Venous Thromboembolism Associated with Assisted Reproductive Technology: A Systematic Review and Meta-analysis

Hormonal exposure leads to an increased risk of venous thromboembolism (VTE) but the risk of VTE associated with assisted reproductive technology (ART) is not clearly determined.We searched in PubMed, EMBASE, Web of Science, and the Cochrane Library databases and identified all relevant articles published up to February 1, 2021.The primary objective was to determine the frequency of VTE associated with ART. Secondary objectives were to determine (1) the risk of VTE associated with ART as compared to pregnancy without ART; (2) the risk of VTE associated with ovarian hyperstimulation syndrome (OHSS); and (3) to determine potential risk factors of VTE related to ART.Fourteen studies were included. The overall frequency of VTE associated with ART was 0.23% (95% confidence interval [CI]: 0.07-0.46). Women undergoing ART had a two- to threefold increased risk of VTE as compared to spontaneous pregnancy (relative risk [RR]: 2.66; 95% CI: 1.60-4.43). The overall frequency of VTE specifically related to OHSS was <0.001%. The risk of VTE after ART complicated by OHSS, as compared to ART without OHSS, was higher but not statistically significant (RR: 14.83; 95% CI: 0.86-255.62). Risk factors of VTE associated with ART were in vitro fertilization procedure (RR, odds ratio [OR], and hazard ratio varying from 1.77, 95% CI: 1.41-2.23 to 4.99, 95% CI: 1.24-20.05), hyperhomocysteinemia (OR: 15.2; 95% CI: 2.0-115.0), polycystic ovarian syndrome (PCOS) (RR: 4.8; 95% CI: 1.7-13.4), successful ART leading to pregnancy (OR: 13.94; 95% CI: 1.41-137.45).Further large prospective studies on risk factors of VTE in women undergoing ART are needed in order to optimize thromboprophylaxis in this context.

[1]  E. Mayo-Wilson,et al.  The PRISMA 2020 statement: an updated guideline for reporting systematic reviews , 2021, BMJ.

[2]  M. Bottai,et al.  Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilization with fresh respectively frozen‐thawed embryo transfer: Nationwide cohort study , 2020, Journal of thrombosis and haemostasis : JTH.

[3]  C. Tromeur,et al.  [Diagnostic and therapeutic management of venous thromboembolic disease in obese patients]. , 2020, Revue des maladies respiratoires.

[4]  B. Luke,et al.  INCREASED RISK OF SEVERE MATERNAL MORBIDITY AMONG INFERTILE WOMEN: ANALYSIS OF US CLAIMS DATA. , 2020, American journal of obstetrics and gynecology.

[5]  M. Humbert,et al.  2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): supplementary data , 2019 .

[6]  M. Humbert,et al.  2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS) , 2019, European Respiratory Journal.

[7]  C. Deneux-Tharaux,et al.  Arterial and venous complications after fertility treatment: A French nationwide cohort study. , 2019, European journal of obstetrics, gynecology, and reproductive biology.

[8]  Z. Williams,et al.  Life-threatening complications among women with severe ovarian hyperstimulation syndrome. , 2019, American journal of obstetrics and gynecology.

[9]  P. Girard,et al.  [Recommendations of good practice for the management of thromboembolic venous disease in adults. Short version]. , 2019, Revue des maladies respiratoires.

[10]  S. Laporte,et al.  [Recommendations of good practice for the management of thromboembolic venous disease in adults. Short version]. , 2019, Revue des maladies respiratoires.

[11]  B. Rochwerg,et al.  American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. , 2018, Blood advances.

[12]  U. Knudsen,et al.  Low risk of venous thromboembolism following early pregnancy loss in pregnancies conceived by IVF , 2018, Human reproduction.

[13]  J. Gris,et al.  Benefit of Risk Score-Guided Prophylaxis in Pregnant Women at Risk of Thrombotic Events: A Controlled Before-and-After Implementation Study , 2018, Thrombosis and Haemostasis.

