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

doi:10.1186/s12884-019-2444-y

Abstract

BackgroundSpontaneous 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.MethodsOTTILIA (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.DiscussionAlthough 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 registrationNCT 02385461, retrospectively registered 5 March 2015 (OTTILIA); NCT 02685800, registered 10 February 2016 (FIRST).

Highlights

Spontaneous pregnancy loss and implantation failure after assisted reproductive technologies (ART) are very common occurrences
randomized clinical trials (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
RCTs in pregnant/infertile women are often stopped before completing, due to poor and slow recruitment. To cover these unmet needs and to have further data mainly based on the real-life clinical management, we are currently conducting the OTTILIA (Observational sTudy on antiThrombotic prevention in thrombophILIA and pregnancy loss – NCT 02385461) and FIRST registries, respectively

Summary

Methods

Aims Primary aims of the OTTILIA and FIRST registries are: (1) to identify and evaluate all possible factors associated with reproductive outcome and improve risk stratification of women, (2) to assess the best clinical management strategies (including a potential benefit of prophylaxis with LMWH) in improving outcome, (3) to evaluate characteristics of women who possibly benefit from an antithrombotic treatment. Study size estimation In the literature, the likelihood of observing live births without any treatment is estimated to range between 55 and 80% [2]; a multicentre Italian study [9] showed the occurrence of complications in 50% of all untreated women during pregnancy Given these estimates, for the OTTILIA register, in order to observe an absolute increase of 15–20% (statistical power: 80%, significance level: 0.05), we calculated the inclusion of 190–340 thrombophilic women and, simultaneously, a cohort of pregnant women with the same clinical history (see inclusion criteria) not carrying inherited thrombophilia, in a ratio of at least 1:1. An additional period of 9 months from the date of the last enrollment will be considered

Discussion

Background

Findings