Thrombophilia, Antithrombotic Therapy, and Recurrent Pregnancy Loss: A Call for Pragmatism in the Face of Unknowns.

Abstract

A diagnosis of recurrent pregnancy loss (RPL) may represent one of the darkest times for a couple trying to build a family. While aneuploidy and anatomical or functional abnormalities of the reproductive systemmayexplain someRPLs,many patients are left without an explanation for recurrent miscarriages, andmore importantly, without a clear therapeutic strategy for conception and live birth. While many of these couples turn to assisted reproductive therapy (ART), failed cycles, especially after transfer of euploid embryos, often result in further physical, emotional, psychological, and financial hardship. Although epidemiological studies suggest inherited and acquired thrombophilia as a potential risk factor for RPL and failed ART cycles, data have not been consistent, and causality remains unproven.1 Furthermore, implementation of treatment strategies to prevent RPL and failed ART cycles, such as antithrombotic and antiplatelet therapy, has been hindered by lack of high-quality randomized controlled trial (RCT) data.2 The design and execution of adequately powered RCTs have been hampered by several obstacles, including scarcity of funding opportunities and slow enrollment.3 Ultimately, the dilemma facing investigators, clinicians, and patients is whether to wait for definitive RCTs that may be logistically difficult to execute or find new and innovative scientific approaches to illuminate the pathway forward. In the absence of adequate data to drive guideline recommendations, some clinicians may be reluctant to prescribe antithrombotic therapy for patients with RPL who may benefit, while others may be too quick and too broad in advising such treatments, resulting in an unfavorable balance of safety and efficacy. The growth in the number of women with RPL undergoing ART in the United States and Europe has steadily outpaced research focused on the link between miscarriage and thrombophilia and potential therapeutic interventions.4,5 Root causes of this dichotomy include limited advocacy and leadership, scarce research funding, and study enrollment challenges. The social stigma of infertility, lack of public awareness surrounding thrombophilia, and limited clinical recognition of thrombosis as a contributor to RPL undermine advocacy efforts that would increase support for such research. Clinical expertise and scientific investigation focused on thrombophilia and infertility are typically limited to a few centers of excellence in each region or country resulting in a paucity of collaborative research networks necessary to champion RCTs. Funding continues to be a key obstacle to definitive research focused on thrombophilia and infertility, especially since RCTs typically incur the greatest expense. While professional societies such as the American Society for Reproductive Medicine (ASRM) and European Society of Human Reproduction and Embryology (ESHRE) provide a critical Elvira Grandone, MD, PhD Gregory Piazza, MD, MS