Cumulative live birth rates following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF: a population-based retrospective cohort study.

Is there a difference in the odds of a live birth following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF? After adjusting for indication bias, there was not enough evidence to suggest a difference in the odds of live birth following blastocyst- versus cleavage-stage embryo transfer in the first complete cycle of IVF. Replacement of blastocyst-stage embryos has become the dominant practice in IVF but there is uncertainty about whether this technique offers an improved chance of cumulative live birth over all fresh and frozen-thawed embryo transfer attempts associated with a single oocyte retrieval. National population-based retrospective cohort study of 100 610 couples who began their first IVF/ICSI treatment at a licenced UK clinic between 1 January 1999 and 30 July 2010. Data from the Human Fertilisation and Embryology Authority (HFEA) register on IVF/ICSI treatments using autologous gametes between 1999 and 2010 were analysed. The primary outcome was the live birth rate over the first complete cycle of IVF. Cumulative live birth rates (CLBR) were compared for couples who underwent blastocyst and cleavage transfer, and the adjusted odds of live birth over the first complete cycle were estimated for each group using binary logistic regression. This analysis was repeated within groups of female age, oocytes collected and primary versus secondary infertility. Inverse probability of treatment weighting was used to account for the imbalance in couple characteristics between treatment groups. In total, 94 294 (93.7%) couples had a cleavage-stage embryo transfer while 6316 (6.3%) received blastocysts. Over the first complete cycle of IVF/ICSI (incorporating all fresh and frozen-thawed embryo transfers associated with the first oocyte retrieval), the CLBR was increased in those who underwent blastocyst transfer (56.5%) compared to cleavage-stage embryo transfer (34.8%). However, after accounting for the imbalance between exposures, blastocyst transfer did not significantly influence the odds of live birth over the first complete cycle (adjusted odds ratio: 1.03 (0.96, 1.10)). Limitations of our study include the retrospective nature of the HFEA dataset and availability of linked data up until 2010. We were unable to adjust for some confounders, such as smoking status, BMI and embryo quality, as these data are not collected at national level by the HFEA. Similarly, there may be unknown couple, treatment or clinic variables that may influence our results. We were unable to assess the intended stage of embryo transfer for women who did not have an embryo replaced, and therefore excluded them from our study. Perinatal outcomes were not included in our analyses and would be a useful basis for future study. Our findings show that blastocyst-stage embryo transfer may offer an improved chance of live birth in both the first fresh and the first complete cycle of IVF/ICSI compared to cleavage-stage transfer, even in couples with typically poorer prognoses. Where possible, offering blastocyst transfer to a wider range of couples may increase cumulative success rates. N.J.C. received a Wolfson Foundation Intercalated Degree Research Fellowship funded by the Wolfson Foundation, through the Royal College of Physicians. This work was supported by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06) held by D.J.M. The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office or the Wolfson Foundation. The funders did not have any role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. None of the authors has any conflicts of interest to declare. N/A.

Cameron NJ ，Bhattacharya S ，McLernon DJ 《-》

Cumulative live birth rates following miscarriage in an initial complete cycle of IVF: a retrospective cohort study of 112 549 women.