[14]  Christine Wyns,et al.  ART in Europe, 2015: results generated from European registries by ESHRE† , 2020, Human reproduction open.

[15]  M. Margaglione,et al.  Venous thromboembolism in assisted reproductive technologies: comparison between unsuccessful versus successful cycles in an Italian cohort , 2018, Journal of Thrombosis and Thrombolysis.

[16]  M. Hellgren,et al.  Thromboembolism and in vitro fertilization – a systematic review , 2017, Acta obstetricia et gynecologica Scandinavica.

[17]  G. Tiscia,et al.  Pregnancy-related venous thrombosis: comparison between spontaneous and ART conception in an Italian cohort , 2015, BMJ Open.

[18]  J. Douketis,et al.  Factors that predict thrombosis in relatives of patients with venous thromboembolism. , 2014, Blood.

[19]  U. Kesmodel,et al.  Increased venous thrombosis incidence in pregnancies after in vitro fertilization. , 2014, Human reproduction.

[20]  C. Tromeur,et al.  Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism , 2013, Thrombosis and Haemostasis.

[21]  O. Hovatta,et al.  Incidence of pulmonary and venous thromboembolism in pregnancies after in vitro fertilisation: cross sectional study , 2013, BMJ.

[22]  U. Kesmodel,et al.  No evidence that assisted reproduction increases the risk of thrombosis: a Danish national cohort study. , 2012, Human reproduction.

[23]  D. Veenstra,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. , 2012, Chest.

[24]  P. Lindqvist,et al.  Venous thromboembolism in relation to in vitro fertilization: an approach to determining the incidence and increase in risk in successful cycles. , 2012, Fertility and sterility.

[25]  Y. Lien,et al.  Update on management of ovarian hyperstimulation syndrome. , 2011, Taiwanese journal of obstetrics & gynecology.

[26]  H. Shin,et al.  Pregnancy-Induced Hypertension, But Not Gestational Diabetes Mellitus, Is a Risk Factor for Venous Thromboembolism in Pregnancy , 2011, Korean circulation journal.

[27]  J. Gris,et al.  Use of the Delphi method to facilitate antithrombotics prescription during pregnancy. , 2010, Thrombosis research.

[28]  C. Négrier,et al.  A risk score for the management of pregnant women with increased risk of venous thromboembolism: a multicentre prospective study , 2009, British journal of haematology.

[29]  W. Chan.  The ‘ART’ of thrombosis: a review of arterial and venous thrombosis in assisted reproductive technology , 2009, Current opinion in obstetrics & gynecology.

[30]  P. Sandset,et al.  Ante‐ and postnatal risk factors of venous thrombosis: a hospital‐based case–control study , 2008, Journal of thrombosis and haemostasis : JTH.

[31]  W. Chan,et al.  The "ART" of thromboembolism: a review of assisted reproductive technology and thromboembolic complications. , 2008, Thrombosis research.

[32]  R. Pauzner,et al.  Safety of IVF under anticoagulant therapy in patients at risk for thrombo-embolic events. , 2006, Reproductive biomedicine online.

[33]  M. Sedler,et al.  Management of ovarian hyperstimulation syndrome , 2006 .

[34]  M. Margaglione,et al.  Age and homocysteine plasma levels are risk factors for thrombotic complications after ovarian stimulation. , 2004, Human reproduction.

[35]  J. Schenker,et al.  Pulmonary manifestations of severe ovarian hyperstimulation syndrome: a multicenter study. , 1999, Fertility and sterility.

[36]  J. Schenker,et al.  Febrile morbidity in severe and critical ovarian hyperstimulation syndrome: a multicentre study. , 1998, Human reproduction.

[37]  P. Drakakis,et al.  Oocyte donation to women over 40 years of age: pregnancy complications. , 1996, European journal of obstetrics, gynecology, and reproductive biology.

[38]  P. Frappé,et al.  Recommandations de bonne pratique pour la prise en charge de la maladie veineuse thromboembolique chez l’adulte – Version longue , 2022, Revue des Maladies Respiratoires.