BACKGROUND In Europe, the number of frozen embryo transfer (FET) cycles is steadily increasing, now accounting for more than 190 000 cycles per year. It is standard clinical practice to postpone FET for at least one menstrual cycle following a failed fresh transfer or after a freeze-all cycle. The purpose of this practice is to minimise the possible residual negative effect of ovarian stimulation on the resumption of a normal ovulatory cycle and receptivity of the endometrium. Although elective deferral of FET may unnecessarily delay time to pregnancy, immediate FET may be inefficient in a clinical setting, following an increased risk of irregular ovulatory cycles and the presence of functional cysts, increasing the risk of cycle cancellation. OBJECTIVE AND RATIONALE This review explores the impact of timing of FET in the first cycle (immediate FET) versus the second or subsequent cycle (postponed FET) following a failed fresh transfer or a freeze-all cycle on live birth rate (LBR). Secondary endpoints were implantation, pregnancy and clinical pregnancy rates (CPR) as well as miscarriage rate (MR). SEARCH METHODS We searched PubMed (MEDLINE) and EMBASE databases for MeSH and Emtree terms, as well as text words related to timing of FET, up to March 2020, in English language. There were no limitations regarding year of publication or duration of follow-up. Inclusion criteria were subfertile women aged 18-46 years with any indication for treatment with IVF/ICSI. Studies on oocyte donation were excluded. All original studies were included, except for case reports, study protocols and abstracts only. Covidence, a Cochrane-tool, was used for sorting and screening of literature. Risk of bias was assessed using the Robins-I tool and the quality of evidence using the Grading of Recommendations, Assessment, Development and Evaluation framework. OUTCOMES Out of 4124 search results, 15 studies were included in the review. Studies reporting adjusted odds ratios (aOR) for LBR, CPR and MR were included in meta-analyses. All studies (n = 15) were retrospective cohort studies involving a total of 6,304 immediate FET cycles and 13,851 postponed FET cycles including 8,019 matched controls. Twelve studies of very low to moderate quality reported no difference in LBR with immediate versus postponed FET. Two studies of moderate quality reported a statistically significant increase in LBR with immediate FET and one small study of very low quality reported better LBR with postponed FET. Trends in rates of secondary outcomes followed trends in LBR regarding timing of FET. The meta-analyses showed a significant advantage of immediate FET (n =2,076) compared to postponed FET (n =3,833), with a pooled aOR of 1.20 (95% CI 1.01–1.44) for LBR and a pooled aOR of 1.22 (95% CI 1.07–1.39) for CPR. WIDER IMPLICATIONS The results of this review indicate a slightly higher LBR and CPR in immediate versus postponed FET. Thus, the standard clinical practice of postponing FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle may not be best clinical practice. However, as only retrospective cohort studies were assessed, the presence of selection bias is apparent, and the quality of evidence thus seems low. Randomised controlled trials including data on cancellation rates and reasons for cancellation are highly needed to provide high-grade evidence regarding clinical practice and patient counselling.
IntroductionDespite the high number of frozen embryo transfer (FET) cycles being conducted (190 000 cycles/year) in Europe, the timing of blastocyst transfer and the use of luteal phase progesterone support in modified natural cycle FET (mNC-FET) in assisted reproductive technologies are controversial. In mNC-FET, the timing of blastocyst warming and transfer is determined according to the time of implantation in a natural cycle, aiming to reach blastocyst endometrial synchronicity. However, the optimal day of blastocyst transfer following ovulation trigger is not determined. In addition, the value of luteal phase support to maintain the endometrium remains uncertain. Thus, there is a need to identify the optimal timing of blastocyst warming and transfer and the effect of luteal phase support in a randomised controlled trial design. The aim of this randomised controlled trial is to investigate if progesterone supplementation from the early luteal phase until gestational age 8 weeks is superior to no progesterone supplementation and to assess if blastocyst warming and transfer 6 days after ovulation trigger is superior to 7 days after ovulation trigger in mNC-FET with live birth rates as the primary outcome.Methods and analysisMulticentre, randomised, controlled, single-blinded trial including 604 normo-ovulatory women aged 18–41 years undergoing mNC-FET with a high-quality blastocyst originating from their first to third in vitro fertilisation/intracytoplasmic sperm injection cycle. Participants are randomised (1:1:1:1) to either luteal phase progesterone or no luteal phase progesterone and to blastocyst warming and transfer on day 6 or 7 after human chorionic gonadotropin trigger. Only single blastocyst transfers will be performed.Ethics and disseminationThe study is approved by the Danish Committee on Health Research Ethics (H-18025839), the Danish Medicines Agency (2018061319) and the Danish Data Protection Agency (VD-2018-381). The results of the study will be publicly disseminated.Trial registration numberThe study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.
