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What exactly do we mean by ‘recurrent implantation failure’? A systematic review and opinion

Reproductive BioMedicine Online, Volume 28, Issue 4, Pages 409–423, April 2014

Abstract

Recurrent implantation failure (RIF) is an iatrogenic condition, being the result of repetitive unsuccessful cycles of IVF or intracytoplasmic sperm injection (ICSI) treatment. The aim of this review was to assess the definitions of RIF used in literature as well as suggest a uniform definition of this condition. A systematic search of MEDLINE, Embase and Cochrane Library was conducted. The most commonly stated definitions described RIF as ‘three or more failed treatment cycles’ or ‘two or more failed cycles’. Other identified definitions were based solely on the number of embryos transferred in previous cycles or combined the number of previously failed cycles with the number of transferred embryos. Several other definitions were also identified. This review highlights the lack of uniformity of the definition of RIF. Based on the available literature and the expert opinion of the authors, RIF should be defined as the absence of implantation after two consecutive cycles of IVF, ICSI or frozen embryo replacement cycles where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, with all embryos being of good quality and of appropriate developmental stage.

Recurrent implantation failure (RIF) is a condition resulting from repetitive unsuccessful cycles of IVF or intracytoplasmic sperm injection (ICSI) treatment. The aim of this review was to assess the definitions of RIF used in literature as well as suggest a uniform definition of this condition. A systematic search of MEDLINE, Embase and Cochrane Library was conducted. The most commonly stated definitions described RIF as ‘three or more failed treatment IVF or ICSI cycles’ or ‘two or more’ failed cycles. Other identified definitions were based only on the number of embryos transferred in previous cycles or combined the number of previously failed cycles with the number of transferred embryos. This review highlights the lack of consistency of the definition of recurrent implantation failure. Based on the available literature and the expert opinion of the authors, RIF should be defined as the absence of attachment of the embryo to the lining of the womb after two consecutive cycles of IVF, ICSI or frozen embryo replacement cycles where the cumulative number of transferred embryos was no less than four for day-2 embryos and no less than 2 for day-5 embryos (blastocysts), with all embryos being of good quality and of appropriate developmental stage. We hope that adopting a standard definition will allow for good-quality research to be conducted into this distressing condition preventing couples from having offspring.

Keywords: assisted reproduction treatment, definition, implantation, IVF/ICSI, recurrent implantation failure, systematic review.

Introduction

Human reproduction is a relatively ineffective process, with only 20–25% of apparently fertile couples becoming pregnant during a single menstrual cycle assuming tubal patency, ovulation and viable spermatozoa (Short, 1979 and Stevens, 1997). Based on this generally accepted level of fecundity, the likelihood of achieving pregnancy has been estimated at 74%, 93% and 100% after 6, 12 and 24 months, respectively of unprotected, regular intercourse (Evers, 2002 and Teklenburg et al, 2010).

Events leading to a successful pregnancy commence with fertilization of the oocyte. Research suggests that the early embryo undergoes the same stages of implantation as an activated, migrating leukocyte when transgressing vascular endothelium: namely, rolling, apposition, adhesion and invasion ( Genbacev et al., 2003 ). Taking this model into consideration, implantation should be considered only until the invasion of the embryo is complete and the latter is formally embedded within the endometrium. This phase will be heralded by an increase in serum human chorionic gonadotrophin (HCG) concentrations. In-vitro studies confirm secretion of the β subunit of HCG by the developing embryo 7 days after fertilization (Dokras et al, 1991, Marshall et al, 1968, and Woodward et al, 1993). It is unclear, however, at what time point implantation can be formally confirmed and, by default therefore, when implantation failure can be diagnosed. This is obviously a contentious issue but an important one at least as far as semantics are concerned. The ability to unequivocally state when implantation occurred, would allow differentiation between the failure of implantation and miscarriage. These clinically distinct entities are often confused and in combination are collectively referred to as ‘recurrent reproductive failure’, which suggests that they are different manifestations of the same underlying problem ( Farquharson et al., 2005 ). This is not a universal view, however, and yet many couples with recurrent implantation failure are investigated and managed in a similar, if not identical, way to those with recurrent miscarriage ( Christiansen et al., 2006 ).

