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Is a freeze-all policy the optimal solution to circumvent the effect of late follicular elevated progesterone? A multicentric matched-control retrospective study analysing cumulative live birth rate in 942 non-elective freeze-all cycles
Abstract
STUDY QUESTION
Is late follicular elevated progesterone (LFEP) in the fresh cycle hindering cumulative live birth rates (CLBRs) when a freeze only strategy is applied?
SUMMARY ANSWER
LFEP in the fresh cycle does not affect the CLBR of the frozen transfers in a freeze only approach, nor the embryo freezing rate.
WHAT IS KNOWN ALREADY
Ovarian stimulation promotes the production of progesterone (P) which has been demonstrated to have a deleterious effect on IVF outcomes. While there is robust evidence that this elevation produces impaired endometrial receptivity, the impact on embryo quality remains a matter of debate. In particular, previous studies have shown that LFEP is associated with a hindered CLBR. However, most clinical insight on the effect of progesterone on embryo quality in terms of CLBRs have focused on embryo transfers performed after the fresh transfer, thus excluding the first embryo of the cohort. To be really informative on the possible detrimental effects of LFEP, evidence should be derived from freeze-all cycles where no fresh embryo transfer is performed in the presence of progesterone elevation, and the entire cohort of embryos is cryopreserved.
STUDY DESIGN, SIZE, DURATION
This was a matched case-control, multicentre (three centres), retrospective analysis including all GnRH antagonist ICSI cycles in which a freeze all (FA) policy of embryos on day 3/5/6 of embryonic development was applied between 2012 and 2018. A total of 942 patients (471 cases with elevated P and 471 matched controls with normal P values) were included in the analysis. Each patient was included only once.
PARTICIPANTS/MATERIALS, SETTING, METHODS
The sample was divided according to the following P levels on the day of ovulation triggering: <1.50 ng/ml and ≥1.50 ng/ml. The matching of the controls was performed according to age (±1 year) and number of oocytes retrieved (±10%). The main outcome was CLBR defined as a live-born delivery after 24 weeks of gestation.
MAIN RESULTS AND THE ROLE OF CHANCE
The baseline characteristics of the two groups were similar. Estradiol levels on the day of trigger were significantly higher in the elevated P group. There was no significant difference in terms of fertilisation rate between the two groups. The elevated P group had significantly more cleavage stage frozen embryos compared to the normal P group while the total number of cryopreserved blastocyst stage embryos was the same. The CLBR did not differ between the two study groups (29.3% and 28.2% in the normal versus LFEP respectively, P = 0.773), also following confounder adjustment using multivariable GEE regression analysis (accounting for age at oocyte retrieval, total dose of FSH, progesterone levels on the day of ovulation trigger, day of freezing, at least one top-quality embryo transferred and number of previous IVF cycles, as the independent variables).
LIMITATIONS, REASONS FOR CAUTION
This is a multicentre observational study based on a retrospective data analysis. Better extrapolation of the results could be validated by performing a prospective analysis.
WIDER IMPLICATIONS OF THE FINDINGS
This is the first study demonstrating that LFEP in the fresh cycle does not hinder CLBR of the subsequent frozen cycles in a FA approach. Thus, a FA strategy circumvents the issue of elevated P in the late follicular phase.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was received for this study. Throughout the study period and manuscript preparation, authors were supported by departmental funds from: Centre for Reproductive Medicine, Brussels, Belgium; Infertility Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; Centro Scienze Natalità, San Raffaele Scientific Institute, Milan, Italy; and IVI-RMA, Lisbon, Portugal. E.S. has competing interests with Ferring, Merck-Serono, Theramex and Gedeon-Richter outside the submitted work. E.P. reports grants from Ferring, grants and personal fees from Merck-Serono, grants and personal fees from MSD and grants from IBSA outside the submitted work. All the other authors have no conflicts of interest to declare.
TRIAL REGISTRATION NUMBER
N/A.
... However, none of the studies exploring the associations between the hormonal milieu during OS and neonatal outcomes after FET has accounted for late follicular P levels. We therefore conducted the first study assessing the relationship between P levels at the end of OS and birthweight of singletons born at term after FET by encompassing a secondary analysis of our previous study on the live-birth outcomes of a freeze-all (or segmented) strategy in presence of normal versus elevated P levels [27] and enlarging the study cohort with additional consecutive patients undergoing a segmented (or freeze-all) ART cycle. P levels at trigger was studied both in terms of actual circulating P levels and in terms of P levels per oocyte retrieved, as this might estimate follicular exposure of each oocyte to P, with implications on quality [28]. ...
... Data collection was carried out at three tertiary care hospitals (Centro Scienze Natalita, San Raffaele Scientific Institute, Milan, Italy; Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Brussels IVF, Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, Belgium). First, the cohort of women enrolled in our recent study on CLBR in freezeall antagonist-suppressed ICSI cycles with or without P elevation was included [27]. Then, consecutive FET cycles following homologous Gn-RH antagonist protocol ICSI treatment from January 2019 to January 2020 and resulting in a singleton uncomplicated pregnancy that achieved delivery at early (37 to 38 + 6 weeks of pregnancy), full (39 to 40 + 6 weeks of pregnancy), or late term (41 to 41 + 4 weeks of pregnancy) were also included. ...
... Patients with pre-term birth or with pregnancy complications such as gestational diabetes, hypertensive disorders, or antiphospholipid syndrome were excluded from the analysis. Indications for the freeze-all strategy, Gn-RH antagonist ART protocols, laboratory procedures for insemination, embryo quality assessment, cryopreservation, and endometrial preparation for the FET were standardized among the three centers and described in a recent publication of our groups [27]. In more detail, all FETs were performed in a postponed cycle, not immediately following oocyte retrieval. ...
Purpose
To evaluate the association between serum progesterone (P) at the day of ovulation trigger and neonatal birthweight in singletons born after frozen-thawed embryo transfer in segmented ART cycles.
Methods
A retrospective multicenter cohort study involving data from patients who achieved uncomplicated pregnancy and term delivery of ART-conceived singleton babies following a segmented GnRH antagonist cycle. The main outcome was birthweight’s z-score of the neonate. Univariate and multivariate linear logistic regression analyses were made to investigate the relation of z-score with variables inherent to the patient and to the ovarian stimulation. The variable P per oocyte was created by dividing the value of progesterone at ovulation trigger by the number of oocytes retrieved at oocyte retrieval.
Results
A total of 368 patients were included in the analysis. At univariate linear regression, the birthweight z-score of the neonate appeared to be inversely related to both P levels at the ovulation trigger (− 0.101, p = 0.015) and P levels per oocyte at trigger (− 1.417, p = 0.001), while it was directly related to the height of the mother (0.026, p = 0.002) and to the number of previous live births (0.291, p = 0.016). In multivariate analysis, both serum P (− 0.1; p = 0.015) and P per oocyte (− 1.347, p = 0.002) maintained the significant inverse association with birthweight z-score after adjusting for height and parity.
Conclusions
Serum progesterone level on the day of ovulation trigger inversely correlates with normalized birthweight of neonates in segmented GnRH antagonist ART cycles.
... Two studies [42,43] found that PPE in the fresh cycle did not hamper CLBR in subsequent FET cycles using a freeze-all approach. It was also demonstrated that in oocyte donation cycles, PPE had greater number of oocytes obtained and good quality cleavage stage embryos. ...
... Impact of elevated P on trigger day on oocyte and embryo quality remains contentious even today. Ten studies have been published evaluating the impact of PPE on oocyte and embryo quality since the systematic review of Venetis et al. [6,[42][43][44]47,[53][54][55][56][57] [ Table 2]. They are all retrospective cohort studies using a P threshold of 1.5-2.0 ...
... However, the remaining six studies indicated a similar number of top-quality embryos in both groups with no obvious detrimental effect of PPE on oocyte and embryo quality. [42][43][44]47,54,57] The euploidy rate after PGT-A was also similar in most studies. [45][46][47][48] In summary, existing evidence on the influence of PPE on oocyte and embryo quality is conflicting though largely reassuring. ...
The impact of premature elevation of progesterone (PPE) on the day of the trigger on pregnancy outcome in in vitro fertilisation (IVF) cycles has been a matter of contention and debate for decades. Research over the last 30 years has indicated that PPE >1.5 ng/ml is associated with declining live birth rates following fresh embryo transfer. Freeze-only approach has become a universal solution to overcome the issue of PPE. However, the topic is still mired with controversy. Few studies have not shown a negative impact on pregnancy rates. The impact of PPE on embryological parameters such as oocyte and embryo quality and ploidy is still very controversial. An important contentious issue is the choice of the threshold P value above which it is considered abnormal and a freeze-all strategy would be cost-effective. Currently, though a cutoff of >1.5 ng/ml is widely used, practices are not uniform and varying thresholds from 0.4 to 3 ng/ml are utilised. This review addresses the current understanding of PPE in IVF and the above controversies. The incidence, aetiology and source of progesterone rise, impact on endometrial receptivity, oocyte and embryo quality, impact on live birth and cumulative live birth and impact on frozen embryo transfer and donor oocyte cycles are discussed. Current controversies regarding the optimal threshold, assay performance and future directions are addressed.
... However, data in this study may aid clinicians to more precisely predict probability of live birth and stage of embryos at transfer tailored to individual value of progesterone at the day of hCG trigger. Similar to our analysis, the study published by Racca et al., [33] suggested that fresh transfer of the top-quality embryos in patients with elevated progesterone might have been the main cause of the decreased cumulative pregnancy outcomes. The safest strategy in the case of LFPE would be to apply to freeze-all and then transfer in a subsequent thawed embryos cycle when the hormonal effect on the endometrium will have faded [33,34]. ...
... Similar to our analysis, the study published by Racca et al., [33] suggested that fresh transfer of the top-quality embryos in patients with elevated progesterone might have been the main cause of the decreased cumulative pregnancy outcomes. The safest strategy in the case of LFPE would be to apply to freeze-all and then transfer in a subsequent thawed embryos cycle when the hormonal effect on the endometrium will have faded [33,34]. There is still an urgent need for providing solid evidence regarding the most effective way of managing women with premature progesterone on the day of hCG administration. ...
Background
Late follicular phase progesterone elevation (LFPE) during ovarian stimulation is associated with reduced live birth rates (LBRs) after cleavage-stage embryo transfer. However, due to better synchronization with a stimulated endometrium, prior studies shown that LFPE had no effect on transferring embryos at blastocyst stage. The study aim to exam whether the developmental stage of embryos and serum progesterone levels on the day of human chorionic gonadotropin (hCG) administration jointly affect the odds of live birth in fresh fresh IVF/intracytoplasmic sperm injection (ICSI) cycles.
Methods
The single-center retrospective cohort study included a total of 4,471 fresh embryo transfer cycles with 2,342 at cleavage stage versus 2,129 at blastocyst stage. Patients underwent IVF/ICSI with ovarian stimulation in gonadotropin-releasing hormone antagonist protocol. The serum progesterone level was examined both as a continuous variable and as a categorical variable by quartiles. Analysis was performed using the generalized estimating equations framework and multivariate regression models.
