BACKGROUND The number of frozen embryo transfers (FET) has increased dramatically over the past decade. Based on current evidence, there is no difference in pregnancy rates when natural cycle FET (NC-FET) is compared to artificial cycle FET (AC-FET) in subfertile women. However, NC-FET seems to be associated with lower risk of adverse obstetric and neonatal outcomes compared with AC-FET cycles. Currently, there is no consensus about whether NC-FET needs to be combined with luteal phase support (LPS) or not. The question of how to prepare the endometrium for FET has now gained even more importance and taken the dimension of safety into account as it should not simply be reduced to the basic question of effectiveness. OBJECTIVE AND RATIONALE The objective of this project was to determine whether NC-FET, with or without LPS, decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET. SEARCH METHODS A systematic review and meta-analysis was carried out. A literature search was performed using the following databases: CINAHL, EMBASE, and MEDLINE from inception to 10 October 2022. Observational studies, including cohort studies, and registries comparing obstetric and neonatal outcomes between singleton pregnancies after NC-FET and those after AC-FET were sought. Risk of bias was assessed using the ROBINS-I tool. The quality of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. We calculated pooled odds ratios (ORs), pooled risk differences (RDs), pooled adjusted ORs, and prevalence estimates with 95% CI using a random effect model, while heterogeneity was assessed by the I2. OUTCOMES The conducted search identified 2436 studies, 890 duplicates were removed and 1546 studies were screened. Thirty studies (NC-FET n = 56 445; AC-FET n = 57 231) were included, 19 of which used LPS in NC-FET. Birthweight was lower following NC-FET versus AC-FET (mean difference 26.35 g; 95% CI 11.61–41.08, I2 = 63%). Furthermore NC-FET compared to AC-FET resulted in a lower risk of large for gestational age (OR 0.88, 95% 0.83–0.94, I2 = 54%), macrosomia (OR 0.81; 95% CI 0.71–0.93, I2 = 68%), low birthweight (OR 0.81, 95% CI 0.77–0.85, I2 = 41%), early pregnancy loss (OR 0.73; 95% CI 0.61–0.86, I2 = 70%), preterm birth (OR 0.80; 95% CI 0.75–0.85, I2 = 20%), very preterm birth (OR 0.66, 95% CI 0.53–0.84, I2 = 0%), hypertensive disorders of pregnancy (OR 0.60, 95% CI 0.50–0.65, I2 = 61%), pre-eclampsia (OR 0.50; 95% CI 0.42–0.60, I2 = 44%), placenta previa (OR 0.84, 95% CI 0.73–0.97, I2 = 0%), and postpartum hemorrhage (OR 0.43; 95% CI 0.38–0.48, I2 = 53%). Stratified analyses on LPS use in NC-FET suggested that, compared to AC-FET, NC-FET with LPS decreased preterm birth risk, while NC-FET without LPS did not (OR 0.75, 95% CI 0.70–0.81). LPS use did not modify the other outcomes. Heterogeneity varied from low to high, while quality of the evidence was very low to moderate. WIDER IMPLICATIONS This study confirms that NC-FET decreases the risk of adverse obstetric and neonatal outcomes compared with AC-FET. We estimate that for each adverse outcome, use of NC-FET may prevent 4 to 22 cases per 1000 women. Consequently, NC-FET should be the preferred treatment in women with ovulatory cycles undergoing FET. Based on very low quality of evidence, the risk of preterm birth be decreased when LPS is used in NC-FET compared to AC-FET. However, because of many uncertainties—the major being the debate about efficacy of the use of LPS—future research is needed on efficacy and safety of LPS and no recommendation can be made about the use of LPS.

中文翻译：

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自然周期冷冻胚胎移植与人工周期冷冻胚胎移植后的产科和新生儿结局以及黄体期支持的作用：系统评价和荟萃分析

背景技术冷冻胚胎移植（FET）的数量在过去十年中急剧增加。根据目前的证据，生育力低下的女性中，自然周期 FET (NC-FET) 与人工周期 FET (AC-FET) 的妊娠率没有差异。然而，与 AC-FET 周期相比，NC-FET 似乎与不良产科和新生儿结局的风险较低相关。目前，对于NC-FET是否需要与黄体期支持（LPS）相结合，尚未达成共识。如何为 FET 准备子宫内膜的问题现在变得更加重要，并考虑到安全性，因为它不应简单地简化为有效性的基本问题。目的和理由 该项目的目的是确定与 AC-FET 相比，有或没有 LPS 的 NC-FET 是否可以降低不良产科和新生儿结局的风险。检索方法进行了系统评价和荟萃分析。使用以下数据库进行文献检索：从开始到 2022 年 10 月 10 日的 CINAHL、EMBASE 和 MEDLINE。观察性研究，包括队列研究和登记比较 NC-FET 后和 AC-FET 后单胎妊娠的产科和新生儿结局被寻找。使用 ROBINS-I 工具评估偏倚风险。使用建议评估、制定和评估分级方法对证据质量进行了评估。我们使用随机效应模型计算了汇总比值比 (OR)、汇总风险差 (RD)、汇总调整 OR 和 95% CI 的患病率估计值，同时通过 I2 评估异质性。结果 进行的检索确定了 2436 项研究，删除了 890 项重复研究，筛选了 1546 项研究。纳入了 30 项研究（NC-FET n = 56 445；AC-FET n = 57 231），其中 19 项在 NC-FET 中使用了 LPS。NC-FET 与 AC-FET 相比，出生体重较低（平均差 26.35 g；95% CI 11.61–41.08，I2 = 63%）。此外，与 AC-FET 相比，NC-FET 导致大于胎龄（OR 0.88，95% 0.83–0.94，I2 = 54%）、巨大儿（OR 0.81；95% CI 0.71–0.93，I2 = 68）的风险较低%)、低出生体重（OR 0.81，95% CI 0.77–0.85，I2 = 41%）、早期妊娠流产（OR 0.73；95% CI 0.61–0.86，I2 = 70%）、早产（OR 0.80；95%） CI 0.75–0.85，I2 = 20%），极早产（OR 0.66，95% CI 0.53–0.84，I2 = 0%），妊娠高血压疾病（OR 0.60，95% CI 0.50–0.65，I2 = 61%） ）、先兆子痫（OR 0.50；95% CI 0.42–0.60，I2 = 44%）、前置胎盘（OR 0.84，95% CI 0.73–0.97，I2 = 0%）和产后出血（OR 0.43；95%） CI 0.38–0.48，I2 = 53%）。对 NC-FET 中 LPS 使用的分层分析表明，与 AC-FET 相比，含有 LPS 的 NC-FET 可以降低早产风险，而不含 LPS 的 NC-FET 则不会（OR 0.75，95% CI 0.70-0.81）。LPS 的使用不会改变其他结果。异质性从低到高不等，而证据质量从非常低到中等。更广泛的影响 这项研究证实，与 AC-FET 相比，NC-FET 可以降低不良产科和新生儿结局的风险。我们估计，对于每种不良后果，使用 NC-FET 可以预防每 1000 名女性 4 至 22 例。因此，对于有排卵周期并接受 FET 的女性来说，NC-FET 应该是首选治疗方法。基于非常低质量的证据，与 AC-FET 相比，在 NC-FET 中使用 LPS 时早产的风险会降低。然而，由于存在许多不确定性——主要是关于 LPS 使用功效的争论——未来需要对 LPS 的功效和安全性进行研究，并且不能对 LPS 的使用提出建议。