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

Michela Villani, Domenico Baldini, Pasquale Totaro, Giovanni Larciprete, Mirjana Kovac, Domenico Carone, Serena Maria Passamonti, Eleonora Tamborini Permunian, Tiziana Bartolotti, Andrea Lojacono, Rossella Cacciola, Giuliano Lo Pinto, Eugenio Bucherini, Valerio De Stefano, Corrado Lodigiani, Cristina Lavopa, Yoon Sung Cho, Caterina Pizzicaroli, Donatella Colaizzo, Elvira Grandone, Michela Villani, Domenico Baldini, Pasquale Totaro, Giovanni Larciprete, Mirjana Kovac, Domenico Carone, Serena Maria Passamonti, Eleonora Tamborini Permunian, Tiziana Bartolotti, Andrea Lojacono, Rossella Cacciola, Giuliano Lo Pinto, Eugenio Bucherini, Valerio De Stefano, Corrado Lodigiani, Cristina Lavopa, Yoon Sung Cho, Caterina Pizzicaroli, Donatella Colaizzo, Elvira Grandone

Abstract

Background: Spontaneous pregnancy loss and implantation failure after assisted reproductive technologies (ART) are very common occurrences. Although 50-60% of all cases remains unexplained, various predisposing factors, including thrombophilias, have been identified. Thus, the potential benefit of a prophylaxis with low-molecular-weight heparins in improving outcomes has been often investigated over the years. However, the majority of studies are observational and results from randomized clinical trials (RCTs) are inconclusive, probably due to heterogeneity and limited sample size. To cover these unmet needs and to have further data mainly based on the real-life clinical management, we designed these multicenter registries.

Methods: OTTILIA (Observational sTudy on antiThrombotic prevention in thrombophILIA and pregnancy loss) and FIRST (recurrent Failures in assIsted Reproductive Techniques) registries are two prospective, multicenter, observational studies to evaluate pregnancy or ART outcomes in consecutive women with previous reproductive failures after spontaneous or assisted conception, respectively. All enrolled women are observed from their first visit after positive pregnancy test (OTTILIA) or before commencing a new ART cycle (FIRST) until the end of pregnancy or ART procedure (negative pregnancy test/end of pregnancy, if successful cycle), respectively. Data are collected by means of questionnaires and recorded in a central database. Follow-up investigations are performed during hospital stay, routine clinical follow-up visits or telephone interviews. Primary outcome is live birth rate in the OTTILIA register and clinical pregnancy rate in the FIRST.

Discussion: Although RCTs are the 'gold standard' for evaluating treatment outcomes, we believe that our registries represent a valid alternative in improving knowledge on mechanisms involved in reproductive failures and supporting future clinical decisions.

Trial registration: NCT02385461 , retrospectively registered 5 March 2015 (OTTILIA); NCT02685800 , registered 10 February 2016 (FIRST).

Keywords: Assisted reproductive technologies; Heparins; Implantation failure; Observational study; Pregnancy loss; Risk factors; Thrombophilia.

Conflict of interest statement

The authors declare that they have no competing interests.