Results
LBRs were inversely associated with progesterone as a continuous variable on the day of hCG in both the cleavage-stage (crude OR 0.87, 95%CI 0.73–1.03; adjusted OR 0.80, 95% CI 0.65–0.98) and the blastocyst-stage (crude OR 0.66, 95%CI 0.56–0,78; adjusted OR 0.61, 95%CI 0.50–0.73) groups. The interaction testing was highly significant ( P = 0.018) indicating an effect modifying role of stage of embryos transferred on the association of pregesterone values with the LBRs in fresh cycles. A similar pattern for a greater reduction in ORs for live birth in cycles with blastocysts transfer was also observed when progesterone was analyzed by interquartile ranges. The findings remained unchanged in subgroup analysis stratified by types of ovarian response.
Conclusions
In fresh cycles, detrimental effect of late follicular phase progesterone elevation on live birth was more prominent in blastocyst-stage group compared with that in clevaged-stage group.
... The presence of a deleterious impact of PPE on embryo competence was also investigated by Racca et al. [12], reporting the association of PPE with a decrease in embryo utilization and cumulative live births rate. However, a subsequent multicenter retrospective study, which evaluated only freeze-all cycles, reported no differences in cumulative live birth rate [13]. ...
... The effect of progesterone on the endometrial implantation window shift has been widely addressed [1][2][3]. In this contest, the freezeall strategy has been extensively studied as the best approach to avoid the endometrial impairment of P increase during COS [5,6], and Racca et al. [13] showed that progesterone elevation during COS did not impair clinical live birth rate (CLBR) if a freeze-all strategy was adopted. However, when approaching the PPE question in ART, some issues still need to be clarified from the embryo's side. ...
Purpose
To evaluate the association between progesterone (P) level on the day of trigger and time to blastulation in IVF cycles.
Methods
This was a retrospective cohort study with autologous IVF cycles performed at our Institution from January 2019 to December 2021. A total of 1109 IVF cycles were included. The primary outcome was to compare time to blastulation in terms of percentage of expanded (grade 3) blastocysts on day 5 according to progesterone level at trigger.
Results
A total of 3517 blastocysts were analyzed. After dividing progesterone level in quartiles (Q1, P < 0.50 ng/ml; Q2 0.50 ng/ml ≤ P ≤ 0.78 ng/ml; Q3, 0.79 ng/ml ≤ P ≤ 1.15 ng/ml; Q4, P > 1.15 ng/ml), we observed a delay in blastocyst development according to the increasing level of progesterone at trigger (analysis by rank, P-value = 0.01). After adjusting for confounding factors at the multivariate analysis, the percentage of day 5 blastocysts was reduced for Q3 (− 13.8%, 95% CI from − 20.5 to − 7.0%, p < 0.001) and Q4 (− 7.7%, 95% CI from − 15.5 to 0.0%, p = 0.05) compared to Q1 (reference).
Conclusions
Progesterone levels on day of trigger correlate to the percentage of expanded (grade 3) blastocysts on day 5 and a delayed blastocyst development day 5 is expected for high progesterone levels.
... Progesterone values were measured at the Centre for Reproductive Medicine, Universitair Ziekenhuis Brussel, using a validated electrochemiluminescence immunoassay (Cobas 8000 e801, Roche Diagnostics, Roche Diagnostics, France) with a measured sensitivity and total imprecision (coefficient of variation) of 0.03 mg/l and less than 7%, respectively (Racca et al., 2021). In a previously published paper (Lim et al., 2019), this analyser demonstrated an acceptable performance concerning precision, linearity, reference range validation and correlation. ...
... In recent years, how to promote the pregnancy rate of fresh embryo transfer with GnRH-ant protocol has become a research hotspot. Several studies have shown that serum luteinizing hormone (LH) levels, progesterone levels, trigger methods, and the method of GnRH antagonist usage during COH are associated with adverse pregnancy outcomes, but there is still a lot of controversy (7)(8)(9)(10)(11)(12)(13). ...
Introduction
Gonadotropin-releasing hormone antagonist (GnRH-ant) protocol is widely used in the world for controlled ovarian hyperstimulation (COH). However, previous studies have shown that pregnancy outcomes of fresh embryo transfer with GnRH-ant protocol are not ideal. Current studies have demonstrated the value of growth hormone (GH) in improving the pregnancy outcome of elderly women and patients with diminished ovarian reserve, but no prospective studies have confirmed the efficacy of GH in fresh embryo transfer with GnRH-ant protocol, and its potential mechanism is still unclear. This study intends to evaluate the impact of GH on IVF/ICSI outcomes and endometrial receptivity of patients undergoing GnRH-ant protocol with fresh embryo transfer, and preliminarily explore the possible mechanism.
Methods
We designed a randomized controlled trial of 120 infertile patients with normal ovarian response (NOR) who will undergo IVF/ICSI from April 2023 to April 2025, at Department of Reproductive Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. The patients will be divided into the depot gonadotropin-releasing hormone agonist (GnRH-a) protocol group, GnRH-ant protocol control group, and GnRH-ant protocol plus GH intervention group at a ratio of 1:1:1 by block randomization design. Patients will be followed on enrollment day, trigger day, embryo transfer day, 7 days after oocytes pick-up, 15 days after embryo transfer, 28 days after embryo transfer, and 12 weeks of gestation. The primary outcome is the ongoing pregnancy rate. Secondary outcomes include the gonadotropin dosage, duration of COH, endometrial thickness and pattern, luteinizing hormone, estradiol, progesterone level on trigger day, numbers of retrieved oocytes, high-quality embryo rate, biochemical pregnancy rate, clinical pregnancy rate, implantation rate, ectopic pregnancy rate, early miscarriage rate, multiple pregnancy rate and incidence of moderate and severe ovarian hyperstimulation syndrome. The endometrium of certain patients will be collected and tested for endometrial receptivity.
Ethics and dissemination
The study was approved by the Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology [approval number: TJ-IRB20230236; approval date: February 10, 2023]. The research results will be presented at scientific/medical conferences and published in academic journals.
Clinical trial registration
Chinese Clinical Trial Registry; identifier: ChiCTR2300069397.
... These effects include not only impairment of endometrial receptivity but also detrimental effects on embryo quality (3)(4)(5). However, other studies have shown contradictory results indicating that elevated P concentrations are not detrimental to pregnancy outcomes or euploidy rates (6)(7)(8). Most studies used an absolute P concentration of 0.8 to 2.0 ng/mL on the day of human chorionic gonadotropin (hCG) administration (1,9). ...
Objective
To investigate the impact of the progesterone concentration on the human chorionic gonadotropin (hCG) trigger day on clinical outcomes with an antagonist protocol.
Methods
The retrospective cohort study included a total of 1,550 fresh autologous ART cycles with one top-quality embryo transfer. Multivariate regression analysis, curve fitting, and threshold effect analysis were performed.
Results
A significant association was found between the progesterone concentration and clinical pregnancy rate (adjusted OR, 0.77; 95% CI, 0.62–0.97; P = 0.0234), especially in blastocyst transfer (adjusted OR, 0.56; 95% CI, 0.39–0.78; P = 0.0008). The association between the progesterone concentration and the ongoing pregnancy rate was insignificant. The clinical pregnancy rate showed a linear relationship with an increased progesterone concentration in cleavage-stage embryo transfer. In blastocyst transfer, as the progesterone concentration increased, the clinical and ongoing pregnancy rates showed a parabolic reverse-U curve; the curve initially increased before declining at high progesterone concentrations. The clinical pregnancy rate increased with a progesterone concentration up to 0.80 ng/mL rather than tended to be stable. The clinical pregnancy rate significantly decreased when the progesterone concentration was ≥0.80 ng/mL.
Conclusion
The progesterone concentration on the hCG trigger day exhibits a curvilinear relationship with pregnancy outcomes in blastocyst transfer cycles, and the optimal threshold of the progesterone concentration is 0.80 ng/mL.
... Our findings have several clinical implications. First, there has been robust evidence that LFEP impairs endometrial receptivity, but LFEP in the fresh cycle does not affect the cumulative birth rate of the frozen transfers in a freeze-only approach (18). A freeze-all policy should be proposed for LFEP patients to avoid the adverse impact of LFEP (19)(20)(21). ...
Background
The objective of this study was to explore whether the duration of LFEP (late-follicular elevated progesterone) affected pregnancy outcomes in IVF ( in vitro fertilization) patients treated with pituitary downregulation protocols.
Method
Patients with their first IVF/ICSI cycles between January 2016 and December 2016 were included. LFEP was set either at P > 1.0ng/ml or P > 1.5ng/ml. Clinical pregnancy rate was compared among three different groups (no LFEP; LFEP for 1 day; LFEP for ≥ 2 days). Then multivariate logistic regression analysis was performed to explore the influencing factors of clinical pregnancy rate.
Results
This retrospective analysis involved 3,521 first IVF/ICSI cycles with fresh embryo transfers. Clinical pregnancy rate was the lowest in patients with a LFEP duration of ≥ 2 days, irrespective of whether LFEP was defined as P > 1.0 ng/ml (68.79% vs. 63.02% vs. 56.20%; P = 0.000) or as P > 1.5 ng/ml (67.24% vs. 55.95% vs. 45.51%; P = 0.000). In addition, LFEP duration was significantly associated with clinical pregnancy outcomes in unadjusted logistic regression analysis. However, in multivariate regression models after adjusting confounders, adjusted OR for LFEP duration (≥ 2 days) in the two models was 0.808 ( P = 0.064; LFEP as P > 1.0 ng/ml) and 0.720 ( P = 0.098; LFEP as P > 1.5 ng/ml), respectively.
Conclusion
LFEP adversely affects clinical pregnancy outcomes. However, the duration of LFEP seems to have no influence on the clinical pregnancy rate in pituitary downregulation treatment cycles.
... The practice of frozen-thawed embryo transfer (FET) has increased over the past decades in connection with technological improvements resulting in higher cumulative live birth rates (1)(2)(3)(4)(5). FET enables single embryo transfer, reduces the risk of ovarian hyperstimulation syndrome, optimizes endometrial receptivity and facilitates fertility preservation (2)(3)(4)(5)(6)(7)(8). According to the 2020 annual report of the French Biomedicine Agency, FET was performed in up to 33 350 couples, representing 41.6% of in vitro Fertilization (IVF) transfers, of which 65% were transfers of frozen-thawed blastocysts. ...
Background
Risks of maternal morbidity are known to be reduced in pregnancies resulting from frozen embryo transfer (FET) compared to fresh-embryo transfer ( fresh -ET), except for the risk of pre-eclampsia, reported to be higher in FET pregnancies compared to fresh -ET or natural conception. Few studies have compared the risk of maternal vascular morbidities according to endometrial preparation for FET, either with ovulatory cycle (OC-FET) or artificial cycle (AC-FET). Furthermore, maternal pre-eclampsia could be associated with subsequent vascular disorders in the offspring.
