Progesterone elevation and probability of pregnancy after IVF: a systematic review and meta-analysis of over 60 000 cycles
TL;DR: 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.
Abstract: 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. METHODS A 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. RESULTS Sixty-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.
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TL;DR: EFET significantly decreases the risk of moderate and severe OHSS, albeit at the expense of an increased risk of pre-eclampsia, and the effectiveness of eFET in comparison to fresh embryo transfer in different subgroups of patients undergoing IVF/ICSI cycles is evaluated.
Abstract: Background Elective freezing of all good quality embryos and transfer in subsequent cycles, i.e. elective frozen embryo transfer (eFET), has recently increased significantly with the introduction of the GnRH agonist trigger protocol and improvements in cryo-techniques. The ongoing discussion focuses on whether eFET should be offered to the overall IVF population or only to specific subsets of patients. Until recently, the clinical usage of eFET was supported by only a few randomized controlled trials (RCT) and meta-analyses, suggesting that the eFET not only reduced ovarian hyperstimulation syndrome (OHSS), but also improved reproductive outcomes. However, the evidence is not unequivocal, and recent RCTs challenge the use of eFET for the general IVF population. Objective and rationale This systematic review and meta-analysis aimed at evaluating whether eFET is advantageous for reproductive, obstetric and perinatal outcomes compared with fresh embryo transfer in IVF/ICSI cycles. Additionally, we evaluated the effectiveness of eFET in comparison to fresh embryo transfer in different subgroups of patients undergoing IVF/ICSI cycles. Search methods We conducted a systematic review, using PubMed/Medline and EMBASE to identify all relevant RCTs published until March 2018. The participants included infertile couples undergoing IVF/ICSI with or without preimplantation genetic testing for aneuploidy (PGT-A). The primary outcome was the live birth rate (LBR), whereas secondary outcomes were cumulative LBR, implantation rate, miscarriage, OHSS, ectopic pregnancy, preterm birth, pregnancy-induced hypertension, pre-eclampsia, mean birthweight and congenital anomalies. Subgroup analyses included normal and hyper-responder patients, embryo developmental stage on the day of embryo transfer, freezing method and the route of progesterone administration for luteal phase support in eFET cycles. Outcomes Eleven studies, including 5379 patients, fulfilling the inclusion criteria were subjected to qualitative and quantitative analysis. A significant increase in LBR was noted with eFET compared with fresh embryo transfer in the overall IVF/ICSI population [risk ratio (RR) = 1.12; 95% CI: 1.01-1.24]. Subgroup analyses indicated higher LBRs by eFET than by fresh embryo transfer in hyper-responders (RR = 1.16; 95% CI: 1.05-1.28) and in PGT-A cycles (RR = 1.55; 95% CI: 1.14-2.10). However, no differences were observed for LBR in normo-responders (RR = 1.03; 95% CI: 0.91-1.17); moreover, the cumulative LBR was not significantly different in the overall population (RR = 1.04; 95% CI: 0.97-1.11). Regarding safety, the risk of moderate/severe OHSS was significantly lower with eFET than with fresh embryo transfer (RR = 0.42; 95% CI: 0.19-0.96). In contrast, the risk of pre-eclampsia increased with eFET (RR = 1.79; 95% CI: 1.03-3.09). No statistical differences were noted in the remaining secondary outcomes. Wider implications Although the use of eFET has steadily increased in recent years, a significant increase in LBR with eFET was solely noted in hyper-responders and in patients undergoing PGT-A. Concerning safety, eFET significantly decreases the risk of moderate and severe OHSS, albeit at the expense of an increased risk of pre-eclampsia.
286 citations
TL;DR: The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby.
Abstract: Background Improvements in vitrification now make frozen embryo transfers (FETs) a viable alternative to fresh embryo transfer, with reports from observational studies and randomized controlled trials suggesting that: (i) the endometrium in stimulated cycles is not optimally prepared for implantation; (ii) pregnancy rates are increased following FET and (iii) perinatal outcomes are less affected after FET. Methods This review integrates and discusses the available clinical and scientific evidence supporting embryo transfer in a natural cycle. Results Laboratory-based studies demonstrate morphological and molecular changes to the endometrium and reduced responsiveness of the endometrium to hCG, resulting from controlled ovarian stimulation. The literature demonstrates reduced endometrial receptivity in controlled ovarian stimulation cycles and supports the clinical observations that FET reduces the risk of ovarian hyperstimulation syndrome and improves outcomes for both the mother and baby. Conclusions This review provides the basis for an evidence-based approach towards changes in routine IVF, which may ultimately result in higher delivery rates of healthier term babies.
253 citations
Cites background from "Progesterone elevation and probabil..."
...…in progesterone is associated with a reduced probability of clinical pregnancy in fresh embryo transfer cycles, but not in frozen/thawed or donor–recipient IVF cycles (Venetis et al., 2013), implying that both appropriate concentrations and timing of steroid hormones are critical to receptivity....
