Findings from a multicentre, observational study on reproductive outcomes in women with unexplained recurrent pregnancy loss: the OTTILIA registry
Authors: Grandone Elvira , Tiscia Giovanni L , Mastroianno Mario , Larciprete Giovanni , Kovac Mirjana , Tamborini Permunian Eleonora , Lojacono Andrea , Barcellona Doris , Bitsadze Victoria , Khizroeva Jamilya , Makatsarya Alexander , Cacciola Rossella , Martinelli Ida , Bucherini Eugenio , De Stefano Valerio , Lodigiani Corrado , Colaizzo Donatella , De Laurenzo Antonio , Piazza Gregory , Margaglione Maurizio 
Published: June 2021

Abstract

STUDY QUESTION
What evaluation and care is offered to women after unexplained recurrent pregnancy loss (RPL) or intra-uterine foetal death (IUFD) and what are the reproductive outcomes?

SUMMARY ANSWER
Women are assessed for thrombophilia and often treated with low-molecular weight heparin (LMWH) and/or low-dose aspirin (ASA).

WHAT IS KNOWN ALREADY
Randomized controlled trials (RCTs) on possible efficacy of heparins and/or aspirin have been inconclusive due to limited power to detect a difference and patient heterogeneity.

STUDY DESIGN, SIZE, DURATION
Prospective multicentre cohort study performed in 12 hospitals in three countries between 2012 and 2019.

PARTICIPANTS/MATERIALS, SETTING, METHODS
All consecutive pregnant women with recurrent PL (≥3 losses or 2 losses in the presence of at least one euploid foetal karyotype) or at least one IUFD. Eligible women may have undergone thrombophilia testing before conception, at the discretion of local providers. The possible assignment of women to treatments (such as LMWH) was not decided a priori but was determined based on the responsible provider’s current practice. Aims of the study were: (i) to evaluate factors associated with pregnancy outcome; (ii) to compare clinical management strategies in women with and without a subsequent successful pregnancy; and (iii) to evaluate characteristics of women who may benefit from antithrombotic therapy. A propensity score matching method was used to balance the differences in baseline characteristics.

MAIN RESULTS AND THE ROLE OF CHANCE
A matched sample of 265 pregnant women was analysed, with all undergoing thrombophilia screening; 103 out of 119 (86.6%) with and 98/146 (67.1%) without thrombophilia were prescribed with LMWH and/or ASA. Overall, live-births were recorded in 204 cases (77%), PL or IUFD in 61 (23%) pregnancies. Logistic regression showed a significant interaction between thrombophilia and treatment with LMWH (P = 0.03). Findings from sensitivity analysis showed odds ratio (OR) for pregnancy loss in women with inherited or acquired thrombophilia in absence of any treatment was 2.9 (95% CI, 1.4–6.1); the administration of LMWH (with or without ASA) was associated with higher odds of live-birth (OR, 10.6; 95% CI, 5.0–22.3). Furthermore, in women without thrombophilia, the odds of live-birth was significantly and independently associated with LMWH prophylaxis (alone or in association with ASA) (OR, 3.6; 95% CI, 1.7–7.9).

LIMITATIONS, REASONS FOR CAUTION
While the propensity score matching allows us to balance the differences in baseline characteristics, it does not eliminate all confounding.

WIDER IMPLICATIONS OF THE FINDINGS
Antithrombotic prophylaxis during pregnancy may be effective in women with otherwise unexplained PL or IUFD, and even more useful in those with thrombophilia.

STUDY FUNDING/COMPETING INTEREST(S)
The study was funded by Italian Ministry of Health (Ricerca Corrente 2018-2020). Dr G.P. has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr E.G. has received consultant fees from Italfarmaco and Sanofi. All other authors declare that they have no conflict of interest.

TRIAL REGISTRATION NUMBER
NCT02385461.