Methods
A 2013-2018 French nationwide cohort study comparing maternal vascular morbidities in 3 groups of single pregnancies was conducted: FET with either OC or AC preparation, and fresh -ET. Data were extracted from the French National Health System database. Results were adjusted for maternal characteristics and infertility (age, parity, smoking, obesity, history of diabetes or hypertension, endometriosis, polycystic ovary syndrome and premature ovarian insufficiency).
Results
A total of 68025 single deliveries were included: fresh -ET (n=48152), OC-FET (n=9500), AC-FET (n=10373). The risk of pre-eclampsia was higher in AC-FET compared to OC-FET and fresh -ET groups in univariate analysis (5.3% vs. 2.3% and 2.4%, respectively, P <0.0001). In multivariate analysis the risk was significantly higher in AC-FET compared to fresh -ET: aOR=2.43 [2.18-2.70], P <0.0001). Similar results were observed for the risk of other vascular disorders in univariate analysis (4.7% vs . 3.4% and 3.3%, respectively, P =0.0002) and in multivariate analysis (AC-FET compared to fresh -ET: aOR=1.50 [1.36-1.67], P <0.0001). In multivariate analysis, the risk of pre-eclampsia and other vascular disorders were comparable in OC-FET and fresh -ET: aOR=1.01 [0.87-1.17, P = 0.91 and aOR=1.00 [0.89-1.13], P =0.97, respectively).Within the group of FET, the risks of pre-eclampsia and other vascular disorders in multivariate analysis were higher in AC-FET compared to OC-FET (aOR=2.43 [2.18-2.70], P <0.0001 and aOR=1.5 [1.36-1.67], P <0.0001, respectively).
Conclusion
This nationwide register-based cohort study highlights the possibly deleterious role of prolonged doses of exogenous estrogen-progesterone supplementation on gestational vascular pathologies and the protective role of the corpus luteum present in OC-FET for their prevention. Since OC-FET has been demonstrated not to strain the chances of pregnancy, OC preparation should be advocated as first-line preparation in FET as often as possible in ovulatory women.
... For example, Bosch et al. (25) observed by trend analysis that when the serum P level on the trigger day was 1.5 ng/ml, it reached the critical threshold level at which P would have a negative effect on pregnancy outcomes. Racca et al. (12) concluded that the triggerday P 1.5 ng/ml group had considerably decreased embryo and (29) discovered that on the trigger day, the mean number of top-quality blastocysts was lower in the P≥1.5 ng/ml group than in the P<1.5 ng/ml group. Two large retrospective studies (14,15) also indicated that high P was relevant to a reduced rate of top-quality blastocysts. ...
Objective
To assess whether progesterone (P) levels on the trigger day during preimplantation genetic testing (PGT) cycles are associated with embryo quality and pregnancy outcomes in the subsequent first frozen-thawed blastocyst transfer (FET) cycle.Methods
In this retrospective analysis, 504 eligible patients who underwent ICSI followed by frozen-thawed embryo transfer (FET) with preimplantation genetic test (PGT) between December 2014 and December 2019 were recruited. All patients adopted the same protocol, namely, the midluteal, short-acting, gonadotropin-releasing hormone agonist long protocol. The cutoff P values were 0.5 and 1.5 ng/ml when serum P was measured on the day of human chorionic gonadotropin (HCG) administration, and cycles were grouped according to P level on the day of HCG administration. Furthermore, the effect of trigger-day progesterone on embryo quality and the subsequent clinical outcome of FET in this PGT population was evaluated.ResultsIn total, 504 PGT cycles were analyzed. There was no significant difference in the number of euploid blastocysts, top-quality blastocysts, euploidy rate, or miscarriage rate among the three groups (P>0.05). The 2PN fertilization rate (80.32% vs. 80.17% vs. 79.07%) and the top-quality blastocyst rate (8.71% vs. 8.24% vs. 7.94%) showed a downward trend with increasing P, and the between-group comparisons showed no significant differences (P>0.05). The clinical pregnancy rate (41.25% vs. 64.79%; P<0.05) and live birth rate (35.00% vs. 54.93%; P<0.05) in subsequent FET cycles were substantially lower in the high-P group than in the P ≤ 0.5 ng/ml group. After adjustments were made for confounding variables, multivariate logistic regression analysis revealed that the high-P group had a lower clinical pregnancy rate (adjusted OR, 0.317; 95% CI, 0.145–0.692; P=0.004) and live birth rate (adjusted OR, 0.352; 95% CI, 0.160–0.773; P=0.009) than the low-P group in subsequent FET cycles, and the differences were significant.Conclusion(s)This study demonstrates that in the PGT population, elevated P on the trigger day may diminish the top-quality blastocyst rate (although there is no difference in the euploidy rate). Trigger-day P is an important factor influencing clinical outcomes in subsequent FET cycles.
... Also Racca et al. (29) found that the lower embryo quality scores which have been linked to cycles did not result in a worse live birth rate in freeze all cycles despite having higher late follicular phase progesterone levels. ...
... Elevated progesterone levels on the trigger day were negatively correlated with live births in the fresh embryos transfer cycle but not in the subsequent frozen embryo transfer cycles (25,26). Therefore, the freeze-all strategy was performed to reduce the effect of elevated progesterone on live birth rates when progesterone exceeds 1.5-2ng/ ml (27). ...
Objective
To evaluate different starting doses of recombinant human follicle-stimulating hormone (rhFSH) on pregnancy outcomes for patients with normal ovarian reserve during gonadotropin- releasing hormone antagonist (GnRH-ant) protocol-controlled ovarian stimulation of in vitro fertilization (IVF) cycles.Methods
In this retrospective study, a total of 1138 patients undergoing IVF cycles following the GnRH-ant protocol were enrolled. Patients were divided into two groups according to the starting dose of rhFSH. 617 patients received a starting dose of rhFSH of 150 IU, and 521 patients received a starting dose of rhFSH of 225 IU. We compared demographic characteristics, ovarian stimulation and embryological characteristics, and pregnancy and birth outcomes between the two groups. Multivariate logistic regression analysis was performed to examine the possible effects of the known potential confounding factors on pregnancy outcomes.ResultsThe number of oocytes retrieved in the 150 IU rhFSH group was significantly lower than those in the 225 IU rhFSH group. There was no significant difference between the two groups referring to embryological characteristics. The proportion of fresh embryo transfer in the 150 IU rhFSH group was significantly higher than that in the 225 IU rhFSH group (48.30% vs. 40.90%), and there was no difference in the risk of ovarian hyperstimulation syndrome and pregnancy outcomes between the two groups.Conclusions
In conclusion, the starting dose of rhFSH of 150 IU for ovarian stimulation has a similar pregnancy outcome as starting dose of rhFSH of 225 IU in GnRH-ant protocol for patients with normal ovarian reserve. Considering the potential cost-effectiveness and shorter time to live birth, the starting dose of rhFSH of 150 IU may be more suitable than 225 IU.
... Patients allocated in IVF arm will undergo three complete IVF cycles (i.e. three oocyte retrievals regardless of the number of embryo transfers performed). Women will be managed according to a routine clinical protocol as reported elsewhere [16][17][18]. Pre-procedure aspiration of the endometrioma is not part of the local policies of the participating centers and will not be performed. Surgery will be achieved according to local standards [5,6,19]. ...
The management of endometriosis-related infertility is still a challenging issue. Women can be managed with either surgery or in vitro fertilization (IVF). The decision is tailored to the patients considering pros and cons of both approaches. Surgery might increase the chances of natural conception and relieve symptoms. IVF may be more effective, but costs are higher and unoperated women face some peculiar additional risks during the procedure and pregnancy. The unavailability of randomized trials comparing the two strategies hampers the possibility to provide precise estimates. This Randomized Controlled Trial (RCT) aims at filling this gap. This is a multicenter, non-blinded, randomized controlled trial with parallel groups and allocation 1:1. Three Italian Academic Infertility Units will be involved. Main inclusion criteria are infertility for more than one year, age less than 40 years and a sonographic diagnosis of endometriosis (ovarian endometriomas or deep peritoneal lesions). Previous IVF and previous surgery for endometriosis are exclusion criteria. Women will be randomized to either surgery and then natural pregnancy seeking or a standard program of three IVF cycles. The primary aim is the comparison of live birth rate between the two groups (IVF versus surgery) within one year of randomization. The secondary aim is the evaluation of cost-effective profile of the two interventions. The present study can influence the clinical practice of infertility treatment in women with endometriosis. From a public health perspective, information on the more cost-effective clinical management strategy would consent a wiser allocation of resources.
Trial registration: NCT04743167 , registered on 8 February 2021.
... These findings were reinforced in subsequent studies [13,14]. However, while embryos derived from cycles with elevated late follicular phase progesterone have been associated with lower embryo quality score, this did not result in lower live birth rate (LBR) in freeze-all cycles [15]. Two recent studies, by Kofinas et al. and Hernandez-Niento et al., have eliminated the subjective aspect of embryo quality score and examined the effect of elevated progesterone on PGT-A. ...
Purpose
To evaluate the relationship between progesterone and oocyte maturity rate via estradiol to progesterone ratio (E/P) at the time of ovulatory trigger.
Methods
This is a retrospective cohort study of first autologous IVF cycles from January to December 2018 from a private practice fertility center. Serum estradiol and progesterone levels were measured on the day of ovulatory trigger. E/P was calculated to control for degree of response. Embryos were cultured to the blastocyst stage for trophectoderm biopsy. Preimplantation genetic testing for aneuploidy (PGT-A) was performed using next-generation sequencing (NGS). Oocyte retrieval rate (oocytes retrieved/follicles ≥ 13 mm), maturity rate (MII/oocytes retrieved), and euploid rate (euploid/total biopsied embryos) were calculated. Clinical pregnancy, ongoing pregnancy (> 10 weeks), and live births following frozen embryo transfer (FET) were examined in relation to E/P. Regression analyses were performed to analyze E/P as a categorical value (defined by quartile) on oocyte maturity.
Results
Two hundred eleven women underwent controlled ovarian hyperstimulation and had steroid levels at trigger available. Mean E at trigger was 3449 ± 2040 pg/mL while mean P was 1.13 ± 0.58 ng/mL, with mean E/P of 3.36 + 2.04. There were no differences between quartiles of E/P with respect to retrieval, maturity rate, or euploid rate. Two hundred eleven IVF cycles resulted in 138 euploid frozen embryo transfers. There were no differences between quartiles of E/P with respect to clinical pregnancy, ongoing pregnancy, or live birth rate.
Conclusion
E/P ratio at the time of trigger does not impact oocyte retrieval rate, maturity rate, or euploid rate. Pregnancy and live birth outcomes were also not impacted.
... Men provided semen samples after 2 to 4 days of abstinence. IUI and IVF were standardized and performed as previously described (8)(9)(10). For IVF, oocyte collection was performed 36 h after triggering of ovulation. ...