The pressures of society, modern lifestyles and changes within the environment all combine to make it more difficult for couples to start a family, and subfertility appears to becoming more common with a current, estimated prevalence of 10–15% (Evers, 2002 and Shreeve and Sadek, 2012). Since the introduction of IVF in the 1980s, some couples that may have otherwise remained childless have had an opportunity to become parents. Assisted reproduction treatment is, however, no more efficient, and possibly less effective, than normal human reproduction, with implantation rates consistently in the region of 20–30% ( Voullaire et al., 2002 ). Life table analyses of cumulative pregnancy rates following multiple cycles of IVF have shown that assisted reproduction treatment is not the panacea it was once proposed to be and that a proportion of couples remain childless despite multiple cycles of treatment. Cumulative pregnancy rates after treatment have been estimated to be 40–55% after three IVF cycles (Guzick et al, 1986, Roest et al, 1998, and Simon et al, 1993) and 51–75% after six consecutive cycles (Alsalili et al, 1995, Dor et al, 1996, Guzick et al, 1986, and Simon et al, 1993). Cumulative pregnancy rates do not significantly increase thereafter, and pregnancy rates per cycle tend to fall after the third unsuccessful treatment (Croucher et al, 1998, Osmanagaoglu et al, 1999, and Sharma et al, 2002). Mathematical modelling has also demonstrated a steady decrease in live birth following a failed IVF cycle. A 50% reduction in live birth was noted after the 10th failed cycle for double-embryo transfers and lower rates were associated with single-embryo transfer (Roberts and Stylianou, 2012, Roberts et al, 2010, and Roberts et al, 2011). Failure to conceive after repeated attempts of treatment is often referred to as ‘recurrent implantation failure’ (RIF). However, the exact definition of this entity remains unclear and current descriptions incorporate the number of previously failed cycles and whether these were fresh or frozen, the number of embryos transferred and/or their respective quality, or a combination of these factors.

This article provides an up-to-date overview of the definitions of RIF currently being used in the scientific literature. The aim is to clarify the terminology used and standardize the inclusion criteria in future studies of RIF to allow a more appropriate comparison between patient populations.

Materials and methods

Eligibility criteria

Inclusion criteria were any type of study where the definition of RIF in human subjects was used. Case reports and conference abstracts, if deemed appropriate, were included. Review articles and letters to the editor were excluded. There was no limitation on language, publication date or publication status. In cases where suitability for inclusion could not be ascertained after analysis of the abstract, the complete article was obtained. Reference lists from included articles were manually screened for articles that could have been missed during the initial search.

The following databases were searched electronically: Cochrane Central Register of Controlled Trials (CENTRAL), Medical Literature Analysis and Retrieval System Online (MEDLINE) and Embase, spanning the years from 1946 to June 2013.

Search terms

The following search terms were used, adjusting for each database as necessary: recurrent implantation failure, recurrent failure to implant, repeat failure to implant, implantation failure, repeatimplantation failure, recurrent failed implantation, repeat failed implantation, RIF, recurrent reproductive failure, repeat reproductive failure, poor implantation, artificial reproductive treatment, ART, in-vitro fertilization, IVF, intracytoplasmic sperm injection and ICSI. MESH terms were expanded appropriately to gain the maximum number of options.

Study selection

Two independent reviewers (LTP and MNB) screened the retrieved titles and abstracts selecting and excluding those that clearly did not meet the eligibility criteria; disagreements between reviewers were resolved by consensus or a third party (NRF). One author (LTP) obtained full articles of all potentially relevant studies, which were examined for eligibility independently by two reviewers (LTP and MNB). Disagreements between the reviewers were again resolved by consensus, or when not possible, by consulting a third author (NRF).

Duplicates were removed and only studies with human subjects were included to undergo further analysis.

Data collection process

One review author (LTP) extracted the data from included studies using a data extraction form designed and pilot-tested by the authors. One author (MNB) independently checked the extracted data. If there were data queries, the corresponding author of the study was contacted. Disagreements were resolved by consensus. The names of article authors and titles of the included studies were juxtaposed to identify duplicate publication; in case of duplicates both articles were considered as a unique study. Analysis of the abstracts and full text articles was subject to the use of the term ‘recurrent implantation failure’ or ‘RIF’ within the article. Full text articles were analysed in detail by two assessors (MNB and LTP). Definition of RIF along with supporting information was extracted from the article and recorded for further analysis. No meta-analysis was performed and only descriptive statistics were applied.

Risk of bias in individual studies

The studies were not assessed for bias, and heterogeneity as meta-analysis was not performed due to the nature of this review.

Results

The electronic database search identified 794 potential papers. No further papers were identified by manual searches of reference lists. Removal of duplicates left 507 articles. Following review of titles and abstracts, 325 papers were selected for review of the full manuscript, of which 206 were subsequently excluded as the definition of RIF was not clearly stated ( Figure 1 ). A total of 119 studies met the inclusion criteria and were included in the systematic review. In three articles, neither ‘RIF’ nor ‘recurrent implantation failure’ were used by the authors to define the populations studied but these included patients with more than three failed treatment cycles (Pehlivan et al, 2003, Raziel et al, 2002, and Raziel et al, 2007). None of the studies provided a sound rationale for the number of cycles, the number of transferred embryos, the use of fresh or frozen embryos or embryo quality or a combination of these factors as the basis for defining RIF.

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Figure 1 Flow-chart showing the selection process for suitable studies. Full text articles (n = 206) were excluded if the definition of RIF was not clearly stated.