Introduction Today, it is widespread practice to postpone frozen embryo transfer (FET) in a modified natural cycle (mNC) for at least one menstrual cycle after oocyte retrieval and failed fresh embryo transfer or freeze-all. The rationale behind this practice is the concern that suboptimal ovarian, endometrial or endocrinological conditions following ovarian stimulation may have a negative impact on endometrial receptivity and implantation. However, two recent systematic reviews and meta-analyses based on retrospective data did not support this practice. As unnecessary delay in time to transfer and pregnancy should be avoided, the aim of this study is to investigate if immediate single blastocyst transfer in mNC-FET is non-inferior to standard postponed single blastocyst transfer in mNC-FET in terms of live birth rate. Methods and analysis Multicentre randomised controlled non-blinded trial including 464 normo-ovulatory women aged 18–40 years undergoing single blastocyst mNC-FET after a failed fresh or freeze-all cycle. Participants are randomised 1:1 to either FET in the first menstrual cycle following the stimulated cycle (immediate FET) or FET in the second or subsequent cycle following the stimulated cycle (postponed FET). The study is designed as a non-inferiority trial and primary analyses will be performed as intention to treat and per protocol. Ethics and dissemination Ethical approval has been granted by the Scientific Ethical Committee of the Capital Region of Denmark (J-nr.: H-19086300). Data will be handled according to Danish law on personal data protection in accordance with the general data protection regulation. Participants will complete written consent forms regarding participation in the study and storage of blood samples in a biobank for future research. The study will be monitored by a Good Clinical Practice (GCP)-trained study nurse not otherwise involved in the study. The results of this study will be disseminated by publication in international peer-reviewed scientific journals. Trial registration number NCT04748874; Pre-results.
Study question Do women undergoing mNC-FET with progesterone supplementation experience mental health adverse effects at a greater rate compared to a control group. Summary answer Progesterone supplementation does not affect mental wellbeing in women undergoing mNC-FET. What is known already Women and men undergoing assisted reproductive treatment more likely to experience stress and other adverse psychological effects than the background population. Various factors such as parental age, cause of infertility and treatment method have been shown to affect patient well-being. Progesterone supplementation is known to cause various physical adverse effects, yet few studies have investigated the potential mental health adverse effects of progesterone supplementation in FET. Study design, size, duration This is a sub-study of an ongoing RCT investigating the effect of luteal phase progesterone supplementation in mNC-FET. The aim is to investigate possible mental health adverse effects of progesterone. From 2019–2021 a total of 164 women were included (n = 84 and n = 82 in the progesterone and control group, respectively). The health and wellbeing self-reporting survey was fulfilled after randomization on hCG trigger + 11 days. Participants/materials, setting, methods A validated, electronic questionnaire in Danish was used to measure mental wellbeing in women aged 18–41 years undergoing mNC-FET with and without use of progesterone supplementation in the luteal phase at seven Danish public hospitals. Women were randomized to either progesterone treatment or no progesterone by a computerized randomization algorithm with minimization for female age > =37 years, previous oocyte retrievals and previous FET. Comparisons of survey responses were performed by chi-square tests. Main results and the role of chance The survey response rate was 68%. We observed no significant differences in any of the three items between the progesterone group and the control group. On the first item “to which degree have you felt sensitive due to treatment”, 56% and 52% responded “to a large degree” or “to some degree” sensitive in the progesterone vs. control group, while 25% and 34% vs. 19% and 13% responded “to a lesser extent” or “not at all” sensitive in progesterone vs. controls (P = 0.35). On the second item, “to which degree have you felt aggressive due to treatment”, 10% and 9% responded “to a large degree” or “to some degree”, 29% and 22% answered “to a lesser degree” and 62% and 70% responded “not at all” in the progesterone vs control group (P = 0.57). On the third item “to which degree have you cried unexpectedly due to treatment” 25% and 18% responded “to a large degree” or “to some degree” in the progesterone vs control group, 20% and 27% answered “to a lesser extent”, while 55% in both groups answered “not at all” (P = 0.44). Limitations, reasons for caution In a self-reported survey selection bias, due to a less than 100% response rate, and reporting bias cannot be excluded. However with the possibility to answer the survey online at leisure, the risk of reporting bias is minimized. Wider implications of the findings: A large concern for clinicians working with ART is patient wellbeing. Our study suggests that luteal phase support does not cause extra emotional distress, though further research is needed. Trial registration number NCT03795220
