The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony.

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.

Does elevated progesterone on day of oocyte maturation play a role in the racial disparities in IVF outcomes?

The aim of this study was to evaluate if premature progesterone elevation on the last day of assisted reproduction technique stimulation contributes to racial disparities in IVF outcome. A total of 3289 assisted reproduction technique cycles were evaluated in Latino, Asian, African American, and white women. Live birth was more likely in white women (42.6%) compared with Asian (34.8%) and African American women (36.3%), but was similar to Latino women (40.7%). In all racial groups, progesterone was negatively associated with live birth and the negative effect of progesterone persisted when adjusting for confounders. Although the effect of elevated progesterone was similar in all racial groups, the prevalence of elevated progesterone differed. Progesterone > 1.5 ng/ml occurred in only 10.6% of cycles in white women compared with 18.0% in Latino and 20.2% in Asian women. Progesterone > 2 ng/ml occurred in only 2.3% of cycles in white women compared with 6.3% in Latino, 5.9% in Asian and 4.4% in African American women. The increased prevalence of premature elevated progesterone persisted when controlling for IVF stimulation parameters. In conclusion, premature progesterone elevation had a negative effect on live birth in all racial groups studied. The prevalence of elevated progesterone was higher in racial minorities.

Intrauterine adhesion prevention after hysteroscopy: a systematic review and meta-analysis.

BACKGROUND: Despite years of studies evaluating prevention strategies for intrauterine adhesion formation after operative hysteroscopy, it is still unclear which strategies are most effective. OBJECTIVE: The objective of the study was to perform a systematic review and meta-analysis to evaluate the effectiveness of postoperative prevention strategies on intrauterine adhesion formation following operative hysteroscopy. STUDY DESIGN: Literature searches were conducted in MEDLINE, Embase, ClinicalTrials.gov, and Cochrane Library databases. Inclusion criteria were published randomized controlled clinical trials from 1989 to 2014 comparing any postoperative preventative measures of intrauterine adhesion after hysteroscopy. The main outcome measure was a reduction in postoperative intrauterine adhesion. Heterogeneity of the studies was evaluated using a Q test and an I(2) index. Analyses were performed using a random-effects model with outcome data reported as relative risk with 95% confidence interval. RESULTS: Twelve studies were included in the systematic review. Eight studies compared similar treatment methods and were included in the meta-analysis. Three studies evaluated hyaluronic acid gel, of which 2 reported a significant decrease in intrauterine adhesion with treatment. The meta-analysis demonstrated a significant reduction of intrauterine adhesion when using hyaluronic acid gel. Two studies evaluated polyethylene oxide-sodium carboxymethylcellulose gel, 1 of which demonstrated a decrease in intrauterine adhesion with treatment. A meta-analysis showed a significant reduction of intrauterine adhesion with polyethylene oxide-sodium carboxymethyl cellulose gel. However, these 3 studies demonstrating a benefit of the gels in preventing adhesion formation were all conducted by the same research group. Other research groups have not confirmed these results. A sensitivity analysis excluding these trials from this single group demonstrated no benefit to adhesion prevention with either gel formation. Three studies investigated oral estrogen therapy after hysteroscopy and found no difference in intrauterine adhesion. A meta-analysis showed no decrease in intrauterine adhesion with estrogen therapy after hysteroscopy. Data were lacking to perform metaanalyses on the use of intrauterine balloon, intrauterine device, and other adhesion prevention barriers in preventing intrauterine adhesion. CONCLUSION: There was a lack of definitive evidence to conclude that any treatment is effective in preventing posthysteroscopy uterine adhesion formation. The available literature has significant heterogeneity and a high risk of bias, making any definitive conclusions difficult.

Defining thresholds for abnormal premature progesterone levels during ovarian stimulation for assisted reproduction technologies.

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.

Revisiting the progesterone to oocyte ratio.

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.

Seminal vesicle sperm aspiration from wounded warriors.

OBJECTIVE: To assess whether seminal vesicle sperm aspiration (SVSA) is an option for wounded warriors with severe genital and testicular injuries, with the goal of cryopreservation to use in future assisted reproductive technology (ART) cycles. DESIGN: Retrospective case series. SETTING: Tertiary care military hospital. PATIENT(S): Six wounded warriors. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Seminal vesicle fluid analysis after harvest, after thaw analysis, fertilization rates, pregnancy rates (PRs), live birth. RESULT(S): Six patients with lower extremity, pelvic, and genital injuries from dismounted improvised explosive devices underwent SVSA within 5-12 days of the initial injury. Sperm retrieved were analyzed (volume, 0.4-1.8 mL; concentration, 40-2,200 K; motility, 0-5%), washed, and cryopreserved. Two patients underwent IVF/intracytoplasmic sperm injection (ICSI) cycles using their samples. In one couple, fertilization rate was 38%. One grade V embryo was transferred with a negative pregnancy test. The second couple underwent two cycles. In their first cycle, fertilization rate was 44%, with one blastocyst transferred and a negative pregnancy test. In the second cycle, fertilization rate was 47%. Two blastocysts were cryopreserved due to ovarian hyperstimulation syndrome (OHSS) concerns. One blastocyst was later transferred in a frozen cycle resulting in a live birth. CONCLUSION(S): The SVSA is a reasonable option to retrieve sperm in wounded warriors or trauma patients with extensive genital injuries.

Is the effect of premature elevated progesterone augmented by human chorionic gonadotropin versus gonadotropin-releasing hormone agonist trigger?

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.

Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles?

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.

Optimal oocyte retrieval and embryo transfer techniques: where we are and how we got here.

Oocyte retrieval is most safely accomplished with conscious sedation via a transvaginal approach under ultrasound guidance with low-pressure aspiration. Follicle flushing has not been shown to improve outcomes. The type of vaginal surgical preparation and the use of antibiotics have not been demonstrated to affect outcomes. As the final step in a rigorous assisted reproductive technology (ART) cycle, precise technique in embryo transfer is essential. Based on current findings, the recommended embryo transfer technique includes the use of an ultrasound-guided transcervical approach with a full bladder using a soft catheter. The transfer depth of the embryo should be in the mid-portion of the uterus with a quick steady insertion followed by pressure on the syringe during withdrawal of the catheter. It is acceptable to encourage immediate ambulation after embryo transfer.

Are good patient and embryo characteristics protective against the negative effect of elevated progesterone level on the day of oocyte maturation?

OBJECTIVE: To evaluate if an elevated progesterone (P) level on the day of human chorionic gonadotropin (hCG) administration is associated with a decrease in live-birth rate in patients with a good prognosis. DESIGN: Retrospective cohort study. SETTING: Large, private, assisted reproductive technology (ART) practice. PATIENT(S): One thousand six hundred twenty fresh autologous ART cycles. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Live-birth rate. RESULT(S): A total of 934 blastocyst and 686 cleavage-stage embryo transfer (ET) cycles were evaluated. Serum P levels were not associated with markers of oocyte or embryo quality, including fertilization, embryo stage at transfer, and embryos available for cryopreservation. Patient age, stage of ET, embryo quality, the number of embryos transferred, and P level on the day of hCG administration were all significantly associated with live birth. Higher P levels were associated with decreased odds of live birth for cleavage- and blastocyst-stage embryos, poor-fair and good-quality embryos, and poor- and high-responder patients. The nonsignificance of interaction tests of P levels with embryo stage, embryo quality, patient age, and ovarian response indicated that the relationship between P level and live birth was similar regardless of these factors. CONCLUSION(S): An elevated serum P level on the day of hCG administration was negatively associated with live birth, even in ETs with a good prognosis.