Number of unsuccessful cycles alone

Three different definitions based on the number of unsuccessful cycles were used. Three authors used consecutive treatment cycles in the definition (Kling et al, 2008a, Rufas-Sapir et al, 2004, and van den Heuvel et al, 2007). The most commonly used definition of RIF was ‘three or more unsuccessful or failed cycles’, which was stated in 37 of the 119 (31.6%) articles. The type of treatment used was described in 31 of these 37 studies. In 22 articles, the definition only included unsuccessful IVF cycles (Achache et al, 2010a, Achache et al, 2010b, Brosens et al, 2009, Choi et al, 2011, Debrock et al, 2009, Guan-Gui et al, 2011, Jee et al, 2009, Kling et al, 2008a, Kling et al, 2008b, Ledee-Bataille et al, 2004a, Ledee-Bataille et al, 2004b, Ledee-Bataille et al, 2005, Levran et al, 2002, Mantzouratou et al, 2007, Matsubayashi et al, 2007, Pagidas et al, 2008, Pantos et al, 2004, Prakash et al, 2008, Qublan et al, 2006, Rufas-Sapir et al, 2004, van den Heuvel et al, 2007, and Weissman et al, 2007), IVF or ICSI in five (Ghobara et al, 2006, Kim et al, 2011, Loutradis et al, 2004, Platteau et al, 2006, and Sacks et al, 2012), embryo transfer cycles in three (de Placido et al, 1991, Germeyer et al, 2010, and Tiboni et al, 2011), one of which included gamete intra-Fallopian transfer and/or transcervical embryo replacements ( De Placido et al., 1991 ) and ICSI cycles only in one case ( Rubio et al., 2001 ). Eight studies commented on the embryos transferred as being ‘fresh and/or frozen’ (Achache et al, 2010b, Debrock et al, 2009, Kling et al, 2008b, Levran et al, 2002, Prakash et al, 2008, Sacks et al, 2012, Weissman et al, 2007, and Yakin et al, 2008) and the embryos were described as being of good quality in eight studies (Achache et al, 2010a, Brosens et al, 2009, Germeyer et al, 2010, Kim et al, 2011, Ledee-Bataille et al, 2004a, Ledee-Bataille et al, 2005, Loutradis et al, 2004, and Prakash et al, 2008). The day of embryo transfer was not provided in any of the included studies.

The second most common definition used was ‘two or more failed treatment cycles’ which was used in 25 studies. In this group, the treatment cycle involved the use of IVF in 11 cases (Chou et al, 2011, Fukui et al, 2006, Gianaroli et al, 1997, Huang et al, 2011, Ivanov et al, 2012, Kalu et al, 2008, Martinuzzo et al, 2005, Matsubayashi et al, 2001, Sermondade et al, 2012, Spandorfer et al, 2002, and Vaquero et al, 2006), ICSI in two cases (Berker et al, 2011 and Oliveira et al, 2011), IVF or ICSI in two cases (Eyheremendy et al, 2010 and Lodigiani et al, 2011) and was not clarified in 10 studies (Foulk et al, 2007, Hiraoka et al, 2008, Kahraman et al, 2000, Petersen et al, 2005, Schoolcraft et al, 2010, Stephenson and Fluker, 2000, Takahashi et al, 2011, Tsoumpou et al, 2010, Urman et al, 2009, and Valojerdi et al, 2008). Six of the authors identified the transferred embryos as being ‘fresh and or frozen’ (Eyheremendy et al, 2010, Hiraoka et al, 2008, Petersen et al, 2005, Stephenson and Fluker, 2000, Takahashi et al, 2011, and Urman et al, 2009). Stage of embryo transferred was mentioned in one study as ‘cleavage stage’ but precise data were not given ( Hiraoka et al., 2008 ).

One study defined RIF as unsuccessful treatment after ‘three or more fresh cycles’ or ‘two or more fresh cycles and two or more frozen embryo replacement cycles’ ( Tuckerman et al., 2010 ).

Number of embryos transferred

The number of embryos transferred was used to define RIF in 16 studies (Coulam and Roussev, 2002, Coulam et al, 2006, Coulam et al, 2008, Firouzabadi et al, 2009, Goodman et al, 2008, Goodman et al, 2009, Hapangama et al, 2008, Inagaki et al, 2003, Quenby et al, 2009, Russell et al, 2011, Sauer et al, 2010, Tremellen and Russell, 2011, Vialard et al, 2007, Vialard et al, 2008, Voullaire et al, 2007, and Wilton et al, 2003). All of these studies considered the cumulative number of embryos transferred. The quality of the embryos replaced was also only used in three studies (Hapangama et al, 2008, Quenby et al, 2009, and Tremellen and Russell, 2011).

The most common definition included the ‘cumulative transfer of eight cleavage-stage embryos or four blastocysts over several cycles of assisted reproduction treatment’ (two to six), which was used in seven studies (Coulam and Roussev, 2002, Coulam et al, 2006, Coulam et al, 2008, Firouzabadi et al, 2009, Goodman et al, 2008, Goodman et al, 2009, and Sauer et al, 2010). The next most popular definitions were the cumulative transfer of ‘10 or more embryos’, which was used by five authors (Inagaki et al, 2003, Vialard et al, 2007, Vialard et al, 2008, Voullaire et al, 2007, and Wilton et al, 2003), and ‘five or more good-quality embryos’ which was given as the definition in two studies (Hapangama et al, 2008 and Quenby et al, 2009).

