A systematic review and meta-analysis of chronic endometritis and recurrent miscarriage.

Abstract Study question How does the septate uterus and his metroplasty influence pregnancy rate (PR), live birth rate (LBR), spontaneous abortion rates (SA) and preterm labour rates (PL)? Summary answer Uterine septum is associated with a poor reproductive outcome. Metroplasty reduce the rate of SA but non-conclusive evidence can be extrapolated about PR and PL. What is known already Different studies evaluated the correlation between uterine septum and reproductive outcomes. On one hand, studies reported its association with poor obstetrics outcomes. On the other hand, recent studies raised doubts about the effectiveness of septum metroplasty to improve reproductive outcomes, although recent position papers continue to propose metroplasty in patients with a septate uterus and a history of infertility or miscarriages. Debate is still ongoing on reproductive outcomes of uterine septum on infertile patients and especially on patients with recurrent miscarriage, leading to an unanswered question whether or not these women should be treated. Study design, size, duration Systematic review and meta-analysis of published studies that evaluated the clinical impact of uterine septum and its metroplasty on reproductive and obstetrics outcomes. The meta-analysis included study with infertile patients or patients with a history of recurrent miscarriage. Searches were conducted using the following search terms: uterine septum, septate uterus, metroplasty, pregnancy rate, live birth rate, spontaneous miscarriage, infertility, preterm delivery. Primary outcomes were PR and LBR. Secondary outcomes were SA and PL. Participants/materials, setting, methods The meta-analysis was written following the PRISMA guidelines. Fifty-nine full-text articles were preselected based on title and abstract. Endpoints were evaluated in three subgroups: 1) infertile/recurrent miscarriage patients with septum versus no septum 2) infertile/recurrent miscarriage patients with treated versus untreated septum 3) infertile/recurrent miscarriage patients before-after septum removal. Odds-ratios (OR) with 95% confidence intervals (CI) were calculated for outcome measures. Random-effect meta-analysis was performed and a p-value less than 0.05 was considered statistically significant. Main results and the role of chance Data from 37 articles were extracted. In the first subgroup (10 studies), a lower PR and LBR were associated with septate uterus vs. controls, respectively (OR 0.39, 95% CI 0.26 to 0.58; p < 0.000; low-heterogeneity and OR 0.21, 95% CI 0.12 to 0.39; p < 0.0001; small-heterogeneity) and a higher proportion of SA and PL was associated with septate uterus vs. controls, respectively (OR 4.17, 95% CI 2.83 to 6.15; p < 0.000; moderate-heterogeneity and OR 2.18, 95% CI 1.27 to 3.76; p = 0.005; low-heterogeneity). In the second subgroup (8 studies), PR and PL were not different in removed vs. unremoved septum, respectively (OR 1.10, 95% CI 0.49 to 2.49; p = 0.82; moderate heterogeneity and OR 0.44, 95% CI 0.18 to 1.08; p = 0.08;low-heterogeneity) and a lower proportion of SA was associated with removed vs. unremoved septum (OR 0.40, 95% CI 0.17 to 0.95; p = 0.001; substantial-heterogeneity). In the third subgroup (19 studies), the proportion of LBR was higher after the removal of septum (OR 49.58, 95% CI 29.93 to 82.13; p < 0.0001; moderate-heterogeneity) and the proportion of SA and PL was lower after the removal of septum, respectively (OR 0.02, 95% CI 0.02 to 0.04; p < 0.000; moderate-heterogeneity and OR 0.05, 95% CI 0.03 to 0.08; p = <0.000; low-heterogeneity). Limitations, reasons for caution The present meta-analysis is limited by the observational design of included studies because, in literature, there are no prospective randomized controlled trials (RCTs). In the second and third subgroup of analysis clinical heterogeneity within and between studies represents another limitation. Wider implications of the findings The results of this meta-analysis confirm the detrimental effect of uterine septum on PR, LBR, SA and PL. Its treatment seems to reduce the rate of SA. Metroplasty should still be considered as good clinical practice in patients with a history of infertility and recurrent abortion. Trial registration number Not applicable © The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For permissions, please e-mail: [email protected].