In women undergoing IVF/ICSI who miscarry in their first complete cycle, what is the chance of a live birth in subsequent complete cycles, and how does this compare with those whose first complete cycle ends with live birth or without a pregnancy? After two further complete cycles of IVF/ICSI, women who had miscarried or had a live birth in their first complete cycle had a higher chance of live birth (40.9 and 49.0%, respectively) than those who had no pregnancies (30.1%). Cumulative live birth rates (CLBRs) after one or more complete cycles of IVF have been reported previously, as have some of the risk factors associated with miscarriage, both in general populations and in those undergoing IVF. Chances of cumulative live birth after a number of complete IVF cycles involving replacement of fresh followed by frozen embryos after an initial miscarriage in a population undergoing IVF treatment have not been reported previously. National population-based cohort study of 112 549 women who started their first IVF treatment between 1999 and 2008. Data from the UK Human Fertilisation and Embryology Authority (HFEA) register on IVF/ICSI treatments, using autologous gametes were analysed. CLBRs were estimated in women who (i) had miscarriage (and no live birth), (ii) at least one live birth or (iii) no pregnancy in their first complete cycle of IVF/ICSI (including fresh and frozen embryo transfers following a single oocyte retrieval episode). A multivariable analysis was performed to assess the effect of first complete cycle outcome on subsequent CLBRs after adjusting for confounding factors such as female age, duration of infertility and cause of infertility. In their first complete cycle, 9321 (8.3%) women had at least one miscarriage (and no live birth); 33 152 (29.5%) had at least one live birth and 70 076 (62.3%) had no pregnancies. After two further complete cycles, conservative CLBRs (which assume that women who discontinued treatment subsequently never had a live birth) were 40.9, 49.0 and 30.1%, while optimal CLBRs (which assume that women who discontinue have the same chance of live birth as those treated) were 49.5, 57.9 and 38.4% in the miscarriage, live birth and no pregnancy groups respectively. Odds of cumulative live birth for women who miscarried in their first complete cycle were 42% higher than those who had no pregnancy [odds ratio (95% CI) = 1.42 (1.34, 1.50)], and twice as high for live birth versus no pregnancy [2.04 (1.89, 2.20)]. Negative predictors for live birth in all women included tubal infertility [0.88 (0.82, 0.94)] and increasing age [18-40 years = 0.94 (0.94, 0.95); >40 years = 0.63 (0.59, 0.66) per year]. CLBRs could not be estimated for treatments occurring after September 2008 due to potentially incomplete data following regulatory changes regarding consent for data use in research. Additionally, covariates not included in the HFEA database (including BMI, smoking, previous history of miscarriage and gestational age at miscarriage) could not be adjusted for in our analysis. Miscarriage following IVF can be devastating for couples who are uncertain about their ultimate prognosis. Our findings will provide reassurance to these couples as they consider their options for continuing treatment. N.J.C. received an Aberdeen Summer Research Scholarship funded by the Institute of Applied Health Sciences (University of Aberdeen), through the Aberdeen Clinical Academic Training Scheme. This work was supported by a Chief Scientist Office Postdoctoral Training Fellowship in Health Services Research and Health of the Public Research (Ref PDF/12/06). The views expressed here are those of the authors and not necessarily those of the Chief Scientist Office or the University of Aberdeen. The funders did not have any role in the study design; in the collection, analysis and interpretation of data; in the writing of the report; nor in the decision to submit the paper for publication. None of the authors has any conflicts of interest to declare.

Cameron NJ ，Bhattacharya S ，Bhattacharya S ，McLernon DJ ... -  《-》

Cumulative live birth rates after one or more complete cycles of IVF: a population-based study of linked cycle data from 178,898 women.

McLernon DJ ，Maheshwari A ，Lee AJ ，Bhattacharya S ... -  《-》

External validation of models for predicting cumulative live birth over multiple complete cycles of IVF treatment.