Three other definitions were used including the cumulative transfer of ‘three or more good-quality embryos’ ( Tremellen and Russell, 2011 ), ‘four to six cleavage-stage embryos’ ( Firouzabadi et al., 2009 ), and ‘10 or more cleavage-stage embryos or five blastocysts’ ( Russell et al., 2011 ).

Number of unsuccessful cycles in combination with number of transferred embryos

The combination of the number of failed treatment cycles and the number of embryos transferred without achieving pregnancy was used to define RIF in 40 articles. The most common number of unsuccessful cycles considered was three or more ( Table 1 ), and then two or more ( Table 2 ). Several other definitions were also given ( Table 3 ).

Table 1 Studies using a definition of RIF of three or more failed treatment cycles, alone or in combination with the number of embryos replaced.

Publication Treatment modality in previous cycles No. of embryos transferred Embryo quality Additional comments
De Placido et al. (1991) Embryo transfers
Carp et al. (1994) IVF 3 or more each time
Stein et al. (1995) IVF 3 or 4 each time Good
Creus et al. (1998) IVF 2 or more each time
Rubio et al. (2001) ICSI Poor
Levran et al. (2002) IVF, fresh cycles
Loutradis et al. (2004) IVF or ICSI Good
Rufas-Sapir et al. (2004) IVF Consecutive failed cycles
Pehlivan et al. (2003) IVF 10 or more Good
Ledee-Bataille et al. (2004b) IVF Good ovarian reserve (FSH <8 IU/l)
Ledee-Bataille et al. (2004a) IVF Good Good ovarian reserve (FSH <8 IU/l) and good response in previous cycle
Primi et al. (2004) Fresh cycles 2 or more each time Good
Pantos et al. (2004) IVF
Ledee-Bataille et al. (2005) IVF Good
Taranissi et al. (2005) IVF 10 or more
Ghobara et al. (2006) IVF or ICSI
Platteau et al. (2006) IVF or ICSI
Qublan et al. (2006) IVF
Mantzouratou et al. (2007) IVF
Quenby et al. (2007) IVF or ICSI 9 or more Good
Matsubayashi et al. (2007) IVF
Weissman et al. (2007) IVF, fresh cycles
van den Heuvel et al. (2007) IVF Consecutive failed cycles
Matteo et al. (2007) IVF, fresh cycles 2 or more each time Good Good ovarian reserve (FSH <8 IU/l) and good response in previous cycle
Kling et al. (2008b) IVF, fresh cycles
Blockeel et al. (2008) IVF 10 or more Good
Prakash et al. (2008) IVF, fresh or frozen Good
Thum et al. (2008) IVF 2 or 3 each time Good
Yakin et al. (2008) Fresh treatment cycles
Simur et al. (2009) IVF 3 or more Good
Kling et al. (2008a) IVF Consecutive failed cycles
Pagidas et al. (2008) IVF
Jee et al. (2009) IVF Good number of oocytes, embryos and adequate transfer
Koler et al. (2009) IVF 10 or more High
Brosens et al. (2009) IVF Good
Debrock et al. (2009) IVF, fresh cycles
Fragouli et al. (2010) IVF 10 or more Good
Germeyer et al. (2010) Embryo transfers Good
Achache et al. (2010b) IVF, fresh cycles
Achache et al. (2010a) IVF Good Good ovarian reserve and age under 40
Chernyshov et al. (2010) IVF 2 or more each time Good
Kim et al. (2011) IVF or ICSI Grade 1 or 2
Maritnez-Zamora et al. (2011) Fresh or frozen cycles 1 or more each time Grade 1 or 2
Choi et al. (2011) IVF
Tiboni et al. (2011) Embryo transfers
Rajaei et al. (2011) IVF or ICSI 10 or more  
Sudoma et al. (2011) 2 or more each time Good
Sacks et al. (2012) Fresh or frozen cycles
Scarpellini and Sbracia (2012) IVF 7 or more Good Age <39, no systemic illness

Table 2 Studies using a definition of RIF of two or more failed treatment cycles, alone or in combination with the number of embryos replaced.

Publication Treatment modality in previous cycles No. of embryos transferred Embryo quality Additional comments
Gianaroli et al. (1997) IVF
Kahraman et al. (2000)
Stephenson and Fluker (2000) Fresh or frozen cycles
Matsubayashi et al. (2001) IVF Visually good
Spandorfer et al. (2002) IVF
Kwak-Kim et al. (2003) IVF 2 or more each time
Kahraman et al. (2004) 3 or more Good
Martinuzzo et al. (2005) IVF Good
Petersen et al. (2005) Fresh or frozen cycles
Fukui et al. (2006) IVF Good
Koscinski et al. (2006) IVF 2 or more Good
Vaquero et al. (2006) IVF
Foulk et al. (2007) Top
Arefi et al. (2008) IVF or ICSI 3 or more Good
Fukui et al. (2008) IVF 4 or more
Hiraoka et al. (2008) Fresh or frozen cycles Cleavage–stage embryos
Kalu et al. (2008) IVF Good
Valojerdi et al. (2008)
Urman et al. (2009) Fresh cycles
Aletebi (2010) 3 or more Good
Berker et al. (2011) ICSI
Eyheremendy et al. (2010) IVF or ICSI, fresh or frozen cycles
Johnston-MacAnanny et al. (2010) IVF 1 or more each time Good
Schoolcraft et al. (2010)
Sharif and Ghunaim (2010) IVF or ICSI, fresh cycles 6 or more Good (G1 or G2)
Tsoumpou et al. (2010) Good
Yang et al. (2010) IVF 2 or more each time
Chou et al. (2011) IVF Good
Huang et al. (2011) IVF Good
Lodigiani et al. (2011) IVF or ICSI
Oliveira et al. (2011) ICSI Morphologically good
Takahashi et al. (2011) Fresh or frozen cycles
Ivanov et al. (2012) IVF
Sermondade et al. (2012) IVF

