title: Frozen-thawed embryo transfer in a natural or mildly hormonally stimulated cycle in women with regular ovulatory cycles: a RCT.
abstract: OBJECTIVE
  Can ovarian stimulation with low dose hMG improve the implantation rate (IR) per frozen-thawed embryo transferred (FET) when compared with natural cycle in an FET programme in women with a regular ovulatory cycle?
  
  
  CONCLUSIONS
  Both IR and live birth rate (LBR) per FET were similar in the group with mild ovarian stimulation and the natural cycle group.
  
  
  BACKGROUND
  Different cycle regimens for endometrial preparation are used prior to FET: spontaneous ovulatory cycles, cycles with artificial endometrial preparation using estrogen and progesterone hormones, and cycles stimulated with gonadotrophins or clomiphene citrate. At present, it is not clear which regimen results in the highest IR or LBR. More specifically, there are no RCTs in ovulatory women comparing reproductive outcome after FET during a natural cycle and during a hormonally stimulated cycle.
  
  
  METHODS
  A total of 410 women scheduled for FET during 579 cycles (December 2003-September 2013) were enrolled in an open-label RCT to natural cycle (NC FET group, n = 291) or to a cycle hormonally stimulated with s.c. gonadotrophins (hMG FET group, 37.5-75 IU per day, n = 288). A total of 672 embryos were transferred during 434 cycles (332 embryos and 213 cycles in the NC FET group; 340 embryos and 221 cycles in the hMG FET group). Assuming a = 0.05 and 80% power, it was calculated that 219 frozen-thawed embryos were required for transfer in each group to demonstrate a difference of 10% in IR.
  
  
  METHODS
  Women were eligible according to the following inclusion criteria: regular ovulatory cycle, female age ≥21 years and ≤45 years, informed consent. FET cycles with preimplantation genetic screening were excluded. The primary outcome was IR per embryo transferred. Secondary outcomes included IR with fetal heart beat (FHB), LBR per embryo transferred and endometrial thickness on the day of hCG administration. Statistical analysis was by intention to treat and controlled for the presence of multiple measures, as eligible women could be randomized in more than one cycle. Chi-square and independent t-test were used to compare categorical and continuous variables. The relative risk (RR) was estimated using a Poisson model with log link. Hierarchical models with random intercepts for patient and cycle were considered to account for clustering of cycles within patients and of embryos within cycles.
  
  
  RESULTS
  The primary outcome, IR per embryo transferred, was not statistically different between the NC FET group (41/332 (12.35%)) and in the hMG FET group (55/340 (16.18%)) (RR 1.3 (95% confidence interval (CI) 0.9-2.0), P = 0.19). Similarly, the secondary outcome, IR with FHB per embryo transferred, was 34/332 (10.24%) in the NC FET group and 48/340 (14.12%) in the hMG FET group (RR 1.4 (95% CI 0.9-2.1), P = 0.15). The LBR per embryo transferred was 32/332 (9.64%) in the NC FET group and 45/340 (13.24%) in the hMG FET group (RR 1.4 (95% CI 0.9-2.2), P = 0.17). Endometrial thickness was also similar in both groups [8.9 (95% CI 8.7-9.1) in the NC FET group and 8.9 (95% CI 8.7-9.1) in the hMG FET group]. The duration of the follicular phase was significantly shorter (P < 0.001) in the hMG FET group [13.7 days (95% CI 13.2-14.2)] than in the NC FET group [15.4 days (95% CI 14.8-15.9)].
  
  
  CONCLUSIONS
  Randomization of cycles instead of patients; open-label design; relatively long period of recruitment.
  
  
  CONCLUSIONS
  Our observation that the IR per embryo transferred is not significantly increased after FET during natural or gonadotrophin stimulated cycle, suggests that the effect of mild hormonal stimulation with gonadotrophins is smaller than what was considered clinically relevant with respect to reproductive outcome after FET. These data suggest that endometrial receptivity is not relevantly improved, but also not impaired after hormonal stimulation with gonadotrophins. Since FET during a natural cycle is cheaper and more patient-friendly, we recommend this regimen as the treatment of choice for women with regular cycles undergoing FET.
  
  
  BACKGROUND
  clinicaltrials.gov NCT00492934.
  26 June 2007.
  1 December 2003.
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium karen.peeraer@uzleuven.be.
authors.forename: Karen
authors.initials: K
authors.lastname: Peeraer
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Couck
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Debrock
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Diane
authors.initials: D
authors.lastname: De Neubourg
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Peter
authors.initials: P
authors.lastname: De Loecker
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Carla
authors.initials: C
authors.lastname: Tomassetti
authors.affiliation: Leuven Biostatistics and Statistical Bioinformatics Centre, Leuven, Belgium.
authors.forename: Annouschka
authors.initials: A
authors.lastname: Laenen
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Myriam
authors.initials: M
authors.lastname: Welkenhuysen
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Luc
authors.initials: L
authors.lastname: Meeuwis
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Sofie
authors.initials: S
authors.lastname: Pelckmans
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Christel
authors.initials: C
authors.lastname: Meuleman
authors.affiliation: Leuven University Fertility Center, UZ Leuven Campus Gasthuisberg, 3000 Leuven, Belgium.
authors.forename: Thomas
authors.initials: T
authors.lastname: D'Hooghe
mesh_terms: D000328:Adult; D015925:Cryopreservation / Q000379:methods*; D010064:Embryo Implantation / Q000187:drug effects / Q000502:physiology*; D004624:Embryo Transfer / Q000379:methods*; D005260:Female; D005300:Fertility Agents, Female / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D008596:Menotropins / Q000008:administration & dosage / Q000494:pharmacology*; D017063:Outcome Assessment, Health Care; D010062:Ovulation Induction / Q000379:methods*
chemical_list: D005300:Fertility Agents, Female; D008596:Menotropins
keywords: ART; HMG; RCT; frozen–thawed embryo transfer; natural cycle