Marte Saupstad

Objective: Infertility is a major health issue, and fertility treatments, including frozen embryo transfer (FET), are common. Progesterone, essential for endometrium development and receptivity, is used to improve implantation rates. This study investigates the effect of luteal phase support with progesterone on thyroid function in modified natural FET cycles. Methods: This is a sub-study of a randomized controlled trial (FET optimizing trial). Data were collected at two fertility centers from January 2019 to October 2022. Euthyroid women receiving single frozen–thawed embryo transfer in a modified natural cycle were included. The study participants were categorized into two groups: the luteal phase support (LPS) and the no LPS groups. The LPS group received vaginal progesterone 100 mg three times daily starting at day 4 after ovulation trigger with human chorionic gonadotropin (day 0). A pregnancy test was performed on day 16. Thyroid function was repeatedly measured. Linear mixed modeling was used to test the effect of progesterone on thyrotropin (TSH, primary outcome) and free thyroxine (fT4). Interaction with thyroid autoimmunity was tested. Results: In total, 85 women were included: 45 received progesterone LPS and 40 did not. Participants were 34 ± 4 years of age and had a BMI of 23 (IQR: 21; 26), and 25% were positive for thyroid autoimmunity. Serum progesterone increased with LPS, but TSH and fT4 levels were not affected by LPS. There was no interaction with thyroid autoimmunity. In the progesterone LPS group, 44% conceived compared with 55% in the no LPS group, P = 0.33. Conclusion: Progesterone LPS does not affect thyroid function during the luteal phase. Trial registration number: This trial was registered with ClinicalTrials.gov (NCT03795220) and EudraCT (2018-002207-34) and was completed.

Do ovarian and reproductive hormone characteristics and risk of cycle cancellation differ between immediate and postponed modified natural cycle (mNC) frozen embryo transfer (FET) cycles? Ovarian morphology, early follicular phase levels of progesterone and LH, and follicular phase length differed significantly between immediate and postponed mNC-FET. Cancellation rates differed numerically. The optimal timing of mNC-FET following ovarian stimulation and oocyte retrieval is heavily debated. Concerns about suboptimal ovarian and hormonal conditions in the NC immediately following ovarian stimulation have led to the widespread practice of postponing FET for at least 1 month. However, emerging evidence suggests that reproductive outcomes in immediate programmed FET cycles are comparable, or even superior, to those achieved in postponed cycles. Studies of the NC immediately following ovarian stimulation and oocyte retrieval are lacking, leaving a limited understanding of its functionality, cycle characteristics, hormonal profiles, and ovarian morphology. This descriptive study is based on data from a recently completed Danish multicentre randomised controlled non-inferiority trial (RCT) evaluating the optimal timing of FET following ovarian stimulation and oocyte retrieval. Women were randomised 1:1 to mNC-FET in the cycle immediately following ovarian stimulation and oocyte retrieval, or after a 1-month delay. Data from 468 women, collected from March 2021 to May 2025, were included in this study. Women with a regular menstrual cycle, aged 18–40 years, and undergoing autologous single blastocyst mNC-FET were eligible for inclusion. The presence of cystic intraovarian structures > 10 mm and plasma levels of FSH, LH, estradiol, and progesterone from cycle initiation to blastocyst transfer were assessed, as were the length of the follicular phase and cancellation rates between groups. The number of cystic ovarian structures was significantly higher in the immediate group than in the postponed group on Days 2–5 of the treatment cycle (median, 3 [IQR, 1–6] vs 0 [IQR, 0–1]; P < 0.001) as well as on the day of ovulation trigger (median, 1 [IQR, 0–2] vs 0 [IQR, 0–1]; P < 0.001). In the early follicular phase, plasma progesterone levels were higher (median, 1.2 [IQR, 0.7–1.7] vs 0.8 [IQR, 0.6–1.5] nmol/L; P < 0.001) in the immediate compared to postponed cycles, and plasma LH levels were lower (median, 4.1 [IQR, 2.7–6.1] vs 5.9 [IQR, 4.7–7.5] IU/L; P < 0.001), as were FSH levels (median, 6.6 [IQR, 