Table 3 Studies using less common inclusion criteria of RIF into study populations.

Publication No. of previous failed cycles Treatment modality in previous cycles No. of embryos transferred Embryo quality Additional comments
Huang et al. (1999) 5 or more IVF or ICSI 3 or more each time
Raziel et al. (2002) 6 or more 15 or more
Voullaire et al. (2002) Multiple failed cycles IVF 10 or more
Elram et al. (2005) 7 or more Fresh cycles At least 2 each time Good
Varla-Leftherioti et al. (2007) 5 or more IVF More than 2 each time   <38 years
Ledee et al. (2008) Several failed cycles Fresh or frozen cycles 10 or more Fragmentation <20% and at least 4-cell stage by day 2 Unexplained failure of treatment cycles
Brinsden et al. (2009) 2 or more or 3 or more Assisted reproduction treatment cycles, fresh 2 or more or 1 or more each time, respectively Grade A or B
Karimzadeh et al. (2009) 2–6 cycles IVF 10 or more Good <40 years, good responders (>4 follicles at HCG), good ovarian reserve (FSH <10 IU/l), no uterine anomalies, endometriomas, hydrosalpinges or coagulation disorders
Tuckerman et al. (2010) 3 fresh or more or 2 fresh and 2 frozen cycles IVF, fresh or frozen Good
Dos Santos et al. (2012) Several failed cycles IVF, fresh or frozen 10 or more Fragmentation <20% and at least 4-cell stage by day 2 Good hormonal reserve (FSH <10 IU/l) and good response to previous treatment

Unsuccessful treatment after ‘three or more treatment cycles’ in combination with the number of embryos transferred was used by 18 authors (Blockeel et al, 2008, Carp et al, 1994, Chernyshov et al, 2010, Creus et al, 1998, Fragouli et al, 2010, Koler et al, 2009, Maritnez-Zamora et al, 2011, Matteo et al, 2007, Pehlivan et al, 2003, Primi et al, 2004, Quenby et al, 2007, Rajaei et al, 2011, Scarpellini and Sbracia, 2012, Simur et al, 2009, Stein et al, 1995, Sudoma et al, 2011, Taranissi et al, 2005, and Thum et al, 2008). IVF was the treatment modality in 13 of these studies (Blockeel et al, 2008, Carp et al, 1994, Chernyshov et al, 2010, Creus et al, 1998, Fragouli et al, 2010, Koler et al, 2009, Matteo et al, 2007, Pehlivan et al, 2003, Scarpellini and Sbracia, 2012, Simur et al, 2009, Stein et al, 1995, Taranissi et al, 2005, and Thum et al, 2008), IVF or ICSI in two cases (Quenby et al, 2007 and Rajaei et al, 2011) or not stated in three cases (Maritnez-Zamora et al, 2011, Primi et al, 2004, and Sudoma et al, 2011). The term ‘fresh embryos’ in the definition was used once ( Matteo et al., 2007 ). The most commonly stated numbers of embryos transferred during three or more failed cycles were ‘two or more embryos’ (Chernyshov et al, 2010, Creus et al, 1998, Matteo et al, 2007, Primi et al, 2004, Sudoma et al, 2011, and Thum et al, 2008) and the ‘cumulative transfer of 10 or more embryos’ (Blockeel et al, 2008, Fragouli et al, 2010, Koler et al, 2009, Pehlivan et al, 2003, Rajaei et al, 2011, and Taranissi et al, 2005) both of which were used in six studies. The next most common definition in this category included the transfer of ‘three or more embryos’, which was used in three studies (Carp et al, 1994, Simur et al, 2009, and Stein et al, 1995). Other definitions included the transfer of ‘one or more embryos’ during three cycles ( Maritnez-Zamora et al., 2011 ), transfer of ‘seven or more embryos’ ( Scarpellini and Sbracia, 2012 ) and the ‘cumulative transfer of nine embryos’ ( Quenby et al., 2007 ) which were used once each. The quality of the embryos used was not stated in four articles (Carp et al, 1994, Creus et al, 1998, Rajaei et al, 2011, and Taranissi et al, 2005), whereas the remaining authors described the embryos as being of ‘good quality’ but exact grades were not stated ( Table 1 ).