Can two prediction models developed using data from 1999 to 2009 accurately predict the cumulative probability of live birth per woman over multiple complete cycles of IVF in an updated UK cohort? After being updated, the models were able to estimate individualized chances of cumulative live birth over multiple complete cycles of IVF with greater accuracy. The McLernon models were the first to predict cumulative live birth over multiple complete cycles of IVF. They were converted into an online calculator called OPIS (Outcome Prediction In Subfertility) which has 3000 users per month on average. A previous study externally validated the McLernon models using a Dutch prospective cohort containing data from 2011 to 2014. With changes in IVF practice over time, it is important that the McLernon models are externally validated on a more recent cohort of patients to ensure that predictions remain accurate. A population-based cohort of 91 035 women undergoing IVF in the UK between January 2010 and December 2016 was used for external validation. Data on frozen embryo transfers associated with these complete IVF cycles conducted from 1 January 2017 to 31 December 2017 were also collected. Data on IVF treatments were obtained from the Human Fertilisation and Embryology Authority (HFEA). The predictive performances of the McLernon models were evaluated in terms of discrimination and calibration. Discrimination was assessed using the c-statistic and calibration was assessed using calibration-in-the-large, calibration slope, and calibration plots. Where any model demonstrated poor calibration in the validation cohort, the models were updated using intercept recalibration, logistic recalibration, or model revision to improve model performance. Following exclusions, 91 035 women who underwent 144 734 complete cycles were included. The validation cohort had a similar distribution age profile to women in the development cohort. Live birth rates over all complete cycles of IVF per woman were higher in the validation cohort. After calibration assessment, both models required updating. The coefficients of the pre-treatment model were revised, and the updated model showed reasonable discrimination (c-statistic: 0.67, 95% CI: 0.66 to 0.68). After logistic recalibration, the post-treatment model showed good discrimination (c-statistic: 0.75, 95% CI: 0.74 to 0.76). As an example, in the updated pre-treatment model, a 32-year-old woman with 2 years of primary infertility has a 42% chance of having a live birth in the first complete ICSI cycle and a 77% chance over three complete cycles. In a couple with 2 years of primary male factor infertility where a 30-year-old woman has 15 oocytes collected in the first cycle, a single fresh blastocyst embryo transferred in the first cycle and spare embryos cryopreserved, the estimated chance of live birth provided by the post-treatment model is 46% in the first complete ICSI cycle and 81% over three complete cycles. Two predictors from the original models, duration of infertility and previous pregnancy, which were not available in the recent HFEA dataset, were imputed using data from the older cohort used to develop the models. The HFEA dataset does not contain some other potentially important predictors, e.g. BMI, ethnicity, race, smoking and alcohol intake in women, as well as measures of ovarian reserve such as antral follicle count. Both updated models show improved predictive ability and provide estimates which are more reflective of current practice and patient case mix. The updated OPIS tool can be used by clinicians to help shape couples' expectations by informing them of their individualized chances of live birth over a sequence of multiple complete cycles of IVF. This study was supported by an Elphinstone scholarship scheme at the University of Aberdeen and Aberdeen Fertility Centre, University of Aberdeen. S.B. has a commitment of research funding from Merck. D.J.M. and M.B.R. declare support for the present manuscript from Elphinstone scholarship scheme at the University of Aberdeen and Assisted Reproduction Unit at Aberdeen Fertility Centre, University of Aberdeen. D.J.M. declares grants received by University of Aberdeen from NHS Grampian, The Meikle Foundation, and Chief Scientist Office in the past 3 years. D.J.M. declares receiving an honorarium for lectures from Merck. D.J.M. is Associate Editor of Human Reproduction Open and Statistical Advisor for Reproductive BioMed Online. S.B. declares royalties from Cambridge University Press for a book. S.B. declares receiving an honorarium for lectures from Merck, Organon, Ferring, Obstetric and Gynaecological Society of Singapore, and Taiwanese Society for Reproductive Medicine. S.B. has received support from Merck, ESHRE, and Ferring for attending meetings as speaker and is on the METAFOR and CAPRE Trials Data Monitoring Committee. N/A.

Ratna MB ，Bhattacharya S ，McLernon DJ 《-》

Cumulative live birth rates after one ART cycle including all subsequent frozen-thaw cycles in 1050 women: secondary outcome of an RCT comparing GnRH-antagonist and GnRH-agonist protocols.