References

    1. Regan L, Braude PR, Trembath PL. Influence of past reproductive performance on risk of spontaneous abortion. BMJ. 1989;299:541–545. doi: 10.1136/bmj.299.6698.541.
    1. Stirrat GM. Recurrent miscarriage. Lancet. 1990;336:673–675. doi: 10.1016/0140-6736(90)92159-F.
    1. European IVF-Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE) Calhaz-Jorge C, de Geyter C, Kupka MS, de Mouzon J, Erb K, Mocanu E, et al. Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod. 2016;31:1638–1652. doi: 10.1093/humrep/dew151.
    1. Rey Evelyne, Kahn Susan R, David Michèle, Shrier Ian. Thrombophilic disorders and fetal loss: a meta-analysis. The Lancet. 2003;361(9361):901–908. doi: 10.1016/S0140-6736(03)12771-7.
    1. Di Nisio M., Rutjes A. W. S., Ferrante N., Tiboni G. M., Cuccurullo F., Porreca E. Thrombophilia and outcomes of assisted reproduction technologies: a systematic review and meta-analysis. Blood. 2011;118(10):2670–2678. doi: 10.1182/blood-2011-03-340216.
    1. Sergi C., Al Jishi T., Walker M. Factor V Leiden mutation in women with early recurrent pregnancy loss: a meta-analysis and systematic review of the causal association. Archives of Gynecology and Obstetrics. 2014;291(3):671–679. doi: 10.1007/s00404-014-3443-x.
    1. Grandone E, Brancaccio V, Colaizzo D, Sciannamé N, Pavone G, Di Minno G, et al. Preventing adverse obstetric outcomes in women with genetic thrombophilia. Fertil Steril. 2002;78:371–375. doi: 10.1016/S0015-0282(02)03222-3.
    1. Grandone Elvira, De Stefano Valerio, Rossi Elena, Cappucci Filomena, Colaizzo Donatella, Margaglione Maurizio. Antithrombotic prophylaxis during pregnancy in women with deficiency of natural anticoagulants. Blood Coagulation & Fibrinolysis. 2008;19(3):226–230. doi: 10.1097/MBC.0b013e3282f54545.
    1. Tormene D, Grandone E, De Stefano V, Tosetto A, Palareti G, Margaglione M, et al. Obstetric complications and pregnancy-related venous thromboembolism: the effect of low-molecular-weight heparin on their prevention in carriers of factor V Leiden or prothrombin G20210A mutation. Thromb Haemost. 2012;107:477–484. doi: 10.1160/TH11-07-0470.
    1. Grandone Elvira, Villani Michela, Tiscia Giovanni L., Dentali Francesco, Colaizzo Donatella, Cappucci Filomena, Fischetti Lucia, Ageno Walter, Margaglione Maurizio. Clinical Utility of Antithrombotic Prophylaxis in ART Procedures: An Italian Experience. PLoS ONE. 2014;9(5):e97604. doi: 10.1371/journal.pone.0097604.
    1. Grandone E., Villani M., Tiscia G.L., Dentali F., Colaizzo D., Cappucci F., Chinni E., Ageno W., Margaglione M. Clinical Pregnancies and Live Births in women approaching ART: A follow-up analysis of 157 women after thrombophilia screening. Thrombosis Research. 2014;133(2):168–172. doi: 10.1016/j.thromres.2013.11.016.
    1. Grandone E., Villani M., Dentali F., Tiscia G.L., Colaizzo D., Cappucci F., Fischetti L., Ageno W., Margaglione M. Low-molecular –weight heparin in pregnancies after ART -A retrospective study- Thrombosis Research. 2014;134(2):336–339. doi: 10.1016/j.thromres.2014.06.004.
    1. Kaandorp Stef P., Goddijn Mariëtte, van der Post Joris A.M., Hutten Barbara A., Verhoeve Harold R., Hamulyák Karly, Mol Ben Willem, Folkeringa Nienke, Nahuis Marleen, Papatsonis Dimitri N.M., Büller Harry R., van der Veen Fulco, Middeldorp Saskia. Aspirin plus Heparin or Aspirin Alone in Women with Recurrent Miscarriage. New England Journal of Medicine. 2010;362(17):1586–1596. doi: 10.1056/NEJMoa1000641.
    1. Clark P., Walker I. D., Langhorne P., Crichton L., Thomson A., Greaves M., Whyte S., Greer I. A. SPIN (Scottish Pregnancy Intervention) study: a multicenter, randomized controlled trial of low-molecular-weight heparin and low-dose aspirin in women with recurrent miscarriage. Blood. 2010;115(21):4162–4167. doi: 10.1182/blood-2010-01-267252.
    1. Visser Jantien, Ulander Veli-Matti, Helmerhorst Frans, Lampinen Katja, Morin-Papunen Laure, Bloemenkamp Kitty, Kaaja Risto. Thromboprophylaxis for recurrent miscarriage in women with or without thrombophilia. Thrombosis and Haemostasis. 2011;105(02):295–301. doi: 10.1160/TH10-05-0334.
    1. REY E., GARNEAU P., DAVID M., GAUTHIER R., LEDUC L., MICHON N., MORIN F., DEMERS C., KAHN S. R., MAGEE L. A., RODGER M. Dalteparin for the prevention of recurrence of placental-mediated complications of pregnancy in women without thrombophilia: a pilot randomized controlled trial. Journal of Thrombosis and Haemostasis. 2009;7(1):58–64. doi: 10.1111/j.1538-7836.2008.03230.x.
    1. Skeith L., Carrier M., Kaaja R., Martinelli I., Petroff D., Schleussner E., Laskin C. A., Rodger M. A. A meta-analysis of low-molecular-weight heparin to prevent pregnancy loss in women with inherited thrombophilia. Blood. 2016;127(13):1650–1655. doi: 10.1182/blood-2015-12-626739.
    1. Rodger Marc A, Gris Jean-Christophe, de Vries Johanna I P, Martinelli Ida, Rey Évelyne, Schleussner Ekkehard, Middeldorp Saskia, Kaaja Risto, Langlois Nicole J, Ramsay Timothy, Mallick Ranjeeta, Bates Shannon M, Abheiden Carolien N H, Perna Annalisa, Petroff David, de Jong Paulien, van Hoorn Marion E, Bezemer P Dick, Mayhew Alain D. Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials. The Lancet. 2016;388(10060):2629–2641. doi: 10.1016/S0140-6736(16)31139-4.
    1. de Jong PG, Kaandorp S, Di Nisio M, Goddijn M, Middeldorp S. Aspirin and/or heparin for women with unexplained recurrent miscarriage with or without inherited thrombophilia. Cochrane Database Syst Rev. 2014. 10.1002/14651858.CD004734.pub4.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться