title: Cleavage stage versus blastocyst stage embryo transfer in assisted reproductive technology.
abstract: BACKGROUND
  Advances in cell culture media have led to a shift in in vitro fertilisation (IVF) practice from cleavage stage embryo transfer to blastocyst stage transfer. The rationale for blastocyst transfer is to improve both uterine and embryonic synchronicity and enable self selection of viable embryos, thus resulting in better live birth rates.
  
  
  OBJECTIVE
  To determine whether blastocyst stage (day 5 to 6) embryo transfers improve the live birth rate, and other associated outcomes, compared with cleavage stage (day 2 to 3) embryo transfers.
  
  
  METHODS
  We searched the Cochrane Gynaecology and Fertility Group Specialised Register of controlled trials, Cochrane Central Register of Controlled Trials (CENTRAL; the Cochrane Library; 2016, Issue 4), MEDLINE, EMBASE, PsycINFO, CINAHL, and Bio extracts from inception to 4th April 2016. We also searched registers of ongoing trials and the reference lists of studies retrieved.
  
  
  METHODS
  We included randomised controlled trials (RCTs) which compared the effectiveness of blastocyst versus cleavage stage transfers.
  
  
  METHODS
  We used standard methodological procedures recommended by Cochrane. Our primary outcomes were live birth and cumulative clinical pregnancy rates. Secondary outcomes were clinical pregnancy, multiple pregnancy, high order pregnancy, miscarriage, failure to transfer embryos, and embryo freezing. We assessed the overall quality of the evidence for the main comparisons using GRADE methods.
  
  
  RESULTS
  We included 27 RCTs (4031 couples or women).The live birth rate following fresh transfer was higher in the blastocyst transfer group (odds ratio (OR) 1.48, 95% confidence interval (CI) 1.20 to 1.82; 13 RCTs, 1630 women, I(2) = 45%, low quality evidence) following fresh transfer. This suggests that if 29% of women achieve live birth after fresh cleavage stage transfer, between 32% and 42% would do so after fresh blastocyst stage transfer.There was no evidence of a difference between the groups in rates per couple of cumulative pregnancy following fresh and frozen-thawed transfer after one oocyte retrieval (OR 0.89, 95% CI 0.64 to 1.22; 5 RCTs, 632 women, I(2) = 71%, very low quality evidence).The clinical pregnancy rate was also higher in the blastocyst transfer group, following fresh transfer (OR 1.30, 95% CI 1.14 to 1.47; 27 RCTs, 4031 women, I(2) = 56%, moderate quality evidence). This suggests that if 36% of women achieve clinical pregnancy after fresh cleavage stage transfer, between 39% and 46% would do so after fresh blastocyst stage transfer.There was no evidence of a difference between the groups in rates of multiple pregnancy (OR 1.05, 95% CI 0.83 to 1.33; 19 RCTs, 3019 women, I(2) = 30%, low quality evidence), or miscarriage (OR 1.15, 95% CI 0.88 to 1.50; 18 RCTs, 2917 women, I(2) = 0%, low quality evidence). These data are incomplete as under 70% of studies reported these outcomes.Embryo freezing rates were lower in the blastocyst transfer group (OR 0.48, 95% CI 0.40 to 0.57; 14 RCTs, 2292 women, I(2) = 84%, low quality evidence). This suggests that if 60% of women have embryos frozen after cleavage stage transfer, between 37% and 46% would do so after blastocyst stage transfer. Failure to transfer any embryos was higher in the blastocyst transfer group (OR 2.50, 95% CI 1.76 to 3.55; 17 RCTs, 2577 women, I(2) = 36%, moderate quality evidence). This suggests that if 1% of women have no embryos transferred in (planned) fresh cleavage stage transfer, between 2% and 4% will have no embryos transferred in (planned) fresh blastocyst stage transfer.The evidence was of low quality for most outcomes. The main limitation was serious risk of bias, associated with failure to describe acceptable methods of randomisation, and unclear or high risk of attrition bias.
  
  
  CONCLUSIONS
  There is low quality evidence for live birth and moderate quality evidence for clinical pregnancy that fresh blastocyst stage transfer is associated with higher rates than fresh cleavage stage transfer. There was no evidence of a difference between the groups in cumulative pregnancy rates derived from fresh and frozen-thawed cycles following a single oocyte retrieval, but the evidence for this outcome was very low quality. Thus, although there is a benefit favouring blastocyst transfer in fresh cycles, it remains unclear whether the day of transfer impacts on cumulative live birth and pregnancy rates. Future RCTs should report rates of live birth, cumulative live birth, and miscarriage to enable couples or women undergoing assisted reproductive technology (ART) and service providers to make well informed decisions on the best treatment option available.
authors.affiliation: Reproductive Medicine, CEGYR (Centro de Estudios en Genética y Reproducción), Viamonte 1432,, Buenos Aires, Argentina.
authors.forename: Demián
authors.initials: D
authors.lastname: Glujovsky
authors.forename: Cindy
authors.initials: C
authors.lastname: Farquhar
authors.forename: Andrea Marta
authors.initials: AM
authors.lastname: Quinteiro Retamar
authors.forename: Cristian Roberto
authors.initials: CR
authors.lastname: Alvarez Sedo
authors.forename: Deborah
authors.initials: D
authors.lastname: Blake
mesh_terms: D001755:Blastocyst; D002970:Cleavage Stage, Ovum / Q000637:transplantation*; D004624:Embryo Transfer / Q000379:methods*; D005260:Female; D006801:Humans; D050498:Live Birth / Q000453:epidemiology*; D011247:Pregnancy; D011256:Pregnancy Outcome; D018873:Pregnancy Rate; D011272:Pregnancy, Multiple; D016032:Randomized Controlled Trials as Topic