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Objective: To evaluate methodologies to establish abnormal progesterone (P) levels on the day of trigger for recommending freeze only cycles., Design: Threshold analysis and cost analysis., Setting: Private ART practice., Patient(s): Fresh autologous ART., Interventions(s): None., Main Outcome Measure(s): Live birth., Result(s): Fourteen established statistical methodologies for generating clinical thresholds were evaluated. These methods were applied to 7,608 fresh ART transfer cycles to generate various P thresholds which ranged widely from 0.4 to 3.0 ng/mL. Lower thresholds ranged from 0.4 to 1 ng/mL and classified the majority of cycles as abnormal as well as required very large number needed to treat (NNT) to increase one live birth. Frozen embryo transfer was cost-effective when P was ≥1.5 ng/mL, with 12% of the population having an abnormal test result and an NNT of 13. Statistical and cost-effective thresholds clustered between 1.5 and 2.0 ng/mL., Conclusion(s): Statistically significant thresholds for P were demonstrated as low as 0.4 ng/mL but resulted in a very large NNT to increase one live birth. A clinical benefit to a freeze-only approach was demonstrated above P thresholds ranging from 1.5 to 2.0 ng/dL. At these thresholds, elevated P has a demonstrable and clinically significant negative effect and captures a smaller percentage of the patient population at higher risk for fresh transfer failure, thus making freeze-only a cost-effective option., (Copyright © 2018 American Society for Reproductive Medicine. All rights reserved.)

Recent evidence has shown elevated progesterone (P) advances the endometrium in fresh ART cycles, creating asynchrony with the embryo and thus implantation failure and decreased live birth rates. If the window of implantation is closing as the embryo attempts to implant, there may be difficulty with trophoblastic invasion, leading to failure of early pregnancies. Our objective was to evaluate if P on the day of trigger was associated with spontaneous abortion (SAB) rates in fresh ART transfers. This was a retrospective cohort study involving fresh autologous and FET cycles from 2011 to 2013. The main outcome was spontaneous abortion rates. About 4123 fresh and FET transfer cycles were included which resulted in 1547 fresh and 491 FET pregnancies. The overall SAB rate was 20% among fresh cycles and 19% in FET cycles. P on the day of trigger, as a continuous variable or when > 2 ng/mL, was not associated with SAB in fresh cycles. Similar results were found after adjusting for age, embryo quality, and embryo stage. Despite elevated P likely advancing the window of implantation, once implantation occurs, pregnancies were no longer negatively impacted by progesterone.

Objective: To critically evaluate the P to oocyte (O) ratio (P/O) in the prediction of live birth in assisted reproductive technology (ART) cycles., Design: Retrospective cohort study., Setting: Not applicable., Patient(s): A total of 7,608 fresh autologous ART ET cycles., Intervention(s): None., Main Outcome Measure(s): Live birth., Result(s): Generalized estimating equation (GEE) models and receiver operating characteristic curves assessed the ability of P, O, and the P/O ratio to predict live birth. In univariate GEE models, P, O, and P/O were each associated with live birth. However, in multivariate GEE models, the P/O ratio was not associated with live birth, but P alone was. This suggested that converting P and O into a ratio of P/O was not more helpful than the two independent variables themselves. Measures of overall model fit further suggested that P/O did not increase the predictive ability of the model over P and O alone. Receiver operating characteristic curves using incremental predictors further demonstrated that the P/O provided no incremental improvement in predicting live birth over P and O separately., Conclusion(s): These data suggest that P and O have utility in prediction modeling but demonstrate that additional oocytes were not protective from the negative association of P with live birth. There was no incremental improvement related to the P/O ratio specifically for predicting live birth over each variable independently., (Published by Elsevier Inc.)

Study Question: Is there an association of progesterone (P 4 ) on the day of trigger with live birth in autologous ART transfer cycles on day 5 versus day 6?, Summary Answer: P 4 had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers., What Is Known Already: Premature P 4 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 P 4 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 P 4 as a continuous variable on live birth was more pronounced on day 6 (P < 0.001). Similarly, the effect of P 4 > 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 P 4 was in the normal range (P = 0.04), but became 17% lower when P 4 was > 1.5 ng/ml (P < 0.01). ROC curves for P 4 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 P 4 × day of embryo transfer was highly significant (P < 0.001), further suggesting that the effect of P 4 was more pronounced on day 6 embryo transfer. In fresh oocyte retrieval cycles with elevated P 4 , 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 P 4 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 P 4 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 P 4 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., (Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology 2016. This work is written by (a) US Government employee(s) and is in the public domain in the US.)

Objective: To compare the effect of P on live birth rate between hCG and GnRH agonist (GnRH-a) trigger cycles., Design: Retrospective cohort study., Setting: Large private assisted reproductive technology (ART) practice., Patient(s): A total of 3,326 fresh autologous ART cycles., Intervention(s): None., Main Outcome Measure(s): Live birth., Result(s): A total of 647 GnRH-a trigger cycles were compared with 2,679 hCG trigger cycles. Live birth was negatively associated with P in both the hCG trigger (odds ratio [OR] 0.62, 95% confidence interval [CI] 0.52-0.76) and the agonist trigger cohorts (OR 0.56, 95% CI 0.45-0.69). Interaction testing evaluating P and trigger medication was not significant, indicating that P had a similar negative effect on live birth rates in both cohorts. Progesterone ≥2 ng/mL occurred more commonly in GnRH-a trigger cycles compared with hCG trigger cycles (5.5% vs. 3.1%) and was negatively associated with live birth in both the hCG trigger (OR 0.28, 95% CI 0.11-0.73) and agonist trigger cohorts (OR 0.35, 95% CI 0.14-0.90). When P ≥2 ng/mL, the live birth rates were poor and similar in the hCG and GnRH-a cohorts (5.9% vs. 14.2%), indicating that P ≥2 ng/mL had a similar negative effect on live birth in both cohorts., Conclusion(s): Elevated serum P on the day of hCG was negatively associated with live birth rates in both hCG and GnRH-a trigger cycles., (Published by Elsevier Inc.)

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., (Published by Elsevier Inc.)