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

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

Role of Low Molecular Weight Heparin in the Management of Unexplained Recurrent Pregnancy Loss: A Review of Literature

“…Patients in both groups were monitored until delivery or spontaneous termination of pregnancy. Five out of the seven articles reviewed for live birth rates, with 855 participants reported a significant improvement in the live birth rate of women who had LMWH compared to the control group [4][5][6][12][13][14][15][16][17]. In contrast, two of the articles with a total of 707 participants did not show any statistically significant difference in terms of live birth rate between the group who had LMWH and the control group [10,13].…”

“…Many observational studies and randomized control trials (RCTs) have been conducted concerning the use of LMWH alone or in combination with other agents in the treatment of URPL [1,2,5,6,9,[12][13][14]. Some showed favorable outcomes in live births and reduced complications such as preeclampsia and preterm deliveries [10,11,[15][16][17][18]. However, some were inconclusive [10,11,14].…”

“…However, some were inconclusive [10,11,14]. This finding could be due to heterogeneity and limited sample sizes [10,11,15,16]. This article will explore whether the currently available literature supports recommending the use of LMWH for the treatment of URPL for improving pregnancy outcomes in terms of live birth rates, reduction in pregnancy complications, and side effects.…”

Thrombophilia, Inflammation, and Recurrent Pregnancy Loss: A Case-Based Review

“…16 Arguments against thrombophilia testing have focused on low prevalence in the general population, inconsistency in studies assessing their impact on RPL, cost of hypercoagulability evaluation, and limited data on the efficacy of low-dose injectable antithrombotic therapy in such patients. 15,17 Furthermore, the impact of more prevalent inherited thrombophilias, such as factor V Leiden and prothrombin gene mutation, on RPL remains less clear compared with other hypercoagulable states, such as the confirmed presence of antiphospholipid antibodies. 18,19 Because the next step in care for women like the one presented in the case vignette may be assisted reproductive therapy (ART), evaluation for thrombophilia may have potential importance given the financial, physical, and psychological burden of such fertility treatments and growing recognition of the complication of thromboembolic events associated with in vitro fertilization (IVF).…”

“…31 A major challenge in such randomized controlled trials is slow recruitment. 17 Currently, there are two ongoing registries (FIRST, NCT 02685800; FREYA, NCT04537416) that are prospectively collecting information on ART cycles in the "real-world" with the objective to investigate factors affecting reproductive outcomes and assess the best clinical management strategies.…”