Unsuccessful treatment after ‘two or more treatment cycles’ in combination with the number of embryos transferred was used by nine authors (Aletebi, 2010, Arefi et al, 2008, Fukui et al, 2008, Johnston-Macananny et al, 2010, Kahraman et al, 2004, Koscinski et al, 2006, Kwak-Kim et al, 2003, Sharif and Ghunaim, 2010, and Yang et al, 2010). These studies included only IVF cycles in five cases (Fukui et al, 2008, Johnston-Macananny et al, 2010, Koscinski et al, 2006, Kwak-Kim et al, 2003, and Yang et al, 2010), IVF or ICSI in two studies (Arefi et al, 2008 and Sharif and Ghunaim, 2010) and was not stated in the other two studies (Aletebi, 2010 and Kahraman et al, 2004). The number of embryos transferred included ‘one or more’ ( Johnston-MacAnanny et al., 2010 ), ‘two or more’ (Koscinski et al, 2006, Kwak-Kim et al, 2003, and Yang et al, 2010) ‘or three or more’ (Aletebi, 2010, Arefi et al, 2008, and Kahraman et al, 2004). The cumulative transfer of ‘four or more’ ( Fukui et al., 2008 ) and ‘six or more’ were also used ( Sharif and Ghunaim, 2010 ). The quality of embryos was not stated in three studies (Fukui et al, 2008, Kwak-Kim et al, 2003, and Yang et al, 2010) ( Table 2 ).

As shown in Table 3 , unsuccessful treatment after the transfer of ‘at least two embryos’ in ‘four or more treatment cycles’ (Castelo-Branco et al, 2004, Farhi et al, 2000, Friedler et al, 2007, Kremenska et al, 2010, and Raziel et al, 2007) or ‘five or more IVF or ICSI cycles’ were also used to define RIF (Huang et al, 1999 and Varla-Leftherioti et al, 2007). Other definitions included the cumulative transfer of 10 or more embryos in ‘six or more’, ‘seven or more’, ‘several’ and ‘multiple’ treatment cycles (dos Santos et al, 2012, Elram et al, 2005, Ledee et al, 2008, Raziel et al, 2002, and Voullaire et al, 2002). ‘Two to six’ failed IVF cycles without clinical pregnancy during which ‘10 or more’ embryos were transferred was used by one group ( Karimzadeh et al., 2009 ) whilst another defined RIF as unsuccessful treatment after ‘two or more or three or more IVF or ICSI cycles where two or more or one or more embryos were transferred each time, respectively’ ( Brinsden et al., 2009 ).

Additional factors included in the definition

Several other factors were mentioned as inclusion or exclusion criteria for defining RIF. Good ovarian reserve, defined as ‘FSH <8 IU/l’ was used as an inclusion criterion, whereas poor response to previous treatment, defined as less than four follicles on day of HCG or less than four oocytes retrieved in previous cycles, were used by eight authors as exclusion criteria (Achache et al, 2010a, dos Santos et al, 2012, Jee et al, 2009, Karimzadeh et al, 2009, Ledee-Bataille et al, 2004a, Ledee-Bataille et al, 2004b, Matteo et al, 2007, and Oliveira et al, 2011). The consecutivity of previous failed treatment cycles was only mentioned in three studies (Kling et al, 2008a, Rufas-Sapir et al, 2004, and van den Heuvel et al, 2007). The day of embryo transfer and, by default the stage of embryo development, were stated by eight authors in their inclusion criteria (Coulam and Roussev, 2002, Coulam et al, 2006, Coulam et al, 2008, Firouzabadi et al, 2009, Goodman et al, 2008, Goodman et al, 2009, Hiraoka et al, 2008, and Sauer et al, 2010).

The outcomes of treatment, which defined each unsuccessful cycle, were stated in 42 of all studies. The most frequently stated outcome was ‘failure to achieve a pregnancy’ which was used in 21 studies (Achache et al, 2010b, Carp et al, 1994, Creus et al, 1998, dos Santos et al, 2012, Friedler et al, 2007, Kalu et al, 2008, Ledee et al, 2008, Quenby et al, 2007, Quenby et al, 2009, Raziel et al, 2002, Raziel et al, 2007, Sharif and Ghunaim, 2010, Stein et al, 1995, Taranissi et al, 2005, Tremellen and Russell, 2011, Tsoumpou et al, 2010, van den Heuvel et al, 2007, Vialard et al, 2008, Voullaire et al, 2002, Wilton et al, 2003, and Yakin et al, 2008). A negative serum β-HCG 2 weeks following embryo transfer was used to define treatment outcome by eight authors (Coulam et al, 2006, Debrock et al, 2009, Firouzabadi et al, 2009, Goodman et al, 2008, Goodman et al, 2009, Sacks et al, 2012, Sauer et al, 2010, and Urman et al, 2009). Other treatment outcomes included ‘conception’ (Chou et al, 2011, Fragouli et al, 2010, Huang et al, 2011, and Takahashi et al, 2011), ‘clinical pregnancy’ (Huang et al, 1999 and Johnston-Macananny et al, 2010), ‘implantation’ (Lodigiani et al, 2011, Sermondade et al, 2012, and Vialard et al, 2007), ‘positive serum HCG and subsequent miscarriage’ ( Germeyer et al., 2010 ), ‘negative urinary pregnancy test or chemical pregnancy loss’ ( Coulam et al., 2008 ), ‘failure to maintain a pregnancy’ ( Varla-Leftherioti et al., 2007 ) and ‘failure to implant, biochemical pregnancy failure or spontaneous abortion of less than 8 weeks gestation’ ( Stephenson and Fluker, 2000 ).

