【Cochrane简语概要】供卵受者或冷冻胚胎移植者的子宫内膜准备

系统综述问题

对于接受冷冻胚胎或来自供体卵母细胞的胚胎进行胚胎移植的女性，最有效的子宫内膜准备方法是什么？

（图片来自Medical bag）

研究背景

夫妻因男方因素、女方因素或不明原因不孕而接受相关治疗。在新鲜胚胎移植周期失败后，可以在有冷冻胚胎时进行冻融胚胎移植。子宫内膜的充分激素制备对于卵子捐赠者和冷冻胚胎更换周期而言至关重要，以提供最佳怀孕机会。一些研究者已经尝试了许多药物和各种给药方式，以优化植入率，从而提高胚胎移植程序的成功率：刺激周期（产生内源性雌二醇）、程序周期（使用外源性雌二醇）或自然周期（允许卵巢在没有刺激的情况下产生雌二醇）是一些选择；使用促性腺激素释放激素（gonadotropin-releasing hormone, GnRH）激动剂和拮抗剂避免自发排卵可能会产生一些影响；或使用其他一些可能增强子宫内膜容受性的药物，如阿司匹林或类固醇也进行了评估。

研究特征

我们发现31项随机对照试验比较了不同的干预措施，例如总共有5426名女性，雌激素和孕激素的剂量和给药途径、使用阻止患者过早排卵的药物（GnRH激动剂）以及使用其他药物改善子宫内膜。证据截至2020年6月。

主要结果

我们不确定刺激周期（用来曲唑）与程序周期相比，用于子宫内膜准备是否能改善活产。有证据表明，如果假设程序化周期后的活产几率为24%，那么刺激周期后的活产几率将在13%到51%之间。我们也不确定对流产率和子宫内膜厚度的影响。刺激周期可提高临床妊娠率。关于多胎妊娠、月经取消和其他不良反应的数据缺乏。

我们不确定自然周期与程序周期相比是否能提高活产率、妊娠率、流产率和子宫内膜厚度。缺乏其他所有结局的数据。

我们不确定经皮给药（经皮肤给药）雌激素与口服（经口给药）雌激素相比是否能提高临床妊娠率和流产率。在此比较中，缺乏所有其他结局的数据。

在供体取卵当天或取卵后的第二天开始注射孕激素，可能会增加临床妊娠率并可能降低取消诱导排卵率。我们不确定它是否能降低流产率。缺乏其他所有结局的数据。

与不使用GnRH激动剂相比，使用GnRH激动剂的周期可提高活产率。我们不确定GnRH周期与无GnRH周期对临床妊娠率、流产率和子宫内膜厚度的影响。在此比较中，没有研究报告其他结局。

我们不确定是否有任何GnRH激动剂比其他药物更好：每天服用亮丙瑞林或沉积色氨酸可提高临床妊娠率，或者每天服用醋酸亮丙瑞林或每日服用那法瑞林可降低流产率。没有研究报告其他结局。

与激动剂相比，GnRH拮抗剂可能提高临床妊娠率。对流产率和多胎妊娠率的影响尚不确定。没有研究报告其他结局。

我们不确定服用阿司匹林的周期与不服用阿司匹林的周期相比，是否能改善活产、临床妊娠率或子宫内膜厚度。缺乏其他所有结局的数据。

我们也不确定使用类固醇的周期与不使用类固醇的周期相比，是否能提高活产率、临床妊娠率或流产率。没有研究报告其他结局。

证据质量

证据质量为中等到极低。证据的主要局限性是研究方法报告不佳，以及活产结果缺乏精确性。

作者结论: 

在接受新鲜供体周期和冷冻胚胎移植的妇女中，使用任何特殊干预子宫内膜准备的证据不足。在冷冻胚胎移植中，低质量的证据表明，与程序周期相比，刺激周期的临床妊娠率可能会提高，我们不确定将程序周期与自然周期进行比较的效果。在自然周期中，取消诱导排卵率可能会降低。虽然与不使用GnRH激动剂相比，使用GnRH激动剂可能会提高活产率，但在GnRH拮抗剂周期和激动剂周期中，临床妊娠率可能会提高。

在新鲜的同步卵母细胞供体周期中，当在供体卵母细胞取出后的第一天或第一天开始注射孕激素时，临床妊娠率可能会提高，取消诱导排卵率可能会降低。

需要充分有力的研究来更准确地评估每一种治疗方法。

作者:Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A；译者：赵志慧，武汉大学；审校：靳英辉，武汉大学中南医院循证与转化医学中心；编辑排版：索于思，北京中医药大学循证医学中心

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【Cochrane Plain Language Summary】

Endometrial preparation for egg donor recipients or for frozen embryo transfers

Review question

What is the most effective method for endometrial preparation in women undergoing embryo transfers with frozen embryos or embryos derived from donor oocytes?

