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Review
. 2025 Jun 3;6(6):CD003414.
doi: 10.1002/14651858.CD003414.pub4.

Cycle regimens for endometrial preparation prior to frozen embryo transfer

Tarek Ghobara  1 , Tarek A Gelbaya  2 , Reuben Olugbenga Ayeleke  3
Affiliations
Review

Cycle regimens for endometrial preparation prior to frozen embryo transfer

Tarek Ghobara et al. Cochrane Database Syst Rev. .

Abstract

Background: Frozen-thawed embryo transfer (FET) use increases the cumulative pregnancy rate, reduces cost and is relatively simple to undertake. FET is performed using different cycle regimens: spontaneous ovulatory (natural) cycles; cycles in which the endometrium is artificially prepared by oestrogen and progesterone hormones, commonly known as hormone therapy (HT) FET cycles; and cycles in which ovulation is induced by drugs (ovulation induction FET cycles). HT can be used with or without a gonadotrophin-releasing hormone agonist (GnRHa). This is an update of a Cochrane review; previous versions were published in 2008 and 2017.

Objectives: To compare the effectiveness and safety of natural cycle FET, HT cycle FET and ovulation induction cycle FET, and compare subtypes of these regimens.

Search methods: We used Cochrane Gynaecology and Fertility's Specialised Register, CENTRAL, MEDLINE, Embase, two other databases, four other electronic sources and two trials registers, together with reference checking, citation searching and contact with study authors to identify the studies included in the review. The latest search date was 19 December 2022.

Selection criteria: We included randomised controlled trials (RCTs) comparing the various cycle regimens and different methods used to prepare the endometrium during FET.

Data collection and analysis: We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and miscarriage rates.

Main results: We included 32 RCTs comparing different cycle regimens for FET in 6352 women. The certainty of the evidence was moderate to very low. The main limitations were failure to report important clinical outcomes, poor reporting of study methods and imprecision due to low event rates. Natural cycle FET comparisons Natural cycle FET versus HT FET We are uncertain of a difference in live birth rate (LBR) (odds ratio (OR) 1.18, 95% confidence interval (CI) 0.67 to 2.08; 1 study, 233 participants; low-certainty evidence), miscarriage rate (OR 0.10, 95% CI 0.01 to 1.90; 1 study, 233 participants; low-certainty evidence), ongoing pregnancy rate (OR 1.23, 95% CI 0.7 to 2.16; 1 study, 233 participants; low-certainty evidence) or multiple pregnancy rate (OR 1.26, 95% CI 0.58 to 2.75; 2 studies, 333 participants; very low-certainty evidence) between women in natural cycles and those in HT FET cycles. Natural cycle FET versus HT plus GnRHa suppression There is probably little or no difference in LBR (OR 0.89, 95% CI 0.58 to 1.36; 2 studies, 400 participants; moderate-certainty evidence) or multiple pregnancy rate (OR 1.23, 95% CI 0.60 to 2.51; 2 studies, 400 participants; moderate-certainty evidence) between women who had natural cycle FET and those who had HT FET cycles with GnRHa suppression. We are uncertain of a difference in miscarriage rate (OR 0.09, 95% CI 0.00 to 1.61; 1 study, 241 participants; low-certainty evidence) and ongoing pregnancy rate (OR 1.01, 95% CI 0.59 to 1.74; 1 study, 241 participants; low-certainty evidence). Natural cycle FET versus modified natural cycle FET (human chorionic gonadotrophin (HCG) trigger) We are uncertain of a difference in LBR (OR 0.97, 95% CI 0.65 to 1.45; 3 studies, 442 participants; low-certainty evidence) or multiple pregnancy rate (OR 1.14, 95% CI 0.52 to 2.52; 1 study, 237 participants; low-certainty evidence) between women in natural cycles and women in natural cycles with HCG trigger. There is probably little or no difference in ongoing pregnancy rate (OR 1.29, 95% CI 0.90 to 1.85; 3 studies, 653 participants; moderate-certainty evidence) or in miscarriage rate (OR 0.83, 95% CI 0.43 to 1.61; 4 studies, 798 participants; moderate-certainty evidence). Modified natural cycle FET comparisons Modified natural cycle FET (HCG trigger) versus HT FET We are uncertain of a difference in LBR (OR 1.26, 95% CI 0.90 to 1.77; 2 studies, 1189 participants; low-certainty evidence), ongoing pregnancy (OR 1.22, 95% CI 0.88 to 1.68; 3 studies, 1276 participants; low-certainty evidence), and multiple pregnancy rate (OR 1.05, 95% CI 0.46 to 2.42; 1 study, 230 participants; low-certainty evidence) between the two groups. We are uncertain whether the use of HT FET decreases miscarriage rate compared to modified natural cycle FET (OR 0.51, 95% CI 0.14 to 1.87; 2 studies, 317 participants; very low-certainty evidence). Modified natural cycle FET (HCG trigger) versus HT plus GnRHa suppression We are uncertain of a difference between the two groups in LBR (OR 1.06, 95% CI 0.77 to 1.47; 3 studies, 644 participants; low-certainty evidence), ongoing pregnancy rate (OR 1.03, 95% CI 0.68 to 1.55; 2 studies, 408 participants; low-certainty evidence), miscarriage rate (OR 0.71, 95% CI 0.31 to 1.63; 3 studies, 644 participants; low-certainty evidence) and multiple pregnancy rate (OR 1.39, 95% CI 0.58 to 3.30; 1 study, 238 participants; low-certainty evidence). HT FET comparisons HT FET versus HT plus GnRHa suppression We are uncertain of a difference between the two groups in LBR (OR 0.92, 95% CI 0.71 to 1.19; 5 studies, 1132 participants; moderate-certainty evidence), miscarriage rate (OR 0.85, 95% CI 0.59 to 1.22; 11 studies, 2036 participants; low-certainty evidence), ongoing pregnancy (OR 0.94, 95% CI 0.64 to 1.39; 4 studies, 640 participants; low-certainty evidence) and multiple pregnancy rate (OR 0.86, 95% CI 0.42 to 1.74; 2 studies, 422 participants; very low-certainty evidence).

