Yale Center for Hemostasis and Thrombosis in Women’s and Children’s Health

Michael J. Paidas, M.D., Associate Professor and Center Co-Director, Department of Obstetrics, Gynecology and Reproductive Sciences

Diana S. Beardsley, MD, PhD, Associate Professor and Center Co-Director, Department of Pediatrics

Pregnancy complications such as fetal loss, preeclampsia, intrauterine growth restriction and abruption collectively complicate approximately 8% of pregnancies. Epidemiologic data have suggested that the patients with a poor obstetrical history are at significantly increased risk of recurrence. Inherited thrombophilic conditions are increasingly being implicated in these pregnancy outcomes, yet paradoxically, the majority of patients harboring the most common mutations, such as Factor V Leiden and prothrombin gene mutation G20210A are asymptomatic. Identifying patients at increased risk would represent a significant advance. Recently, we have demonstrated that moderately levels of protein Z, a co-factor for protein Z dependent protease inhibitor of Factor Xa is associated with a fourfold increased risk of pregnancy complications, and may identify the select group of thrombophilic patients at high risk for subsequent pregnancy complications. This work complements a large, population based initiative evaluating the association between family history, obstetric events and genetic determinants in collaboration between University of Copenhagen, Celera Diagnostics, and our Center.

Plasma biomarkers are being evaluated in conjunction with a new Doppler ultrasound technique employing multigate spectral Doppler analysis to study velocity blood flow patterns in the uteroplacental circulation. This new technology is the result of collaboration between the Department of Engineering, University of Florence, University of Milan, Bicocca, and Yale. Presently, conventional uterine artery Doppler evaluation has been an insensitive tool in detecting pregnancies at risk for preeclampsia and fetal growth restriction. Our preliminary experience studying the fetal circulation documented the feasibility of this new approach and currently we are enrolling patients in a prospective study to determine the predictive value of this innovative Doppler modality, which can safely provide the most accurate description of blood velocity profiles in the uteroplacental circulation.

While anticoagulation and antiplatelet agents have helped improve pregnancy outcomes in patients with thrombotic related etiologies, a significant proportion of patients with immune related recurrent pregnancy loss still have unsuccessful pregnancies. We are currently participating in a prospective, randomized, double blinded, placebo controlled study to determine whether preconceptual administration of intravenous gamma-globulin (500mg/kg IVIG) and continuation through the first half of pregnancy will improve reproductive outcome in women who have had at least three consecutive fetal losses, but who have achieved at least one pregnancy beyond 20 wks. The rationale for this approach of passive immunotherapy is based upon the finding of activation of T-cells favoring a Th-1 response associated with pro-inflammatory cytokines, especially tumor necrosis factor alpha, interleulin-1 and interferon. Intravenous gamma-globulin infusion has been associated with a suppression of the number of CD 56+ and natural killer cells, and has shown promise in women with recurrent spontaneous abortion.

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