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...08 ng/ml) confirmed that premature elevation in progesterone is associated with a reduced probability of clinical pregnancy in fresh embryo transfer cycles, but not in frozen/thawed or donor–recipient IVF cycles (Venetis et al., 2013), implying that both appropriate concentrations and timing of steroid hormones are critical to receptivity....
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TL;DR: Interestingly, success rates after frozen-thawed embryo transfer are now nearing the success rates of fresh embryo transfer, which supports the hypothesis of so called freeze-all strategies in IVF, in which all embryos are frozen and no fresh transfer is conducted, to optimize success rates.
223 citations
TL;DR: There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy, but the evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision.
Abstract: Background
In general, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) implies a single fresh and one or more frozen-thawed embryo transfers. Alternatively, the 'freeze-all' strategy implies transfer of frozen-thawed embryos only, with no fresh embryo transfers. In practice, both strategies can vary technically including differences in freezing techniques and timing of transfer of cryopreservation, that is vitrification versus slow freezing, freezing of two pro-nucleate (2pn) versus cleavage-stage embryos versus blastocysts, and transfer of cleavage-stage embryos versus blastocysts.
In the freeze-all strategy, embryo transfers are disengaged from ovarian stimulation in the initial treatment cycle. This could avoid a negative effect of ovarian hyperstimulation on the endometrium and thereby improve embryo implantation. It could also reduce the risk of ovarian hyperstimulation syndrome (OHSS) in the ovarian stimulation cycle by avoiding a pregnancy.
We compared the benefits and risks of the two treatment strategies.
Objectives
To evaluate the effectiveness and safety of the freeze-all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology.
Search methods
We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in November 2016 together with reference checking and contact with study authors and experts in the field to identify additional studies.
Selection criteria
We included randomised clinical trials comparing a freeze-all strategy with a conventional IVF/ICSI strategy which includes fresh transfer of embryos in women undergoing IVF or ICSI treatment.
Data collection and analysis
We used standard methodological procedures recommended by Cochrane. The primary review outcomes were cumulative live birth and OHSS. Secondary outcomes included other adverse effects (miscarriage rate).
Main results
We included four randomised clinical trials analysing a total of 1892 women comparing a freeze-all strategy with a conventional IVF/ICSI strategy. The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules.
There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.91 to 1.31; 4 trials; 1892 women; I2 = 0%; moderate-quality evidence). This suggests that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%.
The prevalence of OHSS was lower after the freeze-all strategy compared to the conventional IVF/ICSI strategy (OR 0.24, 95% CI 0.15 to 0.38; 2 trials; 1633 women; I2 = 0%; low-quality evidence). This suggests that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%.
The freeze-all strategy was associated with fewer miscarriages (OR 0.67, 95% CI 0.52 to 0.86; 4 trials; 1892 women; I2 = 0%; low-quality evidence) and a higher rate of pregnancy complications (OR 1.44, 95% CI 1.08 to 1.92; 2 trials; 1633 women; low-quality evidence). There was no difference in multiple pregnancies per woman after the first transfer (OR 1.11, 95% CI 0.85 to 1.44; 2 trials; 1630 women; low-quality evidence), and no data were reported for time to pregnancy.
Authors' conclusions
We found moderate-quality evidence showing that one strategy is not superior to the other in terms of cumulative live birth rates. Time to pregnancy was not reported, but it can be assumed to be shorter using a conventional IVF/ICSI strategy in the case of similar cumulative live birth rates, as embryo transfer is delayed in a freeze-all strategy. Low-quality evidence suggests that not performing a fresh transfer lowers the OHSS risk for women at risk of OHSS.
219 citations
TL;DR: 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.
192 citations
References
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TL;DR: A new quantity is developed, I 2, which the authors believe gives a better measure of the consistency between trials in a meta-analysis, which is susceptible to the number of trials included in the meta- analysis.
Abstract: Cochrane Reviews have recently started including the quantity I 2 to help readers assess the consistency of the results of studies in meta-analyses. What does this new quantity mean, and why is assessment of heterogeneity so important to clinical practice?
Systematic reviews and meta-analyses can provide convincing and reliable evidence relevant to many aspects of medicine and health care.1 Their value is especially clear when the results of the studies they include show clinically important effects of similar magnitude. However, the conclusions are less clear when the included studies have differing results. In an attempt to establish whether studies are consistent, reports of meta-analyses commonly present a statistical test of heterogeneity. The test seeks to determine whether there are genuine differences underlying the results of the studies (heterogeneity), or whether the variation in findings is compatible with chance alone (homogeneity). However, the test is susceptible to the number of trials included in the meta-analysis. We have developed a new quantity, I 2, which we believe gives a better measure of the consistency between trials in a meta-analysis.
Assessment of the consistency of effects across studies is an essential part of meta-analysis. Unless we know how consistent the results of studies are, we cannot determine the generalisability of the findings of the meta-analysis. Indeed, several hierarchical systems for grading evidence state that the results of studies must be consistent or homogeneous to obtain the highest grading.2–4
Tests for heterogeneity are commonly used to decide on methods for combining studies and for concluding consistency or inconsistency of findings.5 6 But what does the test achieve in practice, and how should the resulting P values be interpreted?
