STUDY QUESTION Is there an association between hereditary thrombophilia in pregnant women and risk of recurrent pregnancy loss (RPL)? SUMMARY ANSWER Pregnant women with hereditary thrombophilia have an increased risk of RPL, especially for pregnant women with the G1691A mutation of the factor V Leiden (FVL) gene, the G20210A mutation of the prothrombin gene (PGM), and deficiency of protein S (PS). WHAT IS KNOWN ALREADY Prior studies have suggested that pregnant women with hereditary thrombophilia have a higher risk of RPL, however, the results are inconsistent; furthermore, a complete overview is missing. This lack of information is an obstacle to the risk assessment of RPL in pregnant women with hereditary thrombophilia. A comprehensive meta-analysis on the relation between hereditary thrombophilia and the risk of RPL is needed. STUDY DESIGN, SIZE, DURATION A systematic review and meta-analysis was performed using observational studies published in English before 1 April 2020 to evaluate the relation between hereditary thrombophilia and risk of RPL. PARTICIPANTS/MATERIALS, SETTING, METHODS Relevant studies were identified from PubMed, Web of Science, and EMBASE searches and complemented with perusal of bibliographies of retrieved articles. The exposure of interest was hereditary thrombophilia, including FVL mutation, PGM, deficiency of antithrombin (AT), deficiency of protein C (PC), and deficiency of PS. The overall risk estimates were pooled using random effects models. Subgroup and sensitivity analyses were carried out to explore possible sources of heterogeneity and assess the robustness of the results. MAIN RESULTS AND THE ROLE OF CHANCE A total of 89 studies involving 30 254 individuals were included. Results showed that women with FVL mutation (odds ratio (OR): 2.44, 95% CI: 1.96–3.03), PGM (OR: 2.08, 95% CI: 1.61–2.68), or deficiency of PS (OR: 3.45, 95% CI: 1.15–10.35) had higher risks of developing RPL. Compared with the reference group, there was no observed relation between a deficiency in AT or PC and RPL (all P > 0.05). Heterogeneity in the risk estimates of RPL was partially explained by geographic region, definitions of RPL, types of RPL, and controlled confounders. Sensitivity analyses validated the robustness of the findings. LIMITATIONS, REASONS FOR CAUTION Only 39 of the included studies controlled for one or more confounders, and the heterogeneity across all included studies was high. Based on the data available, we cannot determine whether this association is confounded by other potential risk factors of RPL. WIDER IMPLICATIONS OF THE FINDINGS This systematic review and meta-analysis show a possible association between hereditary thrombophilia and an increased risk of RPL, suggesting that testing for hereditary thrombophilia should be considered in individuals with RPL. STUDY FUNDING/COMPETING INTEREST(S) The study was funded by the Hunan Provincial Key Research and Development Program (Grant number: 2018SK2062) and National Natural Science Foundation Program (Grant number: 81973137). There are no conflicts of interest. REGISTRATION NUMBER N/A.

Introduction: Several studies have demonstrated that there is a higher risk of cardiovascular disease (CVD) in women with a history of hypertensive disorders of pregnancy (HDP). However, effect sizes varied greatly between these studies, and a complete overview of the existing data in the literature is lacking. We aimed to evaluate the association between HDP and the risk of CVD-related morbidity and mortality. Methods: Systematic literature searches were conducted in several electronic databases from inception to July 2019. Exposure of interest was any type of HDP. Outcomes of interest included any CVD, CVD-related mortality, and hypertension. Results: Sixty-six cohort and 7 case-control studies involving > 13 million women were included. The overall combined relative risks (RRs) for women with a history of HDP compared with the reference group were 1.80 (95% confidence interval [CI] 1.67-1.94) for any CVD, 1.66 (1.49-1.84) for coronary artery heart disease, 2.87 (2.14-3.85) for heart failure, 1.60 (1.29-2.00) for peripheral vascular disease, 1.72 (1.50-1.97) for stroke, 1.78 (1.58-2.00) for CVD-related mortality, and 3.16 (2.74-3.64) for hypertension. Significant heterogeneity was partially explained by all or part of the variables including type of exposure, follow-up time, geographic region, and sample source. Conclusions: Women with a history of HDP are at an increased risk of future CVD-related morbidity and mortality. Our study highlights the importance of lifelong monitoring of cardiovascular risk factors in women with a history of HDP.

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Aim: To determine whether the use of low molecular weight heparin (LMWH) improves the pregnancy outcomes in women with inherited thrombophilia by conducting a meta-analysis of randomized controlled trials and observational studies. Methods: A systematic literature search of several databases was conducted through September 19, 2020 to identify relevant studies. The outcomes of interest included live birth and adverse pregnancy outcomes (APOs). The overall risk estimates were pooled using random-effects meta-analysis. Results: Ten randomized controlled trials and 12 cohort studies were included. In the meta-analyses of randomized controlled trials, the effectiveness of LMWH-treatment was found to be statistically significant in decreasing the risk of APOs (risk ratio [RR] = 0.76; 95% confidence interval [CI]: 0.61-0.95; p = 0.020), rather than in increasing the rate of live birth (RR = 1.12; 95% CI: 0.93-1.34; p = 0.230). In the meta-analyses of cohort studies, results showed that the use of LMWH was associated with a significantly higher proportion of live birth (RR = 1.86; 95% CI: 1.09-3.19; p = 0.020) as well as a significantly lower ratio of APOs (RR = 0.46; 95% CI: 0.31-0.69; p < 0.001) in women with inherited thrombophilia. Conclusions: The use of LMWH may have a potentially beneficial effect on reducing the risk of APOs and even increasing the live birth rate in women with inherited thrombophilia. Further well-designed clinical trials with large samples are needed to address the role of LMWH in improving pregnancy outcomes among pregnant women with inherited thrombophilia.