Background

Couples undergo infertility treatments due to male factor, female factors or unexplained infertility. After an unsuccessful fresh embryo transfer cycle, a frozen-thawed embryo transfer can be performed when frozen embryos are available. Adequate hormonal preparation of the endometrium is of utmost importance for both egg donor and frozen embryo replacement cycles to provide the optimal chances of pregnancy. Many drugs and various modes of administration have been tried by several investigators in order to optimise implantation rates and consequently improve the success rates of the embryo transfer procedures: stimulated cycles (to generate endogenous oestradiol), programmed cycles (administering exogenous oestradiol) or natural cycles (allowing the ovaries to produce oestradiol without stimulation) are some of the options; avoiding spontaneous ovulation with gonadotropin-releasing hormone (GnRH) agonists and antagonists could have some impact; or using some other drugs such as aspirin or steroids that could potentially enhance the endometrial receptivity were also evaluated.

Study characteristics

We found 31 randomised controlled trials comparing different interventions such as the dose and route of administration of oestrogens and progestogen, the use of drugs that stop the patient from ovulating prematurely (GnRH agonists), and the use of other medications to improve the endometrium in a total of 5426 women. The evidence is current to June 2020.

Key results

We are uncertain whether a stimulated cycle (with letrozole) compared to a programmed cycle, for endometrial preparation, improves live birth. The evidence suggests that if the chance of live birth following a programmed cycle is assumed to be 24%, the chance following a stimulated cycle would be between 13% and 51%. We are also uncertain of the impact on miscarriage rate and endometrial thickness. A stimulated cycle may improve clinical pregnancy rate. Data were lacking on multiple pregnancy, cycle cancellation and other adverse effects.

We are uncertain whether a natural cycle improves the live birth rate, pregnancy rate, miscarriage rate and endometrial thickness in comparison with a programmed cycle. Data were lacking for all other outcomes.

We are uncertain if transdermal (delivered via the skin) oestrogens compared with oral (by mouth) oestrogens improve clinical pregnancy rate and miscarriage rate. Data were lacking for all other outcomes in this comparison.

Starting progestogen on the day of the donor oocyte retrieval or the day after probably increases the clinical pregnancy rate and probably reduces the cycle cancellation rate. We are uncertain if it reduces the miscarriage rate. Data were lacking for all other outcomes.

A cycle with GnRH agonist compared to without may improve live birth rate. We are uncertain of the effect of a GnRH cycle compared to no GnRH for the outcomes of clinical pregnancy rate, miscarriage rate, and endometrial thickness. No study reported on the other outcomes for this comparison.

We are uncertain if any GnRH agonist is better than other: a cycle with daily leuprolide or with deposit tryptorelin improves clinical pregnancy rate, or if daily acetate leuprolide or daily nafarelin reduces the miscarriage rate. Other outcomes were not reported.

GnRH antagonists compared to agonists probably improve clinical pregnancy rate. We are uncertain of the effect on miscarriage rate and multiple pregnancy rate. No study reported the other outcomes.

We are uncertain whether a cycle with aspirin compared to a cycle without improves live birth, clinical pregnancy rate or endometrial thickness. Data were lacking for all other outcomes.

We are also uncertain whether a cycle with steroids compared to a cycle without steroids improves live birth rate, clinical pregnancy rate or miscarriage rate. No study reported on the other outcomes.

Quality of the evidence

The evidence was of moderate to very low-quality. The main limitations in the evidence were poor reporting of study methods, and lack of precision in the findings for live birth.

Authors' conclusions: 

There is insufficient evidence on the use of any particular intervention for endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers. In frozen embryo transfers, low-quality evidence showed that clinical pregnancy rates may be improved in a stimulated cycle compared to a programmed one, and we are uncertain of the effect when comparing a programmed cycle to a natural cycle. Cycle cancellation rates are probably reduced in a natural cycle. Although administering a GnRH agonist, compared to without, may improve live birth rates, clinical pregnancy rates will probably be improved in a GnRH antagonist cycle over an agonist cycle.

In fresh synchronised oocyte donor cycles, the clinical pregnancy rate is probably improved and cycle cancellation rates are probably reduced when starting progestogen the day of or day after donor oocyte retrieval.

Adequately powered studies are needed to evaluate each treatment more accurately.

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