5.0–8.2] vs 6.9 [IQR, 5.9–7.9] IU/L; P = 0.047). The time to ovulation trigger was longer in the immediate than in the postponed group (mean, 15.0 [SD, 3.9] vs 13.0 [SD, 3.0] days; P < 0.001): an effect driven by freeze-all cycles. As a natural consequence of the increased time to ovulation trigger, more follicular scans were performed in the immediate group (median, 3 [IQR, 2–3] vs 2 [IQR, 1–3]; P < 0.001). Cycle cancellation was more frequent in immediate cycles, however, the difference was not statistically significant (10.3% vs 6.2%; P = 0.078). The main endpoints of this study were specified in the study protocol of the RCT, but some post hoc analyses were performed to explore unexpected findings. Due to variations in clinical practice, data were subjected to multiple subdivisions. No power calculations were performed for the reported endpoints. The follicular phase of immediate cycles seems to differ from postponed cycles in terms of ovarian morphology, follicular phase length, and early follicular phase levels of progesterone and LH. The rate of cycle cancellation raises concerns about the clinical feasibility of immediate FET treatment in NCs. The RCT is supported by Rigshospitalet’s Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. M.S. benefitted from a grant from Gedeon Richter and received support for meeting attendance from the same. M.S. received payment for lectures from IBSA and Gedeon Richter. J.W.B. received support from meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. N.C.F. received consulting fees and honoraria for a presentation from Merck A/S and Ferring Pharmaceuticals and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. B.O.-M. received support for meeting attendance from Gedeon Richter and Ferring Pharmaceuticals and participate on a board for Ferring Pharmaceuticals. B.N. benefitted from grants from Merck A/S and Gedeon Richter. B.N. received support for meeting attendance from Gedeon Richter and participate on a board for Ferring Pharmaceuticals. E.L. received honoraria from Pfizer and Gedeon Richter, and support for meeting attendance from Gedeon Richter, Merck A/S, and Astellas. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, and Merck A/S as payment to the institution. A.P. received consulting fees from Ferring Pharmaceuticals, Gedeon Richter, and Merck A/S, and honoraria from Ferring Pharmaceuticals, Gedeon Richter, Abbott, and Merck A/S. K.L. received a grant from Gedeon Richter as payment to the institution. K.L. received consulting fees and honoraria from Ferring Pharmaceuticals and support for attending meetings from Ferring Pharmaceuticals, Gedeon Richter, and Merck A/S. A.S.J., T.V.D., I.B.-M., M.H., and N.S. declare no conflicts of interest. The study is registered at ClinicalTrials.gov: NCT04748874.

STUDY QUESTION: Can use of progesterone luteal phase support (LPS) and timing of blastocyst transfer, at 6 versus 7 days following hCG-trigger, improve the live birth rate (LBR) in modified natural cycle (mNC) frozen-thawed embryo transfer (FET)? SUMMARY ANSWER: Use of LPS and advanced timing of blastocyst transfer did not significantly improve the LBR in mNC-FET. WHAT IS KNOWN ALREADY: Transfer of a frozen-thawed blastocyst in the mNC protocol is routinely conducted 7 days after the ovulation trigger, and progesterone LPS is commonly used despite limited evidence. STUDY DESIGN, SIZE, DURATION: This multicentre, single-blinded, randomised controlled superiority trial investigated the effect of LPS and timing of blastocyst transfer on live birth rates following mNC-FET conducted from January 2019 to February 2024. Using an online randomisation programme, patients were randomised 1:1:1:1 to: (A) transfer day 6 following ovulation trigger (day 0) with LPS; (B) transfer day 7 with LPS; (C) transfer day 6 without LPS; (D) transfer day 7 without LPS. Use of LPS was masked to treating clinicians. The sample size calculation required 604 women to participate to detect an increase in live birth rate from 21% in control groups (LPS: C + D, Timing: B + D) to 31% in intervention groups (LPS: A + B, Timing: A + C). In total, 679 women were enrolled, and 610 women were randomised. Ultimately, 602 women (A: n = 151; B: n = 150; C: n = 149; D: n = 152) were included in the per-transfer analyses. PARTICIPANTS/MATERIALS, SETTING, METHODS: Participants were