Deferred Versus Fresh Embryo Transfers
Condition: Infertility, Female
MeSH terms: Infertility; Infertility, Female
Study type: Interventional

Summary: 
      Controlled ovarian stimulation (COS) enhances the efficacy of ART (Assisted reproductive
      technology) by permitting multiple-oocyte yields, but also alters endometrial receptivity
      (ER) by an advancement of endometrial development which contributes to diminished pregnancy
      chances. Previous reports suggest that pregnancy rates are increased following deferred
      frozen embryo transfers. In addition as compared to fresh embryo transfers, frozen embryo
      transfers seem to be associated with less affected perinatal outcomes, in particular lower
      risk of preterm birth, small for gestational age and caesarean section. Unfortunately, most
      of the current evidence is based only on preliminary reports, needing further scientific
      evidence. Thus, whether differing embryo transfers could restore optimal ER leading to higher
      live birth rate (LBR) and better obstetrical outcomes as compared to fresh embryo transfers,
      is actually still under investigation.
    

Detailed description: 
      Controlled ovarian stimulation (COS) enhances the efficacy of ART (Assisted reproductive
      technology) by permitting multiple-oocyte yields, but also alters endometrial receptivity
      (ER) by an advancement of endometrial development which contributes to diminished pregnancy
      chances. Recently, technical improvements in vitrification make frozen embryo transfers
      (FETs) a safe and feasible alternative to fresh embryo transfer (Evans et al., 2014). In case
      of FET the absence of COS avoid the alteration of endometrial receptivity. Previous reports
      suggest that pregnancy rates are increased and perinatal outcomes are less affected following
      FET (Evans et al., 2014). In fact previous studies plead for increased risk of preterm birth,
      small for gestational age, caesarean section after fresh embryo transfer as compared to
      frozen embryo transfer (Maheshwari et al., 2012). Unfortunately, most of the current evidence
      is based only on preliminary reports, needing further scientific evidence. Thus, one of the
      main questions, in the management of infertile women, is to know whether differing embryo
      transfers could restore optimal endometrial receptivity leading to higher live birth rate
      (LBR) and better obstetrical outcomes as compared to fresh embryo transfer. This question is
      actually debated in the literature in many different reviews (Blockeel et al., 2016; Cedars,
      2016; Engmann et al., 2016; Evans et al., 2014; Roque, 2015). However even if the scientific
      rationale is in favour of increased pregnancy rates after differed FET, compelling clinical
      evidence is still lacking and most of the current evidence is based on retrospective and
      uncontrolled studies. Currently the best evidence come from a very recent randomized control
      trial of fresh versus frozen embryo transfers in a specific population of polycystic ovary
      syndrome affected women (Chen et al., 2016). The authors failed to show any difference in
      pregnancy rate after fresh versus frozen embryo transfers but they found higher rate of
      miscarriages after fresh embryo transfers and in consequence a slight but significant
      decrease in live birth after fresh as compared to frozen embryo transfers (Chen et al.,
      2016). However whether these results, coming from a specific population of polycystic ovary
      syndrome affected women, may be generalizable is actually still unknown. Furthermore some
      evidence come from a meta-analysis, including 3 randomized studies. The conclusions of this
      meta-analysis are that IVF outcomes may be improved by performing FET compared with fresh
      embryo transfer probably through an improvement of endometrial receptivity (Roque et al.,
      2013). Nevertheless, this meta-analysis should be interpreted with caution. One of the
      included studies had been retracted from literature because of methodological problem
      (Aflatoonian et al., 2010). Therefore, this meta-analysis banking on a retracted study seems
      no more valid and therefore its conclusions remained uncertain. Even in absence of solid
      clinical studies and even in absence of valid recommendations, some authors conclude that IVF
      outcomes can be improved using the freeze-all policy with differed FET (Roque et al., 2015).
      In addition they recommend that further randomized clinical trials are needed to confirm the
      advantage of this strategy and determine the population for which it would be most
      beneficial. This last point seems crucial as ART procedures (IVF-ICSI) encompass a mixture of
      different fertility problem more or less sensible to the effects of COS on endometrial
      receptivity. Among the different causes of infertility, endometriosis is quite common and up
      to 20 % of women undergoing ART have associated endometriosis (Kawwass et al., 2015;
      Kuivasaari-Pirinen et al., 2012; Senapati et al., 2016). In addition endometriosis is
      characterized by impaired endometrial receptivity, contributing to the mechanisms by which
      endometriosis interfere with fecundity (de Ziegler et al., 2010). Estimated prevalence of
      endometriosis range from 2 to 10% of women of reproductive age, to 50% of infertile women
      (Eskenazi and Warner, 1997; Meuleman et al., 2009). Reverting to ART in case of endometriosis
      related infertility remain a solid option. However recent meta-analysis evocates decreased
      live birth rate in case of severe endometriosis as compared to disease free women (Hamdan et
      al., 2015). In addition endometriosis may be associated to adverse obstetrical outcomes
      (Leone Roberti Maggiore et al., 2016). Thus, given the existence of altered endometrial
      receptivity in endometriosis, and diminished ART outcomes, it is actually also debated
      whether deferring embryo transfers could restore optimal endometrial receptivity leading to
      higher live birth rate and reduced obstetrical risk in endometriosis affected women.
    

Intervention name(s): fresh transfer; Deferred-frozen embryo transfer
Intervention type(s): Procedure; Procedure
Intervention description(s): Women randomized in the non experimental group will have:
Antagonist stimulation protocol
Ovarian triggering using a single injection of rhCG (Ovitrelle®; Serono, France)
All of their embryo kept in prolonged culture
A fresh single embryo transfer at blastocyst stage (on day 5 or 6 according to blastocyst stage)
Supernumerary blastocysts cryopreserved; Women randomized in the experimental group will have:
Antagonist stimulation protocol
Ovarian triggering using a single injection of 0.2 mg of GnRH agonist triptorelin (Decapeptyl® Ipsen France)
All of their embryo cryopreserved at the blastocyst stage after prolonged embryo culture.
A frozen-thawed single embryo transfer at blastocyst stage, is planned 3-11 weeks after cryopreservation
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Freeze all; IVF; deferred embryo transfer; endometriosis