Study question What is the serum progesterone level on blastocyst transfer day in mNC-FET and is the level related to the ongoing pregnancy rate? Summary answer One-quarter of all women had a progesterone level below 29.4 nmol/L on blastocyst transfer day, but the ongoing pregnancy rate was not compromised. What is known already It is widely recognized that a serum progesterone level above a certain threshold (30-35 nmol/L), at the time of blastocyst transfer improves ongoing pregnancy rates in artificial cycle FET (AC-FET). However, some studies have indicated that the progesterone level may also become too high. Similar results have been found in natural cycle FET; a recent retrospective study reported that low progesterone levels the day before blastocyst transfer was negatively associated with live birth. As for mNC-FET, data on optimal luteal phase progesterone levels are still missing. Study design, size, duration We present data from an ongoing multicentre, randomised, controlled, single-blinded trial planned to include 604 women undergoing mNC-FET with a single good-quality blastocyst. Women are randomised (1:1:1:1) to: 1) Luteal phase support (LPS) and transfer day 6 following hCG trigger 2) LPS and transfer day seven 3) No LPS and transfer day six 4) No LPS and transfer day seven Only women randomized to the groups not receiving LPS were included in this sub-study. Participants/materials, setting, methods The RCT is still ongoing and by the end of December 2021, 188 normo-ovulatory women aged 18-41 had been randomized to study groups 3) and 4). Of these, 170 had blood drawn on the day of blastocyst transfer and were included in this sub-study. All blastocysts transferred were derived from the patient’s oocytes and had a Gardner score ≥3BB at vitrification. No preimplantation genetic testing for aneuploidies was performed. Main results and the role of chance The study participants had the following characteristics: The median (IQR) age was 34 years (30-37), BMI 22.6 kg/m2 (21.0-25.8 kg/m2), cycle length 28 days (27-30 days), and serum AMH level 19 pmol/L (13-29 pmol/L). In mNC-FET without LPS, the median progesterone level on the day of transfer was 36.6 nmol/L, ranging from 9.6 to 91.8 nmol/L (except two outliers). The 25th, 10th, and 5th percentiles were 29.4, 22.0, and 17.7 nmol/L respectively, which means that 25% of the women had a progesterone level below 29.4 nmol/L. The pregnancy rate was 56.1% (23/41) among women with a progesterone level <29.4 nmol/L compared to 60.6% (77/127) among women with a progesterone level above 29.4 nmol/L (P = 0.715). The ongoing pregnancy rate below and above the lowest progesterone quartile was 41.5% (17/41) and 43.8% (53/121) respectively (P = 0.856). Multivariate logistic regression analyses showed no effect of progesterone level on ongoing pregnancy rate, neither in simple analysis nor when adjusting for age and BMI. Limitations, reasons for caution The serum progesterone level on the day of transfer in mNC-FET without LPS was not a primary endpoint of the RCT. Thus, the number of women included might be too small to draw firm conclusions on progesterone levels and ongoing pregnancy rate in mNC-FET. Wider implications of the findings Optimal serum progesterone levels on the day of blastocyst transfer in mNC-FET have yet to be determined and seem to differ substantially from levels in AC-FET. Ongoing pregnancy rates in mNC FET without LPS are good even with progesterone levels in the lowest quartile. Trial registration number 2018-002207-34
Study question Does ovarian morphology and length of the follicular phase differ between immediate and postponed mNC-FET cycles? Summary answer More cystic follicular residue after oocyte pick-up was observed at cycle day 2-5 in immediate vs postponed mNC-FET. The immediate follicular phase was longer. What is known already Whether the optimal timing for treatment with mNC-FET is in the cycle immediately following ovarian stimulation (OS) and oocyte pick-up, or in a subsequent cycle, has been much debated. Recent evidence suggests that reproductive outcomes after immediate vs postponed FET are comparable or even better in programmed-cycle FET. Due to concerns about suboptimal ovarian and endocrinological conditions in the natural cycle immediately following an OS/IVF cycle, postponed FET has become the standard treatment in most settings. However, studies describing attributes of the immediate NC-FET are lacking and little is known about cycle characteristics and ovarian morphology shortly after oocyte pick-up. Study design, size, duration The present descriptive sub-study is based on data from an ongoing Danish, multicentre, randomised controlled