A Randomized Trial of Deferred Versus Fresh Embryo Transfers in Infertile Women Undergoing IVF-ICSI

Brief Summary

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.

Primary Outcomes

Secondary Outcomes

• Number of MII oocytes(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Preterm birth(≥ 35 weeks of gestation after the first single blastocyst embryo transfer a)
• Preterm rupture of membranes(≥ 35 weeks of gestation after the first single blastocyst embryo transfer a)
• Pre-eclampsia(≥ 35 weeks of gestation after the first single blastocyst embryo transfer a)
• Placenta praevia(≥ 35 weeks of gestation after the first single blastocyst embryo transfer a)
• Live birth rates in Endometriosis related infertility(≥ 35 weeks of gestation after the first single blastocyst embryo transfer a)
• Number of oocytes retrieved(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Miscarriage(≥ 35 weeks of gestation after the first single blastocyst embryo transfer a)
• Number of blastocyst(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Number of transferred blastocyst(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• The cancellation rate(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• The rate of started pregnancy(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• The rate of pregnancy confirmed by the Echography (cardiac activity)(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Started pregnancy defined by a rate of HCG>100(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Rate of multiple pregnancy(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Implantation rate(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Cryopreservation thaw rate(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• The incremental cost effectiveness ratio(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)
• Number of embryo(≥ 35 weeks of gestation after the first single blastocyst embryo transfer according to fresh or deferred-frozen transfer.)