With the implementation of COVID-19 vaccine up-take, doubts regarding the impact of immunization on future fertility have begun to emerge. We have examined vaccine safety on male reproductive health. We set up a multicentre (three infertility centers), retrospective study in order to assess semen parameters and fertilization rate of one hundred-six men in a pairwise comparison between the first and second assisted reproduction technology (ART) attempt, performed respectively before and after COVID-19 vaccination. Median time (range) between the first vaccine dose and the second ART cycle was 75 days (39–112). Semen parameters did not change before and after the exposure. Fertilization rate was also similar before and after vaccination. Twenty-five patients (24%) were oligozoospermic before the vaccination while 26 (25%) after the exposure (P = 0.87). Severe asthenozoospermia were present in 11 patients before as well as after the exposure. No difference was observed even after considering different types of vaccines (mRNA or viral vector). COVID-19 vaccination did not affect sperm quality and fertilization capacity of men undergoing ART treatments and should be considered safe for men's reproductive health.
... Therefore, this strategy may provide optimal embryo-endometrium cross-talk and high implantation rates in ART cycles. Evidence reported about premature progesterone rise has gradually been increasing, so this leads to a logical strategy of freezing the embryos when P is elevated in the fresh cycles and then subsequently performing frozenthawed embryo transfer [6,8,[24][25][26]. ...
PurposeTo assess the impact of serum progesterone level and the progesterone/estradiol ratio on determining the appropriate day of embryo transfer in fresh IVF/ICSI cycles without premature progesterone elevation.Methods
This was a retrospective cohort study in a university teaching hospital. Only fresh embryo transfer cycles in the GnRH-antagonist protocol without elevated trigger-day progesterone levels (n = 508) were analyzed after taking into consideration the exclusion criteria. The main outcome measure was to determine the association between below and above of the cut-off values of serum progesterone level and P/E2 ratio regarding clinical pregnancy, ongoing pregnancy and live birth rates. These rates were assessed with the use of percentile and logistic regression analyses according to the threshold levels of serum progesterone levels < 0.85 ng/mL versus ≥ 0.85 ng/mL on the day of hCG administration.
ResultsThe clinical pregnancy rates were significantly lower in fresh cycles with P levels ≥ 0.85 ng/mL on the day of hCG administration than in cycles with P levels < 0.85 ng/mL for the cleavage-stage embryo transfers (26.7% vs. 47.5%, p = 0.001). Blastocyst-stage embryo transfer improved pregnancy results although the P levels were ≥ 0.85 ng/mL (53.8% vs. 51.4%, p > 0.05). The adjusted odds ratio of P levels < 0.85 ng/mL revealed significant differences in only cleavage-stage embryo transfer cycles (aOR = 0.424, p = 0.016).Conclusion
Although serum progesterone levels are below the accepted cut-off level of 1.5 ng/mL, there may be reduced pregnancy outcomes in fresh embryo transfer cycles. A threshold level such as 0.85 ng/mL may ensure the decision to replace the cleavage stage with the blastocyst-stage embryo transfer in fresh cycles without premature progesterone elevation.
STUDY QUESTION
Is there a circadian variation of serum progesterone (P) on the day of frozen embryo transfer (FET) in a modified natural cycle (mNC)?
SUMMARY ANSWER
There is a statistically significant diurnal variation of serum P on the day of a FET in an mNC protocol.
WHAT IS KNOWN ALREADY
In recent years, the proportion of FET cycles has increased dramatically. To further optimize pregnancy outcomes after FET, recent studies have focused on serum luteal P levels in both natural and artificially prepared FET cycles. Despite the different cut-off values proposed to define low serum P in the NC, it is generally accepted that lower serum P values (<10 ng/ml) around the day of FET are associated with negative reproductive outcomes. However, a single serum P measurement is not reliable given that P levels are prone to diurnal fluctuations and are impacted by patients’ characteristics.
STUDY DESIGN, SIZE, DURATION
A prospective cohort study was conducted in a single university-affiliated fertility center, including 22 patients performing a single blastocyst mNC-FET from August 2022 to August 2023. Serum P levels were measured on the day of transfer at 08:00h, 12:00h, 16:00h, and 20:00h. Differences between P levels were compared using the Wilcoxon signed-rank test. The sample size was calculated to detect a difference of 15% between the first and last P measurements with a 5% false-positive rate and a 95% CI.
PARTICIPANTS/MATERIALS, SETTING, METHODS
Patients with a normal BMI, between 18 and 40 years old, without uterine diseases were eligible. Patients utilizing donated oocytes were excluded. The mNC-FET protocol involved monitoring the normal ovarian cycle and triggering ovulation with an injection of 250 μg of choriogonadotropin alfa when a pre-ovulatory follicle (16–20 mm diameter) was visualized. The blastocyst was transferred seven days later. The patients were not supplemented with exogenous P at any time before the day of the FET.
MAIN RESULTS AND THE ROLE OF CHANCE
The mean age and BMI of the study population were 33.6 ± 3.8 years and 22.7 ± 1.8 kg/m2, respectively. Mean P values at 08:00h, 12:00h, 16:00h, and 20:00h were 14.6 ± 4.5, 14.7 ± 4.1, 12.9 ± 3.5, and 14.6 ± 4.3 ng/ml, respectively. The mean P levels at 16:00h were significantly lower compared to all other time points (P < 0.05: P = 0.007 between P at 8:00h and 16:00h; P = 0.003 between P at 12:00h and 16:00h; P = 0.007 between P at 16:00h and 20:00h). No statistically significant difference was observed between P values at the other time points (P > 0.05: P = 0.88 between P at 8:00h and 12:00h; P = 0.96 between P at 8:00h and 20:00h; P = 0.83 between P at 12:00h and 20:00h).
LIMITATIONS, REASONS FOR CAUTION
The study’s limitations include the small sample size that may cause a bias when the results are extrapolated to a larger subfertile population undergoing mNC-FET. Ideally, larger prospective trials including a more heterogeneous patient population would be necessary to validate our findings.
WIDER IMPLICATIONS OF THE FINDINGS
The current study demonstrates the existence of a diurnal fluctuation of serum P on the day of mNC-FET highlighting the importance of a standardized time point for its measurement. This is especially important for considering clinical actions, such as additional exogenous P supplementation, when encountering P values lower than 10 ng/ml on the day of FET.
STUDY FUNDING/COMPETING INTEREST(S)
No funding was obtained for the study. The authors have no conflicts of interest to declare regarding the content of the study.
TRIAL REGISTRATION NUMBER
NCT05511272.
Introduction:
Despite the many unknowns about its exact mechanism, progesterone and progestins are being successfully used to prevent luteinizing hormone (LH) surge during ovarian stimulation for assisted reproductive technology (ART). We will review progestin primed ovarian stimulation (PPOS) protocols in comparison with gonadotropin releasing hormone (GnRH) analogues and each other.
Evidence acquisition:
MEDLINE via PubMed; Cochrane Central Register of Controlled Trials (CENTRAL); Scopus; Web of Science were screened with keywords related to assisted reproductive technology, ovarian stimulation progesterone, GnRH analogue and progesterone in several combinations. Search period was from the date of inception of each database until 20 May 2022.
Evidence synthesis:
Live birth or ongoing pregnancy rate per embryo transfer (ET) was similar in PPOS and GnRH antagonist cycles (RR=1.16, 95%CI 0.93 - 1.44). Clinical pregnancy rate per ET was likewise similar (RR=1.12, 95%CI 0.92 - 1.37). Miscarriage rate per pregnancy was similar with PPOS and GnRH antagonists in autologous cycles (RR=1.01, 95%CI 0.65 - 1.55). Pooled analyses showed similar live birth rate between progestins and short GnRH agonist protocols (RR=1.01, 95%CI 0.49 to 2.09), however, clinical pregnancy rates per ET were significantly higher with progestins (RR=1.31, 95%CI 1.06 to 1.62). Miscarriage rate per pregnancy was similar with progestins (RR=0.82, 95%CI 0.55 to 1.21).
Conclusions:
Progestins seem to be an efficient option for pituitary suppression during ovarian suppression, providing similar outcomes for stimulation and pregnancy. They can be especially beneficial for women for whom fresh ET is not considered.
Abstract Background In recent years, some studies have shown that there is a positive association between the number of oocytes retrieved and the cumulative live birth rate (CLBR) after fresh and frozen cycles of one oocyte retrieval. However, almost no studies have examined the association between the number of oocytes retrieved and the CLBR when using the “freeze-all” strategy. We performed this study to investigate the effects of an extreme oocyte yield during the first “freeze-all” cycle on the cumulative live birth rate among patients younger than 35 years old. Methods This was a retrospective cohort study performed in a university-affiliated reproductive medicine centre. Data obtained from 3276 women aged younger than 35 years who underwent their first “freeze-all” cycle (IVF/ICSI) were collected between January 2009 and December 2016. In all, 5025 frozen cycles took place during the follow-up period from January 2009 to December 2018. Patients were divided into five groups according to oocytes retrieved (group 1: 4–10 oocytes; group 2: 11–20 oocytes; group 3: 21–30 oocytes; group 4: 31–40 oocytes; group 5: > 40 oocytes). The primary outcome was the cumulative live birth rate. Results Unadjusted results showed that the cumulative live birth rate significantly increased as the number of oocytes retrieved increased and reached up to 93.82% in cases with yields of 21–30 oocytes (P 0.05). After adjusting for confounders, our results showed that the number of oocytes retrieved is an independent positive predictor of cumulative live birth rate when using a “freeze-all” strategy. (P
Study question:
Does late follicular-phase elevated serum progesterone (LFEP) during ovarian stimulation for oocyte donation have an impact on embryo quality (EQ) and cumulative live birth rate (CLBR)?
Summary answer:
LFEP does not have an influence on EQ nor CLBR in oocyte donation cycles.
What is known already:
Ovarian stimulation promotes the production of progesterone (P) which, when elevated during the follicular phase, has been demonstrated to have a deleterious effect in autologous fresh IVF outcomes. While there is robust evidence that this elevation results in impaired endometrial receptivity, the impact on EQ remains a matter of debate. The oocyte donation model is an excellent tool to assess the effects of LFEP on EQ from those on endometrium receptivity separately. Previous studies in oocyte donation cycles investigating the influence of elevated P on pregnancy outcomes in oocyte recipients showed conflicting results.
Study design, size, duration:
This is a retrospective analysis including all GnRH antagonist down-regulated cycles for fresh oocyte donation taking place in a tertiary referral university hospital between 2010 and 2017. A total of 397 fresh donor-recipient cycles were included. Each donor was included only once in the analysis and could be associated to a single recipient.
Participants/materials, setting, methods:
The sample was stratified according to serum P levels of ≤1.5 and >1.5 ng/mL on the day of ovulation triggering. The primary endpoint of the study was the top-quality embryo rate on Day 3, and the secondary outcome measure was CLBR defined as a live-born delivery beyond 24 weeks.
