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    The addition of single dose GnRH agonist to luteal phase support in artificial cycle frozen embryo transfer: a randomized clinical trial. Ye Hong,Luo Xiu,Pei Li,Li Fujie,Li Chunli,Chen Yueduo,Zhang Xiaodong,Huang Guoning Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology This prospective randomized clinical trial (RCT) was to evaluate the effect of single-dose gonadotrophin-releasing hormone agonist (GnRHa) in artificial cycle frozen-embryo transfer (AC-FET). A total of 868 FET cycles were included and randomized into two groups: Group A ( = 434) received GnRHa 0.1 mg subcutaneous injection on day 3 after embryo transfer (ET); Group B ( = 434) did not receive GnRHa. The demographic characteristics, primary endpoint (implantation rate) and secondary endpoints (chemical pregnancy rate, clinical pregnancy rate, ongoing pregnancy rate) were compared between two groups and subgroups (aged <35 years and 35-37 years). There were no significant differences in terms of the rates of implantation, clinical pregnancy, ongoing pregnancy, and miscarriage between two groups. While, the subgroups analysis showed the implantation rate was significantly increased in advanced age women (35-37 years) in GnRHa group compared with control group (45.3% vs. 27.8% = .03). In conclusion, single dose of GnRHa (0.1 mg triptorelin acetate) supplementation 3 days after ET in AC-FET cycles did not show significant benefit on pregnancy outcomes as a whole. However, in ageing women subgroup, the implantation rate was increasing by adding up GnRHa in peri-implantation periods, and this tendency needs to be further demonstrated by RCT with larger sample size. 10.1080/09513590.2018.1563888
    Pregnancy outcome and cost-effectiveness comparisons of artificial cycle-prepared frozen embryo transfer with or without GnRH agonist pretreatment for polycystic ovary syndrome: a randomised controlled trial. Luo L,Chen M,Wen Y,Zhang L,Zhou C,Wang Q BJOG : an international journal of obstetrics and gynaecology OBJECTIVE:To compare the live birth rate and cost effectiveness of artificial cycle-prepared frozen embryo transfer (AC-FET) with or without GnRH agonist (GnRH-a) pretreatment for women with polycystic ovary syndrome (PCOS). DESIGN:Open-label, randomised, controlled trial. SETTING:Reproductive centre of a university-affiliated hospital. SAMPLE:A total of 343 women with PCOS, aged 24-40 years, scheduled for AC-FET and receiving no more than two blastocysts. METHODS:The pretreatment group (n = 172) received GnRH-a pretreatment and the control group (n = 171) did not. Analysis followed the intention-to-treat (ITT) principle. MAIN OUTCOME MEASURES:The primary outcome measure was live birth rate. Secondary outcome measures included clinical pregnancy rate, implantation rate, early pregnancy loss rate and direct treatment costs per FET cycle. RESULTS:Among the 343 women randomised, 330 (96.2%) underwent embryo transfer and 328 (95.6%) completed the protocols. Live birth rate according to ITT did not differ between the pretreatment and control groups [85/172 (49.4%) versus 92/171 (53.8%), absolute rate difference -4.4%, 95% CI -10.8% to 2.0% (P = 0.45). Implantation rate, clinical pregnancy rate and early pregnancy loss rate also did not differ between groups, but median direct cost per FET cycle was significantly higher in the pretreatment group (7799.2 versus 4438.9 RMB, OR = 1.9, 95%CI 1.2-3.4, P < 0.001). Median direct cost per live birth was also significantly higher in the pretreatment group (15663.1 versus 8189.9 RMB, odds ratio [OR] = 1.9, 95% CI 1.2-3.8, P < 0.001). CONCLUSIONS:Pretreatment with GnRH-a does not improve pregnancy outcomes for women with PCOS receiving AC-FET, but significantly increases patient cost. TWEETABLE ABSTRACT:For women with PCOS, artificial cycle-prepared FET with GnRH agonist pretreatment provides no pregnancy outcome benefit but incurs higher cost. 10.1111/1471-0528.16461
    Home- or hospital-based monitoring to time frozen embryo transfer in the natural cycle? Patient-reported outcomes and experiences from the Antarctica-2 randomised controlled trial. Zaat T R,de Bruin J P,Goddijn M,Visser J,Kaaijk E M,Lambalk C B,Groenewoud E R,van Wely M,Mol F Human reproduction (Oxford, England) STUDY QUESTION:What are the patient-reported outcomes (PROs) and patient-reported experiences (PREs) in home-based monitoring compared to those in hospital-based monitoring of ovulation for scheduling frozen-thawed embryo transfer (FET)? SUMMARY ANSWER:Women undergoing either home-based or hospital-based monitoring experience an increase in anxiety/sadness symptoms over time, but women undergoing home-based monitoring felt more empowered during the treatment and classified the monitoring as more discreet compared to hospital-based monitoring. WHAT IS KNOWN ALREADY:FET is at the heart of modern IVF. The two types of FET cycles that are mainly are used are artificial cycle FET, using artificial preparation of the endometrium with exogenous progesterone and oestrogen, and natural cycle FET (NC-FET). During a natural cycle FET, women visit the hospital repeatedly and receive an ovulation trigger to time FET (i.e. modified NC-FET or hospital-based monitoring). The previously published Antarctica randomised controlled trial (NTR 1586) showed that modified NC-FET is more cost-effective compared to artificial cycle FET. From the women's point of view a more natural approach using home-based monitoring of ovulation with LH urine tests to time FET may be desired (true NC-FET or home-based monitoring). Currently, the multicentre Antarctica-2 randomised controlled trial (RCT) is comparing the cost-effectiveness of home-based monitoring of ovulation with that of hospital-based monitoring of ovulation. The Antarctica-2 RCT enables us to study PROs, defined as the view of participating women of their healthcare status, and PREs, defined as the perception of the received care of participating women, in both FET strategies. STUDY DESIGN, SIZE, DURATION:PROs and PREs were assessed alongside the Antarctica-2 RCT. PROs were assessed using the validated EuroQol-5D-5L questionnaire. Currently, there are no guidelines for assessing PREs in this population. Therefore, members of the Dutch Patient Organisation for Couples with Fertility Problems (FREYA) filled out an online survey and selected the following PREs to assess (i) anxiety about missing ovulation, (ii) perceived level of partner participation, (iii) level of discretion, (iv) feeling of empowerment and (v) satisfaction with treatment. PARTICIPANTS/MATERIALS, SETTING, METHODS:Women participating in the RCT also participated in PRO and PRE assessment. We assessed PROs and PREs at three time points: (i) before randomisation, (ii) at the time of the FET and (iii) at the time of the pregnancy test. A sample size of 200 participants was needed to find a difference of 0.3 with a standard deviation in both groups of 0.7, an alpha of 5%, power of 80% and a drop-out rate of 10%. We performed mixed model analysis for between-group comparison of treatment and time effects. MAIN RESULTS AND ROLE OF CHANCE:A total of 260 women were randomised. Of these, 132 women were treated with home-based monitoring and 128 women were treated with hospital-based monitoring. Data before randomisation were available for 232 women (home-based monitoring n = 116, hospital-based monitoring n = 116). For the PROs, we found a significant increase in anxiety/sadness symptoms over time (P < 0.001) in both groups. We found no treatment effect of home-based versus hospital-based monitoring for the PROs (P = 0.8). Concerning the PRES, we found that women felt more empowered during home-based monitoring (P = 0.001) and classified the home-based monitoring as more discreet (P = 0.000) compared to the hospital-based monitoring. LIMITATIONS, REASONS FOR CAUTION:The results are applicable only to women undergoing NC-FET and not to women undergoing artificial cycle FET. WIDER IMPLICATIONS OF THE FINDINGS:Apart from clinical outcomes, PROs and PREs are also of importance in clinical decision-making and to support tailoring treatment even more specifically to the wishes of patients. Measurement of PROs and PREs should therefore be incorporated in future clinical research. STUDY FUNDING/COMPETING INTEREST(S):The Antarctica-2 RCT is supported by a grant of the Netherlands Organisation for Health Research and Development (ZonMw 843002807). J.B. receives unconditional educational grants from Merck Serono and Ferring and is a member of the medical advisory board of Ferring. C.L. reports that his department receives unrestricted research grants from Ferring, Merck and Guerbet. E.G. receives personal fees from Titus Health Care outside submitted work. The remaining authors have no conflicts of interest. TRIAL REGISTRATION NUMBER:Trial NL6414 (NTR6590). TRIAL REGISTER DATE:23 July 2017. DATE OF FIRST PATIENT’S ENROLMENT:10 April 2018. 10.1093/humrep/deaa040
    Down-Regulation Ovulation-Induction Leads to Favorable Outcomes in a Single Frozen-Thawed Blastocyst Transfer RCT. Chao Shi-Bin,Wang Yan-Hong,Li Jian-Chun,Cao Wen-Ting,Zhou Yun,Sun Qing-Yuan Frontiers in endocrinology Objective:Elective single embryo transfer (eSET) has been increasingly advocated to achieve the goal of delivering a single healthy baby. A novel endometrial preparation approach down-regulation ovulation-induction (DROI) proposed by our team was demonstrated in an RCT that DROI could significantly improve the reproductive outcome compared with modified natural cycle. We aimed to evaluate whether DROI improved clinic pregnancy rate in this single frozen-thawed blastocyst transfer RCT compared with hormone replace treatment (HRT). Method:Eligible participants were recruited and randomized into one of two endometrial preparation regimens: DROI or HRT between March 15, 2019 and March 12, 2021. The primary outcome was clinical pregnancy rate (CPR). The secondary endpoints included ongoing pregnancy rate (OPR), biochemical miscarriage and first trimester pregnancy loss. This trial is registered at the Chinese Clinical Trial Registry, number ChiCTR2000039804. Result s:A total of 330 women were randomized in a 1:1 ratio between two groups and 289 women received embryo transfer and completed the study (142 DROI; 147HRT). Pregnancy outcomes were significantly different between the two groups. The CPR and OPR in the DROI group were significantly higher than those of the HRT group (64.08% versus 46.94%, P<0.01; 56.34% versus 38.78%,P<0.01). The biochemical miscarriage and first trimester pregnancy loss were comparable between the two groups. Conclusion s:The findings of this RCT support the suggestion that the DROI might be a more efficient and promising alternative endometrial preparation approach for FET. Moreover, DROI could play a critical role in promoting uptake of single embryo transfer strategies in FET. 10.3389/fendo.2022.797121
    Letrozole ovulation induction: an effective option in endometrial preparation for frozen-thawed embryo transfer. Li Song-jun,Zhang Yong-jing,Chai Xiao-shan,Nie Mei-fang,Zhou Yu-yan,Chen Jian-lin,Tao Guang-shi Archives of gynecology and obstetrics PURPOSE:To evaluate the clinical efficacy of letrozole on ovulation induction and hormone replacement therapy (HRT) during endometrial preparation for frozen-thawed embryo transfer (FET). METHODS:We analyzed totally 1,230 cycles of patients that underwent FET from October 2010 to September 2012. Seven hundred and thirteen cycles of patients with ovulation disorders that underwent FET were randomly assigned to two groups by case control study. 359 cycles received letrozole ovulation induction and 354 cycles received HRT during endometrial preparation for FET, respectively. In the corresponding period, 517 cycles of patients with normal ovulation in the natural cycle group for FET endometrial preparation served as controls. Reproduction-related clinical outcomes of patients in the three groups were compared. RESULTS:The embryo implantation rate of patients in letrozole group (30.4 %) was significantly higher than the HRT group (22.8 %, P < 0.05). The clinical pregnancy rate of patients in the letrozole group (53.2 %) was significantly higher than the HRT group (44.4 %, P < 0.05), while no significant difference was observed between the letrozole and natural cycle groups (51.3 %, P > 0.05). Estradiol levels on the day of human chorionic gonadotropin administration in the letrozole group were significantly lower than those in the natural cycle group (280.32 ± 125.39 pg/ml and 351.06 ± 123.03 pg/ml, respectively; P < 0.05). The live birth rate of patients in letrozole group (44.6 %) was significantly higher than the HRT group (32.5 %, P < 0.05), while abortion rate (12.0 %) was significantly lower than the HRT group (21.0 %, P < 0.05). There were no significant differences in number of mature follicles, endometrial thickness, duration of follicle growth between the letrozole and the natural cycle groups, and there were no significant differences in twin birth rate and ectopic pregnancy rate among the three groups (all P values >0.05). CONCLUSIONS:Ovulation induction with letrozole during endometrial preparation for FET has a higher rate of pregnancy success and a lower abortion rate than HRT. Letrozole treatment exhibits clinical progression and outcomes similar to those patients undergoing a natural cycle or normal ovulation cycle. Therefore, letrozole treatment may be an effective option in endometrial preparation for FET in patients with ovulation disorders or irregular menstruation. 10.1007/s00404-013-3044-0
    Pregnancy and neonatal outcomes following letrozole use in frozen-thawed single embryo transfer cycles. Tatsumi T,Jwa S C,Kuwahara A,Irahara M,Kubota T,Saito H Human reproduction (Oxford, England) STUDY QUESTION:Are pregnancy and neonatal outcomes following letrozole use comparable with natural and HRT cycles in patients undergoing single frozen-thawed embryo transfer (FET)? SUMMARY ANSWER:Letrozole use was significantly associated with higher rates of clinical pregnancy, clinical pregnancy with fetal heart beat and live birth, and with a lower rate of miscarriage, compared with natural and HRT cycles. WHAT IS KNOWN ALREADY:Letrozole is the most commonly used aromatase inhibitor for mild ovarian stimulation in ART. However, the effect of letrozole on pregnancy and neonatal outcomes in FET are not well known. STUDY DESIGN SIZE, DURATION:A retrospective cohort study was conducted using data from the Japanese national ART registry between 2012 and 2013. PARTICIPANTS/MATERIALS SETTING METHODS:A total of 110 722 single FET cycles with letrozole (n = 2409), natural (n = 41 470) or HRT cycles (n = 66 843) were included. The main outcomes were the rates of clinical pregnancy, clinical pregnancy with fetal heart beat, miscarriage and live birth. Adjusted odds ratios and relative risks (RRs) were calculated using a generalized estimating equation adjusting for correlations within clinics. MAIN RESULTS AND THE ROLE OF CHANCE:The rates of clinical pregnancy, clinical pregnancy with fetal heart beat, and live birth were significantly higher, while the rate of miscarriage was significantly lower in the letrozole group compared with the natural and HRT groups. In blastocyst stage transfers, the adjusted RRs for clinical pregnancy with fetal heart beat of letrozole compared with natural and HRT cycles were 1.48 (95% CI: 1.41-1.55) and 1.62 (95% CI: 1.54-1.70), respectively. Similarly, the adjusted RRs of letrozole for miscarriage compared with natural and HRT cycles were 0.91 (95% CI: 0.88-0.93) and 0.84 (95% CI: 0.82-0.87), respectively. Neonatal outcomes were mostly similar in letrozole, natural and HRT cycles. LIMITATIONS REASONS FOR CAUTION:Important limitations of this study included the lack of information concerning the reasons for selecting the specific FET method, parity, the number of previous ART failures, embryo quality and the dose and duration of letrozole intake. WIDER IMPLICATIONS OF THE FINDINGS:These results suggest that letrozole use may improve clinical pregnancy, clinical pregnancy with fetal heart beat, and live births and reduce the risk of miscarriage in patients undergoing single FET cycles. STUDY FUNDING/COMPETING INTEREST(S):No external funding was used for this study. There are no conflicts of interest. TRIAL REGISTRATION NUMBER:Not applicable. 10.1093/humrep/dex066
    Frozen embryo transfer: a review on the optimal endometrial preparation and timing. Mackens S,Santos-Ribeiro S,van de Vijver A,Racca A,Van Landuyt L,Tournaye H,Blockeel C Human reproduction (Oxford, England) STUDY QUESTION:What is the optimal endometrial preparation protocol for a frozen embryo transfer (FET)? SUMMARY ANSWER:Although the optimal endometrial preparation protocol for FET needs further research and is yet to be determined, we propose a standardized timing strategy based on the current available evidence which could assist in the harmonization and comparability of clinic practice and future trials. WHAT IS KNOWN ALREADY:Amid a continuous increase in the number of FET cycles, determining the optimal endometrial preparation protocol has become paramount to maximize ART success. In current daily practice, different FET preparation methods and timing strategies are used. STUDY DESIGN, SIZE, DURATION:This is a review of the current literature on FET preparation methods, with special attention to the timing of the embryo transfer. PARTICIPANTS/MATERIALS, SETTING, METHODS:Literature on the topic was retrieved in PubMed and references from relevant articles were investigated until June 2017. MAIN RESULTS AND THE ROLE OF CHANCE:The number of high quality randomized controlled trials (RCTs) is scarce and, hence, the evidence for the best protocol for FET is poor. Future research should compare both the pregnancy and neonatal outcomes between HRT and true natural cycle (NC) FET. In terms of embryo transfer timing, we propose to start progesterone intake on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hCG + 7 or LH + 6 in modified or true NC, respectively. LIMITATIONS REASONS FOR CAUTION:As only a few high quality RCTs on the optimal preparation for FET are available in the existing literature, no definitive conclusion for benefit of one protocol over the other can be drawn so far. WIDER IMPLICATIONS OF THE FINDINGS:Caution when using HRT for FET is warranted since the rate of early pregnancy loss is alarmingly high in some reports. STUDY FUNDING/COMPETING INTEREST(S):S.M. is funded by the Research Fund of Flanders (FWO). H.T. and C.B. report grants from Merck, Goodlife, Besins and Abbott during the conduct of the study. TRIAL REGISTRATION NUMBER:Not applicable. 10.1093/humrep/dex285
