Glujovsky Demián, Pesce Romina, Sueldo Carlos, Quinteiro Retamar Andrea Marta, Hart Roger J, Ciapponi Agustín
Reproductive Medicine, CEGYR (Centro de Estudios en Genética y Reproducción), Buenos Aires, Argentina.
Reproductive Medicine, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina.
Cochrane Database Syst Rev. 2020 Oct 28;10(10):CD006359. doi: 10.1002/14651858.CD006359.pub3.
A frozen embryo transfer (FET) cycle is when one or more embryos (frozen during a previous treatment cycle) are thawed and transferred to the uterus. Some women undergo fresh embryo transfer (ET) cycles with embryos derived from donated oocytes. In both situations, the endometrium is primed with oestrogen and progestogen in different doses and routes of administration.
To evaluate the most effective endometrial preparation for women undergoing transfer with frozen embryos or embryos from donor oocytes with regard to the subsequent live birth rate (LBR).
The Cochrane Gynaecology and Fertility Group trials register, CENTRAL, MEDLINE, Embase, PsycINFO, LILACS, trials registers and abstracts of reproductive societies' meetings were searched in June 2020 together with reference checking and contact with study authors and experts in the field to identify additional studies.
Randomised controlled trials (RCTs) evaluating endometrial preparation in women undergoing fresh donor cycles and frozen embryo transfers.
We used standard methodological procedures recommended by Cochrane. We analysed all available interventions versus placebo, no treatment, or between each other. The primary review outcome was live birth rate. Secondary outcomes were clinical and multiple pregnancy, miscarriage, cycle cancellation, endometrial thickness and adverse effects.
Thirty-one RCTs (5426 women) were included. Evidence was moderate to very low-quality: the main limitations were serious risk of bias due to poor reporting of methods, and serious imprecision. Stimulated versus programmed cycle We are uncertain whether a letrozole-stimulated cycle compared to a programmed cycle, for endometrial preparation, improves LBR (odds ratio (OR) 1.26, 95% confidence interval (CI) 0.49 to 3.26; 100 participants; one study; very low-quality evidence). Stimulating with follicle stimulating hormone (FSH), letrozole or clomiphene citrate may improve clinical pregnancy rate (CPR) (OR 1.63, 95% CI 1.12 to 2.38; 656 participants; five studies; I = 11%; low-quality evidence). We are uncertain if they reduce miscarriage rate (MR) (OR 0.79, 95% CI 0.36 to 1.71; 355 participants; three studies; I = 0%; very low-quality evidence). Endometrial thickness (ET) may be reduced with clomiphene citrate (mean difference(MD) -1.04, 