Main results and the role of chance:
Three hundred ninety-seven fresh oocyte donation cycles were included in the analysis, of which 314 (79%) had a serum P ≤ 1.5 ng/mL and 83 (20.9%) had a serum P > 1.5 ng/mL. The average age of the oocyte donors was 31.4 ± 4.7 and 29.9 ± 4.5 years, respectively, for normal and elevated P (P = 0.017). The mean number of oocytes retrieved was significantly higher in the elevated P group with 16.6 ± 10.6 vs 11.5 ± 6.9 in the P ≤ 1.5 group (P < 0.001).In parallel, the total number of embryos on Day 3, as well as the number of good-quality embryos at this stage, was significantly higher in the elevated P group (6.6 ± 5.6 vs 4.15 ± 3.5 and 8.7 ± 6.3 vs 6.1 ± 4.4; respectively, P < 0.001). However, maturation and fertilization rates did not vary significantly between the two study groups and neither did the top- and good-quality embryo rate and the embryo utilization rate, all evaluated on Day 3 (P = 0.384, P = 0.405 and P = 0.645, respectively). A multivariable regression analysis accounting for P groups, age of the donor, number of retrieved oocytes and top-quality embryo rate as potential confounders showed that LFEP negatively influenced neither the top-quality embryo rate nor the CLBR.
Limitations, reasons for caution:
This is an observational study based on a retrospective data analysis. Better extrapolation of the results could be validated by performing a prospective trial. Furthermore, this study was focused on oocyte donation cycles and hence the results cannot be generalized to the entire infertile population.
Wider implications of the findings:
This is the first study providing evidence that LFEP does not influence CLBR and is adding strong evidence to the existing literature that LFEP does not harm EQ in oocyte donation programs.
Study funding/competing interests:
Not applicable.
Purpose
To investigate the cumulative live birth (cLB) rate of one complete freeze-all-IVF cycle in a general infertile population and to investigate patient and treatment variables that predict blastocyst development and live birth (LB).
Method
In a retrospective observational study, the data of all IVF cycles performed between 1 February 2015 and 31 January 2016 at a single IVF centre was investigated. In the study, patient-couples were followed up for 18 months following oocyte retrieval. After exclusions, the patient and treatment variables of 1582 patient-couples who underwent treatment were included in the analyses.
Results
The median time interval between the oocyte retrieval attempt and the frozen embryo transfer (FET) in which LB was achieved was 38.0 (35.0–67.0) days. The variables of freeze-all-IVF cycles with single blastocyst FET selected by multiple logistic regression to predict LB significantly were female age, infertility duration, FET number (i.e. 1st, 2nd, or ≥ 3rd FET), and blastocyst quality. In a regression adjusting for female age, the number of blastocysts transferred, and oocyte number group (1–3, 4–9, 10–15, and > 15), none of the oocyte number groups were selected to predict LB of 1st FET, significantly. While the per transfer LB rates decreased linearly from the 1st (56.5%) to the 3rd (36.4%) FET, the cLB rate increased from 47.3% after the 1st FET to 55.0% after a 3rd possible FET.
Conclusion
The cLB rate of one complete freeze-all-IVF cycle of a general infertile population, with 18-month follow-up, was 55.0%. In freeze-all-IVF, ovarian reserve variables were not selected by regression models to predict LB, significantly.
Study question:
Can a consensus and evidence-driven set of terms and definitions be generated to be used globally in order to ensure consistency when reporting on infertility issues and fertility care interventions, as well as to harmonize communication among the medical and scientific communities, policy-makers, and lay public including individuals and couples experiencing fertility problems?
Summary answer:
A set of 283 consensus-based and evidence-driven terminologies used in infertility and fertility care has been generated through an inclusive consensus-based process with multiple stakeholders.
What is known already:
In 2006 the International Committee for Monitoring Assisted Reproductive Technologies (ICMART) published a first glossary of 53 terms and definitions. In 2009 ICMART together with WHO published a revised version expanded to 87 terms, which defined infertility as a disease of the reproductive system, and increased standardization of fertility treatment terminology. Since 2009, limitations were identified in several areas and enhancements were suggested for the glossary, especially concerning male factor, demography, epidemiology and public health issues.
Study design, size, duration:
Twenty-five professionals, from all parts of the world and representing their expertise in a variety of sub-specialties, were organized into five working groups: clinical definitions; outcome measurements; embryology laboratory; clinical and laboratory andrology; and epidemiology and public health. Assessment for revisions, as well as expansion on topics not covered by the previous glossary, were undertaken. A larger group of independent experts and representatives from collaborating organizations further discussed and assisted in refining all terms and definitions.
Participants/materials, setting, methods:
Members of the working groups and glossary co-ordinators interacted through electronic mail and face-to-face in international/regional conferences. Two formal meetings were held in Geneva, Switzerland, with a final consensus meeting including independent experts as well as observers and representatives of international/regional scientific and patient organizations.
Main results and the role of chance:
A consensus-based and evidence-driven set of 283 terminologies used in infertility and fertility care was generated to harmonize communication among health professionals and scientists as well as the lay public, patients and policy makers. Definitions such as 'fertility care' and 'fertility awareness' together with terminologies used in embryology and andrology have been introduced in the glossary for the first time. Furthermore, the definition of 'infertility' has been expanded in order to cover a wider spectrum of conditions affecting the capacity of individuals and couples to reproduce. The definition of infertility remains as a disease characterized by the failure to establish a clinical pregnancy; however, it also acknowledges that the failure to become pregnant does not always result from a disease, and therefore introduces the concept of an impairment of function which can lead to a disability. Additionally, subfertility is now redundant, being replaced by the term infertility so as to standardize the definition and avoid confusion.
Limitations, reasons for caution:
All stakeholders agreed to the vast majority of terminologies included in this glossary. In cases where disagreements were not resolved, the final decision was reached after a vote, defined before the meeting as consensus if passed with 75%. Over the following months, an external expert group, which included representatives from non-governmental organizations, reviewed and provided final feedback on the glossary.
Wider implications of the findings:
Some terminologies have different definitions, depending on the area of medicine, for example demographic or clinical as well as geographic differences. These differences were taken into account and this glossary represents a multinational effort to harmonize terminologies that should be used worldwide.
Study funding/competing interests:
None.
Trial registration number:
N/A.
Study question:
Is elevated late-follicular phase progesterone (EP) associated with a deleterious impact on embryo quality (EQ) and cumulative live birth rates (LBRs)?
Summary answer:
EP was associated with a decrease in embryo utilization and cumulative LBRs.
What is known already:
Ovarian stimulation promotes the production of progesterone (P) which adversely affects IVF pregnancy outcomes. However, evidence regarding a potential association between EP an EQ is lacking.
Study design, size, duration:
A retrospective analysis of all GnRH antagonist down-regulated ICSI cycles followed by a fresh embryo transfer (ET) between 2010 and 2015 was performed. The sample was stratified according to the following P levels on the day of ovulation triggering: ≤0.50, 0.51-1.49 and ≥1.50 ng/ml. The primary outcomes were embryo utilization rates (number of embryos transferred or cryopreserved) and cumulative LBR, defined as the occurrence of the first live-birth after either the fresh or one of the subsequent frozen ET.
Participants/materials, setting, methods:
Overall, 3400 cycles were included in the analysis, using multivariable regression to account for potential confounding.
Main results and the role of chance:
Female age and the number of oocytes retrieved increased significantly with increasing serum P values. Utilization rates decreased linearly as P increased for Day 3 embryos (72.3, 63.0 and 45.4%, respectively), while for Day 5 embryos only the EP group was associated with a significant decrease (48.8, 47.8 and 38.8%, respectively). EP was also associated with decreased fresh and cumulative LBRs.
Limitations reasons for caution:
The main limitations of this study were its retrospective nature and the fact that it was restricted to GnRH antagonist cycles.
Wider implications of the findings:
These results raise the question whether EP may also be associated with a decrease in cumulative pregnancy outcomes by increasing embryo wastage. Further studies may evaluate the potential benefit of additional measures besides the freeze-all strategy to avoid this issue, such as lowering the stimulation dose or applying a step-down protocol.
Study funding/competing interest(s):
None.
Cycles with progesterone elevation during controlled ovarian stimulation (COS) for IVF/ICSI are commonly managed with a “freeze-all” strategy, due to a well-recognized detrimental effect of high progesterone levels on endometrial receptivity. However, also a detrimental effect of elevated progesterone on day-3 embryo quality has recently been found with regards to top quality embryo formation rate. Because blastocyst culture and cryopreservation are largely adopted, we deemed relevant to determine whether this detrimental effect is also seen on blastocyst quality on day 5–6. This issue was investigated through a large two-center retrospective study including 986 GnRH antagonist IVF/ICSI cycles and using top quality blastocyst formation rate as the main outcome. Results showed that on multivariate analysis sperm motility (p<0.01) and progesterone levels at ovulation triggering (p = 0.01) were the only two variables that significantly predicted top quality blastocyst formation rate after adjusting for relevant factors including female age, BMI, basal AMH and total dose of FSH used for COS. More specifically, progesterone levels at induction showed an inverse relation with top quality blastocyst formation (correlation coefficient B = -1.08, 95% CI -1.9 to -0.02) and ROC curve analysis identified P level >1.49 ng/ml as the best cut-off for identification of patients at risk for the absence of top quality blastocysts (AUC 0.55, p<0.01). Our study is the first to investigate the top quality blastocyst formation rate in relation to progesterone levels in IVF/ICSI cycles, showing that increasing progesterone is associated with lower rates of top quality blastocyst. Hence, the advantages of prolonging COS to maximize the number of collected oocytes might eventually be hindered by a decrease in top quality blastocysts available for transfer, if increasing progesterone levels are observed. This observation extends the results of two recent studies focused on day-3 embryos and deserves further research.
In contrast to the impact of elevated progesterone on endometrial receptivity, the data on whether increased progesterone levels affects the quality of embryos is still limited. This study retrospectively enrolled 4,236 fresh in vitro fertilization (IVF) cycles and sought to determine whether increased progesterone is associated with adverse outcomes with regard to top quality embryos (TQE). The results showed that the TQE rate significantly correlated with progesterone levels on the day of human chorionic gonadotropin (hCG) trigger (P = 0.009). Multivariate linear regression analysis of factors related to the TQE rate, in conventional IVF cycles, showed that the TQE rate was negatively associated with progesterone concentration on the day of hCG (OR was -1.658, 95% CI: -2.806 to -0.510, P = 0.005). When the serum progesterone level was within the interval 2.0-2.5 ng/ml, the TQE rate was significantly lower (P <0.05) than when the progesterone level was < 1.0 ng/ml; similar results were obtained for serum progesterone levels >2.5 ng/ml. Then, we choose a progesterone level at 1.5ng/ml, 2.0 ng/ml and 2.5 ng/ml as cut-off points to verify this result. We found that the TQE rate was significantly different (P <0.05) between serum progesterone levels < 2.0 ng/ml and >2.0 ng/ml. In conclusion, the results of this study clearly demonstrated a negative effect of elevated progesterone levels on the day of hCG trigger, on TQE rate, regardless of the basal FSH, the total gonadotropin, the age of the woman, or the time of ovarian stimulation. These data demonstrate that elevated progesterone levels (>2.0 ng/ml) before oocyte maturation were consistently detrimental to the oocyte.
