The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony
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 INTEREST(S) No external funding was received for this study. There are no conflicts of interest to declare. TRIAL REG
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