95% CI -1.59 to -0.49; 92 participants; one study; low-quality evidence). Other outcomes were not reported. Natural versus programmed cycle We are uncertain of the effect from a natural versus programmed cycle for LBR (OR 0.97, 95% CI 0.74 to 1.28; 1285 participants; four studies; I = 0%; very low-quality evidence) and CPR (OR 0.79, 95% CI 0.62 to 1.01; 1249 participants; five studies; I = 60%; very low-quality evidence), while a natural cycle probably reduces the cycle cancellation rate (CCR) (OR 0.60, 95% CI 0.44 to 0.82; 734 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and ET. No study reported other outcomes. Transdermal versus oral oestrogens From low-quality evidence we are uncertain of the effect transdermal compared to oral oestrogens has on CPR (OR 0.86, 95% CI 0.59 to 1.25; 504 participants; three studies; I = 58%) or MR (OR 0.55, 95% CI 0.27 to 1.09; 414 participants; two studies; I = 0%). Other outcomes were not reported. Day of starting administration of progestogen When doing a fresh ET using donated oocytes in a synchronised cycle starting progestogen on the day of oocyte pick-up (OPU) or the day after OPU, in comparison with recipients that start progestogen the day prior to OPU, probably increases the CPR (OR 1.87, 95% CI 1.13 to 3.08; 282 participants; one study, moderate-quality evidence). We are uncertain of the effect on multiple pregnancy rate (MPR) or MR. It probably reduces the CCR (OR 0.28, 95% CI 0.11 to 0.74; 282 participants; one study; moderate-quality evidence). No study reported other outcomes. Gonadotropin-releasing hormone (GnRH) agonist versus control A cycle with GnRH agonist compared to without may improve LBR (OR 2.62, 95% CI 1.19 to 5.78; 234 participants; one study; low-quality evidence). From low-quality evidence we are uncertain of the effect on CPR (OR 1.08, 95% CI 0.82 to 1.43; 1289 participants; eight studies; I = 20%), MR (OR 0.85, 95% CI 0.36 to 2.00; 828 participants; four studies; I = 0%), CCR (OR 0.49, 95% CI 0.21 to 1.17; 530 participants; two studies; I = 0%) and ET (MD -0.08, 95% CI -0.33 to 0.16; 697 participants; four studies; I = 4%). No study reported other outcomes. Among different GnRH agonists From very low-quality evidence we are uncertain if cycles among different GnRH agonists improves CPR or MR. No study reported other outcomes. GnRH agonists versus GnRH antagonists GnRH antagonists compared to agonists probably improves CPR (OR 0.62, 95% CI 0.42 to 0.90; 473 participants; one study; moderate-quality evidence). We are uncertain of the effect on MR and MPR. No study reported other outcomes. Aspirin versus control From very low-quality evidence we are uncertain whether a cycle with aspirin versus without improves LBR, CPR, or ET. Steroids versus control From very low-quality evidence we are uncertain whether a cycle with steroids compared to without improves LBR, CPR or MR. No study reported other outcomes.