In order to explore the relationship between serum progesterone (P) level on the day of human chorionic gonadotrophin (HCG) administration and cumulative live birth rate in patients with different ovarian response during in vitro fertilization (IVF), we carried out this retrospective cohort study including a total of 4,651 patients undergoing their first IVF cycles from January 2011 to December 2012. All patients with a final live birth outcome (4,332 patients) were divided into three groups according to ovarian response: poor ovarian responder (≤5 oocytes, 785 patients), intermediate ovarian responder (6-19 oocytes, 3065 patients) and high ovarian responder (≥20 oocytes, 482 patients). The thresholds for serum P elevation were 1.60 ng/ml, 2.24 ng/ml, and 2.50 ng/ml for poor, intermediate, and high ovarian responders, respectively. Cumulative live birth rate per oocyte retrieval cycle was calculated in each group. The relationship between serum P level and cumulative live birth rate was evaluated by both univariate and multivariate logistic regression analysis. Cumulative live birth rate per oocyte retrieval cycle was inversely associated with serum P level in patients with different ovarian response. For all responders, patients with elevated P level had significantly higher number of oocytes retrieved, but lower high quality embryo rate, and lower cumulative live birth rate compared with patients with normal serum P level. In addition, serum P level adversely affected cumulative live birth rate by both univariate and multivariate logistic regression analysis, independent of ovarian response. Serum P elevation on the day of HCG administration adversely affects cumulative live birth rate per oocyte retrieval cycle in patients with different ovarian response.
Is the effect of cell loss on further cleavage and implantation different for vitrified than for slowly frozen Day 3 embryos?
Vitrified embryos develop better overnight than slowly frozen embryos, regardless of the number of cells lost, but have similar implantation potential if further cleavage occurs overnight.
After slow-freezing, similar implantation rates have been obtained for intact 4-cell embryos or 4-cell embryos with 1 cell damaged. For slowly frozen Day 3 embryos, lower implantation rates have been observed when at least 25% of cells were lost. Other studies reported similar implantation potential for 7- to 8-cell embryos with 0, 1 or 2 cells damaged. No data are available on further development of vitrified embryos in relation to cell damage.
Survival and overnight cleavage were retrospectively assessed for 7664 slowly frozen Day 3 embryos (study period: January 2004-December 2008) and 1827 vitrified embryos (study period: April 2010-September 2011). Overnight cleavage was assessed according to cell stage at cryopreservation and post-thaw cell loss for both protocols. The relationship between cell loss and implantation rate was analysed in a subgroup of single-embryo transfers (SETs) with 780 slowly frozen and 294 vitrified embryos.
Embryos with ≥6 blastomeres and ≤20% fragmentation were cryopreserved using slow controlled freezing [with dimethyl sulphoxide (DMSO) as cryoprotectant] or closed vitrification [with DMSO-ethylene glycol (EG)-sucrose (S) as cryoprotectants]. Only embryos with ≥50% of cells intact after thawing were cultured overnight and were only transferred if further cleaved. For each outcome, logistic regression analysis was performed.
Survival was 94 and 64% after vitrification and slow-freezing respectively. Logistic regression analysis showed that overnight cleavage of surviving embryos was higher after vitrification than after slow-freezing (P < 0.001) and decreased according to the degree of cell damage (P < 0.001). If the embryo continued to cleave after thawing, there was no effect of the number of cells lost or the cryopreservation method on its implantation potential. The implantation rates of embryos with 0, 1 or 2 cells damaged were, respectively, 21% (n = 114), 21% (n = 28) and 20% (n = 12) after slow-freezing and 20% (n = 50), 21% (n = 5) and 27% (n = 4) after vitrification.
This analysis is retrospective and study periods for vitrification and slow-freezing are different. The number of SETs with vitrified embryos is limited. However, a large number of vitrified embryos were available to analyse the further cleavage of surviving embryos.
Although it is not proved that vitrified embryos are more viable than slowly frozen embryos in terms of pregnancy outcome, vitrification yields higher survival rates, better overnight development and higher transfer rates per embryo warmed. This increases the number of frozen transfer cycles originating from a single treatment and might result in a better cumulative clinical outcome. Based on the present data, the policy to warm an extra embryo before overnight culture depends on the cell stage at cryopreservation and the cell damage after warming. For 8-cell embryos, up to two cells may be damaged compared with only one cell for 6- to 7-cell embryos, before an additional embryo is warmed.
none.
BACKGROUND
The aim of this meta-analysis was to evaluate the association of progesterone elevation (PE) on the day of hCG administration with the probability of pregnancy in fresh, frozen-thawed and donor/recipient IVF cycles.METHODSA literature search in MEDLINE, SCOPUS, COCHRANE CENTRAL and ISI Web of Science was performed aiming to identify studies comparing the probability of pregnancy in patients with or without PE after ovarian stimulation with gonadotrophins and GnRH analogues. Standard meta-analytic methodology was used for the synthesis of results and meta-regression for exploration of heterogeneity.RESULTSSixty-three eligible studies were identified evaluating 55 199 fresh IVF cycles, nine studies evaluating 7229 frozen-thawed cycles and eight studies evaluating 1330 donor/recipient cycles. In fresh IVF cycles, a decreased probability of pregnancy achievement was present in women with PE (when PE was defined using a threshold ≥0.8 ng/ml) when compared with those without PE. The pooled effect sizes were 0.8-1.1 ng/ml: odds ratio (OR) = 0.79; 1.2-1.4 ng/ml: OR = 0.67; 1.5-1.75 ng/ml: OR = 0.64; 1.9-3.0 ng/ml: OR: 0.68 (P < 0.05 in all cases). No adverse effect of PE on achieving pregnancy was observed in the frozen-thawed and the donor/recipient cycles.CONCLUSIONS
Based on the analysis of more than 60 000 cycles, it can be supported that PE on the day of hCG administration is associated with a decreased probability of pregnancy achievement in fresh IVF cycles in women undergoing ovarian stimulation using GnRH analogues and gonadotrophins. On the other hand, an adverse effect of PE does not seem to be present in frozen-thawed and donor/recipient cycles.
Elevated serum progesterone levels at the end of the follicular phase in controlled ovarian stimulation (COS) leads to a poorer ongoing pregnancy rate in IVF cycles due to reduced endometrial receptivity. The objective of this study was to use microarray technology to compare endometrial gene expression profiles at the window of implantation according to the levels of circulating progesterone.
For this prospective cohort study, microarray data were obtained from endometrial biopsies from 12 young healthy oocyte donors undergoing COS with pituitary suppression by either gonadotrophin-releasing hormone (GnRH) agonists or antagonists, and recombinant FSH. On the day of recombinant chorionic gonadotrophin (rCG) administration, six women had serum progesterone levels (P) >1.5 ng/ml (study group) and six had serum P levels <1.5 ng/ml (control group). Endometrial samples were collected using a Pipelle catheter 7 days after the rCG injection.
Using the parametric test, we identified 140 genes significantly dysregulated (64 up- and 76 down-regulated) in the study group endometria compared with the control endometria, regardless of the GnRH analogue employed. These genes are related to cell adhesion, developmental processes, the immune system and others, which are all required for normal endometrial function development. Of the 25 gene targets previously proposed as markers for endometrial receptivity, 13 appeared over-regulated in the study group.
Our results reveal that elevated progesterone levels on the day of rCG administration can induce significant alterations in the gene expression profile of the endometrium.
The influence of elevated serum progesterone levels during in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI) cycles on pregnancy rates is a matter of continued debate among fertility clinicians. Efforts to resolve this question have been impeded by the various assays used to measure progesterone and the different, arbitrary threshold values for defining 'high' progesterone levels.
A non-interventional, retrospective, observational, single-centre cohort study evaluated the relationship between serum progesterone levels on the day of human chorionic gonadotrophin (hCG) administration and the ongoing pregnancy rate in 4032 patients undergoing IVF/ICSI cycles using gonadotrophin-releasing hormone (GnRH) analogues for pituitary down-regulation.
Ongoing pregnancy rates were inversely associated with serum progesterone levels on the day of hCG (P < 0.001 for overall trend), irrespective of the GnRH analogue used for pituitary down-regulation. Patients with serum progesterone levels < or = 1.5 ng/ml had significantly higher ongoing pregnancy rates than those with progesterone levels >1.5 ng/ml (31.0 versus 19.1%; P = 0.00006); odds ratio, 0.53 (95% confidence interval, 0.38-0.72). Multivariate regression analysis showed that daily follicle-stimulating hormone dose, number of oocytes and estradiol values on the day of hCG administration were positively associated with progesterone levels (P < 0.0001 for all). Serum progesterone levels were significantly greater in women treated with GnRH agonists (n = 1177) versus antagonists (n = 2855; 0.84 +/- 0.67 versus 0.75 +/- 0.66 ng/ml; P = 0.0003).
Elevated serum progesterone levels on the day of hCG administration is associated with reduced ongoing pregnancy rates. In particular, serum progesterone levels of >1.5 ng/ml were associated with lower ongoing pregnancy rates following IVF/ICSI cycles irrespective of the GnRH analogue used for pituitary down-regulation.
Several evidences indicate that premature luteinization (PL) may affect IVF outcome. The primary end-point of the present study was to verify the effect of PL on the pregnancy rate (PR) of our oocyte-donation programme.
PL was defined as serum progesterone > or = 1.2 ng/ml on the day of HCG. We analysed retrospectively 240 oocyte-donation cycles in which 120 women donated twice, with PL in the first donation cycle and no PL in the following one, acting as its own control. Recipients (n = 240) were divided in two groups according to the presence of PL (n = 120) or not (n = 120). Both groups were compared regarding donor cycle parameters and recipient cycle outcome.
There was no difference in PR between the groups (55.7 versus 54.4%, respectively). The number of total oocytes (18.2 +/- 0.6 versus 20.8 +/- 0.6; P = 0.003) and the number of mature oocytes retrieved (16.9 +/- 0.6 versus 19.4 +/- 0.6; P = 0.005) were different among donors with progesterone < 1.2 ng/ml and PL, respectively. There were no differences between the oocyte recipients in fertilization, cleavage, embryo division on day 3, blastocyst development or fragmentation rates. The number of embryos transferred, number of embryos cryopreserved, and implantation and miscarriage rates were similar between the groups.
PL does not appear to have a negative impact on ongoing PR in our oocyte-donation programme.
Controlled ovarian hyperstimulation (COH) determines an anticipation of endometrial maturation and a premature occurrence of the implantation window, as shown by histological, histochemical, and molecular studies and indirectly by clinical trials. There is growing agreement that in patients hyper-responding to COH and in those undergoing transfer at the blastocyst stage, deferring the transfer in a subsequent frozen cycle could increase pregnancy outcomes. For blastocysts, implantation after a fresh transfer may be limited as the implantation window is already closed while, in hyper-responders to COH, the anticipation magnitude could be more marked thus hampering implantation also for cleavage-stage embryos. Research should focus in depth on pregnancy outcomes and on the most suitable modality to prepare the endometrium for frozen transfers.
