What is the optimal means of preparing the endometrium in frozen–thawed embryo transfer cycles? A systematic review and meta-analysis
TL;DR: All of the current methods of endometrial preparation appear to be equally successful in terms of ongoing pregnancy rate, however, in some comparisons predominantly retrospective studies were included leaving these comparisons subject to selection and publication bias.
Abstract: BACKGROUND Frozen-thawed embryo transfer (FET) enables surplus embryos derived from IVF or IVF-ICSI treatment to be stored and transferred at a later date. In recent years the number of FET cycles performed has increased due to transferring fewer embryos per transfer and improved laboratory techniques. Currently, there is little consensus on the most effective method of endometrium preparation prior to FET. METHODS Using both MEDLINE and EMBASE database a systematic review and meta-analysis of literature was performed. Case-series, case-control studies and articles in languages other than English, Dutch or Spanish were excluded. Those studies comparing clinical and ongoing pregnancy rates as well as live birth rates in (i) true natural cycle FET (NC-FET) versus modified NC-FET, (ii) NC-FET versus artificial cycle FET (AC-FET), (iii) AC-FET versus artificial with GnRH agonist cycle FET and (iv) NC-FET versus artificial with GnRH agonist cycle FET were included. Forest plots were constructed and relative risks or odds ratios were calculated. RESULTS A total of 43 publications were selected for critical appraisal and 20 articles were included in the final review. For all comparisons, no differences in the clinical pregnancy rate, ongoing pregnancy rate or live birth rate could be found. Based on information provided in the articles no conclusions could be drawn with regard to cancellation rates. CONCLUSIONS Based on the current literature it is not possible to identify one method of endometrium preparation in FET as being more effective than another. Therefore, all of the current methods of endometrial preparation appear to be equally successful in terms of ongoing pregnancy rate. However, in some comparisons predominantly retrospective studies were included leaving these comparisons subject to selection and publication bias. Also patients' preferences as well as cost-efficiency were not addressed in any of the included studies. Therefore, prospective randomized studies addressing these issues are needed.
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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 "What is the optimal means of prepar..."
...Importantly, over 1000 patients have already been recruited for a new multicentre randomized trial (The ANTARCTICA trial) to assess the effect of natural and artificial FET cycles on numerous outcomes such as live birth rate, health costs, adverse events and patient burden (Groenewoud et al., 2013) and its outcomes are keenly awaited....
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...…already been recruited for a new multicentre randomized trial (The ANTARCTICA trial) to assess the effect of natural and artificial FET cycles on numerous outcomes such as live birth rate, health costs, adverse events and patient burden (Groenewoud et al., 2013) and its outcomes are keenly awaited....
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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
Cites background or methods from "What is the optimal means of prepar..."
...For frozen-thawed embryo transfers in natural or artificial cycles, no differences have been reported regarding pregnancy rates or live birth rates (13, 69)....
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...Multiple variables, such as the selection criteria for embryos to be cryopreserved (10), the method of freezing and thawing (11), the synchronization between embryo and endometrial development (12), hormone supplementation during the frozen-thawed embryo transfer cycle (13), and patient characteristics, such as age of the woman (14, 15), determine the efficacy of embryo cryopreservation programs....
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TL;DR: A standardized timing strategy based on the current available evidence which could assist in the harmonization and comparability of clinic practice and future trials is proposed, with special attention to the timing of the embryo transfer.
Abstract: Study question What is the optimal endometrial preparation protocol for a frozen embryo transfer (FET)? Summary answer Although the optimal endometrial preparation protocol for FET needs further research and is yet to be determined, we propose a standardized timing strategy based on the current available evidence which could assist in the harmonization and comparability of clinic practice and future trials. What is known already Amid a continuous increase in the number of FET cycles, determining the optimal endometrial preparation protocol has become paramount to maximize ART success. In current daily practice, different FET preparation methods and timing strategies are used. Study design, size, duration This is a review of the current literature on FET preparation methods, with special attention to the timing of the embryo transfer. Participants/materials, setting, methods Literature on the topic was retrieved in PubMed and references from relevant articles were investigated until June 2017. Main results and the role of chance The number of high quality randomized controlled trials (RCTs) is scarce and, hence, the evidence for the best protocol for FET is poor. Future research should compare both the pregnancy and neonatal outcomes between HRT and true natural cycle (NC) FET. In terms of embryo transfer timing, we propose to start progesterone intake on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hCG + 7 or LH + 6 in modified or true NC, respectively. Limitations reasons for caution As only a few high quality RCTs on the optimal preparation for FET are available in the existing literature, no definitive conclusion for benefit of one protocol over the other can be drawn so far. Wider implications of the findings Caution when using HRT for FET is warranted since the rate of early pregnancy loss is alarmingly high in some reports. Study funding/competing interest(s) S.M. is funded by the Research Fund of Flanders (FWO). H.T. and C.B. report grants from Merck, Goodlife, Besins and Abbott during the conduct of the study. Trial registration number Not applicable.