A test for heterogeneity examines the null hypothesis that all studies are evaluating the same effect. The usual test statistic …
45,105 citations
"Progesterone elevation and probabil..." refers methods in this paper
...In addition, the use of the I(2) index was employed in order to indicate the proportion of inconsistency between studies that could not be attributed to chance, with I(2) ≥ 50% indicating significant heterogeneity (Higgins et al., 2003)....
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...In addition, the use of the I2 index was employed in order to indicate the proportion of inconsistency between studies that could not be attributed to chance, with I2 ≥ 50% indicating significant heterogeneity (Higgins et al., 2003)....
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TL;DR: Funnel plots, plots of the trials' effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials.
Abstract: Objective: Funnel plots (plots of effect estimates against sample size) may be useful to detect bias in meta-analyses that were later contradicted by large trials. We examined whether a simple test of asymmetry of funnel plots predicts discordance of results when meta-analyses are compared to large trials, and we assessed the prevalence of bias in published meta-analyses. Design: Medline search to identify pairs consisting of a meta-analysis and a single large trial (concordance of results was assumed if effects were in the same direction and the meta-analytic estimate was within 30% of the trial); analysis of funnel plots from 37 meta-analyses identified from a hand search of four leading general medicine journals 1993-6 and 38 meta-analyses from the second 1996 issue of the Cochrane Database of Systematic Reviews . Main outcome measure: Degree of funnel plot asymmetry as measured by the intercept from regression of standard normal deviates against precision. Results: In the eight pairs of meta-analysis and large trial that were identified (five from cardiovascular medicine, one from diabetic medicine, one from geriatric medicine, one from perinatal medicine) there were four concordant and four discordant pairs. In all cases discordance was due to meta-analyses showing larger effects. Funnel plot asymmetry was present in three out of four discordant pairs but in none of concordant pairs. In 14 (38%) journal meta-analyses and 5 (13%) Cochrane reviews, funnel plot asymmetry indicated that there was bias. Conclusions: A simple analysis of funnel plots provides a useful test for the likely presence of bias in meta-analyses, but as the capacity to detect bias will be limited when meta-analyses are based on a limited number of small trials the results from such analyses should be treated with considerable caution. Key messages Systematic reviews of randomised trials are the best strategy for appraising evidence; however, the findings of some meta-analyses were later contradicted by large trials Funnel plots, plots of the trials9 effect estimates against sample size, are skewed and asymmetrical in the presence of publication bias and other biases Funnel plot asymmetry, measured by regression analysis, predicts discordance of results when meta-analyses are compared with single large trials Funnel plot asymmetry was found in 38% of meta-analyses published in leading general medicine journals and in 13% of reviews from the Cochrane Database of Systematic Reviews Critical examination of systematic reviews for publication and related biases should be considered a routine procedure
37,989 citations
"Progesterone elevation and probabil..." refers methods in this paper
...The presence of publication bias was assessed by constructing and visually examining funnel plots, as well as by performing Egger’s test (Egger et al., 1997)....
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TL;DR: This paper examines eight published reviews each reporting results from several related trials in order to evaluate the efficacy of a certain treatment for a specified medical condition and suggests a simple noniterative procedure for characterizing the distribution of treatment effects in a series of studies.
33,234 citations
Book•
23 Sep 2019TL;DR: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.
Abstract: The Cochrane Handbook for Systematic Reviews of Interventions is the official document that describes in detail the process of preparing and maintaining Cochrane systematic reviews on the effects of healthcare interventions.
21,235 citations
Book•
01 Jan 1985
TL;DR: In this article, the authors present a model for estimating the effect size from a series of experiments using a fixed effect model and a general linear model, and combine these two models to estimate the effect magnitude.
Abstract: Preface. Introduction. Data Sets. Tests of Statistical Significance of Combined Results. Vote-Counting Methods. Estimation of a Single Effect Size: Parametric and Nonparametric Methods. Parametric Estimation of Effect Size from a Series of Experiments. Fitting Parametric Fixed Effect Models to Effect Sizes: Categorical Methods. Fitting Parametric Fixed Effect Models to Effect Sizes: General Linear Models. Random Effects Models for Effect Sizes. Multivariate Models for Effect Sizes. Combining Estimates of Correlation Coefficients. Diagnostic Procedures for Research Synthesis Models. Clustering Estimates of Effect Magnitude. Estimation of Effect Size When Not All Study Outcomes Are Observed. Meta-Analysis in the Physical and Biological Sciences. Appendix. References. Index.
9,769 citations
"Progesterone elevation and probabil..." refers methods in this paper
...These results were combined for meta-analysis using the inverse variance method (Hedges and Olkin, 1985), when using the fixed effects model, and the DerSimonian and Laird method (DerSimonian and Laird, 434 Venetis et al. 1986), when using the random effects model....
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...These results were combined for meta-analysis using the inverse variance method (Hedges and Olkin, 1985), when using the fixed effects model, and the DerSimonian and Laird method (DerSimonian and Laird, 434 Venetis et al....
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