M.W. Healy

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.

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.

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 INTEREST(S) No external funding was received for this study. There are no conflicts of interest to declare. TRIAL REGISTRATION NUMBER Not applicable.

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.

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.

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.

Does premature elevated progesterone on the day of trigger increase spontaneous abortion rates in fresh and subsequent frozen embryo transfers

Abstract 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.

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.

Adverse effect of prematurely elevated progesterone in in vitro fertilization cycles: a literature review

Abstract Premature progesterone (P) elevation was commonly seen in IVF prior to the utilization of GnRH analogues for suppression of endogenous gonadotropin release. The cause and effect of premature P elevation has finally been better elucidated in the past decade. Although still occurring in 5–38% of all IVF cycles, the adverse effects of premature P elevation on pregnancy outcomes are now well known.