195 citations
Cites background from "What is the optimal means of prepar..."
...Retrospective data have left physicians with conflicting information in terms of clinical outcome (Ghobara and Vandekerckhove, 2008; Givens et al., 2009; Chang et al., 2011; Groenewoud et al., 2013; Guan et al., 2016)....
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TL;DR: There have been reports of greater implantation and pregnancy rates with FET than with fresh autologous embryo transfer, suggesting superior endometrial receptivity in the absence of ovarian stimulation.
183 citations
Cites background from "What is the optimal means of prepar..."
...A recent metaanalysis (58) found the success rates were not significantly different when comparing natural cycle FET vs....
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University of Illinois at Chicago1, Art Institute of Washington2, University of Melbourne3, Cornell University4, National Institutes of Health5, Mount Sinai Hospital6, University of California, Berkeley7, University of South Florida8, McGill University9, University of Southern California10, Case Western Reserve University11, University of Gothenburg12, Université catholique de Louvain13, Cliniques Universitaires Saint-Luc14, FIU Herbert Wertheim College of Medicine15, University of Kent16, Salk Institute for Biological Studies17, Hudson Institute of Medical Research18, University of California, San Francisco19, University of Adelaide20, Stanford University21, Zhengzhou University22, Hebrew University of Jerusalem23, Bar-Ilan University24, Merck KGaA25, Katholieke Universiteit Leuven26, Yale University27, Utrecht University28, Aristotle University of Thessaloniki29, University of California, San Diego30, Lunenfeld-Tanenbaum Research Institute31, Free University of Brussels32, Brown University33, New York Institute of Technology College of Osteopathic Medicine34, NewYork–Presbyterian Hospital35, Baylor College of Medicine36, Minia University37, Boston University38, Northwestern University39, Ghent University40, Vrije Universiteit Brussel41, Western Michigan University42, American Society for Reproductive Medicine43, University of Alabama at Birmingham44, University of Cincinnati Academic Health Center45
TL;DR: This monograph, written by the pioneers of IVF and reproductive medicine, celebrates the history, achievements, and medical advancements made over the last 40 years in this rapidly growing field.
180 citations
References
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TL;DR: The data provide a relatively precise picture of the hormonal changes preceding the onset of the gonadotropin surge and the temporal relationship between the multiphasic P4 rise and pituitary-ovarian function.
Abstract: The dynamics of ovarian and pituitary hormone changes during the midcycle period were evaluated. Changes in hormone levels were determined at 2-h intervals for 5 consecutive days during the periovulatory phase of the cycle in five women. During the 50 h preceding the onset of the surge, the rates of increments for estradiol (E2), progesterone (P4), and LH were similar, with doubling times of 57-61 h. The onset of LH and FSH surges was found to occur abruptly (LH doubled within 2 h). They were temporally associated with the attainment of peak E2 levels and occurred 12 h after the initiation of a rapid rise of P4. The mean duration of the surge was 48 h, with a rapidly ascending limb (doubling time, 5.2 h) lasting 14 h accompanied by a rapid decline of E2 and a continued rise of P4. The surge was followed by a peak plateau of gonadotropin levels lasting for 14 h and a transient leveling of P4. The longer descending limb (half-time, 9.6 h), lasting for 20 h, was associated with a second rapid rise of P4, beginning 36 h after surge onset or 12 h before termination of the surge. By using the onset of the LH surge as a reference point, our data provide a relatively precise picture of the hormonal changes preceding the onset of the gonadotropin surge and the temporal relationship between the multiphasic P4 rise and pituitary-ovarian function.
477 citations
Additional excerpts
...ments (Hoff et al., 1983; Frydman et al., 1984; Miller and Soules 1996)....
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TL;DR: It is demonstrated here that levels of estrogen within a very narrow range determine the duration of the window of uterine receptivity, and it is suggested that careful regulation of estrogen levels is one of the important factors for improvement of female fertility in IVF/ET programs.