women aged 18–41 years undergoing mNC-FET with a single autologous good-quality blastocyst, from eight public fertility clinics at tertiary care centres across Denmark. MAIN RESULTS AND THE ROLE OF CHANCE: Our study found that use of LPS did not significantly affect the LBR compared with no LPS: 34.9% (105/301) versus 31.9% (96/301) (adjusted risk difference (aRD) 3.18, 95% CI: −4.13 to 10.49; p = 0.39). Comparing blastocyst transfer on day 6 versus day 7, there was again no significant difference in LBR: 33.8% (99/300) versus 33.0% (99/302) (aRD −0.62, 95% CI: −7.99 to 6.75; p = 0.87). LIMITATIONS, REASONS FOR CAUTION: The sample size calculation was based on LBRs of studies using transfer of slow-frozen and cleavage stage embryos, but today’s LBRs are higher. Consequently, the sample size might not have been sufficient to detect discrete differences in reproductive outcomes under present conditions. Further, despite using liberal inclusion criteria, most women participating were young (≤35 years) and lean, and had a good quality embryo available for transfer, giving them an a priori good treatment prognosis. Hence, our findings might not apply to all women undergoing mNC-FET. WIDER IMPLICATIONS OF THE FINDINGS: This RCT demonstrates that supplementary progesterone likely does not improve live birth rates, and that flexibility in scheduling blastocyst transfers is possible, for most women undergoing mNC-FET following their first to third IVF/ICSI treatment. Our results pave the way for a less restricted approach to FET, hence reducing patient burden and costs without compromising success rates. STUDY FUNDING/COMPETING INTEREST(S): Study funding was from Rigshospitalet’s Research Foundation and Gedeon Richter (Forward Grant, FORWARD2018_5). The funders of the study had no role in study design, data collection, data analysis, data interpretation, writing of this report or the decision to submit the article for publication. MS reports an unrestricted research grant paid to institution from Gedeon Richter to fund present work, a travel grant from Gedeon Richter paid to institution, and personal honoraria for lectures from Gedeon Richter and IBSA. LP reports payments to institution for travel from IBSA, Ferring Pharmaceuticals and Merck and payment to institution from Ferring Pharmaceuticals for participation on a data safety monitoring board or advisory board. NlCF reports research grants paid to institution from Gedeon Richter, Merck and Cryos, personal consulting fee from Merck, personal honoraria for lectures from Merck, and travel grants paid to institution from Merck, Ferring Pharmaceuticals, IBSA and Gedeon Richter. Additionally, NlCF is chair in the steering committee for the guideline groups for The Danish Fertility Society (unpaid). AK reports personal honoraria for lectures from Organon and Merck and travel grants paid to institution from Merck and Ferring Pharmaceuticals. BSOM reports travel grants paid to institution by Gedeon Richter and personal fees for participation on a data safety monitoring board or advisory board from Ferring Pharmaceuticals. PH reports research grants paid to institution from Merck and Gedeon Richter and personal honoraria for lectures from Merck, IBSA and Gedeon Richter. ECLL reports personal honoraria for lectures from Pfizer and Gedeon Richter, travel grants from Merck and Gedeon Richter, and payment to institution for participation on a data safety monitoring board or advisory board from Astellas Pharma. KL reports a research grant paid to institution from Gedeon Richter, personal consulting fees from Ferring Pharmaceuticals, personal honorarium for lecture from Ferring Pharmaceuticals, and personal travel grants from Ferring Pharmaceuticals and Merck. AP reports research grants from Gedeon Richter, Ferring Pharmaceuticals, and Merck, personal consulting fees from Gedeon Richter, Ferring Pharmaceuticals and Merck, personal honoraria for lectures from Gedeon Richter, Ferring Pharmaceuticals, Merck and Abbott, and a travel grant from Gedeon Richter. All other authors declare no competing interests. TRIAL REGISTRATION NUMBER: The trial was registered with ClinicalTrials.gov (NCT03795220) and EudraCT (2018-002207-34) and is completed. TRIAL REGISTRATION DATE: The study was registered at clinicaltrials.gov on 4 December 2018. DATE OF FIRST PATIENT’S ENROLMENT: The...

