title: The slow growing embryo and premature progesterone elevation: compounding factors for embryo-endometrial asynchrony.
abstract: 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?
  
  
  
  P4had a greater negative effect on live birth in day 6 fresh transfers compared to day 5 fresh transfers.
  
  
  
  Premature P4elevation 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 P4on the day of trigger is different on live birth rates with a day 5 compared to a day 6 embryo transfer.
  
  
  
  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.
  
  
  
  Patients from a large private ART practice were included. Analysis was performed with generalized estimating equations (GEE) modeling and receiver operating characteristic (ROC) curves.
  
  
  
  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 P4as 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 P4was in the normal range (P = 0.04), but became 17% lower when P4was > 1.5 ng/ml (P < 0.01). ROC curves for P4predicting 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 P4was 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 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 P4of 1.5 versus 1.8 ng/ml.
  
  
  
  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 P4may 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 P4on the day of trigger among these slower growing embryos that reach blastocyst staging on day 6.
  
  
  
  No external funding was received for this study. There are no conflicts of interest to declare.
  
  
  
  Not applicable.
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD , USA mae.healy@mail.nih.gov.|Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, MD , USA.
authors.forename: Mae Wu
authors.initials: MW
authors.lastname: Healy
authors.affiliation: Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, MD , USA.
authors.forename: Meghan
authors.initials: M
authors.lastname: Yamasaki
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD , USA.
authors.forename: George
authors.initials: G
authors.lastname: Patounakis
authors.affiliation: Shady Grove Fertility Science Center, Rockville, MD , USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Richter
authors.affiliation: Shady Grove Fertility Science Center, Rockville, MD , USA.
authors.forename: Kate
authors.initials: K
authors.lastname: Devine
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD , USA.
authors.forename: Alan H
authors.initials: AH
authors.lastname: DeCherney
authors.affiliation: Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda MD , USA.|Department of Obstetrics and Gynecology, Walter Reed National Military Medical Center, Bethesda, MD , USA.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Hill
mesh_terms: D000328:Adult; D001723:Birth Rate; D004624:Embryo Transfer / Q000379:methods; D047108:Embryonic Development / Q000502:physiology*; D005260:Female; D005307:Fertilization in Vitro / Q000379:methods*; D006801:Humans; D050498:Live Birth; D010062:Ovulation Induction / Q000379:methods; D011247:Pregnancy; D018873:Pregnancy Rate; D011374:Progesterone / Q000097:blood*; D012189:Retrospective Studies
chemical_list: D011374:Progesterone
keywords: day 5 versus day 6 embryo transfer cycles; elevated progesterone; fresh transfer versus frozen embryo transfer cycles; live birth