Abstract: Many underlying causes of human infertility have been overcome by using in vitro fertilization (IVF) and embryo transfer (ET) techniques. Nevertheless, implantation rates in IVF programs remain low despite the transfer of apparently healthy embryos. This suggests that there are problems with the differentiation of the uterus to the receptive state in response to the ovarian hormones estrogen and progesterone. The molecular basis of this receptive state when the uterine environment is conducive to blastocyst acceptance and implantation remains poorly understood. Normally, the “window” of uterine receptivity lasts for a limited time. Using ETs and the progesterone-treated delayed-implantation model in mice, we demonstrate here that levels of estrogen within a very narrow range determine the duration of the window of uterine receptivity. Although estrogen at different physiological concentrations can initiate implantation, we find that the window of uterine receptivity remains open for an extended period at lower estrogen levels but rapidly closes at higher levels. The uterine refractoriness that follows the receptive state at high estrogen levels is accompanied by aberrant uterine expression of implantation-related genes. These results suggest that careful regulation of estrogen levels is one of the important factors for improvement of female fertility in IVF/ET programs.
464 citations
"What is the optimal means of prepar..." refers background in this paper
...Some suggest that higher levels of E2 lead to alteration in features of the endometrium and moment of closure of the window of implantation (Ma et al., 2003; Adams et al., 2004)....
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TL;DR: The relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction using progesterone, hCG or GnRH agonist supplementation in ART cycles was determined.
Abstract: Background
Progesterone prepares the endometrium for pregnancy by stimulating proliferation in response to human chorionic gonadotropin (hCG) produced by the corpus luteum in the luteal phase of the menstrual cycle. In assisted reproduction techniques (ART), progesterone and/or hCG levels are low, so the luteal phase is supported with progesterone, hCG or gonadotropin-releasing hormone (GnRH) agonists to improve implantation and pregnancy rates.
Objectives
To determine the relative effectiveness and safety of methods of luteal phase support provided to subfertile women undergoing assisted reproduction.
Search methods
We searched databases including the Cochrane Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PsycINFO and trial registers up to November 2014. Further searches were undertaken in August 2015.
Selection criteria
Randomised controlled trials (RCTs) of luteal phase support using progesterone, hCG or GnRH agonist supplementation in ART cycles.
Data collection and analysis
We used standard methodological procedures expected by Cochrane. Our primary outcome was live birth or ongoing pregnancy. The overall quality of the evidence was assessed using GRADE methods.
Main results
Ninety-four RCTs (26,198 women) were included. Most studies had unclear or high risk of bias in most domains. The main limitations in the evidence were poor reporting of study methods and imprecision due to small sample sizes.
1. hCG vs placebo/no treatment (five RCTs, 746 women)
Findings suggested benefit for the hCG group in live birth or ongoing pregnancy rates when data were analysed with a fixed-effect model (OR 1.76, 95% CI 1.08 to 2.86, three RCTs, 527 women, I2 = 24%, very low-quality evidence) but there was no clear evidence of a difference using a random-effects model (OR 1.67, 95% CI 0.90 to 3.12). hCG may increase ovarian hyperstimulation syndrome (OHSS) rates (OR 4.28, 95% CI 1.91 to 9.6, one RCT, 387 women, low-quality evidence).
2. Progesterone vs placebo/no treatment (eight RCTs, 875 women)
Findings suggested benefit for the progesterone group in live birth or ongoing pregnancy rates when data were analysed with a fixed-effect model (OR 1.77, 95% CI 1.09 to 2.86, five RCTs, 642 women, I2 = 35%, very low-quality evidence) but there was no clear evidence of a difference using a random-effects model (OR 1.77, 95% CI 0.96 to 3.26). OHSS was not reported.
3. Progesterone vs hCG regimens (16 RCTs, 2162 women)
hCG regimens included hCG alone and hCG with progesterone. There was no evidence of a difference between progesterone and hCG regimens in live birth or ongoing pregnancy rates (OR 0.95, 95% CI 0.65 to 1.38, five RCTs, 833 women, I2 = 0%, low-quality evidence). Progesterone was associated with lower OHSS rates than hCG regimens (OR 0.46, 95% CI 0.30 to 0.71, 5 RCTs, 1293 women , I2=48%).
4. Progesterone vs progesterone with oestrogen (16 RCTs, 2577 women)
There was no evidence of a difference between the groups in rates of live birth or ongoing pregnancy (OR 1.12, 95% CI 0.91 to 1.38, nine RCTs, 1651 women, I2 = 0%, low-quality evidence) or OHSS (OR 0.56, 95% CI 0.2 to 1.63, two RCTs, 461 women, I2 = 0%, low-quality evidence).