STUDY QUESTION: Are there differences in psychosocial and physical wellbeing among women and male partners undergoing modified natural cycle (mNC) frozen embryo transfer (FET) in immediate compared to postponed cycles after ovarian stimulation (OS) and oocyte pick-up (OPU)? SUMMARY ANSWER: Significantly more women in the immediate group reported physical symptoms than women in the postponed group whilst fewer were emotionally affected by waiting time, although the latter difference lost statistical significance after adjustment for multiple testing. WHAT IS KNOWN ALREADY: Infertility and fertility treatment are known to cause psychosocial distress in women and couples longing for a child. The treatment may be long-term and delayed for various reasons, such as the elective postponement of FET after a fresh transfer without pregnancy or an elective freeze-all cycle, possibly further increasing the level of distress. STUDY DESIGN, SIZE, DURATION: Sub-study of an ongoing multicentre randomized controlled, non-inferiority trial assessing the optimal timing for mNC-FET treatment after OS and OPU. Participants were randomized 1:1 to mNC-FET in the cycle immediately following OS or mNC-FET in a subsequent cycle. The study is based on data from the first women (N = 300) and male partners (N = 228) invited to answer a self-reported questionnaire assessing psychosocial and physical wellbeing. Data were collected from April 2021 to March 2024. PARTICIPANTS/MATERIALS, SETTING, METHODS: Questionnaires were distributed to all randomized women and their male partners on cycle day 2–5 of mNC-FET cycles and returned before the administration of ovulation trigger. The questionnaire consisted of validated items originating from the Copenhagen Multicentre Psychosocial Infertility—Fertility Problem Stress Scale (COMPI-FPSS) and Marital Benefit Measure (COMPI-MBM). Emotional reactions to waiting time in fertility treatment, mental health, general quality-of-life, and physical symptoms were also assessed. MAIN RESULTS AND THE ROLE OF CHANCE: Questionnaire response rates were 90.3% for women and 80.0% for male partners in the immediate group, and 82.3% for women and 57.3% for male partners in the postponed group. Approximately 90% of all women worried to some or a great extent about whether the treatment would be successful. More women in the postponed group reported that they were emotionally affected by the waiting time from OPU to blastocyst transfer to some or to a great extent (57.4% versus 73.9% in the immediate versus postponed group, P = 0.014), but the results were not significant after adjustment for multiple testing (P = 0.125). For male partners, no difference in emotional reactions to waiting time between groups was found. There was no significant difference in total infertility-related stress or symptoms of severe depression between the immediate and the postponed group for women or male partners, but women were generally more distressed than their partners. There was a significantly higher incidence of stomach and/or pelvic pain (24.0% versus 9.4%, adjusted P = 0.013), feeling of being bloated (33.8% versus 15.1%, adjusted P = 0.010) and swollen or tender breasts (24.8% versus 0.9%, P < 0.001) in the immediate group. LIMITATIONS, REASONS FOR CAUTION: All items were self-reported. No assessment of psychosocial or physical wellbeing was performed before participant enrolment. The sample size of male partners was relatively small, and female partners were not included in this sub-study due to a very small number of participants in this group. WIDER IMPLICATIONS OF THE FINDINGS: If immediate mNC-FET proves to be effective, physical and emotional factors may play a key role in choosing treatment strategy for the individual patient. This study demonstrated more physical symptoms related to OS in the immediate cycles. STUDY FUNDING/COMPETING INTEREST(S): The RCT was supported by Rigshospitalet’s Research Foundation and an independent research grant from Merck A/S (MS200497_0024). Merck A/S had no role in the design of this study and will not have any role during its execution, analyses, interpretation of data, or decision to submit results. The authors are fully responsible for the content of this manuscript, and the views and opinions described in the publication reflect solely those of the authors. A.P. received grants from Gedeon Richter, Ferring Pharmaceuticals, Merck A/S and Cryos as payment to the institution. A.P. received consulting fees from IBSA, Ferring Pharmaceuticals, Gedeon Richter, Cryos and Merck A/S, and honoraria from Organon, Ferring Pharmaceuticals, Gedeon Richter and Merck A/S. A.P. received support for meeting attendance from Gedeon Richter. M.S. benefitted from a grant from Gedeon Richter. S.B. and C.C. benefitted from a grant from Merck A/S. S.B. is currently employed by Novo Nordisk. N.C.F. received grants from Gedeon Richter, Merck A/S and Cryos as payment to the institution. N.C.F. received consulting fees from Merck A/S and support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, IBSA, and Gedeon Richter. N.C.F. is chair of the steering committee for the guideline groups for The Danish Fertility Society. E.L. received a radiometer contract on blood gas validation as a payment to the institution. E.L. received honoraria from Pfizer and support for meeting attendance from Astella. B.N. received grants from IBSA, Ferring Pharmaceuticals, Merck A/S, and Gedeon Richter as payment to the institution. B.N. received honoraria from Merck A/S and Organon and support for meeting attendance from IBSA and Gedeon Richter. B.N. and L.P. participate in an Advisory Board at Ferring Pharmaceuticals. L.P. received support for meeting attendance from Merck A/S, Ferring Pharmaceuticals, and Gedeon Richter. L.P. declare stocks in Novo Nordisk. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT04748874