Discussion

This systematic review has highlighted the enormous variability in the definition of RIF. Three generic definitions appear to be in current use and these are based on the number of unsuccessful treatment cycles, the number of embryos transferred or a combination of both factors. Very few definitions consider all the aspects of the IVF treatment process and even the most comprehensive definitions lack pertinent embryological data or meaningful outcome definitions (Maritnez-Zamora et al, 2011, Matteo et al, 2007, and Sharif and Ghunaim, 2010). All used definitions remain hypothetical and no justification was given for the use of any selected definition of RIF.

As a descriptive systematic review, the results of this study are solely for the purpose of discussion. As with every definition, it needs to evolve with time and should do so in the light of new developments. A significant limitation of this review is the time period over which the articles have been sourced, which spans more than two decades. Within that time frame, there has been a shift from cleavage-stage embryo to blastocyst-stage embryo replacements and from double- to single-embryo transfers, all factors contributing to an overall increase in success rates. This is reflected, at least partially, in the evolution of the definitions of RIF, which is primarily evident in the decreasing number of embryos transferred, which fell from three or more in the early 1990s (Carp et al, 1994 and Stein et al, 1995) to the elective transfer of one embryo in 2011 ( Maritnez-Zamora et al., 2011 ). Different treatment modalities – IVF and ICSI – result in comparable delivery rates, for IVF ranging from 21.9% in Europe to 33.3% in the USA and for ICSI ranging from 19.9% in Europe to 32.5% in the USA (CDC, 2009 and de Mouzon et al, 2012). Hence, differentiation between these two treatment modalities when defining RIF is not required.

A single-embryo transfer policy has been introduced in many countries to decrease multiple pregnancy rates and their associated health risks. In 2007, 2.5% of embryo transfers in Europe included four or more embryos whilst 21.4% were single-embryo transfers, with Sweden, Finland and Belgium having the highest proportions ( de Mouzon et al., 2012 ). The trend towards single-embryo replacement, suggests that the number of embryos transferred without achieving pregnancy should be closer to a cumulative of two or three, after which RIF should be diagnosed. Single-blastocyst transfer has been associated with similar live-birth rates as the transfer of two cleavage-stage embryos (Blake et al, 2007, Csokmay et al, 2011, Gardner et al, 1998, Gardner et al, 2004, and Zander-Fox et al, 2011), thus equating the developmental potential of a single blastocyst to that of two cleavage-stage embryos, a factor which also should be considered when defining RIF.

Irrespective of the stage of embryo development and numbers of embryos transferred, their quality is another relevant predictor of outcome. The rate of cleavage, as well as the degree of fragmentation, have also been associated with the chance of pregnancy in the reference treatment cycle. Day-2 embryos at the 4-cell stage with less than 21% fragmentation have been shown to exhibit a higher developmental potential than chronologically comparable embryos, demonstrating alternate growth patterns and characteristics (Fauque et al, 2007 and Pelinck et al, 2010). This was highlighted in two of the studies when patients were considered for RIF investigations following a transfer of 10 or more fresh or frozen embryos, each with fragmentation rate below 20% and at the 4-cell stage on day 2 (dos Santos et al, 2012 and Ledee et al, 2008). The same relationship between morphology and success of treatment exists when considering blastocyst quality ( Balaban et al., 2000 ).

Several other potentially contributory factors have been omitted from the definitions of RIF in the analysed literature, most notably culture conditions and the embryo transfer itself ( Das and Holzer, 2012 ). The former could be rectified by rigorous monitoring of the embryo culture conditions (Das and Holzer, 2012 and Gardner et al, 2005) but these are still likely to vary from unit to unit which itself is associated with different success rates. The same is true for embryo transfer, which is operator dependent and influenced by certain patient characteristics. Although poorly defined, difficult embryo transfer has been associated with a 33% relative decrease in clinical pregnancy rates ( Phillips et al., 2013 ). Ultrasound-guided embryo transfer and appropriate unit experience are undoubtedly important (Brown et al, 2010, Das and Holzer, 2012, and Penzias, 2012) but hard if not impossible to control for.

As frozen embryos are the product of stimulated oocyte retrieval cycles, their replacement does contribute to the cumulative pregnancy rate ( de Mouzon et al., 2012 ) and should be pooled together when defining RIF. Cumulative pregnancy rates remain relatively stable until the third treatment cycle, with the highest pregnancy rates being achieved in the first two cycles (Rinehart, 2007, Schroder et al, 2004, Shapiro et al, 2001, and Silberstein et al, 2005).

