Cycle regimens for endometrial preparation prior to frozen embryo transfer

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.