An increasing number of researchers have alluded to the potential benefit of deferring the transfer of embryos produced during assisted reproductive technologies (ARTs) away from ovarian stimulation, using cryopreservation to enable this. The scientific evidence that may justify this recent trend in the use of the so-called 'freeze-all strategy' includes early, mostly small randomised controlled trials that have demonstrated an increase in live birth rates after elective embryo cryopreservation in certain patient populations, as well as evidence from cohort studies and retrospective analyses. What are the risks and benefits of freeze-all strategies in ART, who are the patients in whom it is likely to be advantageous, and does the current evidence allow us to identify situations when deciding that a fresh embryo transfer would be counter-productive? ART professionals are often faced with challenging clinical decisions regarding the best course of treatment for their patient. The purpose of this opinion paper is to provide a clinical guide for whether to perform a fresh embryo transfer or to opt for freezing all embryos in specific situations.
Study question:
Is there significant variability in progesterone levels during the final day of oocyte maturation in women undergoing ovarian stimulation?
Summary answer:
Progesterone levels drop from the basal level up to 44% during the final day of oocyte maturation in women undergoing ovarian stimulation.
What is known already:
It has been suggested that elevated progesterone levels on the final day of ovarian stimulation may be related to poorer outcomes in in vitro fertilization fresh cycles due to a negative impact on the endometrium. However, despite conflicting results regarding the actual effect of progesterone on pregnancy rates and the lack of a well-established cut off, currently many IVF patients have their embryo transfer deferred when progesterone values surpass a threshold of 1.5 ng/ml on the day of ovulation triggering.
Study design, size, duration:
This was a prospective cohort study conducted in 22 oocyte donors of a university-affiliated fertility centre between November 2017 and January 2018. We calculated the sample size to detect a difference of 15% between the first and last progesterone measurements with a 5% false-positive rate in a two-sided test with 80% statistical power and a 95% confidence interval (CI).
Participants/materials, setting, methods:
Progesterone circulating levels were evaluated at four different times during the final day of oocyte maturation (08:00, 12:00, 16:00 and 20:00) before ovulation triggering in healthy oocyte donors. A flexible antagonist protocol was used, and ovarian stimulation was achieved with recombinant follicle-stimulating hormone (FSH) in all cases. The pairwise percentage differences in progesterone levels for each patient were calculated. Univariate linear regression analysis was adopted in order to evaluate variables associated with progesterone levels on the first measurement. The intra-day variability of progesterone was analysed using mixed models.
Main results and the role of chance:
Mean serum progesterone values at 08:00, 12:00, 16:00 and 20:00 were 1.75 ng/ml, 1.40 ng/ml, 1.06 ng/ml and 0.97 ng/ml. The progesterone difference between 08:00 and 20:00 was 0.77 (95% CI, 0.56-0.99), which is equivalent to a 44% decline in the mean progesterone values between the first (08:00) and the last determination (20:00; P < 0.001). Among those patients with basal (08:00) progesterone levels >1.5 ng/ml (n = 10), 70% (n = 7) showed levels reduced to <1.5 ng/ml on the last determination of the day (20:00). A mixed model analysis revealed that the progesterone reduction during the day was significantly associated with time and total recombinant FSH dose administered.
Limitations, reasons for caution:
Only young healthy oocyte donors stimulated with an antagonist protocol using recombinant FSH were included. Extrapolation to the general IVF population, with different stimulation protocols and gonadotropins, needs to be confirmed.
Wider implications of the findings:
This study suggests that a single progesterone determination on the final day of oocyte maturation is not reliable enough to make clinical decisions due to the enormous variation in progesterone during the day. Further studies are needed to better define the impact of the follicular progesterone rise on the endometrium of IVF cycles.
Study funding/competing interest(s):
Funding was granted from Fundació Santiago Dexeus Font. N.P.P. received unrestricted grants and/or lectures fees from Roche Diagnostics, MSD, Merck, Ferring Pharmaceuticals, IBSA, Theramex and BESINS International, not associated with the current study. The remaining authors have no competing interests.
Trial registration number:
Clinicaltrials.gov NCT03366025.
To evaluate the effects of high progesterone prior to oocyte retrieval on the genomic profile of peri-implantation endometrium, we conducted this single-center, prospective cohort study. Depending on whether or not the progesterone level on the day of hCG administration and the day after hCG administration were elevated, a total of 20 women undergoing IVF treatment who did not have fresh embryo transfer were included: Group 1 refers to subjects with normal progesterone level on both days; Group 2 refers to subjects with normal progesterone level on the day of hCG administration and high progesterone level on the day after hCG administration; Group 3 refers to subjects with high progesterone level on the day of hCG administration and normal progesterone level on the day after hCG administration; Group 4 refers to subjects with high progesterone level on both days. Five subjects were included in each group. Endometrial samples were obtained 7 days after hCG administration. We found that high progesterone level prior to oocyte retrieval predominantly affected components of the NK cell mediated cytotoxicity pathway in the endometrium and that significant differences were only seen when progesterone measurements on both the day of and day after hCG administration were considered together.
Study question:
Is there an association of progesterone (P4) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6?
Summary answer:
P4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers.
What is known already:
Premature P4 elevation is associated with lower live birth rates in fresh autologous ART cycles, likely due to worsened endometrial-embryo asynchrony. Few studies have evaluated whether the effect of an elevated P4 on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer.
Study design size, duration:
This was a retrospective cohort study with autologous IVF cycles with fresh embryo transfers on day 5 and day 6 from 2011 to 2014. A total of 4120 day 5 and 230 day 6 fresh autologous embryo transfers were included. The primary outcome was live birth, defined as a live born baby at 24 weeks gestation or later.
Participants/materials, setting, methods:
Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves.
Main results and the role of chance:
Day 6 transfers were less likely to have good quality embryos (73% versus 83%, P < 0.001) but the cohorts had similar rates of blastocyst stage transfer (92% versus 91%, P = 0.92). Live birth was less likely in fresh day 6 versus day 5 embryo transfers (34% versus 46%, P = 0.01) even when controlling for embryo confounders. In adjusted GEE models, the effect of P4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P4 > 1.5 ng/ml on day of trigger was more pronounced on day 6 than day 5 (P < 0.001). Day 6 live birth rates were 8% lower than day 5 when P4 was in the normal range (P = 0.04), but became 17% lower when P4 was > 1.5 ng/ml (P < 0.01). ROC curves for P4 predicting live birth demonstrated a greater AUC in day 6 transfers (AUC 0.59, 95% CI 0.51-0.66) than day 5 (AUC 0.54, 95% CI 0.52-0.55). Interaction testing of P4 × day of embryo transfer was highly significant (P < 0.001), further suggesting that the effect of P4 was more pronounced on day 6 embryo transfer. In fresh oocyte retrieval cycles with elevated P4, a subsequent 760 frozen-thaw transfers did not demonstrate a difference between embryos that were frozen after blastulation on day 5 versus 6.
Limitations reasons for caution:
Limitations include the retrospective design and the inability to control for certain confounding variables, such as thaw survival rates between day 5 and day 6 blastocysts. Also, the data set lacks the known ploidy status of the embryos and the progesterone assay is not currently optimized to discriminate between patients with a P4 of 1.5 versus 1.8 ng/ml.
Wider implications of the findings:
This study suggests further endometrial-embryo asynchrony when a slow growing embryo is combined with an advanced endometrium, ultimately leading to decreased live births. This suggests that premature elevated P4 may be a factor in the lower live birth rates in day 6 fresh embryo transfers. Further studies are needed to evaluate if a frozen embryo transfer cycle can ameliorate the effect of elevated P4 on the day of trigger among these slower growing embryos that reach blastocyst staging on day 6.
Study funding/competing interests:
No external funding was received for this study. There are no conflicts of interest to declare.
Trial registration number:
Not applicable.
In in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone agonist (GnRH-a) suppression, we investigated whether an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration indicates premature luteinization and is associated with a lower pregnancy rate. We retrospectively studied 101 patients treated with the GnRH-a leuprolide acetate, begun in the luteal phase of the prior menstrual cycle and continued until the day of hCG administration. On the day of hCG, 72 patients had P
STUDY QUESTION What is the impact on clinical pregnancy rates when vitrified cleavage stage Day 3 embryos, warmed and cultured overnight
to Day 4, are transferred on the 3rd or 5th day of progesterone administration in an artificial cycle?
Objective:
To compare the effect of progesterone (P) on the day of trigger in fresh assisted reproduction technology (ART) transfer cycles versus its effect on subsequent frozen embryo transfer (FET) cycles.
Design:
Retrospective cohort study.
Setting:
Large private ART practice.
Patient(s):
Fresh autologous and FET cycles from 2011-2013.
Intervention(s):
None.
Main outcome measure(s):
Live birth.
Result(s):
A paired analysis of patients who underwent both a fresh transfer and subsequent FET cycle and an unpaired analysis of data from all fresh transfer cycles and all FET cycles were performed. We analyzed 1,216 paired and 4,124 unpaired cycles, and P was negatively associated with birth in fresh but not FET cycles in all analyses. Interaction testing of P and cycle type indicated P had a different association with birth in fresh versus FET cycles. When P was ≥2 ng/mL at the time of trigger, live birth was more likely in FET versus fresh cycles in the paired analysis (47% vs. 10%), in the unpaired analysis (51% vs. 14%), and in unpaired, good blastocyst only transfer subgroup (51% vs. 29%). Live birth was similar in FET cycles, with P ≥2 ng/mL versus P < 2 ng/mL (51% vs. 49%). Conversely, live birth was lower in fresh cycles, with P ≥2 ng/mL versus P <2 ng/mL (15% vs. 45%).
Conclusion(s):
Elevated P levels on the day of trigger during the initial fresh cycle were negatively associated with live birth in the fresh transfer cycles but not in subsequent FET cycles. Freezing embryos and performing a subsequent FET cycle ameliorates the effect of elevated P on live-birth rates.
To compare in vitro fertilization (IVF) outcomes between fresh embryo transfer (ET) and frozen-thawed ET (the "freeze-all" policy), with fresh ET performed only in cases without progesterone (P) elevation.
Prospective, observational, cohort study.
Private IVF center.
A total of 530 patients submitted to controlled ovarian stimulation (COS) with a gonadotropin-releasing hormone-antagonist protocol, and cleavage-stage, day-3 ET.
None.
Ongoing pregnancy rates.
A total of 530 cycles were included in the analysis: 351 in the fresh ET group (when P levels were ≤1.5 ng/mL on the trigger day); and 179 cycles in the freeze-all group (ET performed after endometrial priming with estradiol valerate, at 6 mg/d, taken orally). For the fresh ET group vs. the freeze-all group, respectively, the implantation rate was 19.9% and 26.5%; clinical pregnancy rate was 35.9% and 46.4%; and ongoing pregnancy rate was 31.1% and 39.7%.