5. Progesterone vs progesterone + GnRH agonist (seven RCTs, 1708 women)
Live birth or ongoing pregnancy rates were lower in the progesterone-only group than the progesterone plus GnRH agonist group (OR 0.62, 95% CI 0.48 to 0.81, nine RCTs, 2861 women, I2 = 55%, random effects, low-quality evidence). Statistical heterogeneity was high but the direction of effect was consistent across studies. OHSS was reported in one study only; there was no evidence of a difference between the groups (OR 1.00, 95% CI 0.33 to 3.01, one RCT, 300 women, very low quality evidence).
6. Progesterone regimens (45 RCTs, 13,814 women)
There were nine different comparisons between progesterone regimens. Findings for live birth or ongoing pregnancy were as follows: intramuscular (IM) versus oral: OR 0.71, 95% CI 0.14 to 3.66 (one RCT, 40 women, very low-quality evidence); IM versus vaginal/rectal: OR 1.37, 95% CI 0.94 to 1.99 (seven RCTs, 2309 women, I2 = 71%, random effects, very low-quality evidence); vaginal/rectal versus oral: OR 1.19, 95% CI 0.83 to 1.69 (four RCTs, 857 women, I2 = 32%, low-quality evidence); low-dose versus high-dose vaginal: OR 0.97, 95% CI 0.84 to 1.11 (five RCTs, 3720 women, I2 = 0%, moderate-quality evidence); short versus long protocol: OR 1.04, 95% CI 0.79 to 1.36 (five RCTs, 1205 women, I2 = 0%, low-quality evidence); micronised versus synthetic: OR 0.9, 95% CI 0.53 to 1.55 (two RCTs, 470 women, I2 = 0%, low-quality evidence); vaginal ring versus gel: OR 1.09, 95% CI 0.88 to 1.36 (one RCT, 1271 women, low-quality evidence); subcutaneous versus vaginal gel: OR 0.92, 95% CI 0.74 to 1.14 (two RCTs, 1465 women, I2 = 0%, low-quality evidence); vaginal versus rectal: OR 1.28, 95% CI 0.64 to 2.54 (one RCT, 147 women, very low-quality evidence). OHSS rates were reported for only two comparisons: IM versus oral, and low versus high-dose vaginal; there was no evidence of a difference between the groups.
7. Progesterone and oestrogen regimens (two RCTs, 1195 women)
The included studies compared two different oestrogen protocols. There was no evidence of a difference in live birth or ongoing pregnancy rates between a short or long protocol (OR 1.08, 95% CI 0.81 to 1.43, one RCT, 910 women, low-quality evidence) or between a low or high dose of oestrogen (OR 0.65, 95% CI 0.37 to 1.13, one RCT, 285 women, very low-quality evidence). Neither study reported OHSS.
Authors' conclusions
hCG or progesterone given during the luteal phase may be associated with higher rates of live birth or ongoing pregnancy than placebo or no treatment, but the evidence is not conclusive. The addition of GnRHa to progesterone appears to improve outcomes. hCG may increase the risk of OHSS compared to placebo. Moreover hCG, with or without progesterone, is associated with higher rates of OHSS than progesterone alone. Neither the addition of oestrogen nor the route of progesterone administration appears to be associated with an improvement in outcomes.
341 citations
TL;DR: There was no evidence of a difference in multiple pregnancy rates between women in natural cycles and those in HT FET cycle, and very low-quality evidence suggested that women innatural cycles (without HCG trigger) may have higher ongoing pregnancy rates.
Abstract: Background
Among subfertile couples undergoing assisted reproductive technology (ART), pregnancy rates following frozen-thawed embryo transfer (FET) treatment cycles have historically been found to be lower than following embryo transfer undertaken two to five days following oocyte retrieval. Nevertheless, FET increases the cumulative pregnancy rate, reduces cost, is relatively simple to undertake and can be accomplished in a shorter time period than repeated in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) cycles with fresh embryo transfer. FET is performed using different cycle regimens: spontaneous ovulatory (natural) cycles; cycles in which the endometrium is artificially prepared by oestrogen and progesterone hormones, commonly known as hormone therapy (HT) FET cycles; and cycles in which ovulation is induced by drugs (ovulation induction FET cycles). HT can be used with or without a gonadotrophin releasing hormone agonist (GnRHa). This is an update of a Cochrane review; the first version was published in 2008.
Objectives
To compare the effectiveness and safety of natural cycle FET, HT cycle FET and ovulation induction cycle FET, and compare subtypes of these regimens.
Search methods
On 13 December 2016 we searched databases including Cochrane Gynaecology and Fertility's Specialised Register, CENTRAL, MEDLINE, Embase, PsycINFO and CINAHL. Other search sources were trials registers and reference lists of included studies.
Selection criteria
We included randomized controlled trials (RCTs) comparing the various cycle regimens and different methods used to prepare the endometrium during FET.
