title: Fresh versus frozen embryo transfers in assisted reproduction.
abstract: BACKGROUND
  In general, in vitro fertilisation (IVF) or intracytoplasmic sperm injection (ICSI) implies a single fresh and one or more frozen-thawed embryo transfers. Alternatively, the 'freeze-all' strategy implies transfer of frozen-thawed embryos only, with no fresh embryo transfers. In practice, both strategies can vary technically including differences in freezing techniques and timing of transfer of cryopreservation, that is vitrification versus slow freezing, freezing of two pro-nucleate (2pn) versus cleavage-stage embryos versus blastocysts, and transfer of cleavage-stage embryos versus blastocysts.In the freeze-all strategy, embryo transfers are disengaged from ovarian stimulation in the initial treatment cycle. This could avoid a negative effect of ovarian hyperstimulation on the endometrium and thereby improve embryo implantation. It could also reduce the risk of ovarian hyperstimulation syndrome (OHSS) in the ovarian stimulation cycle by avoiding a pregnancy.We compared the benefits and risks of the two treatment strategies.
  
  
  OBJECTIVE
  To evaluate the effectiveness and safety of the freeze-all strategy compared to the conventional IVF/ICSI strategy in women undergoing assisted reproductive technology.
  
  
  METHODS
  We searched the Cochrane Gynaecology and Fertility Group Trials Register, the Cochrane Central Register of Studies (CRSO), MEDLINE, Embase, PsycINFO, CINAHL, and two registers of ongoing trials in November 2016 together with reference checking and contact with study authors and experts in the field to identify additional studies.
  
  
  METHODS
  We included randomised clinical trials comparing a freeze-all strategy with a conventional IVF/ICSI strategy which includes fresh transfer of embryos in women undergoing IVF or ICSI treatment.
  
  
  METHODS
  We used standard methodological procedures recommended by Cochrane. The primary review outcomes were cumulative live birth and OHSS. Secondary outcomes included other adverse effects (miscarriage rate).
  
  
  RESULTS
  We included four randomised clinical trials analysing a total of 1892 women comparing a freeze-all strategy with a conventional IVF/ICSI strategy. The evidence was of moderate to low quality due to serious risk of bias and (for some outcomes) serious imprecision. Risk of bias was associated with unclear blinding of investigators for preliminary outcomes of the study, unit of analysis error, and absence of adequate study termination rules.There was no clear evidence of a difference in cumulative live birth rate between the freeze-all strategy and the conventional IVF/ICSI strategy (odds ratio (OR) 1.09, 95% confidence interval (CI) 0.91 to 1.31; 4 trials; 1892 women; I2= 0%; moderate-quality evidence). This suggests that if the cumulative live birth rate is 58% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 56% and 65%.The prevalence of OHSS was lower after the freeze-all strategy compared to the conventional IVF/ICSI strategy (OR 0.24, 95% CI 0.15 to 0.38; 2 trials; 1633 women; I2= 0%; low-quality evidence). This suggests that if the OHSS rate is 7% following a conventional IVF/ICSI strategy, the rate following a freeze-all strategy would be between 1% and 3%.The freeze-all strategy was associated with fewer miscarriages (OR 0.67, 95% CI 0.52 to 0.86; 4 trials; 1892 women; I2= 0%; low-quality evidence) and a higher rate of pregnancy complications (OR 1.44, 95% CI 1.08 to 1.92; 2 trials; 1633 women; low-quality evidence). There was no difference in multiple pregnancies per woman after the first transfer (OR 1.11, 95% CI 0.85 to 1.44; 2 trials; 1630 women; low-quality evidence), and no data were reported for time to pregnancy.
  
  
  CONCLUSIONS
  We found moderate-quality evidence showing that one strategy is not superior to the other in terms of cumulative live birth rates. Time to pregnancy was not reported, but it can be assumed to be shorter using a conventional IVF/ICSI strategy in the case of similar cumulative live birth rates, as embryo transfer is delayed in a freeze-all strategy. Low-quality evidence suggests that not performing a fresh transfer lowers the OHSS risk for women at risk of OHSS.
authors.affiliation: Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.
authors.forename: Kai Mee
authors.initials: KM
authors.lastname: Wong
authors.affiliation: Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.
authors.forename: Madelon
authors.initials: M
authors.lastname: van Wely
authors.affiliation: Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.
authors.forename: Femke
authors.initials: F
authors.lastname: Mol
authors.affiliation: Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.
authors.forename: Sjoerd
authors.initials: S
authors.lastname: Repping
authors.affiliation: Center for Reproductive Medicine, Academic Medical Center, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands, 1105 AZ.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: Mastenbroek
mesh_terms: D000022:Abortion, Spontaneous / Q000453:epidemiology; D015925:Cryopreservation; D004624:Embryo Transfer / Q000379:methods*; D004622:Embryo, Mammalian; D005260:Female; D006801:Humans; D050498:Live Birth / Q000453:epidemiology; D016471:Ovarian Hyperstimulation Syndrome / Q000453:epidemiology / Q000517:prevention & control; D011247:Pregnancy; D011248:Pregnancy Complications / Q000453:epidemiology; D018873:Pregnancy Rate; D011272:Pregnancy, Multiple / Q000706:statistics & numerical data; D016032:Randomized Controlled Trials as Topic