Authors' conclusions: As the evidence was often of low certainty, and the confidence intervals were wide and therefore consistent with possible benefit and harm, we are uncertain whether one cycle regimen is more effective and safer than another in preparation for FET in subfertile women.

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Conflict of interest statement

Tarek Ghobara: no known conflict of interest Tarek A Gelbaya: no known conflict of interest Reuben Olugbenga Ayeleke: no known conflict of interest

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References

References to studies included in this review

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Macedo 2022 {published data only}
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Pabuccu 2022 {published data only}
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Palmerola 2017 {published data only}
    1. Palmerola KL, Hsu JY, Grossman LC, Sauer MV, Lobo RA. Repeated doses of GnRH antagonist at midcycle in artificial frozen embryo transfer cycles may not affect pregnancy outcomes. Gynecological Endocrinology 2017;33(4):301-5. [PMID: ] - PubMed
Pattinson 1992 {published data only}
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Petriglia 2021 {published data only}
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Pistoljevic 2021 {published data only}
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References to studies awaiting assessment

Aghahoseini 2020 {published data only}
    1. Aghahoseini M, Alyasin A, Rashidi S, Samaei-Nouroozi A, Saeidi H, Shabani-Nashtaei M. The efficacy of gonadotropin-releasing hormone (GNRH) agonist before frozen embryo transfer in improving pregnancy outcome and decreasing miscarriage rate in hyperandrogenic polycystic ovary syndrome women: a randomized clinical trial. Minerva Ginecologica 2020;72(4):212-8. [DOI: 10.23736/S0026-4784.20.044676] - DOI - PubMed
Eftekhar 2012 {published data only}
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References to ongoing studies

Latif 2021 {published data only}
    1. Latif S, Wattar BH, Balachandren N, Lukaszewski T, Saridogan E, Yasmin E, et al. Effectiveness of modified downregulation for women with moderate and severe adenomyosis of the uterus prior to frozen thawed embryo transfer (MODA) study protocol: a pragmatic randomised-controlled trial. BMJ Open 2021;11(10):e050248. [DOI: 10.1136/bmjopen-2021-050248] - DOI - PMC - PubMed
NCT01780610 {published data only}
    1. NCT01780610. The effects of two endometrium preparation protocols in frozen-thawed embryo transfer in women with irregular cycles. clinicaltrials.gov/ct2/show/NCT01780610 (first received 24 January 2013).
NCT02197208 {published data only}
    1. NCT02197208. A randomized controlled comparison of spontaneous natural cycles and human chorionic gonadotrophin-induced natural cycles in frozen-thawed embryos transfer. clinicaltrials.gov/ct2/show/NCT02197208 (first received 20 July 2014).
NCT02251925 {published data only}
    1. NCT02251925. Frozen embryo transfer in natural and hormonal replacement cycles. clinicaltrials.gov/ct2/show/NCT02251925 (first received 23 September 2014).
NCT02825108 {published data only}
    1. NCT02355925. Intrauterine injection of human chorionic gonadotropin injection (HCG) before frozen embryo transfer on cycle outcomes. clinicaltrials.gov/ct2/show/NCT02355925 (received 27 January 2015).
    1. NCT02825108. Evaluation the effect of intrauterine injection of human chorionic gonadotropin injection (HCG) before frozen embryo transfer on implantation and clinical pregnancy rates per cycle, phase 3 randomized double blinded clinical trial. clinicaltrials.gov/ct2/show/NCT02825108 (received 4 July 2016).
NCT02834117 {published data only}
    1. NCT02834117. Comparison of the number of visits and the quality of life versus natural cycle in stimulated cycle before frozen embryo transfer. clinicaltrials.gov/ct2/show/NCT02834117 (first received 3 September 2015).

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