Semin Reprod Med 2021; 39(05/06): 167-169
DOI: 10.1055/s-0041-1735628
Preface

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

1   Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
,
Elvira Grandone
2   Thrombosis and Haemostasis Unit, Fondazione I.R.C.C.S. “Casa Sollievo della Sofferenza,” S. Giovanni Rotondo, Foggia, Italy
3   Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia
› Author Affiliations
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Gregory Piazza, MD, MS
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Elvira Grandone, MD, PhD

“In absentia lucis, tenebrae vincunt.”

-Latin, “In absence of light, darkness prevails.”

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 system may explain some RPLs, many patients are left without an explanation for recurrent miscarriages, and more 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 source of research funding, other avenues for grant support, such as industry, government, and philanthropy, continue to be limited. Since specialists in thrombosis, reproductive medicine, obstetrics, and other disciplines contribute to the care of patients with RPL, no specific field claims ownership over research focused on thrombophilia and infertility. Accordingly, which agencies and organizations should support such research remains unclear.

Even when financial and academic support for definitive studies can be mustered, clinical trials focused on thrombophilia and RPL may be plagued by enrollment challenges.[3] First, randomization, especially to placebo, may be rejected by patients who typically wish to have access to any therapy that may facilitate conception and live birth. Second, recruitment of eligible patients depends on the identification of patients with thrombophilia, the testing of which is not routine and not recommended until two or three pregnancy losses.[6] [7] Finally, investigators and medical centers may have a general reluctance to conduct research in women of childbearing potential.

While the outlook for research in thrombophilia and RPL may appear quite dim based on these observations, alternative study designs, methodological innovation, and an emphasis on collaborative research networks may be the keys to illuminating a pathway forward ([Fig. 1]). The desire to utilize well-powered RCTs to answer pivotal research questions in thrombophilia and RPL is aspirational but often not practical. Alternative nonrandomized study designs such as registry-based science are frequently criticized as vulnerable to bias.[3] However, incorporation of methodological innovations, such as propensity score matching to reduce selection bias between comparison groups[8] and independent blinded adjudication to minimize misclassification bias, can strengthen the validity of such studies. “Real-world evidence” analyses focused on large datasets, including national health registers and payer claims databases, are another type of nonrandomized study that may be somewhat resistant to imbalances in clinical characteristics due to their sheer size and may also offer greater generalizability than clinical trials.[9] Finally, leveraging health information technology tools, ranging from computerized decision support to natural language processing, to generate large datasets rapidly has proven quite fruitful during the COVID-19 pandemic and could be applied to other areas of need, such as thrombophilia and RPL.[10]

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Fig. 1 Pathways for overcoming obstacles in clinical research focused on thrombophilia and recurrent pregnancy loss.

Perhaps the most important stepping stone in the advancement of research in thrombophilia and RPL is the greater development of collaborative research networks. Complex pathophysiology and multidisciplinary nature of clinicians who focus on thrombophilia and infertility beckon for the collaboration of thrombosis experts, infertility specialists, obstetricians, and others. Collaborative research networks not only encourage the stockpiling of expertise and sharing of varied viewpoints but can also pool resources and strengthen recruitment efforts for clinical studies, including RCTs. Furthermore, data-sharing across such networks can further catalyze the development of new hypotheses and foster the development of clinical trials with the greatest likelihood of success.

As we broaden our search for illumination in the field of thrombophilia and RPL, we need only to look at our patients to know that the darkness of uncertainty is not an option. Our patients, clinical colleagues, and guideline writers are looking for research to provide answers. While we should not abandon the pursuit of definitive RCTs, we must be pragmatic and understand that research utilizing innovative alternative study designs will help generate crucial hypotheses, assist in answering clinical research questions, and power the most-likely-to-succeed trials. When we remain open-minded and pursue innovation, we can be those desperately needed beacons of light for our patients and clinical colleagues suffering in the shadows of RPL.

Support

None.


Disclosures

G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Amgen, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. E.G. has received consultant fees from Italfarmaco and Sanofi.




Publication History

Article published online:
08 November 2021

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  • References

  • 1 Malinowski AK. The pathophysiology of hypercoagulability and infertility. Semin Reprod Med 2021; 39 (1–02): 34-61
  • 2 Grandone E, Piazza G. Thrombophilia, inflammation, and recurrent pregnancy loss: a case-based review. Semin Reprod Med 2021; Mar;39(1-02): 62-68
  • 3 Villani M, Baldini D, Totaro P. et al. Rationale and design of two prospective, multicenter, observational studies on reproductive outcome in women with recurrent failures after spontaneous or assisted conception: OTTILIA and FIRST registries. BMC Pregnancy Childbirth 2019; 19 (01) 292
  • 4 Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion. Division of Reproductive Health. Accessed October 22, 2018 at: http://nccd.cdc.gov/drh_art
  • 5 Calhaz-Jorge C, de Geyter C, Kupka MS. et al; European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod 2016; 31 (08) 1638-1652
  • 6 Bates SM, Greer IA, Middeldorp S. et al. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141: e691S-e736S
  • 7 Bender Atik R, Christiansen OB, Elson J. et al; ESHRE Guideline Group on RPL. ESHRE guideline: recurrent pregnancy loss. Hum Reprod Open 2018; 2018 (02) hoy004
  • 8 Grandone E, Tiscia GL, Mastroianno M. et al. Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry. Hum Reprod 2021; 36 (08) 2083-2090
  • 9 Munafò M. Don't let the perfect be the enemy of the good. PLoS Biol 2021; 19 (07) e3001327
  • 10 Piazza G, Campia U, Hurwitz S. et al. Registry of arterial and venous thromboembolic complications in patients with COVID-19. J Am Coll Cardiol 2020; 76 (18) 2060-2072