    Endometrial compaction does not predict live birth in single euploid frozen embryo transfers: a prospective study. Human reproduction (Oxford, England) STUDY QUESTION:Is there a relationship between endometrial compaction and live birth in euploid frozen embryo transfer (FET) cycles? SUMMARY ANSWER:Live birth rates (LBRs) were similar in both patients that demonstrated endometrial compaction or no compaction in single euploid FETs. WHAT IS KNOWN ALREADY:There has been increasing interest in the correlation between endometrial compaction and clinical outcomes but there has been conflicting evidence from prior investigations. STUDY DESIGN, SIZE, DURATION:This was a prospective observational study from 1 September 2020 to 9 April 2021. PARTICIPANTS/MATERIALS, SETTING, METHODS:This study was performed at a single, academically affiliated fertility center in which patients who had an autologous single euploid FET using a programmed or modified natural cycle protocol were included. All embryos had trophectoderm biopsy for preimplantation genetic testing for aneuploidy followed by vitrification at the blastocyst stage. Two ultrasound measurements of endometrial thickness (EMT) were obtained. The first measurement (T1) was measured transvaginally within 1 day of initiation of progesterone or ovulation trigger injection, and a second EMT (T2) was measured transabdominally at the time of embryo transfer (ET). The primary outcome (LBR) was based on the presence and proportion of compaction (percentage difference in EMT between T1 and T2). MAIN RESULTS AND THE ROLE OF CHANCE:Of the 186 participants included, 54%, 45%, 35%, 28% and 21% of women exhibited >0%, ≥5%, ≥10%, ≥15% and ≥20% endometrial compaction, respectively. Endometrial compaction was not predictive of live birth at any of the defined cutoffs. A sub-analysis stratified by FET protocol type (n = 89 programmed; n = 97 modified natural) showed similar results. LIMITATIONS, REASONS FOR CAUTION:There was the potential for measurement error in the recorded EMTs. The T2 measurement was performed transabdominally, which may cause potential measurement error, as it is generally accepted that transvaginal measurements of EMT are more accurate, though, any bias is expected to be non-differential. The sub-analysis performed looking at FET protocol type was underpowered and should be interpreted with caution. Our study, however, represents a pragmatic approach, as it allowed patients to avoid having to come in for an extra transvaginal ultrasound the day before or on the day of ET. WIDER IMPLICATIONS OF THE FINDINGS:Assessing endometrial compaction may lead to unnecessary cycle cancellation. However, further studies are needed to determine if routine screening for endometrial compaction would improve clinical outcomes. STUDY FUNDING/COMPETING INTEREST(S):No authors report conflicts of interest or disclosures. There was no study funding. TRIAL REGISTRATION NUMBER:NCT04330066. 10.1093/humrep/deac060
    Obstetric and perinatal outcomes following programmed compared to natural frozen-thawed embryo transfer cycles: a systematic review and meta-analysis. Human reproduction (Oxford, England) STUDY QUESTION:Is there an association between the different endometrial preparation protocols for frozen embryo transfer (FET) and obstetric and perinatal outcomes? SUMMARY ANSWER:Programmed FET protocols were associated with a significantly higher risk of hypertensive disorders of pregnancy (HDP), pre-eclampsia (PE), post-partum hemorrhage (PPH) and cesarean section (CS) when compared with natural FET protocols. WHAT IS KNOWN ALREADY:An important and growing source of concern regarding the use of FET on a wide spectrum of women, is represented by its association with obstetric and perinatal complications. However, reasons behind these increased risks are still unknown and understudied. STUDY DESIGN, SIZE, DURATION:Systematic review with meta-analysis. We systematically searched PubMed, MEDLINE, Embase and Scopus, from database inception to 1 November 2021. Published randomized controlled trials, cohort and case control studies were all eligible for inclusion. The risk of bias was assessed using the Newcastle-Ottawa Quality Assessment Scale. The quality of evidence was also evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. PARTICIPANTS/MATERIALS, SETTING, METHODS:Studies were included only if investigators reported obstetric and/or perinatal outcomes for at least two of the following endometrial preparation protocols: programmed FET cycle (PC-FET) (i.e. treatment with hormone replacement therapy (HRT)); total natural FET cycle (tNC-FET); modified natural FET cycle (mNC-FET); stimulated FET cycle (SC-FET). MAIN RESULTS AND THE ROLE OF CHANCE:Pooled results showed a higher risk of HDP (12 studies, odds ratio (OR) 1.90; 95% CI 1.64-2.20; P < 0.00001; I2 = 50%) (very low quality), pregnancy-induced hypertension (5 studies, OR 1.46; 95% CI 1.03-2.07; P = 0.03; I2 = 0%) (very low quality), PE (8 studies, OR 2.11; 95% CI 1.87-2.39; P < 0.00001; I2 = 29%) (low quality), placenta previa (10 studies, OR 1.27; 95% CI 1.05-1.54; P = 0.01; I2 = 8%) (very low quality), PPH (6 studies, OR 2.53; 95% CI 2.19-2.93; P < 0.00001; I2 = 0%) (low quality), CS (12 studies, OR 1.62; 95% CI 1.53-1.71; P < 0.00001; I2 = 48%) (very low quality), preterm birth (15 studies, OR 1.19; 95% CI 1.09-1.29; P < 0.0001; I2 = 47%) (very low quality), very preterm birth (7 studies, OR 1.63; 95% CI 1.23-2.15; P = 0.0006; I2 = 21%) (very low quality), placenta accreta (2 studies, OR 6.29; 95% CI 2.75-14.40; P < 0.0001; I2 = 0%) (very low quality), preterm premature rupture of membranes (3 studies, OR 1.84; 95% CI 0.82-4.11; P = 0.14; I2 = 61%) (very low quality), post-term birth (OR 1.90; 95% CI 1.25-2.90; P = 0.003; I2 = 73%) (very low quality), macrosomia (10 studies, OR 1.18; 95% CI 1.05-1.32; P = 0.007; I2 = 45%) (very low quality) and large for gestational age (LGA) (14 studies, OR 1.08; 95% CI 1.01-1.16; P = 0.02; I2 = 50%) (very low quality), in PC-FET pregnancies when compared with NC (tNC + mNC)-FET pregnancies. However, after pooling of ORs adjusted for the possible confounding variables, the endometrial preparation by HRT maintained a significant association in all sub-analyses exclusively with HDP, PE, PPH (low quality) and CS (very low quality). LIMITATIONS, REASONS FOR CAUTION:The principal limitation concerns the heterogeneity across studies in: (i) timing and dosage of HRT; (ii) embryo stage at transfer; and (iii) inclusion of preimplantation genetic testing cycles. To address it, we undertook subgroup analyses by pooling only ORs adjusted for a specific possible confounding factor. WIDER IMPLICATIONS OF THE FINDINGS:Endometrial preparation protocols with HRT were associated with worse obstetric and perinatal outcomes. However, because of the methodological weaknesses, recommendations for clinical practice cannot be made. Well conducted prospective studies are thus warranted to establish a safe endometrial preparation strategy for FET cycles aimed at limiting superimposed risks in women with an 'a priori' high-risk profile for obstetric and perinatal complications. STUDY FUNDING/COMPETING INTEREST(S):None. REGISTRATION NUMBER:CRD42021249927. 10.1093/humrep/deac073
    Should women receive luteal support following natural cycle frozen embryo transfer? A systematic review and meta-analysis. Mizrachi Yossi,Horowitz Eran,Ganer Herman Hadas,Farhi Jacob,Raziel Arieh,Weissman Ariel Human reproduction update BACKGROUND:Spontaneous ovulation during a natural menstrual cycle is frequently used for timing frozen embryo transfer (FET). Nevertheless, it remains unclear whether or not women should receive luteal phase support (LPS) following natural cycle frozen embryo transfer (NC-FET). OBJECTIVE AND RATIONALE:The aim of this systematic review and meta-analysis was to study whether the administration of LPS improves the reproductive outcome following NC-FET. SEARCH METHODS:We conducted a systematic search of the literature published in Medline/PubMed, Embase and the Cochrane Library, from January 2000 until December 2020. We included all original English, peer-reviewed articles, irrespective of the study design. The search strategy included keywords related to NC-FET and luteal phase support. Studies reporting the results of artificial or stimulated FET cycles were excluded. OUTCOMES:Our systematic search generated 416 records. After screening, eight studies were included in the review and seven studies were included in the meta-analysis. Two studies (n = 858) used hCG and six studies (n = 1507) used progesterone for luteal support. Four studies were randomised controlled trials (RCTs), whereas the other four were historic cohort studies. In a meta-analysis using a random effects model, hCG administration for LPS did not increase the clinical pregnancy rate (CPR) (two studies, odds ratio (OR) 0.85, 95% CI 0.64-1.14). On the other hand, progesterone LPS was associated with a higher CPR (five studies, OR 1.48, 95% CI 1.14-1.94), and a higher live birth rate (LBR) (three studies, OR 1.67, 95% CI 1.19-2.36). The association between progesterone LPS and the LBR remained significant after excluding non-randomised studies. WIDER IMPLICATIONS:The available evidence indicates that progesterone administration for LPS is beneficial following NC-FET. There is no evidence to support the administration of hCG for LPS in these cases. Additional large RCTs are necessary to improve the quality of evidence and validate our findings. 10.1093/humupd/dmab011
    Factors affecting the outcome of frozen-thawed embryo transfer. Veleva Zdravka,Orava Mauri,Nuojua-Huttunen Sinikka,Tapanainen Juha S,Martikainen Hannu Human reproduction (Oxford, England) STUDY QUESTION:Which clinical and laboratory factors affect live birth rate (LBR) after frozen-thawed embryo transfer (FET)? SUMMARY ANSWER:Top quality embryo characteristics, endometrial preparation protocol, number of embryos transferred and BMI affected independently the LBR in FET. WHAT IS KNOWN ALREADY:FET is an important part of present-day IVF/ICSI treatment. There is limited understanding of the factors affecting success rates after FET. STUDY DESIGN, SIZE, DURATION:This is a two-centre retrospective cohort study. Analysis was carried out on 1972 consecutive FET cycles in 1998-2007, with embryos frozen on Day 2. The primary outcome was LBR per cycle. PARTICIPANTS/MATERIALS, SETTING, METHODS:We assessed the independent effect on LBR of the following variables: female age, female age at embryo freezing, BMI, diagnosis, primary versus secondary infertility, fertilization by IVF versus ICSI, pregnancy in the fresh cycle, type (spontaneous, spontaneous with luteal progesterone and estrogen/progesterone substitution) and rank of the FET cycle, as well as number and presence (yes versus no) of top quality embryo(s) at freezing, thawing and transfer, damaged thawed embryos and overnight culture. MAIN RESULTS AND THE ROLE OF CHANCE:In 78% of the cycles with top quality embryos frozen (n = 1319), at least one embryo still had high-quality morphology after thawing. Top quality embryo morphology observed at any stage of culture improved the outcome even if high-quality characteristics disappeared before transfer. LBRs after the transfer of a top quality embryo were similar in the FET (24.9%) and fresh cycles of the same period (21.9%). The chance of live birth increased significantly if ≥1 top quality embryo was present at freezing (odds ratio (OR) 1.85, 95% confidence interval (CI) 1.10-3.14), at thawing (OR 1.93, CI 1.20-3.11) or at transfer (OR 3.41, CI 2.12-5.48). Compared with spontaneous cycles with luteal support, purely spontaneous cycles (OR 0.58, CI 0.40-0.84) and hormonally substituted FET (OR 0.47, CI 0.32-0.69) diminished the odds of pregnancy. BMI (OR 0.96, CI 0.92-0.99) and transfer of two embryos versus one (OR 1.45, CI 1.08-1.94) were other factors that improved LBR after FET. LIMITATIONS, REASONS FOR CAUTION:The sample sizes available in some subanalyses were small, limiting the power of the study. WIDER IMPLICATIONS OF THE FINDINGS:The presence of ≥1 top quality embryo at any step of the freezing and thawing process increases the chance of pregnancy. The data do not support the freezing of all embryos for transfer in order to improve the outcome. A top quality embryo transferred in FET may even have the same potential as in a fresh cycle. On the contrary, LBR in the group with no top quality embryos frozen was quite low (10.4%), raising the question of whether a re-evaluation of freezing criteria is necessary to avoid costly treatments with a low success rate. 10.1093/humrep/det251
    Human menopausal gonadotrophin increases pregnancy rate in comparison with clomiphene citrate during replacement cycles of frozen/thawed pronucleate ova. Van der Auwera I,Meuleman C,Koninckx P R Human reproduction (Oxford, England) In a prospective randomized study, the effect of two ovulation induction regimens on implantation rate of frozen/thawed pronucleate ova was investigated. Patients received either human menopausal gonadotrophin (HMG) or clomiphene/HMG. Ovulation induction was done on an individual basis using ultrasound and plasma 17 beta-oestradiol concentrations. Ovulation was induced with human chorionic gonadotrophin (HCG) when the leading follicle reached a diameter of 18 mm. Pronucleate ova had been frozen using the slow-freezing method of Lassalle et al. (1985) (Fertil. Steril., 44, 645-651) and were thawed in synchrony with the age of the endometrium. Both groups of patients were comparable for age, indication for in-vitro fertilization, pre-ovulatory 17 beta-oestradiol concentration, number of large follicles and number and quality of embryos transferred. The only difference found was that HCG was administered 1 day earlier in the HMG group compared to the clomiphene/HMG group (P < 0.01). Using univariate analysis, the pregnancy rate was higher in patients stimulated with HMG alone compared to those stimulated with clomiphene/HMG (27 versus 15% respectively; P < 0.03), when HCG was administered later in the menstrual cycle (P < 0.01) and when more and better quality embryos were transferred (P < 0.01). Using multivariate regression analysis, the influence of the stimulation on pregnancy rate was even more pronounced (P < 0.01) when the day of HCG administration and the number and quality embryos transferred were taken into account. Therefore, we conclude that HMG alone increases pregnancy rate compared to clomiphene/HMG during replacement cycles of frozen/thawed pronucleate ova. These data suggest that HMG results in a better endometrium receptivity for embryos.(ABSTRACT TRUNCATED AT 250 WORDS) 10.1093/oxfordjournals.humrep.a138748
    Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle. Fatemi Human Mousavi,Kyrou Dimitra,Bourgain Claire,Van den Abbeel Etienne,Griesinger Georg,Devroey Paul Fertility and sterility OBJECTIVE:To assess whether there is a difference in the ongoing pregnancy rate after transferring frozen-thawed embryos in natural cycles with spontaneous LH-P rise compared with natural cycles controlled by hCG for final oocyte maturation and ovulation. DESIGN:Randomized controlled trial. SETTING:Tertiary referral center. PATIENT(S):A total of 168 patients were assigned randomly to undergo frozen ET on day 3 from October 2007 until November 2008. Finally, analysis was performed in 124 patients; 61 belonged to the spontaneous LH group and 63 to the hCG group. INTERVENTION(S):In the spontaneous LH group the transfer was planned 5 days after the LH surge. In the hCG group, the cryopreserve ET was planned 5 days after the administration of 5000 IU of hCG, when an endometrial thickness of ≥7 mm and a follicle of ≥17 mm were present on ultrasound examination. MAIN OUTCOME MEASURE(S):Ongoing pregnancy rate. RESULT(S):The study was terminated early, when a prespecified interim analysis found a significantly higher ongoing pregnancy rate in the spontaneous LH group as compared with the hCG group (31.1% vs. 14.3%; difference 16.9%, 95% confidence interval 4.4%-28.8%). CONCLUSION(S):The results suggest the superiority of the natural cycle as compared with the natural cycle controlled by hCG administration in cryothawed ET cycles. 10.1016/j.fertnstert.2009.11.036
    Is frozen embryo transfer cycle associated with a significantly lower incidence of ectopic pregnancy? An analysis of more than 30,000 cycles. Huang Bo,Hu Dan,Qian Kun,Ai Jihui,Li Yufeng,Jin Lei,Zhu Guijin,Zhang Hanwang Fertility and sterility OBJECTIVE:To analyze the incidence of ectopic pregnancy (EP) in fresh compared with frozen-thawed cycles. DESIGN:Retrospective cohort study. SETTING:Teaching hospital. PATIENT(S):Thirty-one thousand nine hundred twenty-five women undergoing in vitro fertilization-embryo transfer (IVF-ET) from January 2006 to December 2013. INTERVENTION(S):Fresh IVF-ET compared with frozen-thawed ET (FET). MAIN OUTCOME MEASURE(S):Incidence of EP with fresh IVF-ET compared with frozen-thawed ET cycles, clinical pregnancy rate, and rate of EP per clinical pregnancy. RESULT(S):For the fresh IVF cycles, 19,173 patients underwent oocyte retrieval; 15,042 had an ET, 6,431 of these patients (42.7%) had a clinical pregnancy, and among these 297 (1.97%) appeared to have an EP. The group of patients undergoing frozen-thawed ET (12,752 patients) included 12,255; there were 5,564 pregnancies (45.4%) and 124 ectopic implants (1.01%). The incidence of an EP per clinical pregnancy was 4.62% for the fresh transfer group compared with 2.22% for the frozen-thawed cycle group; this difference was statistically significant. In addition, the fresh ET cycles had the highest risk of EP, followed by day-3 embryo FET cycles; blastocyst FET cycles had the lowest risk of EP, and the differences were all statistically significant. CONCLUSION(S):Frozen-thawed ET cycles were associated with a statistically significantly lower risk of EP when compared with fresh cycles. These findings are consistent with ovarian stimulation being associated with an increased risk of EP. 10.1016/j.fertnstert.2014.07.1245
    Greater estimated fetal weight and birth weight in IVF/ICSI pregnancies after thawed as compared with fresh blastocyst transfer: prospective cohort study with novel unified modeling methodology. Cavoretto P I,Farina A,Gaeta G,Seidenari A,Pozzoni M,Spinillo S,Morano D,Alteri A,Viganò P,Candiani M Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology OBJECTIVES:To compare growth trajectories from second trimester to birth of standardized unified estimated fetal weight (EFW) or birthweight (BW) measurements in IVF/ICSI pregnancies obtained after thawed versus fresh blastocyst transfers (BT). METHODS:Prospective longitudinal cohort study performed in the Fetal Medicine and Obstetric Departments of San Raffaele Hospital in Milan, from 2016 to 2020. Singleton viable gestations conceived by autologous IVF/ICSI conceptions from fresh or thawed BT with BW measurements and ultrasound standard fetal biometry performed at 19-36 weeks by doctors blinded to the employment of cryopreservation. Twins, significant pre-gestational diseases, miscarriages, abnormalities and other types of medically assisted reproduction techniques were excluded. EFW and BW Z-scores and their trajectories were analyzed with general linear model (GLM) and logistic regression (LR) with a unified modelling methodology based upon the Fetal Medicine Foundation fetal and neonatal population weight charts and adjusting for major confounders. Differences between prenatal EFW and postnatal BW centiles were assessed and compared with contingency tables, X test and convension of prenatal to postnatal centiles. RESULTS:631 IVF/ICSI pregnancies were considered (fresh BT n=263; thawed BT n=368) with a total of 1795 EFW observations (fresh BT n=715; thawed BT n=1080; median: 3 per patient). EFW and BW small for gestational age (SGA) <10 centile were significantly more frequent in the fresh vs thawed BT group (p=0.003 in both); EFW and BW large for gestational age (LGA) >90 centile were significantly more frequent in thawed vs fresh BT group (p=0.042 and p=0.003). GLM showed significantly decreasing EFW Z-scores with advancing gestational age (GA) assuming equal effect of GA in both study groups (no significant interaction GA and x group was found). Both smoothed mean EFW Z-scores from 19 weeks to term and smoothed mean BW Z-scores were significantly greater in thawed vs fresh BT (EFW Z-scores: 0.70±1.29 vs. 0.28±1.43; p<0.001; BW Z-scores: -0.31±1.28 vs 0.04±1.08; p=0.005). According to GA categorization, mean smooted EFW Z-score values in thawed vs fresh BT were respectively: 1.01±0.12 and 0.60±0.08 (19-27 wks), 0.36±0.07 and -0.06±0.04 (28-35 wks), -0.88±0.02 and -0.66±0.01 (36-41 wks). Mean smooted BW Z-score values in thawed vs fresh BT were respectively: -0.80± 0.14 and -1.20±0.10 (28-35 weeks), 0.22±0.16 and -0.24±0.14 (36-41 weeks). Comparison of prenatal EFW and postnatal BW data showed significantly greater rate of postnatal confirmation for prenatally predicted weight categories of SGA<10 centile in fresh vs thawed (p<0.001), whereas that of LGA>90 centile was significantly greater in frozen (p<0.001). LR showed: smoothed rate of EFW <3rd centile was about 6-fold higher in fresh vs. thawed (p<0.001); smoothed rate of EFW <10th centile was about double in fresh vs thawed (p=0.002); smoothed rates of EFW >90th and >97th centile were nearly doubled in thawed vs. fresh (p<0.001 in both). CONCLUSIONS:Robust novel unified prenatal-postnatal modelling in IVF/ICSI pregnancies after thawed or fresh BT from 19 weeks to birth showed non-divergent growth trajectories with greater EFW and BW Z-scores in frozen vs. fresh BT. Mean EFW Z-scores in both IVF/ICSI groups were greater as expected for natural conception up to 32 weeks in fresh BT and 35 weeks in thawed BT, with maximum effect at mid-trimester, decreasing with advancing gestation. Mean BW Z-scores were negative in both groups, with lower values in premature fetuses and increasing with advancing gestation. IVF/ICSI conceptions from thawed as compared to fresh BT present increased rate of LGA and reduced rate of SGA both prenatally or postnatally. The proportion of SGA fesuses across gestation increases rapidly in fresh and smoothly in thawed, whereas that of LGA fetuses decreases rapidly in thawed vs smoothly in fresh. Prediction models of SGA-LGA may be improved considering: 1. mode of conception with use of blastocyst cryopreservation; 2.unified prenatal-postnatal curves; 3. greater efficiency of prenatal prediction of SGA for fresh and for LGA in thawed. This article is protected by copyright. All rights reserved. 10.1002/uog.24806
    Low serum progesterone on the day of embryo transfer is associated with a diminished ongoing pregnancy rate in oocyte donation cycles after artificial endometrial preparation: a prospective study. Labarta E,Mariani G,Holtmann N,Celada P,Remohí J,Bosch E Human reproduction (Oxford, England) STUDY QUESTION:Is there a relationship between serum progesterone (P) and endometrial volume on the day of embryo transfer (ET) with ongoing pregnancy rate (OPR) in artificial endometrium preparation cycles? SUMMARY ANSWER:Patients with serum P < 9.2 ng/ml on the day of ET had a significantly lower OPR but endometrial volume was not related with OPR. WHAT IS KNOWN ALREADY:A window of optimal serum P levels during the embryo implantation period has been described in artificial endometrium preparation cycles. A very low endometrial volume is related to poor reproductive outcome. STUDY DESIGN, SIZE, DURATION:Prospective cohort study with 244 patients who underwent ET in an oocyte donation cycle after an artificial endometrial preparation cycle with estradiol valerate and vaginal micronized progesterone (400 mg/12 h). The study period went from 22 February 2016 to 25 October 2016 (8 months). Sample size was calculated to detect a 20% difference in OPR (35-55%) between two groups according to serum P levels in a two-sided test (80% statistical power, 95% confidence interval (CI)). PARTICIPANTS/MATERIALS, SETTING, METHODS:Patients undergoing their first/second oocyte donation cycle, aged <50, BMI < 30 kg/m2, triple layer endometrium >6.5 mm and 1-2 good quality transferred blastocysts. A private infertility centre. Serum P determination and 3D ultrasound of uterine cavity were performed on the day of ET. Endometrial volume measurements were taken using a virtual organ computer-aided analysis (VOCAL™) system. The primary endpoint was OPR beyond pregnancy week 12. MAIN RESULTS AND ROLE OF CHANCE:About 211 of the 244 recruited patients fulfilled all the inclusion/exclusion criteria. Mean serum P on the day of embryo transfer was 12.7 ± 5.4 ng/ml (Centiles 25, 9.2; 50, 11.8; 75,15.8). OPRs according to serum P quartiles were: Q1: 32.7%; Q2: 49.1%; Q3: 58.5%; Q4: 50.9%. The OPR of Q1 was significantly lower than Q2-Q4: 32.7% versus 52.8%; P = 0.016; RR (95% CI): 0.62 (0.41-0.94). The mean endometrial volume was 3.4 ± 1.9 ml. Serum P on the day of ET did not correlate with endometrial volume. A logistic regression analysis, adjusted for all the potential confounders, showed that OPR significantly lowered between women with serum P < 9.2 ng/ml versus ≥9.2 ng/ml (OR: 0.297; 95%CI: 0.113-0.779); P = 0.013. The ROC curve showed a significant predictive value of serum P levels on the day of ET for OPR, with an AUC (95%CI) = 0.59 (0.51-0.67). LIMITATIONS, REASONS FOR CAUTION:Only the women with normal uterine cavity, appropriate endometrial thickness and good quality blastocysts transfer were included. Extrapolation to an unselected population or to other routes and/or doses of administering P needs to be validated. The role of endometrial volume could not be fully defined as very few patients presented a very low volume. WIDER IMPLICATIONS OF THE FINDINGS:The present study suggests a minimum threshold of serum P values on the day of ET that needs to be reached in artificial endometrial preparation cycles to optimize outcome. No upper threshold could be defined. STUDY FUNDING/COMPETING INTEREST(S):None. TRIAL REGISTRATION NUMBER:NCT02696694. 10.1093/humrep/dex316
    Pharmacokinetics of vaginal progesterone in pregnancy. Boelig Rupsa C,Zuppa Athena F,Kraft Walter K,Caritis Steve American journal of obstetrics and gynecology BACKGROUND:Characterization of pharmacokinetics is lacking for vaginal progesterone in pregnancy. Dosing of vaginal progesterone for preterm birth prevention has been empirical. Owing to pregnancy-related changes in vaginal and uterine blood flow, hepatic metabolism, renal clearance, and endogenously elevated serum progesterone, studies outside of pregnancy may not be applicable. The lack of the pharmacokinetics profile of vaginally administered progesterone in pregnancy limits the ability to define the exposure-response relationship needed to optimize dosing, which has implications for its use in research and clinical care regarding management of short cervix, prevention of recurrent preterm birth, and prevention of recurrent miscarriage. OBJECTIVE:This was a study to establish the feasibility of using serum progesterone to establish basic pharmacokinetic parameters of vaginal progesterone in pregnancy for preterm birth prevention. STUDY DESIGN:This is a prospective study of 6 low-risk singletons at 18 0/7 to 23 6/7 weeks' gestation with body mass index 20-40. Exclusion criteria were current vaginitis, abnormal Pap smear, prescription medication use, cervical length ≤25 mm, prior preterm birth, and contraindication to progesterone. Participants received a single dose of 200 mg micronized vaginal progesterone and serum progesterone levels were evaluated every 2 hours from 0 to 12 hours and then 24 hours post dose. Primary outcome was concentration/time profile of serum progesterone. RESULTS:Median (range) maternal age was 27 (21.5-33.3) years, median body mass index was 26.5 (23.3-29.0) kg/m, and median gestational age was 22.9 (21.0-23.4) weeks. Median baseline serum progesterone was 47 (40-52) ng/mL, median peak concentration was 54 (48-68) ng/mL, and median time to peak was 12 (4-15) hours. There was a trend in rising serum progesterone over baseline with a median change in peak concentration of 11 ng/mL and interquartile range of 2-22. Median percent change from baseline was an increase by 24% (interquartile range, 4%-53%). However, there was no clear elimination phase and the median area under the curve was 112 ng*h/mL with an interquartile range of -43 to 239. CONCLUSION:Unlike in nonpregnant individuals, administration of vaginal progesterone in pregnant individuals only minimally impacts systemic exposure. There is a limited trend of rising serum progesterone over baseline levels, with significant inter-individual variability. Serum progesterone is unlikely to be a good candidate for establishing pharmacokinetics or dosing of vaginal progesterone in pregnancy for preterm birth prevention. 10.1016/j.ajog.2019.06.019
    Serum luteal phase progesterone in women undergoing frozen embryo transfer in assisted conception: a systematic review and meta-analysis. Melo Pedro,Chung Yealin,Pickering Oonagh,Price Malcolm J,Fishel Simon,Khairy Mohammed,Kingsland Charles,Lowe Philip,Petsas Georgios,Rajkhowa Madhurima,Sephton Victoria,Tozer Amanda,Wood Simon,Labarta Elena,Wilcox Mark,Devall Adam,Gallos Ioannis,Coomarasamy Arri Fertility and sterility OBJECTIVE:To investigate the association between luteal serum progesterone levels and frozen embryo transfer (FET) outcomes. DESIGN:Systematic review and meta-analysis. SETTING:Not applicable. PATIENT(S):Women undergoing FET. INTERVENTION(S):We conducted electronic searches of MEDLINE, PubMed, CINAHL, EMBASE, the Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and grey literature (not widely available) from inception to March 2021 to identify cohort studies in which the serum luteal progesterone level was measured around the time of FET. MAIN OUTCOME MEASURE(S):Ongoing pregnancy or live birth rate, clinical pregnancy rate, and miscarriage rate. RESULT(S):Among the studies analyzing serum progesterone level thresholds <10 ng/mL, a higher serum progesterone level was associated with increased rates of ongoing pregnancy or live birth (relative risk [RR] 1.47, 95% confidence interval [CI] 1.28 to 1.70), higher chance of clinical pregnancy (RR 1.31, 95% CI 1.16 to 1.49), and lower risk of miscarriage (RR 0.62, 95% CI 0.50 to 0.77) in cycles using exclusively vaginal progesterone and blastocyst embryos. There was uncertainty about whether progesterone thresholds ≥10 ng/mL were associated with FET outcomes in sensitivity analyses including all studies, owing to high interstudy heterogeneity and wide CIs. CONCLUSION(S):Our findings indicate that there may be a minimum clinically important luteal serum concentration of progesterone required to ensure an optimal endocrine milieu during embryo implantation and early pregnancy after FET treatment. Future clinical trials are required to assess whether administering higher-dose luteal phase support improves outcomes in women with a low serum progesterone level at the time of FET. PROSPERO NUMBER:CRD42019157071. 10.1016/j.fertnstert.2021.07.002
    Fresh versus frozen blastocyst transfer. Zaat Tjitske,Mol Femke,van Wely Madelon,Wilkinson Jack,Mastenbroek Sebastiaan Lancet (London, England) 10.1016/S0140-6736(19)31392-3
    Fresh versus frozen blastocyst transfer. Roque Matheus,Bedoschi Giuliano,Cecchino Gustavo N,Esteves Sandro C Lancet (London, England) 10.1016/S0140-6736(19)31393-5
    Elective frozen embryo transfer for all? Coutifaris Christos Lancet (London, England) 10.1016/S0140-6736(19)30426-X
    Increased pregnancy complications following frozen-thawed embryo transfer during an artificial cycle. Jing Shuang,Li Xiao Feng,Zhang Shuoping,Gong Fei,Lu Guangxiu,Lin Ge Journal of assisted reproduction and genetics PURPOSE:This study aimed to clarify the risks of adverse pregnancy outcomes in patients and their offspring after frozen embryo transfer (FET) during an artificial cycle (AC). METHODS:We conducted a retrospective cohort study that included all FET cycles and subsequent deliveries in a single centre between August 2013 and March 2016. Pregnancy, obstetric and neonatal outcomes were compared among patients treated during an AC or a natural cycle with luteal phase support (NC-LPS). Multivariate logistic regression was performed to evaluate the relationship between endometrial preparation schemes and pregnancy, obstetric and neonatal outcomes. RESULTS:AC-FET was not a significant risk factor for clinical pregnancy rate, multiple birth rate or miscarriage rate after adjusting for potential confounders. However, AC-FET was a significant risk factor for ectopic pregnancy rate (adjusted odds ratio (AOR), 1.738; 95% confidence interval (CI), 1.086-2.781) and live birth rate (AOR, 0.709; 95% CI, 0.626-0.802). Regarding obstetric outcomes, AC-FET was found to be associated with an increased risk for hypertension disorder (AOR, 1.780; 95% CI, 1.262-2.510) and caesarean section (AOR, 1.507; 95% CI, 1.195-1.900). In multiples, birth weight (2550 g (2150-2900 g) in AC-FET vs. 2600 g (2350-2900 g) in NC-LPS; P = 0.023), gestational age (36.6 weeks (35.3-37.6 weeks) vs. 37.1 weeks (36.1-37.9 weeks); P < 0.001), and z-score (- 0.5 (- 1.1, - 0.0) vs. - 0.4 (- 1.0, 0.2); P = 0.009) were higher in the NC-LPS group than in the AC-FET group, although there were no differences in these variables among singletons. CONCLUSION:Compared with NC-LPS, AC-FET seemed to have a negative effect on obstetric outcomes. 10.1007/s10815-019-01420-1
    Crinone Gel for Luteal Phase Support in Frozen-Thawed Embryo Transfer Cycles: A Prospective Randomized Clinical Trial in the Chinese Population. Wang Yang,He Yaqiong,Zhao Xiaoming,Ji Xiaowei,Hong Yan,Wang Yuan,Zhu Qinling,Xu Bin,Sun Yun PloS one UNLABELLED:To compare Crinone vaginal progesterone gel with intramuscularly injected progesterone for luteal phase support in progesterone-supplemented frozen-thawed embryo transfer (FET) cycles, a randomized prospective study of patients qualified for FET was conducted between September 2010 and January 2013 at a hospital in Shanghai, China. From the day of transformation into secretory phase endometrium (day 0), Crinone vaginal gel (90 mg/d) was administered to patients in the Gel Group, while progesterone (40 mg/d) was injected intramuscularly in patients in the Inj Group (n = 750 per group). All patients received oral dydrogesterone (20 mg/d) and estradiol valerate (4–8 mg/d). Day 3 embryos with the highest pre-frozen scores were transferred to patients in the two groups and the clinical outcomes compared. This study comprised 1,500 cycles (750 in each group). Twenty-nine cycles in the Gel Group and 24 in the Inj Group were withdrawn. There were no significant differences between groups in age, endometrial thickness, endometrial preparation time or number of embryos transferred. No significant differences were observed between the Gel Group and Inj Group in the rates of live birth (32.6% vs. 31.7%, P = 0.71), clinical pregnancy (40.1% vs. 40.6%, P = 0.831), implantation (25.8% vs. 25.3%, P = 0.772), abortion (16.3% vs. 18.3%, P = 0.514) or ectopic pregnancy (2.8% vs. 4.4%, P = 0.288). Multivariate logistic regression analysis revealed that the odds ratios (95% confidence intervals) for the rates of live birth, clinical pregnancy, abortion and ectopic pregnancy (Gel Group relative to Inj Group) were 1.036 (0.829–1.295), 0.971 (0.785–1.200), 0.919 (0.595–1.420) and 0.649 (0.261–1.614), respectively. Our study revealed that using Crinone vaginal gel in FET cycles achieved similar pregnancy outcomes to intramuscular progesterone, indicating that vaginal gel is a viable alternative to intramuscular injection. TRIAL REGISTRATION:Chinese Clinical Trial Registry ChiCTR-TRC-14004565. 10.1371/journal.pone.0133027
    Effect of male age on pregnancy and neonatal outcomes in the first frozen-thawed embryo transfer cycles of IVF/ICSI treatment. Kong Pengcheng,Liu Yanan,Zhu Qianqian,Yin Mingru,Teng Xiaoming Andrology BACKGROUND:The effect of male age on pregnancy outcomes after assisted reproductive technology (ART) treatment shown in the previous literature is controversial. In addition, the influence of male age on neonatal outcomes following ART treatment has less been investigated. OBJECTIVES:The aim of this study was to evaluate the effect of male age on reproductive and neonatal outcomes in couples following ART treatment. MATERIALS AND METHODS:A retrospective cohort study was performed in two centers for assisted reproduction from June 2010 to February 2019. A total of 5512 frozen-thawed embryo transfer (FET) cycles were included according to the criteria. The primary outcome measures were pregnancy and neonatal outcomes. Patients were categorized into five groups according to male age (younger than 30, 31-35, 36-40, 41-45, and older than 45), and the group younger than 30 years old was treated as the reference group. RESULTS:The logistic regression analysis showed that clinical pregnancy and live birth were all no statistic difference among the male age-groups compared with the reference group (p values, 0.743, 0.979, 0.948, 0.28; p values, 0.823, 0.342, 0.817, 0.381, respectively). Furthermore, no significant differences were found in the preterm birth rate, child sex, neonatal malformation, birth weight, and gestational age (p > 0.05). The advanced male age was not associated with a higher risk of adverse neonatal outcomes. DISCUSSION AND CONCLUSION:This study showed that there were no effects of male age on pregnancy or neonatal outcomes in infertile couples following their first FET cycles when females were younger than 36 years old. 10.1111/andr.13031
    Comparison of vaginal progesterone gel combined with oral dydrogesterone versus intramuscular progesterone for luteal support in hormone replacement therapy-frozen embryo transfer cycle. Xu Hong,Zhang Xi-Qian,Zhu Xiu-Lan,Weng Hui-Nan,Xu Li-Qing,Huang Li,Liu Feng-Hua Journal of gynecology obstetrics and human reproduction BACKGROUND:It remains under subject of debate regarding the optimal route of luteal support for hormone replacement therapy- frozen embryo transfer (HRT-FET) cycles. We compared efficacy of vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone for HRT-FET lutein support. METHODS:This is a retrospective observational study. After matching for propensity score of getting vaginal + oral treatment, a total of 208 FET cycles in the vaginal progesterone combined with oral dydrogesterone and 624 cycles in the intramuscular progesterone group were enrolled. Pregnancy outcomes and neonatal outcomes including chemical pregnancy rate, clinical pregnancy rate, implantation rate, spontaneous abortion rate, live birth rate, gestational weeks, pre-term delivery, birth weight, and congenital anomalies rate were compared. RESULTS:No significant differences were observed in patient characteristics such as age, duration of infertility, type of infertility, or hormone level after matching. Chemical pregnancy rate (68.3 % versus 70.5 %), clinical pregnancy rate (64.9 % versus 64.4 %), implantation rate (52.3 % versus 50.2 %), spontaneous abortion rate (21.5 % versus 18.4 %), and live birth rate (49.0 % versus 51.3 %) were similar in both group without statistically significant difference. No significant differences in neonatal outcomes were observed between the two groups. CONCLUSION:We observed similar pregnancy outcomes in both vaginal progesterone gel combined with oral dydrogesterone and intramuscular progesterone protocol. Vaginal progesterone gel combined with oral dydrogesterone can be substituted for intramuscular progesterone given that vaginal plus oral use has good safety and is more convenient and may be associated with less side effect caused by intramuscular injection. 10.1016/j.jogoh.2021.102110
    Progesterone Intramuscularly or Vaginally Administration May Not Change Live Birth Rate or Neonatal Outcomes in Artificial Frozen-Thawed Embryo Transfer Cycles. Liu Yuan,Wu Yu Frontiers in endocrinology Backgrounds:Previous studies suggested that singletons from frozen-thawed embryo transfer (FET) were associated with higher risk of large, post-date babies and adverse obstetrical outcomes compared to fresh transfer and natural pregnancy. No data available revealed whether the adverse perinatal outcomes were associated with aberrantly high progesterone level from different endometrium preparations in HRT-FET cycle. This study aimed to compare the impact of progesterone intramuscularly and vaginally regimens on neonatal outcomes in HRT-FET cycles. Methods:A total of 856 HRT-FET cycles from a fertility center from 2015 to 2018 were retrospectively analyzed. All patients had their first FET with two cleavage-staged embryos transferred. Endometrial preparation was performed with sequential administration of estrogen followed by progesterone intramuscularly 60 mg per day or vaginal gel Crinone 90 mg per day. Pregnancy outcomes including live birth rate, singleton birthweight, large for gestational age (LGA) rate, small for gestational age (SGA) rate, and preterm delivery rate were analyzed. Student's t test, Mann-Whitney U-test, Chi square analysis, and multivariable logistic regression were used where appropriate. Differences were considered significant if p < 0.05. Results:No significant difference of live birth rate was found between different progesterone regimens (Adjusted OR 1.128, 95% CI 0.842, 1.511, p = 0.420). Neonatal outcomes like singleton birthweight (p = 0.744), preterm delivery rate (Adjusted OR 1.920, 95% CI 0.603, 6.11, p = 0.269), SGA (Adjusted OR 0.227, 95% CI 0.027, 1.934, p = 0.175), and LGA rate (Adjusted OR 0.862, 95% CI 0.425, 1.749, p=0.681) were not different between two progesterone regimens. Serum P level >41.82 pmol/L at 14 day post-FET was associated with higher live birth rate than serum P level ≤41.82 pmol/L in HRT-FET cycles when progesterone was intramuscularly delivered (Adjusted OR 1.690, 95% CI 1.002, 2.849, p = 0.049). But singleton birthweight, preterm delivery rate, SGA and LGA rate were not different between these two groups. Conclusions:Relatively higher serum progesterone level induced by intramuscular regimen did not change live birth rate or neonatal outcomes compared to vaginal regimen. Monitoring serum progesterone level and optimizing progesterone dose of intramuscular progesterone as needed in HRT-FET cycles has a role in improving live birth rate without impact on neonatal outcomes. 10.3389/fendo.2020.539427
    Frozen-thawed embryo transfer: the potential importance of the corpus luteum in preventing obstetrical complications. Singh Bhuchitra,Reschke Lauren,Segars James,Baker Valerie L Fertility and sterility The use of frozen-thawed embryo transfer (FET) has increased over the past decade with improvements in technology and increasing live birth rates. FET facilitates elective single-embryo transfer, reduces ovarian hyperstimulation syndrome, optimizes endometrial receptivity, allows time for preimplantation genetics testing, and facilitates fertility preservation. FET cycles have been associated, however, with an increased risk of hypertensive disorders of pregnancy for reasons that are not clear. Recent evidence suggests that absence of the corpus luteum (CL) could be at least partly responsible for this increased risk. In a recent prospective cohort study, programmed FET cycles (no CL) were associated with higher rates of preeclampsia and preeclampsia with severe features compared with modified natural FET cycles. FET cycles are commonly performed in the context of a programmed cycle in which the endometrium is prepared with the use of exogenous E and P. In these cycles, ovulation is suppressed and therefore the CL is absent. The CL produces not only E and P, but also vasoactive products, such as relaxin and vascular endothelial growth factor, which are not replaced in a programmed FET cycle and which are hypothesized to be important for initial placentation. Emerging evidence has also revealed other adverse obstetrical and perinatal outcomes, including postpartum hemorrhage, macrosomia, and post-term birth specifically in programmed FET cycles compared with natural FET cycles. Despite the widespread use of FET, the optimal protocol with respect to live birth rate, maternal health, and perinatal outcomes has yet to be determined. Future practice regarding FET should be based on high-quality evidence, including rigorous controlled trials. 10.1016/j.fertnstert.2019.12.007
    Genome-wide microRNA expression profiling in placentae from frozen-thawed blastocyst transfer. Hiura Hitoshi,Hattori Hiromitsu,Kobayashi Norio,Okae Hiroaki,Chiba Hatsune,Miyauchi Naoko,Kitamura Akane,Kikuchi Hiroyuki,Yoshida Hiroaki,Arima Takahiro Clinical epigenetics BACKGROUND:Frozen-thawed embryo transfer (FET) is increasingly available for the improvement of the success rate of assisted reproductive technologies other than fresh embryo transfer (ET). There have been numerous findings that FET provides better obstetric and perinatal outcomes. However, the birth weight of infants conceived using FET is heavier than that of those conceived via ET. In addition, some reports have suggested that FET is associated with perinatal diseases such as placenta accreta and pregnancy-induced hypertension (PIH). RESULTS:In this study, we compared the microRNA (miRNA) expression profiles in term placentae derived from FET, ET, and spontaneous pregnancy (SP). We identified four miRNAs, miR-130a-3p, miR-149-5p, miR-423-5p, and miR-487b-3p, that were significantly downregulated in FET placentae compared with those from SP and ET. We found that DNA methylation of -DMR, not but IG-DMR, was associated with miRNA expression of the imprinted domain in the human placenta. In functional analyses, GO terms and signaling pathways related to positive regulation of gene expression, growth, development, cell migration, and type II diabetes mellitus (T2DM) were enriched. CONCLUSIONS:This study supports the hypothesis that the process of FET may increase exposure of epigenome to external influences. 10.1186/s13148-017-0379-6
    Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan. Ishihara Osamu,Araki Ryuichiro,Kuwahara Akira,Itakura Atsuo,Saito Hidekazu,Adamson G David Fertility and sterility OBJECTIVE:To evaluate the relationship between frozen-thawed single blastocyst transfer (BT) and maternal and neonatal outcomes of pregnancy. DESIGN:Retrospective analysis. SETTING:Japanese nationwide registry of assisted reproductive technology (ART) with mandatory reporting for all ART clinics in Japan. PATIENT(S):Registered from 2008 through 2010 undergoing single embryo transfer cycles (n = 277,042). INTERVENTION(S):None. MAIN OUTCOME MEASURE(S):Rates of preterm birth (PTB; <37 weeks' gestation), low birth weight (LBW; <2,500 g), small for gestational age (SGA), large for gestational age (LGA), placenta previa, placenta abruption, placenta accreta, and pregnancy-induced hypertension (PIH) after fresh/frozen-thawed and cleaved-embryo/blastocyst transfers were performed. RESULT(S):Frozen-thawed embryo transfer (FET) was associated with a significantly reduced occurrence of PTB, LBW, and SGA but increased rate of LGA. FET was also associated with a higher incidence of placenta accreta (odds ratio 3.16) and PIH (odds ratio 1.58). BT was associated with a significantly decreased rate of SGA and increased rate of LGA. There was no significant association between BT and maternal complications. CONCLUSION(S):Frozen-thawed BT is associated with improved general perinatal outcomes of pregnancy but significantly increased maternal risks of placenta accreta and PIH. This finding requires further investigation to assure maternal safety of patients undergoing ART treatment. 10.1016/j.fertnstert.2013.09.025
    Pregnancy-related complications and perinatal outcomes resulting from transfer of cryopreserved versus fresh embryos in vitro fertilization: a meta-analysis. Sha Tingting,Yin Xunqiang,Cheng Wenwei,Massey Isaac Yaw Fertility and sterility OBJECTIVE:To provide an updated comparison of pregnancy-related complications and adverse perinatal outcomes of pregnancies conceived after frozen embryo transfer (FET) versus fresh embryo transfer (fresh ET). DESIGN:Meta-analysis. SETTING:University. PATIENT(S):Pregnancies resulting from FET versus fresh ET. INTERVENTIONS(S):Pubmed, Embase, Cochrane Library, Google Scholar, and Chinese databases, including the China National Knowledge Infrastructure Database, Wanfang, and Chinese Scientific Journals Full-Text Database were searched by two independent reviewers from January 1980 to September 2017. The results were expressed as risk ratios with 95% confidence intervals. MAIN OUTCOME MEASURE(S):Pregnancy-related complications and perinatal outcomes. RESULT(S):Our search retrieved 1,397 articles, of which 31 studies were included. Pregnancies resulting from FET were associated with lower relative risks of placenta previa, placental abruption, low birth weight, very low birth weight, very preterm birth, small for gestational age, and perinatal mortality compared with fresh ET. Pregnancies occurring from FET were associated with increased risks of pregnancy-induced hypertension, postpartum hemorrhage, and large for gestational age compared with fresh ET. The risks of gestational diabetes mellitus, preterm premature rupture of the membranes, and preterm birth (PTB) showed no differences between the two groups. CONCLUSION(S):Our analysis demonstrated that FET results in lower risks of placenta previa, placental abruption, low birth weight, very low birth weight, very preterm birth, small for gestational age, and perinatal mortality than fresh ET, some differences that are attributed to the increased risks of pregnancy-induced hypertension, large for gestational age, and postpartum hemorrhage. Although cryotechnology keeps improving, for comprehensive consideration, individual approaches remain appropriate to balance the options of FET or fresh ET at present. 10.1016/j.fertnstert.2017.10.019
    Letrozole-induced frozen embryo transfer cycles are associated with a lower risk of hypertensive disorders of pregnancy among women with polycystic ovary syndrome. Zhang Jie,Wei Mengjie,Bian Xuejiao,Wu Ling,Zhang Shuo,Mao Xiaoyan,Wang Bian American journal of obstetrics and gynecology BACKGROUND:Observational retrospective data suggest that an artificial cycle frozen embryo transfer may be associated with a higher risk of hypertensive disorder of pregnancy than a natural cycle frozen embryo transfer among women with regular ovulatory cycles. The corpus luteum, which is not present in the artificial frozen cycles, is at least partly responsible for this poor obstetrical outcome. However, an artificial cycle is the most frequently used regimen for women with polycystic ovary syndrome undergoing frozen embryo transfer. Whether the risk of hypertensive disorder of pregnancy could be mitigated by employing physiological frozen embryo transfer protocols that lead to the development of a corpus luteum in patients with polycystic ovary syndrome remains unknown. OBJECTIVE:This study aimed to investigate the impact of letrozole use during frozen embryo transfer cycles on obstetrical and perinatal outcomes of singleton and twin pregnancies compared with artificial frozen cycles among women with polycystic ovary syndrome. STUDY DESIGN:This retrospective cohort study involved women with polycystic ovary syndrome who had undergone artificial frozen cycles or letrozole-stimulated frozen cycles during the period from 2010 to 2018 at a tertiary care center. The primary outcome was the incidence of hypertensive disorder of pregnancy. A multivariable logistic regression analysis was performed to control for the relevant confounders. RESULTS:A total of 2427 women with polycystic ovary syndrome were included in the final analysis. Of these women, 1168 underwent artificial cycles and 1259 underwent letrozole treatment, of which 25% of women treated with letrozole alone and 75% of women receiving letrozole combined with gonadotropins. After controlling for maternal characteristics and treatment variables, no significant difference was noticed regarding gestational diabetes mellitus, abnormal placentation, and preterm premature rupture of membranes between groups in both singleton and twin pregnancies. For birth outcomes, the prevalence rates of preterm birth, perinatal death, and birthweight outcomes were all comparable between groups in both singletons and twins. However, singleton pregnancies resulting from letrozole-stimulated cycles had a lower risk of hypertensive disorder of pregnancy than those conceived by artificial cycles (adjusted odds ratio, 0.63; 95% confidence interval, 0.40-0.98). Furthermore, a decreased risk of hypertensive disorder of pregnancy was seen among women with twin deliveries resulting from letrozole-stimulated cycles vs artificial cycles (adjusted odds ratio, 0.52; 95% confidence interval, 0.30-0.87). In addition, the cesarean delivery rate was significantly lower for singletons but not for twins in the letrozole group compared with pregnancies from the artificial cycle group (adjusted odds ratio, 0.63; 95% confidence interval, 0.50-0.78, and adjusted odds ratio, 1.20; 95% confidence interval, 0.65-2.23, respectively). CONCLUSION:In women with polycystic ovary syndrome undergoing frozen embryo transfer, letrozole use for endometrial preparation was associated with a lower risk of hypertensive disorder of pregnancy than artificial cycles for endometrial preparation. Our findings provided a foundation that the increased risk of hypertensive disorder of pregnancy associated with frozen embryo transfer might be mitigated by utilizing physiological endometrial preparation protocols that lead to the development of a corpus luteum, such as a mild ovarian stimulation cycle for oligo- or anovulatory women. 10.1016/j.ajog.2021.01.024
    Endometrial preparation methods for frozen-thawed embryo transfer are associated with altered risks of hypertensive disorders of pregnancy, placenta accreta, and gestational diabetes mellitus. Saito Kazuki,Kuwahara Akira,Ishikawa Tomonori,Morisaki Naho,Miyado Mami,Miyado Kenji,Fukami Maki,Miyasaka Naoyuki,Ishihara Osamu,Irahara Minoru,Saito Hidekazu Human reproduction (Oxford, England) STUDY QUESTION:What were the risks with regard to the pregnancy outcomes of patients who conceived by frozen-thawed embryo transfer (FET) during a hormone replacement cycle (HRC-FET)? SUMMARY ANSWER:The patients who conceived by HRC-FET had increased risks of hypertensive disorders of pregnancy (HDP) and placenta accreta and a reduced risk of gestational diabetes mellitus (GDM) in comparison to those who conceived by FET during a natural ovulatory cycle (NC-FET). WHAT IS KNOWN ALREADY:Previous studies have shown that pregnancy and live-birth rates after HRC-FET and NC-FET are comparable. Little has been clarified regarding the association between endometrium preparation and other pregnancy outcomes. STUDY DESIGN, SIZE, DURATION:A retrospective cohort study of patients who conceived after HRC-FET and those who conceived after NC-FET was performed based on the Japanese assisted reproductive technology registry in 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS:The pregnancy outcomes were compared between NC-FET (n = 29 760) and HRC-FET (n = 75 474) cycles. Multiple logistic regression analyses were performed to investigate the potential confounding factors. MAIN RESULTS AND THE ROLE OF CHANCE:The pregnancy rate (32.1% vs 36.1%) and the live birth rate among pregnancies (67.1% vs 71.9%) in HRC-FET cycles were significantly lower than those in NC-FET cycles. A multiple logistic regression analysis showed that pregnancies after HRC-FET had increased odds of HDPs [adjusted odds ratio, 1.43; 95% confidence interval (CI), 1.14-1.80] and placenta accreta (adjusted odds ratio, 6.91; 95% CI, 2.87-16.66) and decreased odds for GDM (adjusted odds ratio, 0.52; 95% CI, 0.40-0.68) in comparison to pregnancies after NC-FET. LIMITATIONS, REASONS FOR CAUTION:Our study was retrospective in nature, and some cases were excluded due to missing data. The implication of bias and residual confounding factors such as body mass index, alcohol consumption, and smoking habits should be considered in other observational studies. WIDER IMPLICATIONS OF THE FINDINGS:Pregnancies following HRC-FET are associated with higher risks of HDPs and placenta accreta and a lower risk of GDM. The association between the endometrium preparation method and obstetrical complication merits further attention. STUDY FUNDING/COMPETING INTEREST(S):No funding was obtained for this work. The authors declare no conflicts of interest in association with the present study. TRIAL REGISTRATION NUMBER:Not applicable. 10.1093/humrep/dez079
    Neonatal and maternal outcome after frozen embryo transfer: Increased risks in programmed cycles. Ginström Ernstad Erica,Wennerholm Ulla-Britt,Khatibi Ali,Petzold Max,Bergh Christina American journal of obstetrics and gynecology BACKGROUND:Frozen embryo transfer is associated with better perinatal outcome regarding preterm birth and low birthweight, yet higher risk of large for gestational age and macrosomia compared to fresh transfer. Further, higher rates of hypertensive disorders in pregnancy are noted after frozen embryo transfer. Whether these differences are due to the protocol used in frozen cycles remains unknown. OBJECTIVE:To analyze the obstetric outcome after frozen embryo transfer depending on protocol used. Comparison was also made for frozen vs fresh transfer and for frozen transfer vs spontaneous conception. STUDY DESIGN:A population-based retrospective registry study including all singletons born after frozen embryo transfer in Sweden from 2005 to 2015. The in vitro fertilization register was cross-linked with the Medical Birth Register, the Register of Birth Defects, the National Patient Register, the Swedish Neonatal Quality Register, and the Prescribed Drug Register. Singletons after frozen embryo transfer were compared depending on the presence of a corpus luteum in the actual cycle. All frozen transfer singletons were also compared with fresh transfer and spontaneous conception singletons. Primary outcomes were preterm birth (<37 w), low birthweight (<2500 g), hypertensive disorders in pregnancy, and postpartum hemorrhage (>1000 mL). Crude and adjusted odds ratio with 95% confidence interval were calculated and adjustment made for relevant confounders. RESULTS:A total of 9726 singletons were born after frozen embryo transfer (natural cycles, n = 6297; stimulated cycles, n = 1983; programmed cycles, n = 1446), 24,365 after fresh transfer, and 1,127,566 after spontaneous conception. No significant differences were noticed for preterm birth and low birthweight between the different protocols used in frozen embryo transfer. Compared to natural and stimulated frozen cycles, programmed frozen cycles were associated with a higher risk of hypertensive disorders in pregnancy (adjusted odds ratio, 1.78; 95% confidence interval, 1.43-2.21 and adjusted odds ratio, 1.61; 95% confidence interval, 1.22-2,10, respectively) and postpartum hemorrhage (adjusted odds ratio, 2.63; 95% confidence interval, 2.20-3.13 and adjusted odds ratio, 2.87; 95% confidence interval, 2.29-2.60, respectively). Moreover, higher risks for postterm birth (adjusted odds ratio, 1.59; 95% confidence interval, 1.27-2.01 and adjusted odds ratio, 1.98; 95% confidence interval, 1.47-2.68) and macrosomia (adjusted odds ratio, 1.62; 95% confidence interval, 1.26-2.09 and adjusted odds ratio, 1.40; 95% confidence interval, 1.03-1.90) were detected. There were no significant differences in any outcomes between stimulated and natural cycles. Frozen cycles in general compared to fresh cycles and compared to spontaneous conceptions showed neonatal and maternal outcomes in agreement with earlier studies. CONCLUSION:No significant difference could be seen regarding preterm birth and low birthweight between the different protocols. However, higher rates of hypertensive disorders in pregnancy, postpartum hemorrhage, postterm birth, and macrosomia were detected in programmed cycles. Stimulated cycles had outcomes similar to natural cycles. These findings are important in view of the increasing use of frozen cycles and the new policy of freeze-all cycles in in vitro fertilization. The results suggest a link between the absence of corpus luteum and adverse obstetric outcomes. 10.1016/j.ajog.2019.03.010
    Lower risk of adverse perinatal outcomes in natural versus artificial frozen-thawed embryo transfer cycles: a systematic review and meta-analysis. Moreno-Sepulveda José,Espinós Juan Jose,Checa Miguel Angel Reproductive biomedicine online This systematic review of literature and meta-analysis of observational studies reports on perinatal outcomes after frozen embryo transfer (FET). The aim was to determine whether natural cycle frozen embryo transfer (NC-FET) in singleton pregnancies conceived after IVF decreased the risk of adverse perinatal outcomes compared with artificial cycle frozen embryo transfer (AC-FET). Thirteen cohort studies, including 93,201 cycles, met the inclusion criteria. NC-FET was associated with a lower risk of hypertensive disorders in pregnancy (HDP) (RR 0.61, 95% CI 0.50 to 0.73), preeclampsia (RR 0.47, 95% CI 0.42 to 0.53), large for gestational age (LGA) (RR 0.93, 95% CI 0.90 to 0.96) and macrosomia (RR 0.82, 95% CI 0.69 to 0.97) compared with AC-FET. No significant difference was found in the risk of gestational hypertension and small for gestational age. Secondary outcomes assessed were the risk of preterm birth (RR 0.83, 95% CI 0.79 to 0.88); post-term birth (RR 0.48, 95% CI 0.29 to 0.80); low birth weight (RR 0.84, 95% CI 0.80 to 0.89); caesarean section (RR 0.84, 95% CI 0.77 to 0.91); postpartum haemorrhage (RR 0.39, 95% CI 0.35 to 0.45); placental abruption (RR 0.61, 95% CI 0.38 to 0.98); and placenta accreta (RR 0.18, 95% CI 0.10 to 0.33). All were significantly lower with NC-FET compared with AC-FET. In assessing safety, NC-FET significantly decreased the risk of HDP, preeclampsia, LGA, macrosomia, preterm birth, post-term birth, low birth weight, caesarean section, postpartum haemorrhage, placental abruption and placenta accreta. Further randomized controlled trials addressing the effect of NC-FET and AC-FET on maternal and perinatal outcomes are warranted. Clinicians should carefully monitor pregnancies achieved by FET in artificial cycles prenatally, during labour and postnatally. 10.1016/j.rbmo.2021.03.002
    Maternal and perinatal outcomes in programmed versus natural vitrified-warmed blastocyst transfer cycles. Makhijani Reeva,Bartels Chantal,Godiwala Prachi,Bartolucci Alison,Nulsen John,Grow Daniel,Benadiva Claudio,Engmann Lawrence Reproductive biomedicine online RESEARCH QUESTION:Do maternal and perinatal outcomes differ between natural and programmed frozen embryo transfer (FET) cycles? DESIGN:Retrospective cohort study at a university-affiliated fertility centre including 775 patients who underwent programmed or natural FET cycles resulting in a singleton live birth using blastocysts vitrified between 2013 and 2018. RESULTS:A total of 384 natural and 391 programmed FET singleton pregnancies were analysed. Programmed FET resulted in higher overall maternal complications (32.2% [126/391] versus 18.8% [72/384]; P < 0.01), including higher probability of hypertensive disorders of pregnancy (HDP) (15.3% [60/391] versus 6.3% [24/384]; P < 0.01), preterm premature rupture of membranes (2.6% [10/391] versus 0.3% [1/384]; P = 0.02) and caesarean delivery (53.2% [206/387] versus 42.8% [163/381]; P = 0.03) compared with natural FET. After controlling for potential confounders, including age, body mass index, parity, smoking status, history of diabetes or chronic hypertension, infertility diagnosis, number of embryos transferred and use of preimplantation genetic testing, the adjusted odds ratio for HDP was 2.39 (95% CI 1.37 to 4.17) and for overall maternal complications was 2.21 (95% CI 1.51 to 3.22) comparing programmed with natural FET groups. The groups did not significantly differ for any perinatal outcomes analysed, including birth weight (3357.9 ± 671.6 g versus 3318.4 ± 616.2 g; P = 0.40) or rate of birth defects (1.5% [6/391] versus 2.1% [8/384]; P = 0.57), respectively. CONCLUSION:Vitrified-warmed blastocyst transfer in a programmed cycle resulted in a twofold higher probability of HDP compared with transfer in a natural cycle. Natural FET cycle should, therefore, be recommended as first line for all eligible patients undergoing FET to reduce the risk of HDP. 10.1016/j.rbmo.2020.03.009
    Is frozen embryo transfer better for mothers and babies? Can cumulative meta-analysis provide a definitive answer? Maheshwari Abha,Pandey Shilpi,Amalraj Raja Edwin,Shetty Ashalatha,Hamilton Mark,Bhattacharya Siladitya Human reproduction update BACKGROUND:Initial observational studies and a systematic review published 5 years ago have suggested that obstetric and perinatal outcomes are better in offspring conceived following frozen rather than fresh embryo transfers, with reduced risks of preterm birth, small for gestational age, low birth weight and pre-eclampsia. More recent primary studies are beginning to challenge some of these findings. We therefore conducted an updated systematic review and cumulative meta-analysis to examine if these results have remained consistent over time. OBJECTIVE AND RATIONALE:The aim of this study was to perform a systematic review and cumulative meta-analysis (trend with time) of obstetric and perinatal complications in singleton pregnancies following the transfer of frozen thawed and fresh embryos generated through in-vitro fertilisation. SEARCH METHODS:Data Sources from Medline, EMBASE, Cochrane Central Register of Clinical Trials DARE and CINAHL (1984-2016) were searched using appropriate key words. Observational and randomised studies comparing obstetric and perinatal outcomes in singleton pregnancies conceived through IVF using either fresh or frozen thawed embryos. Two independent reviewers extracted data in 2 × 2 tables and assessed the methodological quality of the relevant studies using CASP scoring. Both aggregated as well as cumulative meta-analysis was done using STATA. OUTCOMES:Twenty-six studies met the inclusion criteria. Singleton babies conceived from frozen thawed embryos were at lower relative risk (RR) of preterm delivery (0.90; 95% CI 0.84-0.97) low birth weight (0.72; 95% CI 0.67-0.77) and small for gestational age (0.61; 95% CI 0.56-0.67) compared to those conceived from fresh embryo transfers, but faced an increased risk (RR) of hypertensive disorders of pregnancy (1.29; 95% CI 1.07-1.56) large for gestational age (1.54; 95% CI 1.48-1.61) and high birth weight (1.85; 95% CI 1.46-2.33). There was no difference in the risk of congenital anomalies and perinatal mortality between the two groups. The direction and magnitude of effect for these outcomes have remained virtually unchanged over time while the degree of precision has improved with the addition of data from newer studies. WIDER IMPLICATIONS:The results of this cumulative meta-analysis confirm that the decreased risks of small for gestational age, low birth weight and preterm delivery and increased risks of large for gestational age and high birth weight associated with pregnancies conceived from frozen embryos have been consistent in terms of direction and magnitude of effect over several years, with increasing precision around the point estimates. Replication in a number of different populations has provided external validity for the results, for outcomes of birth weight and preterm delivery. Meanwhile, caution should be exercised about embarking on a policy of electively freezing all embryos in IVF as there are increased risks for large for gestational age babies and hypertensive disorders of pregnancy. Therefore, elective freezing should ideally be undertaken in specific cases such as ovarian hyperstimulation syndrome, fertility preservation or in the context of randomised trials. 10.1093/humupd/dmx031
    Comparison of stimulated versus modified natural cycles for endometrial preparation prior to frozen embryo transfer: a randomized controlled trial. Labrosse Julie,Lobersztajn Annina,Pietin-Vialle Claire,Villette Claire,Dessapt Anne Lucie,Jung Camille,Brussieux Maxime,Bry-Gauillard Helene,Pasquier Maud,Massin Nathalie Reproductive biomedicine online RESEARCH QUESTION:To compare stimulated cycle (STC) versus modified natural cycle (MNC) for endometrial preparation prior to frozen embryo transfer (FET) in terms of convenience and efficacy. DESIGN:Prospective, open-label, randomized controlled study including 119 patients aged 20-38 years, undergoing intra-conjugal IVF/intracytoplasmic sperm injection, having regular cycles, at least two day 2 or day 3 frozen embryos, for whom it was the first or second FET performed, randomized to either MNC (n = 59) or STC (n = 60). Monitoring consisted of ultrasound and hormonal measurements. The number of monitoring visits required was compared between the two groups. RESULTS:STC required a significantly lower number of monitoring visits compared with MNC (3.6 ± 0.9 versus 4.4 ± 1.1, respectively, P < 0.0001), a lower number of blood tests (2.7 ± 0.8 versus 3.5 ± 1.0, respectively, P < 0.0001) and of ultrasounds (1.2 ± 0.4 versus 1.5 ± 0.6, respectively, P = 0.0039). FET during 'non-opening' hours (22.6% versus 27.5%, respectively, P = 0.32) and cancellation rates (11.7% versus 11.9%, respectively, P = 0.97) were comparable between the STC and MNC groups. No difference concerning HCG-positive rates (34.0% versus 23.1%, respectively, P = 0.22) nor live birth rates (24.5% for STC versus 23.1% for MNC, respectively, P = 0.86) was observed. Quality of life as defined by the FertiQol score was not different (P > 0.05 for each item). CONCLUSION:Altogether, these findings can be used for everyday clinical practice to better inform patients when deciding on the protocol to use for FET. These results suggest that MNC is a good option for patients reluctant to have injections, but requires increased monitoring. STC may offer more flexibility for patients and IVF centres. 10.1016/j.rbmo.2020.01.007
    Reply: Freeze-all vs conventional IVF: a valid and valuable RCT. Mol Femke,van Wely Madelon,Mastenbroek Sebastiaan Human reproduction (Oxford, England) 10.1093/humrep/deab113
    Freeze-all versus fresh blastocyst transfer strategy during in vitro fertilisation in women with regular menstrual cycles: multicentre randomised controlled trial. Stormlund Sacha,Sopa Negjyp,Zedeler Anne,Bogstad Jeanette,Prætorius Lisbeth,Nielsen Henriette Svarre,Kitlinski Margaretha Laczna,Skouby Sven O,Mikkelsen Anne Lis,Spangmose Anne Lærke,Jeppesen Janni Vikkelsø,Khatibi Ali,la Cour Freiesleben Nina,Ziebe Søren,Polyzos Nikolaos P,Bergh Christina,Humaidan Peter,Andersen Anders Nyboe,Løssl Kristine,Pinborg Anja BMJ (Clinical research ed.) OBJECTIVE:To compare the ongoing pregnancy rate between a freeze-all strategy and a fresh transfer strategy in assisted reproductive technology treatment. DESIGN:Multicentre, randomised controlled superiority trial. SETTING:Outpatient fertility clinics at eight public hospitals in Denmark, Sweden, and Spain. PARTICIPANTS:460 women aged 18-39 years with regular menstrual cycles starting their first, second, or third treatment cycle of in vitro fertilisation or intracytoplasmic sperm injection. INTERVENTIONS:Women were randomised at baseline on cycle day 2 or 3 to one of two treatment groups: the freeze-all group (elective freezing of all embryos) who received gonadotropin releasing hormone agonist triggering and single frozen-thawed blastocyst transfer in a subsequent modified natural cycle; or the fresh transfer group who received human chorionic gonadotropin triggering and single blastocyst transfer in the fresh cycle. Women in the fresh transfer group with more than 18 follicles larger than 11 mm on the day of triggering had elective freezing of all embryos and postponement of transfer as a safety measure. MAIN OUTCOME MEASURES:The primary outcome was the ongoing pregnancy rate defined as a detectable fetal heart beat after eight weeks of gestation. Secondary outcomes were live birth rate, positive human chorionic gonadotropin rate, time to pregnancy, and pregnancy related, obstetric, and neonatal complications. The primary analysis was performed according to the intention-to-treat principle. RESULTS:Ongoing pregnancy rate did not differ significantly between the freeze-all and fresh transfer groups (27.8% (62/223) 29.6% (68/230); risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.76). Additionally, no significant difference was found in the live birth rate (27.4% (61/223) for the freeze-all group and 28.7% (66/230) for the fresh transfer group; risk ratio 0.98, 95% confidence interval 0.87 to 1.10, P=0.83). No significant differences between groups were observed for positive human chorionic gonadotropin rate or pregnancy loss, and none of the women had severe ovarian hyperstimulation syndrome; only one hospital admission related to this condition occurred in the fresh transfer group. The risks of pregnancy related, obstetric, and neonatal complications did not differ between the two groups except for a higher mean birth weight after frozen blastocyst transfer and an increased risk of prematurity after fresh blastocyst transfer. Time to pregnancy was longer in the freeze-all group. CONCLUSIONS:In women with regular menstrual cycles, a freeze-all strategy with gonadotropin releasing hormone agonist triggering for final oocyte maturation did not result in higher ongoing pregnancy and live birth rates than a fresh transfer strategy. The findings warrant caution in the indiscriminate application of a freeze-all strategy when no apparent risk of ovarian hyperstimulation syndrome is present. TRIAL REGISTRATION:Clinicaltrials.gov NCT02746562. 10.1136/bmj.m2519
    Effects of different cycle regimens for frozen embryo transfer on perinatal outcomes of singletons. Wang Bian,Zhang Jie,Zhu Qianqian,Yang Xiaoyan,Wang Yun Human reproduction (Oxford, England) STUDY QUESTION:Does the endometrial preparation protocol for frozen embryo transfer (FET) have an impact on perinatal outcomes? SUMMARY ANSWER:Singleton newborns from conceptions after an artificial FET cycle had a higher risk of being large for gestational age (LGA). WHAT IS KNOWN ALREADY:Most previous studies have concentrated on the clinical pregnancy, miscarriage and live birth rates of different endometrial preparation protocols for FET. However, the impacts of these cycle regimens on perinatal outcomes including birthweight, gestational age (GA) and related outcomes require more investigation. STUDY DESIGN, SIZE, DURATION:We retrospectively analysed all singletons conceived by women who underwent non-donor FET cycles between July 2014 and July 2017. The propensity score matching (PSM) method using nearest neighbour matching at a proportion of 1:1 was established to adjust for factors that influence the probability of receiving different FET cycle regimens. The main outcomes of the study included birthweight and its related outcomes, Z-score, low birthweight (LBW, <2500 g), small for gestational age (SGA, ≤10th percentile of referential birthweight), LGA (≥90th percentile of referential birthweight) and macrosomia (birthweight >4000 g). The study outcomes also included GA at birth, preterm delivery (<37 weeks), very preterm delivery (<32 weeks), very low birthweight (VLBW, <1500 g), term LBW (at 37 weeks of gestation or greater) and preterm LBW (at <37 weeks of gestation). PARTICIPANTS/MATERIALS, SETTING, METHODS:A total of 9267 cycles with live-born singletons were included in the analysis in our centre between July 2014 and July 2017. Of these, 2224, 4299 and 2744 live-born singletons were conceived by natural cycle FET, stimulated cycle FET and artificial cycle FET, respectively. After PSM, 1947 cycles of natural cycle FET versus stimulated cycle FET, 1682 cycles of stimulated cycle FET versus artificial cycle FET and 2333 cycles of natural cycle FET versus artificial cycle FET were included in the analysis. MAIN RESULTS AND THE ROLE OF CHANCE:A higher mean birthweight and Z-score were observed in the artificial cycle FET group than in the stimulated cycle FET group (P = 0.005; P = 0.004, respectively). Singleton newborns conceived after artificial cycle FET were more likely to be LGA than those born after natural cycle FET or stimulated cycle FET (19.92% versus 16.94% and 19.29% versus 16.12%, respectively). The adjusted ORs (95% CIs) were 1.25 (1.05, 1.49) for artificial cycle FET compared with natural cycle FET (P = 0.014) and 1.26 (1.08, 1.46) for artificial cycle FET compared with stimulated cycle FET (P = 0.003). Newborns conceived after stimulated cycle FET had a lower mean GA at birth and a lower mean birthweight than those born after natural cycle FET or artificial cycle FET. The stimulated cycle FET group had lower adjusted odds of being macrosomia than the natural cycle FET group. No significant differences between natural cycle FET and stimulated cycle FET were found for any of the other outcomes. LIMITATIONS, REASONS FOR CAUTION:This study had the disadvantage of being retrospective, and some cases were excluded due to missing data. The original allocation process was not randomized, which may have introduced bias. We have chosen not to account for multiple comparisons in our statistical analysis. WIDER IMPLICATIONS OF THE FINDINGS:LGA can have long-term consequences in terms of risk for disease, which means that the influences of artificial cycle FET are of clinical significance and deserve more attention. Furthermore, these findings are critical for clinicians to be able to make an informed decision when choosing an endometrial preparation method. STUDY FUNDING/COMPETING INTEREST(S):This work was supported by grants from the National Natural Science Foundation of China (NSFC) (31770989 to Y.W.) and the Shanghai Ninth People's Hospital Foundation of China (JYLJ030 to Y.W.). None of the authors have any conflicts of interest to declare. 10.1093/humrep/deaa093
    Secretory products of the corpus luteum and preeclampsia. Pereira María M,Mainigi Monica,Strauss Jerome F Human reproduction update BACKGROUND:Despite significant advances in our understanding of the pathophysiology of preeclampsia (PE), there are still many unknowns and controversies in the field. Women undergoing frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium have been found to have an unexpected increased risk of PE compared to women who receive embryos in a natural FET cycle. The differences in risk have been hypothesized to be related to the absence or presence of a functioning corpus luteum (CL). OBJECTIVE AND RATIONALE:To evaluate the literature on secretory products of the CL that could be essential for a healthy pregnancy and could reduce the risk of PE in the setting of FET. SEARCH METHODS:For this review, pertinent studies were searched in PubMed/Medline (updated June 2020) using common keywords applied in the field of assisted reproductive technologies, CL physiology and preeclampsia. We also screened the complete list of references in recent publications in English (both animal and human studies) on the topics investigated. Given the design of this work as a narrative review, no formal criteria for study selection or appraisal were utilized. OUTCOMES:The CL is a major source of multiple factors regulating reproduction. Progesterone, estradiol, relaxin and vasoactive and angiogenic substances produced by the CL have important roles in regulating its functional lifespan and are also secreted into the circulation to act remotely during early stages of pregnancy. Beyond the known actions of progesterone and estradiol on the uterus in early pregnancy, their metabolites have angiogenic properties that may optimize implantation and placentation. Serum levels of relaxin are almost undetectable in pregnant women without a CL, which precludes some maternal cardiovascular and renal adaptations to early pregnancy. We suggest that an imbalance in steroid hormones and their metabolites and polypeptides influencing early physiologic processes such as decidualization, implantation, angiogenesis and maternal haemodynamics could contribute to the increased PE risk among women undergoing programmed FET cycles. WIDER IMPLICATIONS:A better understanding of the critical roles of the secretory products of the CL during early pregnancy holds the promise of improving the efficacy and safety of ART based on programmed FET cycles. 10.1093/humupd/dmab003
    Immediate versus delayed frozen embryo transfer in patients following a stimulated IVF cycle: a randomised controlled trial. Li He,Sun Xiaoxi,Yang Junyi,Li Lu,Zhang Wenbi,Lu Xiang,Chen Junling,Chen Hua,Yu Min,Fu Wei,Peng Xiandong,Chen Jiazhou,Ng Ernest Hung Yu Human reproduction (Oxford, England) STUDY QUESTION:Is there any difference in the ongoing pregnancy rate after immediate versus delayed frozen embryo transfer (FET) following a stimulated IVF cycle? SUMMARY ANSWER:Immediate FET following a stimulated IVF cycle produced significantly higher ongoing pregnancy and live birth rate than did delayed FET. WHAT IS KNOWN ALREADY:Embryo cryopreservation is an increasingly important part of IVF, but there is still no good evidence to advise when to perform FET following a stimulated IVF cycle. All published studies are retrospective, and the findings are contradictory. STUDY DESIGN, SIZE, DURATION:This was a randomised controlled non-inferiority trial of 724 infertile women carried out in two fertility centres in China between 9 August 2017 and 5 December 2018. PARTICIPANTS/MATERIALS, SETTING, METHODS:Infertile women having their first FET cycle after a stimulated IVF cycle were randomly assigned to either (1) the immediate group in which FET was performed in the first menstrual cycle following the stimulated IVF cycle (n = 362) or (2) the delayed group in which FET was performed in the second or later menstrual cycle following the stimulated IVF cycle (n = 362). All FET cycles were performed in hormone replacement cycles. The randomisation sequence was generated using an online randomisation program with block sizes of four. The primary outcome was the ongoing pregnancy rate, defined as a viable pregnancy beyond 12 weeks of gestation. The non-inferiority margin was -10%. Analysis was performed by both per-protocol and intention-to-treat approaches. MAIN RESULTS AND THE ROLE OF CHANCE:Women in the immediate group were slightly younger than those in the delayed group (30.0 (27.7-33.5) versus 31.0 (28.5-34.2), respectively, P = 0.006), but the proportion of women ≤35 years was comparable between the two groups (308/362, 85.1% in the immediate group versus 303/362, 83.7% in the delayed group). The ongoing pregnancy rate was 49.6% (171/345) in the immediate group and 41.5% (142/342) in the delayed group (odds ratios 0.72, 95% CI 0.53-0.98, P = 0.034). The live birth rate was 47.2% (163/345) in the immediate group and 37.7% (129/342) in the delayed group (odds ratios 0.68, 95% CI 0.50-0.92, P = 0.012). The miscarriage rate was 13.2% (26 of 197 women) in the immediate group and 24.2% (43 of 178 women) in the delayed group (odds ratios 2.10; 95% CI 1.23-3.58, P = 0.006). The multivariable logistic regression, which adjusted for potential confounding factors including maternal age, number of oocytes retrieved, embryo stage at transfer, number of transferred embryos/blastocysts, reasons for FET, ovarian stimulation protocol and trigger type, demonstrated that the ongoing pregnancy rate was still higher in the immediate group. LIMITATIONS, REASON FOR CAUTION:Despite randomisation, the two groups still differed slightly in the age of the women at IVF. The study was powered to consider the ongoing pregnancy rate, but the live birth rate may be of greater clinical interest. Conclusions relating to the observed differences between the treatment groups in terms of live birth rate should, therefore, be made with caution. WIDER IMPLICATIONS OF THE FINDINGS:Immediate FET following a stimulated IVF cycle had a significantly higher ongoing pregnancy and live birth rate than delayed FET. The findings of this study support immediate FET after a stimulated IVF cycle. STUDY FUNDING/COMPETING INTEREST(S):No external funding was used and no competing interests were declared. TRIAL REGISTRATION NUMBER:ClinicalTials.gov identifier: NCT03201783. TRIAL REGISTRATION DATE:28 June 2017. DATE OF FIRST PATIENT’S ENROLMENT:9 August 2017. 10.1093/humrep/deab071
    Fresh versus elective frozen embryo transfer in IVF/ICSI cycles: a systematic review and meta-analysis of reproductive outcomes. Roque Matheus,Haahr Thor,Geber Selmo,Esteves Sandro C,Humaidan Peter Human reproduction update BACKGROUND:Elective freezing of all good quality embryos and transfer in subsequent cycles, i.e. elective frozen embryo transfer (eFET), has recently increased significantly with the introduction of the GnRH agonist trigger protocol and improvements in cryo-techniques. The ongoing discussion focuses on whether eFET should be offered to the overall IVF population or only to specific subsets of patients. Until recently, the clinical usage of eFET was supported by only a few randomized controlled trials (RCT) and meta-analyses, suggesting that the eFET not only reduced ovarian hyperstimulation syndrome (OHSS), but also improved reproductive outcomes. However, the evidence is not unequivocal, and recent RCTs challenge the use of eFET for the general IVF population. OBJECTIVE AND RATIONALE:This systematic review and meta-analysis aimed at evaluating whether eFET is advantageous for reproductive, obstetric and perinatal outcomes compared with fresh embryo transfer in IVF/ICSI cycles. Additionally, we evaluated the effectiveness of eFET in comparison to fresh embryo transfer in different subgroups of patients undergoing IVF/ICSI cycles. SEARCH METHODS:We conducted a systematic review, using PubMed/Medline and EMBASE to identify all relevant RCTs published until March 2018. The participants included infertile couples undergoing IVF/ICSI with or without preimplantation genetic testing for aneuploidy (PGT-A). The primary outcome was the live birth rate (LBR), whereas secondary outcomes were cumulative LBR, implantation rate, miscarriage, OHSS, ectopic pregnancy, preterm birth, pregnancy-induced hypertension, pre-eclampsia, mean birthweight and congenital anomalies. Subgroup analyses included normal and hyper-responder patients, embryo developmental stage on the day of embryo transfer, freezing method and the route of progesterone administration for luteal phase support in eFET cycles. OUTCOMES:Eleven studies, including 5379 patients, fulfilling the inclusion criteria were subjected to qualitative and quantitative analysis. A significant increase in LBR was noted with eFET compared with fresh embryo transfer in the overall IVF/ICSI population [risk ratio (RR) = 1.12; 95% CI: 1.01-1.24]. Subgroup analyses indicated higher LBRs by eFET than by fresh embryo transfer in hyper-responders (RR = 1.16; 95% CI: 1.05-1.28) and in PGT-A cycles (RR = 1.55; 95% CI: 1.14-2.10). However, no differences were observed for LBR in normo-responders (RR = 1.03; 95% CI: 0.91-1.17); moreover, the cumulative LBR was not significantly different in the overall population (RR = 1.04; 95% CI: 0.97-1.11). Regarding safety, the risk of moderate/severe OHSS was significantly lower with eFET than with fresh embryo transfer (RR = 0.42; 95% CI: 0.19-0.96). In contrast, the risk of pre-eclampsia increased with eFET (RR = 1.79; 95% CI: 1.03-3.09). No statistical differences were noted in the remaining secondary outcomes. WIDER IMPLICATIONS:Although the use of eFET has steadily increased in recent years, a significant increase in LBR with eFET was solely noted in hyper-responders and in patients undergoing PGT-A. Concerning safety, eFET significantly decreases the risk of moderate and severe OHSS, albeit at the expense of an increased risk of pre-eclampsia. 10.1093/humupd/dmy033
    Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence. Evans Jemma,Hannan Natalie J,Edgell Tracey A,Vollenhoven Beverley J,Lutjen Peter J,Osianlis Tiki,Salamonsen Lois A,Rombauts Luk J F Human reproduction update BACKGROUND:Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports from observational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. METHODS:This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. RESULTS:Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometrium to hCG, resulting from controlled ovarian stimulation. The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. CONCLUSIONS:This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies. 10.1093/humupd/dmu027
    A cost-effectiveness analysis of freeze-only or fresh embryo transfer in IVF of non-PCOS women. Le Khoa D,Vuong Lan N,Ho Tuong M,Dang Vinh Q,Pham Toan D,Pham Clarabelle T,Norman Robert J,Mol Ben Willem J Human reproduction (Oxford, England) STUDY QUESTION:Is a freeze-only strategy more cost-effective from a patient perspective than fresh embryo transfer (ET) after one completed In Vitro Fertilization/ Intracytoplasmic Sperm Injection (IVF/ICSI) cycle in women without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER:There is a low probability of the freeze-only strategy being cost-effective over the fresh ET strategy for non-PCOS women undergoing IVF/ICSI. WHAT IS KNOWN ALREADY:Conventionally, IVF embryos are transferred in the same cycle in which oocytes are collected, while any remaining embryos are frozen and stored. We recently evaluated the effectiveness of a freeze-only strategy compared with a fresh ET strategy in a randomized controlled trial (RCT). There was no difference in live birth rate between the two strategies. STUDY DESIGN, SIZE, DURATION:A cost-effectiveness analysis (CEA) was performed alongside the RCT to compare a freeze-only strategy with a fresh ET strategy in non-PCOS women undergoing IVF/ICSI. The effectiveness measure for the CEA was the live birth rate. Data on the IVF procedure, pregnancy outcomes and complications were collected from chart review; additional information was obtained using patient questionnaires, by telephone. PARTICIPANTS/MATERIALS, SETTING, METHODS:For all patients, we measured the direct medical costs relating to treatment (cryopreservation, pregnancy follow-up, delivery), direct non-medical costs (travel, accommodation) and indirect costs (income lost). The direct cost data were calculated from resources obtained from patient records and prices were applied based on a micro-costing approach. Indirect costs were calculated based on responses to the questionnaire. Patients were followed until all embryos obtained from a single controlled ovarian hyperstimulation cycle were used or a live birth was achieved. The incremental cost-effectiveness ratio (ICER) was based on the incremental cost per couple and the incremental live birth rate of the freeze-only strategy compared with the fresh ET strategy. Probabilistic sensitivity analysis (PSA) and a cost-effectiveness acceptability curve (CEAC) were also performed. MAIN RESULTS AND THE ROLE OF CHANCE:Between June 2015 and April 2016, 782 couples were randomized to a freeze-only (n = 391) or a fresh ET strategy (n = 391). Baseline characteristics including mean age, Body Mass Index (BMI), anti-Mullerian hormone, total dose of Follicle Stimulating Hormone (FSH), number of oocytes obtained, good quality Day 3 embryos, fertility outcomes and treatment complications were comparable between the two groups. The live birth rate (48.6% vs. 47.3%, respectively; risk ratio, 1.03; 95% Confidence Interval [CI], 0.89, 1.19; P = 0.78) and the average cost per couple (3906 vs. 3512 EUR, respectively; absolute difference 393.6, 95% CI, -76.2, 863.5; P = 0.1) were similar in the freeze-only group versus fresh ET. Corresponding costs per live birth were 8037 EUR versus 7425 EUR in the freeze-only versus fresh ET group, respectively. The incremental cost for the freeze-only strategy compared with fresh ET was 30 997 EUR per 1% additional live birth rate. The direct non-medical costs and indirect costs of infertility treatment strategies represented ~45-52% of the total cost. PSA shows that the 95% CI of ICERs was -263 901 to 286 681 EUR. Out of 1000 simulations, 44% resulted in negative ICERs, including 13.0% of simulations in which the freeze-only strategy was dominant (more effective and less costly than fresh ET), and 31% of simulations in which the fresh embryo strategy was dominant. In the other 560 simulations with positive ICERs, the 95% CI of ICERs ranged from 2155 to 471 578 EUR. The CEAC shows that at a willingness to pay threshold of 300 000 EUR, the probability of the freeze-only strategy being cost-effective over the fresh ET strategy would be 58%. LIMITATIONS, REASONS FOR CAUTION:Data were collected from a single private IVF center study in Vietnam where there is no public or insurance funding of IVF. Unit costs obtained might not be representative of other settings. Data obtained from secondary sources (medical records, financial and activity reports) could lack authenticity, and recall bias may have influenced questionnaire responses on which direct costs were based. WIDER IMPLICATIONS OF THE FINDINGS:In non-PCOS women undergoing IVF/ICSI, the results suggested that the freeze-only strategy was not cost-effective compared with fresh ET from a patient perspective. These findings indicate that other factors could be more important in deciding whether to use a freeze-only versus fresh ET strategy in this patient group. STUDY FUNDING/COMPETING INTEREST(S):This study was funded by My Duc Hospital; no external funding was received. Ben Willem J. Mol is supported by an NHMRC Practioner Fellowship (GNT 1082548) and reports consultancy for Merck, ObsEva and Guerbet. Robert J. Norman has shares in an IVF company and has received support from Merck and Ferring. All other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:Not applicable. 10.1093/humrep/dey253
    Should we still offer elective freezing of all embryos in all IVF cycles? Ben Rafael Zion Human reproduction (Oxford, England) Elective 'freeze all', also called 'freeze only', refers to an IVF cycle where all embryos are frozen for later embryo transfer in a non-stimulated cycle, with the promise of increased success rates and prevention of ovarian hyperstimulation syndrome (OHSS) in most patients. However, 'freeze all' is associated with significantly higher perinatal complications including eclampsia, preeclampsia, chronic hypertension and large-for-gestational-age infants, without the demonstrated advantages of providing better results, except for a decrease in the incidence of OHSS, which should matter to women with polycystic ovary syndrome (PCOS) and high responders to ovarian stimulation but not to all patients. 'Freeze all' is also suggested for all simulated IVF cycles, due to the alleged 'faulty endometrium' caused by ovarian stimulation. However, there is no direct evidence that asynchronous endometrium exists, and only if preovulatory progesterone level increase, can 'freeze all' confer an advantage. We conclude that an alleged diagnosis of 'faulty endometrium' should not be used as an indication for 'freeze all'. To offset the risk of OHSS more simply, less costly and less risky solutions such as mild ovarian stimulation, to dampen the number of oocytes and to aim for transfer of a single blastocyst, should be the preferred solution to treat women with PCOS and high responders for oocyte retrieval. 10.1093/humrep/deaa204
    Transfer of fresh or frozen embryos: a randomised controlled trial. Wong K M,van Wely M,Verhoeve H R,Kaaijk E M,Mol F,van der Veen F,Repping S,Mastenbroek S Human reproduction (Oxford, England) STUDY QUESTION:Is IVF with frozen-thawed blastocyst transfer (freeze-all strategy) more effective than IVF with fresh and frozen-thawed blastocyst transfer (conventional strategy)? SUMMARY ANSWER:The freeze-all strategy was inferior to the conventional strategy in terms of cumulative ongoing pregnancy rate per woman. WHAT IS KNOWN ALREADY:IVF without transfer of fresh embryos, thus with frozen-thawed embryo transfer only (freeze-all strategy), is increasingly being used in clinical practice because of a presumed benefit. It is still unknown whether this new IVF strategy increases IVF efficacy. STUDY DESIGN, SIZE, DURATION:A single-centre, open label, two arm, parallel group, randomised controlled superiority trial was conducted. The trial was conducted between January 2013 and July 2015 in the Netherlands. The intervention was one IVF cycle with frozen-thawed blastocyst transfer(s) versus one IVF cycle with fresh and frozen-thawed blastocyst transfer(s). The primary outcome was cumulative ongoing pregnancy resulting from one IVF cycle within 12 months after randomisation. Couples were allocated in a 1:1 ratio to the freeze-all strategy or the conventional strategy with an online randomisation programme just before the start of down-regulation. PARTICIPANTS/MATERIALS, SETTING, METHODS:Participants were subfertile couples with any indication for IVF undergoing their first IVF cycle, with a female age between 18 and 43 years. Differences in cumulative ongoing pregnancy rates were expressed as relative risks (RR) with 95% CI. All outcomes were analysed following the intention-to-treat principle. MAIN RESULTS AND THE ROLE OF CHANCE:Two-hundred-and-five couples were randomly assigned to the freeze-all strategy (n = 102) or to the conventional strategy (n = 102). The cumulative ongoing pregnancy rate per woman was significantly lower in women allocated to the freeze-all strategy (19/102 (19%)) compared to women allocated to the conventional strategy (32/102 (31%); RR 0.59; 95% CI 0.36-0.98). LIMITATIONS, REASONS FOR CAUTION:As this was a single-centre study, we were unable to study differences in study protocols and clinic performance. This, and the limited sample size, should make one cautious in using the results as the basis for definitive policy. All patients undergoing IVF, including those with a poor prognosis, were included; therefore, the outcome could differ in women with a good prognosis of IVF treatment success. WIDER IMPLICATIONS OF THE FINDINGS:Our results indicate that there might be no benefit of a freeze-all strategy in terms of cumulative ongoing pregnancy rates. The efficacy of the freeze-all strategy in subgroups of patients, different stages of embryo development, and different freezing protocols needs to be further established and balanced against potential benefits and harms for mothers and children. STUDY FUNDING/COMPETING INTEREST(S):The Netherlands Organisation for Health Research and Development (ZonMW grant 171101007). S.M., F.M. and M.v.W. stated they are authors of the Cochrane review 'Fresh versus frozen embryo transfers in assisted reproduction'. TRIAL REGISTRATION NUMBER:Dutch Trial Register, NTR3187. TRIAL REGISTRATION DATE:9 December 2011. DATE OF FIRST PATIENT’S ENROLMENT:8 January 2013. 10.1093/humrep/deaa305
    Assisted hatching on assisted conception (in vitro fertilisation (IVF) and intracytoplasmic sperm injection (ICSI)). Lacey Lauren,Hassan Sibte,Franik Sebastian,Seif Mourad W,Akhtar M Ahsan The Cochrane database of systematic reviews BACKGROUND:Failure of implantation and conception may result from inability of the blastocyst to escape from its outer coat, which is known as the zona pellucida. Artificial disruption of this coat is known as assisted hatching and has been proposed as a method for improving the success of assisted conception by facilitating embryo implantation. OBJECTIVES:To determine effects of assisted hatching (AH) of embryos derived from assisted conception on live birth and multiple pregnancy rates.  SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register (until May 2020), the Cochrane Central Register of Controlled Trials (CENTRAL; until May 2020), in the Cochrane Library; MEDLINE (1966 to May 2020); and Embase (1980 to May 2020). We also searched trial registers for ongoing and registered trials (http://www.clinicaltrials.gov - a service of the US National Institutes of Health; http://www.who.int/trialsearch/Default.aspx - The World Health Organization International Trials Registry Platform search portal) (May 2020). SELECTION CRITERIA:Two review authors identified and independently screened trials. We included randomised controlled trials (RCTs) of AH (mechanical, chemical, or laser disruption of the zona pellucida before embryo replacement) versus no AH that reported live birth or clinical pregnancy data. DATA COLLECTION AND ANALYSIS:We used standard methodological procedures recommended by Cochrane. Two review authors independently performed quality assessments and data extraction. MAIN RESULTS:We included 39 RCTs (7249 women). All reported clinical pregnancy data, including 2486 clinical pregnancies. Only 14 studies reported live birth data, with 834 live birth events. The quality of evidence ranged from very low to low. The main limitations were serious risk of bias associated with poor reporting of study methods, inconsistency, imprecision, and publication bias. Five trials are currently ongoing. We are uncertain whether assisted hatching improved live birth rates compared to no assisted hatching (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.92 to 1.29; 14 RCTs, N = 2849; I² = 20%; low-quality evidence). This analysis suggests that if the live birth rate in women not using assisted hatching is about 28%, the rate in those using assisted hatching will be between 27% and 34%. Analysis of multiple pregnancy rates per woman showed that in women who were randomised to AH compared with women randomised to no AH, there may have been a slight increase in multiple pregnancy rates (OR 1.38, 95% CI 1.13 to 1.68; 18 RCTs, N = 4308; I² = 48%; low-quality evidence). This suggests that if the multiple pregnancy rate in women not using assisted hatching is about 9%, the rate in those using assisted hatching will be between 10% and 14%. When all of the included studies (39) are pooled, the clinical pregnancy rate in women who underwent AH may improve slightly in comparison to no AH (OR 1.20, 95% CI 1.09 to 1.33; 39 RCTs, N = 7249; I² = 55%; low-quality evidence). However, when a random-effects model is used due to high heterogeneity, there may be little to no difference in clinical pregnancy rate (P = 0.04). All 14 RCTs that reported live birth rates also reported clinical pregnancy rates, and analysis of these studies illustrates that AH may make little to no difference in clinical pregnancy rates when compared to no AH (OR 1.07, 95% CI 0.92 to 1.25; 14 RCTs, N = 2848; I² = 45%). We are uncertain about whether AH affects miscarriage rates due to the quality of the evidence (OR 1.13, 95% CI 0.82 to 1.56; 17 RCTs, N = 2810; I² = 0%; very low-quality evidence). AUTHORS' CONCLUSIONS:This update suggests that we are uncertain of the effects of assisted hatching (AH) on live birth rates. AH may lead to increased risk of multiple pregnancy. The risks of complications associated with multiple pregnancy may be increased without evidence to demonstrate an increase in live birth rate, warranting careful consideration of the routine use of AH for couples undergoing in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI). AH may offer a slightly increased chance of achieving a clinical pregnancy, but data quality was of low grade. We are uncertain about whether AH influences miscarriage rates. 10.1002/14651858.CD001894.pub6
    Cumulative live birth rates following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF: a population-based retrospective cohort study. Cameron N J,Bhattacharya S,McLernon D J Human reproduction (Oxford, England) STUDY QUESTION:Is there a difference in the odds of a live birth following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF? SUMMARY ANSWER:After adjusting for indication bias, there was not enough evidence to suggest a difference in the odds of live birth following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF. WHAT IS KNOWN ALREADY:Replacement of blastocyst-stage embryos has become the dominant practice in IVF but there is uncertainty about whether this technique offers an improved chance of cumulative live birth over all fresh and frozen-thawed embryo transfer attempts associated with a single oocyte retrieval. STUDY DESIGN, SIZE, DURATION:National population-based retrospective cohort study of 100 610 couples who began their first IVF/ICSI treatment at a licenced UK clinic between 1 January 1999 and 30 July 2010. PARTICIPANTS/MATERIALS, SETTING, METHODS:Data from the Human Fertilisation and Embryology Authority (HFEA) register on IVF/ICSI treatments using autologous gametes between 1999 and 2010 were analysed. The primary outcome was the live birth rate over the first complete cycle of IVF. Cumulative live birth rates (CLBR) were compared for couples who underwent blastocyst and cleavage transfer, and the adjusted odds of live birth over the first complete cycle were estimated for each group using binary logistic regression. This analysis was repeated within groups of female age, oocytes collected and primary versus secondary infertility. Inverse probability of treatment weighting was used to account for the imbalance in couple characteristics between treatment groups. MAIN RESULTS AND THE ROLE OF CHANCE:In total, 94 294 (93.7%) couples had a cleavage-stage embryo transfer while 6316 (6.3%) received blastocysts. Over the first complete cycle of IVF/ICSI (incorporating all fresh and frozen-thawed embryo transfers associated with the first oocyte retrieval), the CLBR was increased in those who underwent blastocyst transfer (56.5%) compared to cleavage-stage embryo transfer (34.8%). However, after accounting for the imbalance between exposures, blastocyst transfer did not significantly influence the odds of live birth over the first complete cycle (adjusted odds ratio: 1.03 (0.96, 1.10)). LIMITATIONS, REASONS FOR CAUTION:Limitations of our study include the retrospective nature of the HFEA dataset and availability of linked data up until 2010. We were unable to adjust for some confounders, such as smoking status, BMI and embryo quality, as these data are not collected at national level by the HFEA. Similarly, there may be unknown couple, treatment or clinic variables that may influence our results. We were unable to assess the intended stage of embryo transfer for women who did not have an embryo replaced, and therefore excluded them from our study. Perinatal outcomes were not included in our analyses and would be a useful basis for future study. WIDER IMPLICATIONS OF THE FINDINGS:Our findings show that blastocyst-stage embryo transfer may offer an improved chance of live birth in both the first fresh and the first complete cycle of IVF/ICSI compared to cleavage-stage transfer, even in couples with typically poorer prognoses. Where possible, offering blastocyst transfer to a wider range of couples may increase cumulative success rates. STUDY FUNDING/COMPETING INTEREST(S):N.J.C. received a Wolfson Foundation Intercalated Degree Research Fellowship funded by the Wolfson Foundation, through the Royal College of Physicians. This work was supported by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06) held by D.J.M. The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office or the Wolfson Foundation. The funders did not have any role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. None of the authors has any conflicts of interest to declare. TRIAL REGISTRATION NUMBER:N/A. 10.1093/humrep/deaa186
    Individualised luteal phase support in artificially prepared frozen embryo transfer cycles based on serum progesterone levels: a prospective cohort study. Álvarez Manuel,Gaggiotti-Marre Sofía,Martínez Francisca,Coll Lluc,García Sandra,González-Foruria Iñaki,Rodríguez Ignacio,Parriego Mónica,Polyzos Nikolaos P,Coroleu Buenaventura Human reproduction (Oxford, England) STUDY QUESTION:Does an individualised luteal phase support (iLPS), according to serum progesterone (P4) level the day prior to euploid frozen embryo transfer (FET), improve pregnancy outcomes when started on the day previous to embryo transfer? SUMMARY ANSWER:Patients with low serum P4 the day prior to euploid FET can benefit from the addition of daily subcutaneous P4 injections (Psc), when started the day prior to FET, and achieve similar reproductive outcomes compared to those with initial adequate P4 levels. WHAT IS KNOWN ALREADY:The ratio between FET/IVF has spectacularly increased in the last years mainly thanks to the pursuit of an ovarian hyperstimulation syndrome free clinic and the development of preimplantation genetic testing (PGT). There is currently a big concern regarding the endometrial preparation for FET, especially in relation to serum P4 levels around the time of embryo transfer. Several studies have described impaired pregnancy outcomes in those patients with low P4 levels around the time of FET, considering 10 ng/ml as one of the most accepted reference values. To date, no prospective study has been designed to compare the reproductive outcomes between patients with adequate P4 the day previous to euploid FET and those with low, but restored P4 levels on the transfer day after iLPS through daily Psc started on the day previous to FET. STUDY DESIGN, SIZE, DURATION:A prospective observational study was conducted at a university-affiliated fertility centre between November 2018 and January 2020 in patients undergoing PGT for aneuploidies (PGT-A) IVF cycles and a subsequent FET under hormone replacement treatment (HRT). A total of 574 cycles (453 patients) were analysed: 348 cycles (leading to 342 euploid FET) with adequate P4 on the day previous to FET, and 226 cycles (leading to 220 euploid FET) under iLPS after low P4 on the previous day to FET, but restored P4 levels on the transfer day. PARTICIPANTS/MATERIALS, SETTING, METHODS:Overall we included 574 HRT FET cycles (453 patients). Standard HRT was used for endometrial preparation. P4 levels were measured the day previous to euploid FET. P4 > 10.6 ng/ml was considered as adequate and euploid FET was performed on the following day (FET Group 1). P4 < 10.6 ng/ml was considered as low, iLPS was added in the form of daily Psc injections, and a new P4 analysis was performed on the following day. FET was only performed on the same day when a restored P4 > 10.6 ng/ml was achieved (98.2% of cases) (FET Group 2). MAIN RESULTS AND THE ROLE OF CHANCE:Patient's demographics and cycle parameters were comparable between both euploid FET groups (FET Group 1 and FET Group 2) in terms of age, weight, oestradiol and P4 levels and number of embryos transferred. No statistically significant differences were found in terms of clinical pregnancy rate (56.4% vs 59.1%: rate difference (RD) -2.7%, 95% CI [-11.4; 6.0]), ongoing pregnancy rate (49.4% vs 53.6%: RD -4.2%, 95% CI [-13.1; 4.7]) or live birth rate (49.1% vs 52.3%: RD -3.2%, 95% CI [-12; 5.7]). No significant differences were also found according to miscarriage rate (12.4% vs 9.2%: RD 3.2%, 95% CI [-4.3; 10.7]). LIMITATIONS, REASONS FOR CAUTION:Only iLPS through daily Psc was evaluated. The time for Psc injection was not stated and no serum P4 determinations were performed once the pregnancy was achieved. WIDER IMPLICATIONS OF THE FINDINGS:Our study provides information regarding an 'opportunity window' for improved ongoing pregnancy rates and miscarriage rates through a daily Psc injection in cases of inadequate P4 levels the day previous to FET (P4 < 10.6 ng/ml) and restored values the day of FET (P4 > 10.6 ng/ml). Only euploid FET under HRT were considered, avoiding one of the main reasons of miscarriage and implantation failure and overcoming confounding factors such as female age, embryo quality or ovarian stimulation protocols. STUDY FUNDING/COMPETING INTEREST(S):No external funding was received. B.C. reports personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, IBSA and Gedeon Richter outside the submitted work. N.P. reports grants and personal fees from MSD, Merck Serono, Ferring Pharmaceuticals, Theramex and Besins International and personal fees from IBSA and Gedeon Richter outside the submitted work. The remaining authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:NCT03740568. 10.1093/humrep/deab031
    Immediate versus postponed frozen embryo transfer after IVF/ICSI: a systematic review and meta-analysis. Bergenheim Sara J,Saupstad Marte,Pistoljevic Nina,Andersen Anders Nyboe,Forman Julie Lyng,Løssl Kristine,Pinborg Anja Human reproduction update 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. 10.1093/humupd/dmab002
    Do serum progesterone levels on day of embryo transfer influence pregnancy outcomes in artificial frozen-thaw cycles? Volovsky Michelle,Pakes Cassandra,Rozen Genia,Polyakov Alex Journal of assisted reproduction and genetics PURPOSE:The purpose of this study is to investigate whether progesterone (P4) levels on the day of frozen-thawed embryo transfer (FET) to a hormonally prepared endometrium correlate with pregnancy outcomes. METHODS:This is a large retrospective cohort analysis comprising of N = 2010 FETs. In these cycles, P4 levels on the day of transfer were assessed in relation to pregnancy outcomes. A threshold of 10 ng/mL was used to simulate currently accepted levels for physiological corpus luteal function. Biochemical pregnancy, clinical pregnancy, and live birth rates were compared between those with P4 levels above and below this threshold. Analyses using transfer day P4 thresholds of 5 ng/mL and 20 ng/mL were then completed to see if these could create further prognostic power. RESULTS:When comparing FET outcomes in relation to P4 levels < 10 ng/mL and ≥ 10 ng/mL, we observed no differences in biochemical pregnancy rates (39.53% vs. 40.98%, p = 0.52), clinical pregnancy rates (20.82 vs. 22.78, p = 0.30), and live birth rates (14.25 vs. 16.21 p = 0.23). In patients whose P4 met the threshold of 20 ng/mL, there was similarly no statistically significant improvement in pregnancy outcomes. While there was no difference for biochemical or clinical pregnancy rates, a statistically significant improvement in live birth rates was observed for those with a transfer day P4 level ≥ 5 ng/mL. CONCLUSIONS:We demonstrated that P4 levels at or above 10 ng/mL on the day of FET do not confer a statistically significant improvement in pregnancy outcomes. P4 below 5 ng/mg was associated with lower live birth rates suggesting that there is a threshold below which it is difficult to salvage FET cycles. 10.1007/s10815-020-01713-w
    Fresh versus frozen embryo transfers in assisted reproduction. Zaat Tjitske,Zagers Miriam,Mol Femke,Goddijn Mariëtte,van Wely Madelon,Mastenbroek Sebastiaan The Cochrane database of systematic reviews BACKGROUND:In vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) treatments conventionally consist of a fresh embryo transfer, possibly followed by one or more cryopreserved embryo transfers in subsequent cycles. An alternative option is to freeze all suitable embryos and transfer cryopreserved embryos in subsequent cycles only, which is known as the 'freeze all' strategy. This is the first update of the Cochrane Review on this comparison. OBJECTIVES:To evaluate the effectiveness and safety of the freeze all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology. SEARCH METHODS:We searched the Cochrane Gynaecology and Fertility Group Trials Register, CENTRAL, MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials from inception until 23 September 2020 for relevant studies, checked references of publications found, and contacted study authors to obtain additional data. SELECTION CRITERIA:Two review authors (TZ and MZ) independently selected studies for inclusion, assessed risk of bias, and extracted study data. We included randomised controlled trials comparing a 'freeze all' strategy with a conventional IVF/ICSI strategy including a fresh embryo transfer in women undergoing IVF or ICSI treatment. DATA COLLECTION AND ANALYSIS:The primary outcomes were cumulative live birth rate and ovarian hyperstimulation syndrome (OHSS). Secondary outcomes included effectiveness outcomes (including ongoing pregnancy rate and clinical pregnancy rate), time to pregnancy and obstetric, perinatal and neonatal outcomes. MAIN RESULTS:We included 15 studies in the systematic review and eight studies with a total of 4712 women in the meta-analysis. The overall evidence was of moderate to low quality. We graded all the outcomes and downgraded due to serious risk of bias, serious imprecision and serious unexplained heterogeneity. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study during the interim analysis, unit of analysis error, and absence of adequate study termination rules. There was an absence of high-quality evidence according to GRADE assessments for our primary outcomes, which is reflected in the cautious language below. There is probably little or no difference in cumulative live birth rate between the 'freeze all' strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.08, 95% CI 0.95 to 1.22; I = 0%; 8 RCTs, 4712 women; moderate-quality evidence). This suggests that for a cumulative live birth rate of 58% following the conventional strategy, the cumulative live birth rate following the 'freeze all' strategy would be between 57% and 63%. Women might develop less OHSS after the 'freeze all' strategy compared to the conventional IVF/ICSI strategy (OR 0.26, 95% CI 0.17 to 0.39; I = 0%; 6 RCTs, 4478 women; low-quality evidence). These data suggest that for an OHSS rate of 3% following the conventional strategy, the rate following the 'freeze all' strategy would be 1%. There is probably little or no difference between the two strategies in the cumulative ongoing pregnancy rate (OR 0.95, 95% CI 0.75 to 1.19; I = 31%; 4 RCTs, 1245 women; moderate-quality evidence).  We could not analyse time to pregnancy; by design, time to pregnancy is shorter in the conventional strategy than in the 'freeze all' strategy when the cumulative live birth rate is comparable, as embryo transfer is delayed in a 'freeze all' strategy. We are uncertain whether the two strategies differ in cumulative miscarriage rate because the evidence is very low quality (Peto OR 1.06, 95% CI 0.72 to 1.55; I = 55%; 2 RCTs, 986 women; very low-quality evidence) and cumulative multiple-pregnancy rate (Peto OR 0.88, 95% CI 0.61 to 1.25; I = 63%; 2 RCTs, 986 women; very low-quality evidence). The risk of hypertensive disorders of pregnancy (Peto OR 2.15, 95% CI 1.42 to 3.25; I = 29%; 3 RCTs, 3940 women; low-quality evidence), having a large-for-gestational-age baby (Peto OR 1.96, 95% CI 1.51 to 2.55; I = 0%; 3 RCTs, 3940 women; low-quality evidence) and a higher birth weight of the children born (mean difference (MD) 127 g, 95% CI 77.1 to 177.8; I = 0%; 5 RCTs, 1607 singletons; moderate-quality evidence) may be increased following the 'freeze all' strategy. We are uncertain whether the two strategies differ in the risk of having a small-for-gestational-age baby because the evidence is low quality (Peto OR 0.82, 95% CI 0.65 to 1.05; I = 64%; 3 RCTs, 3940 women; low-quality evidence). AUTHORS' CONCLUSIONS:We found moderate-quality evidence showing that one strategy is probably not superior to the other in terms of cumulative live birth rate and ongoing pregnancy rate. The risk of OHSS may be decreased in the 'freeze all' strategy. Based on the results of the included studies, we could not analyse time to pregnancy. It is likely to be shorter using a conventional IVF/ICSI strategy with fresh embryo transfer in the case of similar cumulative live birth rate, as embryo transfer is delayed in a 'freeze all' strategy. The risk of maternal hypertensive disorders of pregnancy, of having a large-for-gestational-age baby and a higher birth weight of the children born may be increased following the 'freeze all' strategy. We are uncertain if 'freeze all' strategy reduces the risk of miscarriage, multiple pregnancy rate or having a small-for-gestational-age baby compared to conventional IVF/ICSI. 10.1002/14651858.CD011184.pub3
    Cycle regimens for frozen-thawed embryo transfer. Ghobara Tarek,Gelbaya Tarek A,Ayeleke Reuben Olugbenga The Cochrane database of systematic reviews BACKGROUND:Among subfertile couples undergoing assisted reproductive technology (ART), pregnancy rates following frozen-thawed embryo transfer (FET) treatment cycles have historically been found to be lower than following embryo transfer undertaken two to five days following oocyte retrieval. Nevertheless, FET increases the cumulative pregnancy rate, reduces cost, is relatively simple to undertake and can be accomplished in a shorter time period than repeated in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles with fresh embryo transfer. 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; the first version was published in 2008. 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:On 13 December 2016 we searched databases including Cochrane Gynaecology and Fertility's Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. Other search sources were trials registers and reference lists of included studies. SELECTION CRITERIA:We included randomized 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 rates and miscarriage. MAIN RESULTS:We included 18 RCTs comparing different cycle regimens for FET in 3815 women. The quality of the evidence was low or very low. The main limitations were failure to report important clinical outcomes, poor reporting of study methods and imprecision due to low event rates. We found no data specific to non-ovulatory women. 1. Natural cycle FET comparisons Natural cycle FET versus HT FETNo study reported live birth rates, miscarriage or ongoing pregnancy.There was no evidence of a difference in multiple pregnancy rates between women in natural cycles and those in HT FET cycle (odds ratio (OR) 2.48, 95% confidence interval (CI) 0.09 to 68.14, 1 RCT, n = 21, very low-quality evidence). Natural cycle FET versus HT plus GnRHa suppressionThere was no evidence of a difference in rates of live birth (OR 0.77, 95% CI 0.39 to 1.53, 1 RCT, n = 159, low-quality evidence) or multiple pregnancy (OR 0.58, 95% CI 0.13 to 2.50, 1 RCT, n = 159, low-quality evidence) between women who had natural cycle FET and those who had HT FET cycles with GnRHa suppression. No study reported miscarriage or ongoing pregnancy. Natural cycle FET versus modified natural cycle FET (human chorionic gonadotrophin (HCG) trigger)There was no evidence of a difference in rates of live birth (OR 0.55, 95% CI 0.16 to 1.93, 1 RCT, n = 60, very low-quality evidence) or miscarriage (OR 0.20, 95% CI 0.01 to 4.13, 1 RCT, n = 168, very low-quality evidence) between women in natural cycles and women in natural cycles with HCG trigger. However, very low-quality evidence suggested that women in natural cycles (without HCG trigger) may have higher ongoing pregnancy rates (OR 2.44, 95% CI 1.03 to 5.76, 1 RCT, n = 168). There were no data on multiple pregnancy. 2. Modified natural cycle FET comparisons Modified natural cycle FET (HCG trigger) versus HT FETThere was no evidence of a difference in rates of live birth (OR 1.34, 95% CI 0.88 to 2.05, 1 RCT, n = 959, low-quality evidence) or ongoing pregnancy (OR 1.21, 95% CI 0.80 to 1.83, 1 RCT, n = 959, low-quality evidence) between women in modified natural cycles and those who received HT. There were no data on miscarriage or multiple pregnancy. Modified natural cycle FET (HCG trigger) versus HT plus GnRHa suppressionThere was no evidence of a difference between the two groups in rates of live birth (OR 1.11, 95% CI 0.66 to 1.87, 1 RCT, n = 236, low-quality evidence) or miscarriage (OR 0.74, 95% CI 0.25 to 2.19, 1 RCT, n = 236, low-quality evidence) rates. There were no data on ongoing pregnancy or multiple pregnancy. 3. HT FET comparisons HT FET versus HT plus GnRHa suppressionHT alone was associated with a lower live birth rate than HT with GnRHa suppression (OR 0.10, 95% CI 0.04 to 0.30, 1 RCT, n = 75, low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 0.64, 95% CI 0.37 to 1.12, 6 RCTs, n = 991, I = 0%, low-quality evidence) or ongoing pregnancy (OR 1.72, 95% CI 0.61 to 4.85, 1 RCT, n = 106, very low-quality evidence).There were no data on multiple pregnancy. 4. Comparison of subtypes of ovulation induction FET Human menopausal gonadotrophin(HMG) versus clomiphene plus HMG HMG alone was associated with a higher live birth rate than clomiphene combined with HMG (OR 2.49, 95% CI 1.07 to 5.80, 1 RCT, n = 209, very low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 1.33, 95% CI 0.35 to 5.09,1 RCT, n = 209, very low-quality evidence) or multiple pregnancy (OR 1.41, 95% CI 0.31 to 6.48, 1 RCT, n = 209, very low-quality evidence).There were no data on ongoing pregnancy. AUTHORS' CONCLUSIONS: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 modalities for FET are natural cycle with or without HCG trigger or endometrial preparation with HT, with or without GnRHa suppression. We identified only four direct comparisons of these two modalities and there was insufficient evidence to support the use of either one in preference to the other. 10.1002/14651858.CD003414.pub3