Are there any differences in physical and psychosocial well-being among women undergoing modified natural cycle frozen embryo transfer (mNC-FET) with or without vaginal progesterone as luteal phase support (LPS)? Women undergoing mNC-FET with vaginal progesterone supplementation were more likely to experience physical discomfort but there was no difference in psychosocial well-being between the two groups. mNC-FET can be carried out with or without vaginal progesterone as LPS, which has several side-effects. It is commonly known that fertility treatment can cause stress and psychosocial strain, however, most studies on this subject are conducted in fresh cycle regimes, which differ from NC-FET and results may not be comparable. This is a sub-study of an ongoing RCT investigating whether progesterone supplementation has a positive effect on live birth rate in mNC-FET. The RCT is conducted at eight fertility clinics in Denmark from 2019 and is planned to end primo 2024. The sub-study is based on two questionnaires on physical and psychosocial well-being added to the RCT in August 2019. On the time of data extraction 286 women had answered both questionnaires. Women who had answered both questionnaires were included in the sub-study. Participants were equally distributed, with 143 in each of the two groups. Participants in both groups received the same questionnaires at two time-points: on cycle day 2–5 (baseline) and after blastocyst transfer. Participants in the progesterone group had administered progesterone for 7 days upon answering the second questionnaire. All items in the questionnaires were validated. Items on psychosocial well-being originate from the Copenhagen Multi-Centre Psychosocial Infertility—Fertility Problem Stress Scale (COMPI-FPSS) and from the Mental Health Inventory-5. Women receiving progesterone experienced more vaginal itching and/or burning than women in the non-progesterone group (P < 0.001). Women in the progesterone group also experienced more self-reported vaginal yeast infection, this was, however, not significant after adjustment for multiple testing (P/adjusted P = 0.049/0.881). No differences regarding psychosocial well-being were found between the two groups. Within the progesterone group, a shift toward feeling less ‘downhearted and blue’ was found when comparing response distribution at baseline and after blastocyst transfer (P < 0.001). All items on physical symptoms were self-reported. The item on vaginal yeast infection was therefore not diagnosed by a doctor. Inclusion in the study required a few extra visits to the clinic, participants who felt more burdened by fertility treatment might have been more likely to decline participation. Women who experienced a lot of side-effects to progesterone prior to this FET cycle, might be less likely to participate. Our results are in line with previous known side-effects to progesterone. Physical side-effects of progesterone should be considered before administration. The RCT is fully supported by Rigshospitalet’s Research Foundation and a grant from Gedeon Richter. Gedeon Richter were not involved in the design of protocol nor in the conduction of the study or analysis of results. A.P., L.P., and N.I.-C.F. report grants from Gedeon Richter, Ferring and Merck with no relations to this study. N.I.-C.F. has received travel support from Ferring, Merck A/S, & Gideon Richter, and is the head of the steering committee for the Danish Fertility Guidelines made by the members of from the Danish Fertility Society. A.P. reports consulting fees from Preglem, Novo Nordisk, Ferring, Gedeon Richter, Cryos, & Merck A/S, honoraria from Gedeon Richter, Ferring, Merck A/S, Theramex, and Organon, has received travel support from Gedeon Richter (payment to institution), participated on an advisory board for Preglem and was loaned an embryoscope from Gedeon Richter to their institution. A.L.S. has stock options for Novo Nordisk B A/S. B.A. have received unrestricted grant from Gedeon Richter Nordic and Merck and honoraria for lectures from Gedeon Richter, Merck, IBSA, and Marckyrl Pharma. The RCT is registered on ClinicalTrials. gov (NCT03795220) and in EudraCT (2018-002207-34).

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.

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.

Introduction Despite 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 analysis Multicentre, 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 dissemination The 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 number The study is registered in EudraCT (2018-002207-34) and on ClinicalTrials.gov (NCT03795220); Pre-results.