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P–426 Uterine Natural Killer Cells in Recurrent Miscarriage and Implantation Failure: An Updated Systematic Review and Meta-analysis

Human Reproduction ◽

10.1093/humrep/deab130.425 ◽

2021 ◽

Vol 36 (Supplement_1) ◽

Author(s):

E V Woon ◽

O Greer ◽

N Shah ◽

V Male ◽

M Johnson

Keyword(s):

Systematic Review ◽

Nk Cells ◽

Early Pregnancy ◽

Subgroup Analysis ◽

Recurrent Miscarriage ◽

Meta Analysis ◽

Implantation Failure ◽

Significant Difference ◽

Uterine Nk Cells ◽

Definition Of

Abstract Study question Do women with recurrent miscarriage (RM) or implantation failure (RIF) have different levels of uterine Natural Killer (NK) cells compared to fertile controls? Summary answer Women with RIF but not RM are associated with significantly higher levels of CD56+ uterine NK cells compared to controls. What is known already Uterine NK cells (uNK) are different from peripheral NK cells (pNK) and are important in early pregnancy for development of the placenta. The association between uNK and RM/RIF is less clear, but dysfunction of uNK is believed to result in early pregnancy failure. Previous systematic reviews by Seshadri (2014) and Tang (2013) on infertile and RM patients showed no significant difference in uNK levels and highlighted need for further studies. Since, many prospective studies have been published and therefore warrant an updated systematic review. On the other hand, evidence for correlation between uNK and pNK is sparse and needs clarification. Study design, size, duration We have conducted a systematic review and meta-analysis to evaluate three outcomes. The primary outcome was the difference of uNK level in RM/RIF compared to controls. The secondary outcome was livebirth rate in women with RM/RIF with high compared to normal uNK level, and the tertiary outcome was correlation between uNK and pNK in RM/RIF. Participants/materials, setting, methods The electronic database search included MEDLINE, EMBASE, Web of Science and bibliographies from included articles from inception to December 2020 using a combination of MESH and keywords. Search, screen, and data extraction were performed by two reviewers independently. Quality assessment was conducted with ROBINS-I and meta-analysis with Revman 5.3. Out of 4636 studies screened, 43 studies (2539 women) and 3 studies each (598 and 77 women) were analysed for primary, secondary and tertiary outcomes respectively. Main results and the role of chance Our meta-analysis showed that CD56+ uNK were significantly higher in women with RIF but not RM compared to controls (SMD 0.60; 95% CI 0.12–1.08]. Subgroup analysis in RM patients showed no significant difference whether definition of 2 or 3 previous RM was used, in primary/secondary RM compared to controls, or in primary versus secondary RM. CD56+ uNK were significantly higher in RM/RIF when sampled during mid-luteal phase [SMD 0.56; 95% CI 0.19–0.93] but not in the early pregnancy decidua. Interestingly, there was significant difference in CD56+ uNK when analysed by immunohistochemistry [SMD 0.50; CI 0.05–0.94] but not by flow cytometry, and when CD56+ uNK were reported as percentage over total endometrial cells [SMD 0.58; 95% CI 0.10–1.07]. Further subgroup analysis showed significant difference in CD16 + [SMD 0.54; 95% CI 0.18–0.89] but not in CD56+CD16-, CD56+CD16+ or CD57. For pregnancy outcome, there was no significant difference in livebirth rate in RM/RIF patients with high uNK compared to normal uNK [RR 1.06, 95% CI 0.86–1.30]. Mean uNK level in RM patients with subsequent miscarriage was not significantly higher than subsequent livebirth. Finally, the pooled correlation between CD56 pNK and CD56 uNK (r = 0.42; 95% CI –0.04–0.73] was not significant in RM/RIF patients. Limitations, reasons for caution The meta-analysis is limited by quality of some of the studies. Some data were presented in median that was transformed to mean which may result in data skew. Other confounding factors e.g. maternal age, fetal karyotype, number of previous miscarriages and variable definition of controls may contribute to bias. Wider implications of the findings: Clinical interpretation of uNK level needs to be treated with caution because there is significant heterogeneity in method of analysis. There may be a role for uNK measurement in RIF patients however further studies to understand pathophysiology underlying elevated uNK is warranted before recommending it as a diagnostic tool. Trial registration number N/A

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