trial (RCT), investigating if mNC-FET can be performed in the cycle immediately following OS and oocyte pick-up, without compromising pregnancy and live birth rates. Participants were randomized 1:1 to mNC-FET in the immediate vs a subsequent cycle. The first 102 participants were included in the present sub-study. Data was collected between April 2021 and December 2022. Participants/materials, setting, methods Women with a regular menstrual cycle, aged 18-40 years, undergoing single blastocyst mNC-FET were eligible for inclusion. Ovarian morphology and cycle length were compared between immediate and postponed mNC-FET using Chi-squared test for categorical variables, and independent sample T-test or Mann Whitney U-test for continuous variables. Categorical variables were reported as numbers and percentages, continuous variables as mean and standard deviation or median and range. Main results and the role of chance Background characteristics including age, BMI, AMH and normal cycle length were similar for women in the immediate and postponed group, apart from a lower rate of elective freeze all-transfers (30.2% vs 55.1%, p = 0.011) in the OS cycle preceding FET, in the immediate vs the postponed group. The total number of cystic follicular structures (hypo- and non-hypodense) >10 mm (2 (range 0-11) vs 0 (range0-3), p = <0.001) were higher in the immediate vs the postponed group on cycle day (CD) 2-5 of the treatment cycle. On the day of hCG-trigger, there was no significant difference in the total number of cystic follicular structures between the groups, but a higher number of non-hypodense structures was found in the immediate group (p = 0.021). Endometrial thickness was greater in the immediate vs postponed group (8.6 vs 7.8 mm, p = 0.031) while the mean size of the dominant follicle was similar 17.1 vs 17.3 mm between groups (p = 0.410). The average day of hCG-trigger was CD15 (range 9-24) in the immediate group compared to CD12 (range 5-28) in the postponed group (p = 0.001). More ultrasound scans of follicular development were needed in the immediate vs postponed group (3 vs 2, p = 0.012). Limitations, reasons for caution The proportion of elective freeze-all in the OS cycle preceding FET differed between the immediate and postponed group which may bias the results. The sample size limits stratified analyses. Wider implications of the findings The findings of this study indicate that cystic follicular ovarian structures shortly after oocyte pick-up are commonly occurring. However, most of these structures seems to regress before the time of ovulation. The follicular phase was longer in immediate cycles, and whether this effects pregnancy outcomes is yet unknown. Trial registration number NCT04748874
Study question Can frozen embryo transfer (FET) be offered immediately after a stimulated IVF/ICSI cycle without compromising live birth rate (LBR)? Summary answer FET in the menstrual cycle immediately following the stimulated IVF/ICSI cycle was associated with a slightly higher LBR compared to standard postponed FET. What is known already It is standard clinical practice to postpone FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle. This practice is thought to minimize any possible residual negative effect of ovarian stimulation, with excessive steroid levels and multiple corpora lutea, on the resumption of a normal ovulatory cycle and receptivity of the endometrium. Even so, elective deferral of FET is an empirical strategy based on suggestions rather than solid scientific evidence and may unnecessarily delay time to pregnancy, causing frustration and decreased quality of life to couples. Study design, size, duration Systematic review and meta-analysis according to PRISMA guidelines. Original studies on subfertile women aged 18-46 with any indication for treatment with IVF/ICSI investigating the timing of FET after IVF/ICSI were included. Intervention was defined as FET in the menstrual cycle immediately following the stimulated IVF/ICSI cycle. Comparator was defined as FET in the second or subsequent menstrual cycle following IVF/ICSI. Risk of bias was assessed using Robins-I and quality of evidence using GRADE. Participants/materials, setting, methods PubMed (MEDLINE) and EMBASE databases were searched for MeSH and Emtree terms, as well as text words related to timing of FET, up to March 2020. There were no limitations regarding year of publication or duration of follow-up but to English language. The primary outcome was LBR. Secondary outcomes were implantation rate, pregnancy rate, clinical pregnancy rate (CPR), time-to-pregnancy, miscarriage rate (MR), cycle cancellation rate and patient wellbeing. Main results and the role of chance Out of 4124 search results, 15 studies were included in the review. Studies reporting adjusted odds ratios (aOR) for LBR, CPR and MR were included in meta-analyses. All studies (n = 15) were retrospective cohort studies involving a total of 6,304 immediate FET cycles and 13,851 postponed FET cycles including 8,019 matched controls. Twelve studies of very low