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.
冷冻胚胎移植（FET）周期是指将一个或多个（在前一治疗周期中冷冻的）胚胎解冻后移植到子宫内。一些女性会进行新鲜胚胎移植（ET）周期，使用来自捐赠卵母细胞的胚胎。在这两种情况下，子宫内膜都要用不同剂量和给药途径的雌激素和孕激素进行预处理。
评估对于接受冷冻胚胎或来自捐赠卵母细胞的胚胎移植的女性，哪种子宫内膜预处理方法对随后的活产率（LBR）最有效。
2020年6月检索了Cochrane妇科与生育组试验注册库、CENTRAL、MEDLINE、Embase、PsycINFO、LILACS、试验注册库以及生殖协会会议的摘要，并进行参考文献核对，与研究作者和该领域专家联系以识别其他研究。
评估接受新鲜供体周期和冷冻胚胎移植的女性子宫内膜预处理的随机对照试验（RCT）。
我们采用了Cochrane推荐的标准方法程序。我们分析了所有可用的干预措施与安慰剂、不治疗或相互之间的比较。主要综述结果是活产率。次要结果包括临床妊娠和多胎妊娠、流产、周期取消、子宫内膜厚度和不良反应。
纳入了31项RCT（5426名女性）。证据质量为中等至非常低：主要局限性是由于方法报告不佳导致严重的偏倚风险，以及严重的不精确性。刺激周期与程序化周期 我们不确定与程序化周期相比，来曲唑刺激周期用于子宫内膜预处理是否能提高活产率（优势比（OR）1.26，95%置信区间（CI）0.49至3.26；100名参与者；1项研究；非常低质量的证据）。用促卵泡激素（FSH）、来曲唑或枸橼酸氯米芬刺激可能会提高临床妊娠率（CPR）（OR 1.63，95%CI 1.12至2.38；656名参与者；5项研究；I = 11%；低质量的证据）。我们不确定它们是否会降低流产率（MR）（OR 0.79，95%CI 0.36至1.71；355名参与者；3项研究；I = 0%；非常低质量的证据）。枸橼酸氯米芬可能会降低子宫内膜厚度（ET）（平均差（MD） -1.04，95%CI -1.59至 -0.49；92名参与者；1项研究；低质量的证据）。未报告其他结果。自然周期与程序化周期 我们不确定自然周期与程序化周期对活产率（OR 0.97，95%CI 0.74至1.28；1285名参与者；4项研究；I = 0%；非常低质量的证据）和临床妊娠率（OR 0.79，95%CI 0.62至1.01；1249名参与者；5项研究；I = 60%；非常低质量的证据）的影响，而自然周期可能会降低周期取消率（CCR）（OR 0.60，95%CI 0.44至0.82；734名参与者；1项研究；中等质量的证据）。我们不确定对流产率和子宫内膜厚度的影响。没有研究报告其他结果。经皮雌激素与口服雌激素 从低质量证据来看，我们不确定经皮雌激素与口服雌激素相比对临床妊娠率（OR 0.86，95%CI 0.59至1.25；504名参与者；3项研究；I = 58%）或流产率（OR 0.55，95%CI 0.27至1.09；414名参与者；2项研究；I = 0%）的影响。未报告其他结果。孕激素开始给药日 在同步周期中使用捐赠卵母细胞进行新鲜胚胎移植时，在取卵日（OPU）或取卵后一天开始使用孕激素，与在取卵前一天开始使用孕激素的受者相比，可能会提高临床妊娠率（OR 1.87，95%CI 1.13至3.08；282名参与者；1项研究，中等质量的证据）。我们不确定对多胎妊娠率（MPR）或流产率的影响。它可能会降低周期取消率（OR 0.28，95%CI 0.11至0.74；282名参与者；1项研究；中等质量的证据）。没有研究报告其他结果。促性腺激素释放激素（GnRH）激动剂与对照 与不使用GnRH激动剂的周期相比，使用GnRH激动剂的周期可能会提高活产率（OR 2.62，95%CI 1.19至5.78；234名参与者；1项研究；低质量的证据）。从低质量证据来看，我们不确定对临床妊娠率（OR 1.08，95%CI 0.82至1.43；1289名参与者；8项研究；I = 20%）、流产率（OR 0.85，95%CI 0.36至2.00；828名参与者；4项研究；I = 0%）、周期取消率（OR 0.49，95%CI 0.21至1.17；530名参与者；2项研究；I = 0%）和子宫内膜厚度（MD -0.08，95%CI -0.33至0.16；697名参与者；4项研究；I = 4%）的影响。没有研究报告其他结果。在不同的GnRH激动剂之间 从非常低质量证据来看，我们不确定不同GnRH激动剂之间的周期是否能提高临床妊娠率或流产率。没有研究报告其他结果。GnRH激动剂与GnRH拮抗剂 GnRH拮抗剂与激动剂相比可能会提高临床妊娠率（OR 0.62，95%CI 0.42至0.90；473名参与者；1项研究；中等质量的证据）。我们不确定对流产率和多胎妊娠率的影响。没有研究报告其他结果。阿司匹林与对照 从非常低质量证据来看，我们不确定使用阿司匹林与不使用阿司匹林的周期对活产率、临床妊娠率或子宫内膜厚度的影响。类固醇与对照 从非常低质量证据来看，我们不确定使用类固醇与不使用类固醇的周期对活产率、临床妊娠率或流产率的影响。没有研究报告其他结果。
对于接受新鲜供体周期和冷冻胚胎移植的女性，使用任何特定干预措施进行子宫内膜预处理的证据都不足。在冷冻胚胎移植中，低质量证据表明与程序化周期相比，刺激周期可能会提高临床妊娠率，而我们不确定将程序化周期与自然周期进行比较时的效果。自然周期可能会降低周期取消率。虽然与不使用相比，使用GnRH激动剂可能会提高活产率，但GnRH拮抗剂周期可能比激动剂周期更能提高临床妊娠率。在新鲜同步卵母细胞供体周期中，在供体卵母细胞取出当天或取出后一天开始使用孕激素，可能会提高临床妊娠率并降低周期取消率。需要有足够样本量的研究来更准确地评估每种治疗方法。
