Thrombophilia-associated stillbirth risk appears limited to factor V Leiden

1. Maternal factor V Leiden mutations were more common among pregnancies ending in stillbirth.

2. Fetal plasminogen activation inhibitor (PAI)-1 4G/4G polymorphism was associated with decreased odds of stillbirth.

Evidence Rating Level: 3 (Average)

Study Rundown: Stillbirth, defined as fetal demise at ≥20 weeks gestation, affects approximately 6 out of every 1000 births in the United States. Risk factors include nulliparity, advanced maternal age, obesity, and black race. There are many causes of stillbirth, including obstetric complications, placental abnormalities, fetal abnormalities, infection, and maternal hypertension and diabetes. Currently, there are no standardized protocols used to evaluate stillbirth. Previous work suggested that inherited thrombophilias are a risk factor for fetal loss such that while this association is not well defined, many clinicians pursue thrombophilia workup after stillbirth. It has been posited that hypercoagulability due to inherited thrombophilias lead to thromboses in the uteroplacental circulation, which results in placental insufficiency and later, stillbirth. In the present work, the authors assessed the relationship between maternal and fetal inherited thrombophilias and stillbirth in a population-based study. They found that stillbirth was associated only with maternal homozygous factor V Leiden mutation, which is rare. As such, findings suggest that routine assessment for heritable thrombophilias may not be appropriate in the evaluation of stillbirth.

Strengths of the study included population-based dataset and analysis of both maternal and fetal mutations. Limitations included case-control design, post-hoc analysis and incomplete data from all case and control fetuses and mothers. Additional large population-based cohort studies are needed to determine the utility of heritable thrombophilia workup after stillbirth.

Click to read the study in AJOG

Relevant Reading: Thrombophilic disorders and fetal loss: a meta-analysis

In-Depth [case-control study]: This study evaluated the relationship between four heritable thrombophilia mutations and stillbirth among singleton pregnancies resulting in stillbirth (n = 620) and live birth (n = 1871). Thrombophilia marker results were available for 488 stillbirth mothers, 1342 live birth mothers, 405 stillbirth fetuses and 990 live birth fetuses. The mutations of interest were factor V Leiden, prothrombin G20210A, methylene-tetrahydrofolate reductase (MTHFR) C677T and A1298C, and PAI-1 4G/5G.

Stillbirth was associated with maternal factor V Leiden mutations (p = 0.0004), with the strongest odds in women with a homozygous mutation (OR 87.44, CI 7.88-970.92). This association did not persist when the analysis was restricted to cases where cause of death was secondary to placental disease. The PAI-1 4G/4G polymorphism in fetuses was associated with decreased odds of stillbirth (OR 0.64, CI 0.44-0.92); this relationship remained significant in the sub-analysis of stillbirths due to placental pathology (OR 0.36. CI 0.16-0.81).

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