The IVF outcomes were significantly better in the group using the freeze-all policy, compared with the group using fresh ET. These results suggest that even in a select group of patients that underwent fresh ET (P levels ≤1.5 ng/mL), endometrial receptivity may have been impaired by COS, and outcomes may be improved by using the freeze-all policy.
Copyright © 2015 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.
What is the proper way of assessing the effect of progesterone elevation (PE) on the day of hCG on live birth in women undergoing fresh embryo transfer after in vitro fertilization (IVF) using GnRH analogues and gonadotrophins?
This study indicates that a multivariable approach, where the effect of the most important confounders is controlled for, can lead to markedly different results regarding the association between PE on the day of hCG and live birth rates after IVF when compared with the bivariate analysis that has been typically used in the relevant literature up to date.
PE on the day of hCG is associated with decreased pregnancy rates in fresh IVF cycles. Evidence for this comes from observational studies that mostly failed to control for potential confounders.
This is a retrospective analysis of a cohort of fresh IVF/intracytoplasmic sperm injection cycles (n = 3296) performed in a single IVF centre during the period 2001-2013.
Patients in whom ovarian stimulation was performed with gonadotrophins and GnRH analogues. Natural cycles and cycles where stimulation involved the administration of clomiphene were excluded. In order to reflect routine clinical practice, no other exclusion criteria were imposed on this dataset. The primary outcome measure for this study was live birth defined as the delivery of a live infant after 24 weeks of gestation. We compared the association between PE on the day of hCG (defined as P > 1.5 ng/ml) and live birth rates calculated by simple bivariate analyses with that derived from multivariable logistic regression. The multivariable analysis controlled for female age, number of oocytes retrieved, number of embryos transferred, developmental stage of embryos at transfer (cleavage versus blastocyst), whether at least one good-quality embryo was transferred, the woman's body mass index, the total dose of FSH administered during ovarian stimulation and the type of GnRH analogues used (agonists versus antagonists) during ovarian stimulation. In addition, an interaction analysis was performed in order to assess whether the ovarian response (<6, 6-18, >18 oocytes) has a moderating effect on the association of PE on the day of hCG with live birth rates after IVF.
Live birth rates were not significantly different between cycles with and those without PE when a bivariate analysis was performed [odds ratio (OR): 0.78, 95% confidence interval (CI): 0.56-1.09]. However, when a multivariable analysis was performed, controlling for the effect of the aforementioned confounders, live birth rates (OR: 0.68, 95% CI: 0.48-0.97) were significantly decreased in the group with PE on the day of hCG. The number of oocytes retrieved was the most potent confounder, causing a 29.4% reduction in the OR for live birth between the two groups compared. Furthermore, a moderating effect of ovarian response on the association between PE and live birth rates was not supported in the present analysis since no interaction was detected between PE and the type of ovarian response (<6, 6-18, >18 oocytes).
This is a retrospective analysis of data collected during a 12-year period, and although the effect of the most important confounders was controlled for in the multivariable analysis, the presence of residual bias cannot be excluded.
This analysis highlights the need for a multivariable approach when researchers or clinicians aim to evaluate the impact of PE on pregnancy rates in their own clinical setting. Failure to do so might explain why many past studies have failed to identify the detrimental effect of PE in fresh IVF cycles.
None.
© The Author 2015. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
Study question:
Are low serum progesterone levels on the day of human chorionic gonadotrophin (hCG) administration detrimental for live birth delivery rates during in vitro fertilization (IVF)?
Summary answer:
Progesterone levels ≤0.5 ng/ml on the day of hCG administration hinder live birth rates.
What is known already:
Fundamental research has shown that the presence of late follicular phase progesterone is essential for follicular development, ovulation and endometrial receptivity. However, previous studies in patients undergoing ovarian stimulation have only assessed if progesterone levels in the higher range are detrimental for pregnancy or not. That said, information on the effect of the full range of late follicular progesterone on IVF outcomes is still lacking.
Study design, size, duration:
This was a retrospective, single-centre cohort study with 2723 cycles performed in patients aged between 19 and 36 and undergoing controlled ovarian stimulation between January 2006 and March 2012 for their first or second attempt of IVF followed by a fresh embryo transfer (ET).
Participants/materials, setting, methods:
All patients underwent ovarian stimulation using a gonadotrophin-releasing hormone (GnRH) antagonist for pituitary down-regulation. Final oocyte maturation was triggered with hCG 36 h before oocyte retrieval. On the day of hCG administration, serum progesterone evaluation was performed. Live birth delivery rates were compared amongst various ordinal and regular progesterone intervals (≤0.50, 0.50-0.75, 0.75-1.00, 1.00-1.25, 1.25-1.50, >1.50 ng/ml) using logistic regression.
Main results and the role of chance:
The average age of our sample was 30.5 years. Almost 82% of all embryo transfers were of a single embryo and 51.8% were performed with a Day 5 embryo. The average value (±standard deviation) of progesterone on the day of hCG administration was 1.02 ± 0.50 ng/ml and the live birth rate was 23.4%. The live birth rates (according to the above-described ordinal serum progesterone intervals) were 17.1, 25.1, 26.7, 25.5, 21.9 and 16.6%, respectively. The live birth rates were significantly lower in patients with both low (≤0.5 ng/ml) and high (>1.5 ng/ml) late follicular progesterone levels (P < 0.05).
Limitations, reasons for caution:
The main limitation of our study was its retrospective nature. Furthermore, our study was restricted to patients under GnRH antagonist pituitary suppression and requires confirmation in a GnRH agonist setting.
Wider implications of the findings:
This study comprehensively assessed the relationship between live birth delivery rates and progesterone levels on the day of hCG administration during ovarian stimulation for IVF. Clinically relevant lower (≤0.5 ng/ml) and higher (>1.5 ng/ml) progesterone level limits were determined.
Study funding/competing interests:
No funding was received for this study and the authors have no conflicts of interest to declare.
Objective
To compare the precision of progesterone measurements obtained with the use of immunoassays and of liquid chromatography–tandem mass spectrometry (LC-MS/MS).
Design
Comparative study.
Setting
Academic, private practice, and in vitro fertilization (IVF) research centers.
Patient(s)
A total of 189 human serum samples were collected during controlled ovarian hyperstimulation and early pregnancy in women undergoing IVF.
Intervention(s)
Serum progesterone pools (n = 10; 0.2–4 ng/mL) were sent to four laboratory centers that used four different automated immunoassay analyzers. Progesterone was measured by immunoassay in triplicate at three separate time points (n = 9 per pool) and by LC-MS/MS in triplicate once (n = 3 per pool).
Main Outcome Measure(s)
Inter- and intraassay coefficients of variation (CVs) of progesterone measurements were compared for each analyzer and LC-MS/MS.
Result(s)
Progesterone measurements by immunoassay were highly correlated with those by LC-MS/MS. Only two analyzers had intraassay CVs <10% at all three experimental time points, and only two analyzers had an interassay CV <10%. Mean progesterone levels by the analyzers were different across multiple progesterone pools.
Conclusion(s)
Our results indicate that progesterone threshold measurements used for IVF clinical decisions should be interpreted cautiously and based on laboratory- and method-specific data. A validated progesterone standard incorporated into daily immunoassays could improve medical decision accuracy.
G*Power (Erdfelder, Faul, & Buchner, 1996) was designed as a general stand-alone power analysis program for statistical tests commonly used in social and behavioral research. G*Power 3 is a major extension of, and improvement over, the previous versions. It runs on widely used computer platforms (i.e., Windows XP, Windows Vista, and Mac OS X 10.4) and covers many different statistical tests of the t, F, and chi2 test families. In addition, it includes power analyses for z tests and some exact tests. G*Power 3 provides improved effect size calculators and graphic options, supports both distribution-based and design-based input modes, and offers all types of power analyses in which users might be interested. Like its predecessors, G*Power 3 is free.
In in vitro fertilization (IVF) cycles using gonadotropin-releasing hormone agonist (GnRH-a) suppression, we investigated whether an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration indicates premature luteinization and is associated with a lower pregnancy rate. We retrospectively studied 101 patients treated with the GnRH-a leuprolide acetate, begun in the luteal phase of the prior menstrual cycle and continued until the day of hCG administration. On the day of hCG, 72 patients had P less than 0.9 ng/mL and 29 had less than or equal to 0.9 ng/mL. Patients in the high P group had a significantly greater estradiol level on the day of hCG. No significant difference in clinical pregnancy rates or ongoing pregnancy rates occurred between the low P and high P groups. We conclude that in IVF cycles pretreated with GnRH-a, P levels on the day of hCG are not predictive of conceiving in that cycle.
To determine whether IVF or intracytoplasmic sperm injection (ICSI) should be the choice of treatment in case of a previous IVF attempt with unexplained total fertilization failure or low fertilization (<25%).
Prospective study.
Leiden University Medical Center.
Thirty-eight couples undergoing IVF and ICSI on sibling oocytes after a first IVF attempt with total fertilization failure or with low fertilization (<25%).
Performing IVF and ICSI on sibling oocytes.
Fertilization and (ongoing) pregnancy rate.
A total of 271 oocytes were collected in 24 oocyte retrievals in the total fertilization failure group. Hundred nine oocytes were randomly allocated to IVF and 12 were fertilized (11%); 162 sibling oocytes were allocated to ICSI and 78 were fertilized (48%). In 8 of the 24 patients fertilization occurred after IVF. The pregnancy rate after transfer of 1 IVF and 1 ICSI embryo (n = 3) was 67% and after the transfer of 2 ICSI embryos (n = 21) this was 52%. In the low fertilization group 169 oocytes were collected in 14 oocyte retrievals. Seventy-two oocytes were randomly allocated to IVF and 16 were fertilized (22%). Ninety-seven sibling oocytes were allocated to ICSI and 58 were fertilized (60%). In 7 of 14 patients fertilization occurred after IVF. The pregnancy rate after the transfer of 1 IVF and 1 ICSI embryo (n = 5) was 80% and after the transfer of 2 ICSI embryos (n = 9) this was 33%.
Performing ICSI on some oocytes of a cohort may avoid total fertilization failures both in patients with a history of total fertilization failure and in patients with a history of low fertilization, as the percentage of fertilization is higher after ICSI compared to IVF and the recurrence of total fertilization failure and low fertilization is high after IVF treatment.
Assessing the clinical significance of elevated progesterone during Elevated progesterone and non-elective freeze-all
- V S Vanni
- E Alleva
- E Papaleo
- M Candiani
- E Somigliana
- P Viganò
Vanni VS, Alleva E, Papaleo E, Candiani M, Somigliana E, Viganò P.
Assessing the clinical significance of elevated progesterone during
Elevated progesterone and non-elective freeze-all
........................................
controlled ovarian stimulation: the unanswered question about embryo quality
controlled ovarian stimulation: the unanswered question about
embryo quality. Hum Reprod 2018;33:1191-1192.