Data collection and analysis
We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth rates and miscarriage.
Main results
We included 18 RCTs comparing different cycle regimens for FET in 3815 women. The quality of the evidence was low or very low. The main limitations were failure to report important clinical outcomes, poor reporting of study methods and imprecision due to low event rates. We found no data specific to non-ovulatory women.
1. Natural cycle FET comparisons
Natural cycle FET versus HT FET
No study reported live birth rates, miscarriage or ongoing pregnancy.
There was no evidence of a difference in multiple pregnancy rates between women in natural cycles and those in HT FET cycle (odds ratio (OR) 2.48, 95% confidence interval (CI) 0.09 to 68.14, 1 RCT, n = 21, very low-quality evidence).
Natural cycle FET versus HT plus GnRHa suppression
There was no evidence of a difference in rates of live birth (OR 0.77, 95% CI 0.39 to 1.53, 1 RCT, n = 159, low-quality evidence) or multiple pregnancy (OR 0.58, 95% CI 0.13 to 2.50, 1 RCT, n = 159, low-quality evidence) between women who had natural cycle FET and those who had HT FET cycles with GnRHa suppression. No study reported miscarriage or ongoing pregnancy.
Natural cycle FET versus modified natural cycle FET (human chorionic gonadotrophin (HCG) trigger)
There was no evidence of a difference in rates of live birth (OR 0.55, 95% CI 0.16 to 1.93, 1 RCT, n = 60, very low-quality evidence) or miscarriage (OR 0.20, 95% CI 0.01 to 4.13, 1 RCT, n = 168, very low-quality evidence) between women in natural cycles and women in natural cycles with HCG trigger. However, very low-quality evidence suggested that women in natural cycles (without HCG trigger) may have higher ongoing pregnancy rates (OR 2.44, 95% CI 1.03 to 5.76, 1 RCT, n = 168). There were no data on multiple pregnancy.
2. Modified natural cycle FET comparisons
Modified natural cycle FET (HCG trigger) versus HT FET
There was no evidence of a difference in rates of live birth (OR 1.34, 95% CI 0.88 to 2.05, 1 RCT, n = 959, low-quality evidence) or ongoing pregnancy (OR 1.21, 95% CI 0.80 to 1.83, 1 RCT, n = 959, low-quality evidence) between women in modified natural cycles and those who received HT. There were no data on miscarriage or multiple pregnancy.
Modified natural cycle FET (HCG trigger) versus HT plus GnRHa suppression
There was no evidence of a difference between the two groups in rates of live birth (OR 1.11, 95% CI 0.66 to 1.87, 1 RCT, n = 236, low-quality evidence) or miscarriage (OR 0.74, 95% CI 0.25 to 2.19, 1 RCT, n = 236, low-quality evidence) rates. There were no data on ongoing pregnancy or multiple pregnancy.
3. HT FET comparisons
HT FET versus HT plus GnRHa suppression
HT alone was associated with a lower live birth rate than HT with GnRHa suppression (OR 0.10, 95% CI 0.04 to 0.30, 1 RCT, n = 75, low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 0.64, 95% CI 0.37 to 1.12, 6 RCTs, n = 991, I2 = 0%, low-quality evidence) or ongoing pregnancy (OR 1.72, 95% CI 0.61 to 4.85, 1 RCT, n = 106, very low-quality evidence).
There were no data on multiple pregnancy.
4. Comparison of subtypes of ovulation induction FET
Human menopausal gonadotrophin(HMG) versus clomiphene plus HMG
HMG alone was associated with a higher live birth rate than clomiphene combined with HMG (OR 2.49, 95% CI 1.07 to 5.80, 1 RCT, n = 209, very low-quality evidence). There was no evidence of a difference between the groups in either miscarriage (OR 1.33, 95% CI 0.35 to 5.09,1 RCT, n = 209, very low-quality evidence) or multiple pregnancy (OR 1.41, 95% CI 0.31 to 6.48, 1 RCT, n = 209, very low-quality evidence).
There were no data on ongoing pregnancy.
Authors' conclusions
This review did not find sufficient evidence to support the use of one cycle regimen in preference to another in preparation for FET in subfertile women with regular ovulatory cycles. The most common modalities for FET are natural cycle with or without HCG trigger or endometrial preparation with HT, with or without GnRHa suppression. We identified only four direct comparisons of these two modalities and there was insufficient evidence to support the use of either one in preference to the other.
294 citations
TL;DR: Clinical pregnancy and live-birth or ongoing pregnancy rates increase significantly with increasing endometrial thickness, independent of the effects of patient age and embryo quality.
272 citations