTHFR mutation (22 vs. 8%, p = 0.005), prothrombin mutation (10 vs. 3%, p = 0.03) or have a deficiency in protein C, S, or antithrombin III or anticardiolipin antibodies (13 vs. 1%, p < 0.001).

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