Are cumulative live birth rates (CLBRs) similar in GnRH-antagonist and GnRH-agonist protocols for the first ART cycle including all subsequent frozen-thaw cycles from the same oocyte retrieval? The chances of at least one live birth following utilization of all fresh and frozen embryos after the first ART cycle are similar in GnRH-antagonist and GnRH-agonist protocols. Reproductive outcomes of ART treatment are traditionally reported as pregnancies per cycle or per embryo transfer. However, the primary concern is the overall chance of a live birth. After the first ART cycle with fresh embryo transfer, we found live birth rates (LBRs) of 22.8% and 23.8% (P = 0.70) for the GnRH-antagonist and GnRH-agonist protocols, respectively. But with CLBRs including both fresh and frozen embryos from the first oocyte retrieval, chances of at least one live birth increases. There are no previous randomized controlled trials (RCTs) comparing CLBRs in GnRH-antagonist versus GnRH-agonist protocols. Previous studies on CLBR are either retrospective cohort studies including multiple fresh cycles or RCTs comparing single embryo transfer (SET) with double embryo transfer (DET). CLBR was a secondary outcome in a Phase IV, dual-center, open-label, RCT including 1050 women allocated to a short GnRH-antagonist or a long GnRH-agonist protocol in a 1:1 ratio over a 5-year period using a web-based concealed randomization code. The minimum follow-up time from the first IVF cycle was 2 years. The aim was to compare CLBR between the two groups following utilization of all fresh and frozen embryos from the first ART cycle. All women referred for their first ART cycle at two public fertility clinics, <40 years of age were approached. A total of 1050 subjects were allocated to treatment and 1023 women started standardized ART protocols with recombinant human follitropin-β (rFSH) stimulation. Day-2 SET was planned and additional embryos were frozen and used in subsequent frozen-thawed cycles. All pregnancies generated from oocyte retrieval during the first IVF cycle including fresh and frozen-thaw cycles were registered. Ongoing pregnancy was determined by ultrasonography at gestational week 7-9 and live birth was irrespective of the duration of gestation. CLBR was defined as at least one live birth per allocated woman after fresh and frozen cycles. Subjects were censored out after the first live birth. Cox proportional hazard model was used to evaluate the relative prognostic significance of female age, BMI, the number of retrieved oocytes and the diagnosis of infertility in relation to the CLBR. Baseline characteristics were similar and equal proportions of patients continued with frozen-thaw (frozen embryo transfer, FET) cycles after their fresh ART cycle in the GnRH-antagonist and GnRH-agonist arms. When combining all fresh and frozen-thaw embryo transfers from first oocyte retrieval with a minimum of 2-year follow-up, the CLBR was 34.1% (182/534) in the GnRH-antagonist group versus 31.2% (161/516) in the GnRH-agonist group (odds ratio (OR):1.14; 95% CI: 0.88-1.48, P = 0.32). Mean time to the first live birth was 11.0 months in the GnRH-antagonist group compared to 11.5 months in the GnRH-agonist group (P < 0.01). The total number of deliveries from all FET cycles where embryos were thawed were higher in the antagonist group 64/330 (19.4%) compared to the agonist group 43/355 (12.1%) ((OR): 1.74; 95% CI: 1.14-2.66, P = 0.01). The evaluation of prognostic factors showed that more retrieved oocytes were associated with a significantly higher CLBR in both treatment groups. For the subgroup of obese women (BMI >30 kg/m2), the CLBR was significantly higher in the GnRH-antagonist group (P = 0.02). The duration of the trial is a possible limitation with introduction of new methods as 'Freeze all' and 'GnRH-agonist triggering', but as these treatments were used in only few women, a systematic bias is not likely. Blastocyst culture of surplus embryos for freezing was introduced to both groups simultaneously, thereby minimizing the risk of bias. Furthermore, with a minimum of 2-year follow-up, a minority (<1%) still had cryopreserved embryos and no live birth at the end of the trial. The post hoc prognostic covariate analyses with multiple strata should be interpreted with caution. Finally, the physicians were not blinded to GnRH treatment group after randomization. With the improvement of embryo culture, freezing and thawing methods as well as a strategy of elective SET, CLBR until first live birth provides an all-inclusive success rate for ART. When comparing GnRH-antagonist and GnRH-agonist protocols, we find similar CLBRs, despite more oocytes being retrieved in the GnRH-agonist protocol. An unrestricted research grant is funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA (MSD). The funders had no influence on the data collection, analyses or conclusions of the study. No conflict of interests to declare. EudraCT #: 2008-005452-24. ClinicalTrial.gov: NCT00756028. 18 September 2008. 14 January 2009.

Toftager M ，Bogstad J ，Løssl K ，Prætorius L ，Zedeler A ，Bryndorf T ，Nilas L ，Pinborg A ... -  《-》