to moderate quality reported no difference in LBR with immediate versus postponed FET. Two studies of moderate quality reported a statistically significant increase in LBR with immediate FET and one small study of very low quality reported better LBR with postponed FET. Trends in rates of secondary outcomes followed trends in LBR regarding timing of FET. The meta-analyses showed a significant advantage of immediate FET (n = 2,076) compared to postponed FET (n = 3,833), with a pooled aOR of 1.20 (95% CI 1.01-1.44) for LBR and a pooled aOR of 1.22 (95% CI 1.07-1.39) for CPR. Limitations, reasons for caution Limitations include the retrospective design and heterogeneity of studies included, limiting comparison and pooling of data. With little transparency regarding cancellation rates, the risk of selection bias is apparent. Further, confounding by embryo quality is a limitation. Small sample sizes are a limitation to subgroup meta-analyses. Wider implications of the findings The standard clinical practice of postponing FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle may not be best clinical practice. Randomized controlled trials including data on cancellation rates are highly needed to provide high grade evidence regarding clinical practice and patient counseling. Trial registration number not applicable
Study question Can frozen embryo transfer (FET) be offered immediately after a stimulated IVF/ICSI cycle without compromising live birth rate (LBR)? Summary answer FET in the menstrual cycle immediately following the stimulated IVF/ICSI cycle was associated with a slightly higher LBR compared to standard postponed FET. What is known already It is standard clinical practice to postpone FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle. This practice is thought to minimize any possible residual negative effect of ovarian stimulation, with excessive steroid levels and multiple corpora lutea, on the resumption of a normal ovulatory cycle and receptivity of the endometrium. Even so, elective deferral of FET is an empirical strategy based on suggestions rather than solid scientific evidence and may unnecessarily delay time to pregnancy, causing frustration and decreased quality of life to couples. Study design, size, duration Systematic review and meta-analysis according to PRISMA guidelines. Original studies on subfertile women aged 18–46 with any indication for treatment with IVF/ICSI investigating the timing of FET after IVF/ICSI were included. Intervention was defined as FET in the menstrual cycle immediately following the stimulated IVF/ICSI cycle. Comparator was defined as FET in the second or subsequent menstrual cycle following IVF/ICSI. Risk of bias was assessed using Robins-I and quality of evidence using GRADE. Participants/materials, setting, methods PubMed (MEDLINE) and EMBASE databases were searched for MeSH and Emtree terms, as well as text words related to timing of FET, up to March 2020. There were no limitations regarding year of publication or duration of follow-up but to English language. The primary outcome was LBR. Secondary outcomes were implantation rate, pregnancy rate, clinical pregnancy rate (CPR), time-to-pregnancy, miscarriage rate (MR), cycle cancellation rate and patient wellbeing. Main results and the role of chance Out of 4124 search results, 15 studies were included in the review. Studies reporting adjusted odds ratios (aOR) for LBR, CPR and MR were included in meta-analyses. All studies (n = 15) were retrospective cohort studies involving a total of 6,304 immediate FET cycles and 13,851 postponed FET cycles including 8,019 matched controls. Twelve studies of very low to moderate quality reported no difference in LBR with immediate versus postponed FET. Two studies of moderate quality reported a statistically significant increase in LBR with immediate FET and one small study of very low quality reported better LBR with postponed FET. Trends in rates of secondary outcomes followed trends in LBR regarding timing of FET. The meta-analyses showed a significant advantage of immediate FET (n = 2,076) compared to postponed FET (n = 3,833), with a pooled aOR of 1.20 (95% CI 1.01–1.44) for LBR and a pooled aOR of 1.22 (95% CI 1.07–1.39) for CPR. Limitations, reasons for caution: Limitations include the retrospective design and heterogeneity of studies included, limiting comparison and pooling of data. With little transparency regarding cancellation rates, the risk of selection bias is apparent. Further, confounding by embryo quality is a limitation. Small sample sizes are a limitation to subgroup meta-analyses. Wider implications of the findings: The standard clinical practice of postponing FET for at least one menstrual cycle following a failed fresh transfer or a freeze-all cycle may not be best clinical practice. Randomized controlled trials including data on cancellation rates are highly needed to provide high grade evidence regarding clinical practice and patient counseling. Trial registration number Not applicable
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