Key messages
• We did not find sufficient evidence to support the use of one cycle regimen (approach) over another in preparation for frozen-thawed embryo transfer (FET) in women with regular ovulatory cycles who have difficulty getting pregnant (subfertile women).
• Larger, well-conducted studies are needed, particularly those that investigate the simpler or cheaper frozen-thawed embryo transfer approaches.
What is frozen-thawed embryo transfer (FET)?
In subfertile women undergoing assisted reproductive technology, eggs are collected from the ovaries and fertilised by sperm in a laboratory (in vitro fertilisation or IVF). Some or all embryos may be frozen, and are thawed and transferred to the womb at a later stage. This is called frozen-thawed embryo transfer (FET).
Women with regular spontaneous periods (menstrual cycles) may be offered a range of cycle regimens to prepare the womb lining (the endometrium) for FET. Alternatively, FET can be carried out after spontaneous ovulation (release of an egg) in a natural cycle. This is called natural cycle FET.
Women with irregular cycles are either not ovulating or are ovulating randomly. Therefore, natural cycle FET is not suitable for them. These women can be offered either ovulation induction with fertility drugs or hormone therapy (HT) to prepare them for FET.
The most common regimens for FET are natural cycle with or without HCG (human chorionic gonadrotophin) to trigger ovulation, or endometrial preparation with HT with or without a gonadotrophin-releasing hormone agonist (GnRHa) to temporarily suppress ovarian function.
What did we want to find out?
We conducted this review to find out if a particular FET regimen is more effective or safer than others. Our main outcomes were live birth rates and miscarriage rates per woman.
What did we do?
We searched for studies that compared one type of cycle regimen with another in subfertile women (including women with regular ovulation, irregular or random ovulation, or no ovulation). We compared and summarised the results of the studies and rated our confidence in the evidence, based on factors such as study methods and sizes.
What did we find?
We included 32 studies involving 6352 women. Most of the studies included women with regular ovulatory cycles. They provided little to no information about women with irregular or no ovulation cycles. The studies were conducted in Iran (11 studies), Belgium (four studies), Italy (three studies), plus two studies each in China, France, Israel, Turkey, and the UK; and one study each in Egypt, Singapore, Spain and the Netherlands.
Main results
This review did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for FET in subfertile women with regular ovulatory cycles. The most common approaches for FET are natural cycle with or without HCG to trigger ovulation or endometrial preparation with HT, with or without GnRHa suppression. We identified six direct comparisons of these two approaches, and there was insufficient evidence to support the use of one over the other.
What are the limitations of the evidence?
We have little confidence in the evidence because the included studies were small with few results reported.
How current is this evidence?
The evidence is current to 19 December 2022.
Read the full abstract
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 strategy
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.