Limited and often contradictory recommendations exist to guide the necessary and appropriate investigations of RIF. Considering suspected aetiological factors of RIF, various therapies to improve endometrial receptivity, embryo developmental potential and complex maternal conditions have been suggested ( Margalioth et al., 2006 ). Hysteroscopic investigations of the endometrial cavity ( Demirol and Gurgan, 2004 ), endometrial biopsy ( Nastri et al., 2012 ) and low-molecular-weight heparins ( Fiedler and Wurfel, 2004 ) have shown benefit in the form of increased pregnancy rates in couples with failed treatment cycles. Preimplantation genetic diagnosis, embryo coculture and preferential blastocyst transfer can be implemented to minimize the embryonic component in RIF causality ( Margalioth et al., 2006 ). Medical treatment of endometriosis-related RIF has been shown to benefit affected couples ( Sallam et al., 2006 ); however, surgical treatment of the disease still remains controversial ( Adamson, 2005 ). Where hydrosalpinx is suspected as the cause of treatment failure, it should be removed prior to embarking on further treatment ( Johnson et al., 2004 ). Due to the lack of sound scientific evidence, often an empirical approach to investigations and treatment of RIF is taken, resulting in varying success rates.

The findings reported in this article are to be expected and suggest that definition of RIF should be based on consensus and expert opinion.

In a widely accepted and implemented international definition of RIF, each step of the treatment process, from fertilization through to an unambiguous definition of the treatment end point, should be considered. For clarification, when defining ‘implantation’ failure, we refer to the lack of formation of a physical attachment between the embryo and the decidualizing endometrium resulting in a negative serum β-HCG. The definition can be based on the number and quality of embryos used for treatment. As there is a significant trend towards single-embryo replacement and preferential use of blastocyst-stage embryos, these should be used as the gold standard in the proposed definition of RIF.

One foreseeable benefit of standardizing the definition would be the uniformity of collected research data. As the overall numbers of patients with RIF per clinic are small, in order to perform good-quality research into uncertainties surrounding this phenomenon, multicentre and international studies need to be put in place. Data heterogeneity will be minimized when same study populations are considered, making meta-analyses more reliable and accurate. Expert opinion needs also to be pursued and pilot studies using this definition need to be launched in order to test its feasibility in practice. This systematic review is the first step in improving the quality of research into RIF.

Combining all the aspects of the definition, the authors of this review suggest that RIF should be defined as the absence of implantation, itself defined by a negative serum HCG 14 days after oocyte collection, after two consecutive cycles of IVF, ICSI or frozen embryo replacement, where the cumulative number of transferred embryos was no less than four for cleavage-stage embryos and no less than two for blastocysts, with all embryos being of good quality and of appropriate developmental stage. Patients in oocyte donation schemes failing to achieve pregnancy and meeting these criteria should also be treated as being affected by RIF. This definition incorporates all of the relevant information necessary to completely define RIF, including the outcome. Whether the scientific community will acknowledge the suggested definition depends on results of pilot studies and ease of inclusion of patients according to these new, stricter, yet more inclusive and comprehensive, criteria.

The main confounding factor of the review process was considered to be the significant difference in publication dates of analysed studies spanning two decades.

No previous systematic reviews were performed assessing the definition of RIF or any studies attempting to provide basis for the definition exist. Rinehart (2007) and El-Toukhy and Taranissi (2006) attempted to standardize the definition of RIF. These articles were not, however, systematic reviews and as such only represent the authors’ opinion on the subject. No definition was suggested in either article. Tan et al. (2005) aimed to determine the definition of RIF through a questionnaire survey. 79 centres from the HFEA database were asked to participate with an 82% reply rate. The definitions of RIF ranged from two to six failed previous treatment cycles but the majority of centres (63.1%) used three fresh IVF cycles in their definition. Only 18% of centres included frozen embryo transfers in their definition. This survey highlights the discrepancies in defining RIF even within a small geographic area and, by extrapolation, suggests that worldwide differences in defining this iatrogenic condition would be even greater. A more recent opinion suggests RIF should be defined as at least three fresh or frozen unsuccessful cycles with a cumulative transfer of at least four good-quality embryos in a woman under 40 years of age ( Li, 2012 ), but no rationale for this definition is given.

In conclusion, this review of literature has revealed a significant heterogeneity when defining RIF. Various factors are responsible for this iatrogenic condition; however, no definition was identified that fully describes these. A uniform definition of RIF will improve the quality of gathered information and help couples undergoing repeated treatment cycles to achieve a successful, healthy pregnancy. The most likely way to lead to a successful definition of RIF would, however, be through specialist consensus. We propose a new definition, which is still arbitrary as it is based mainly on opinion, but does, however, consider the key determinants of implantation and the IVF treatment process.

References

  • Achache et al., 2010a H. Achache, A. Tsafrir, D. Prus, R. Reich, A. Revel. Cytosolic phospholipase A2 (cPLA2) expression is critical for human embryo implantation. Reprod. Sci.. 2010;17:138A-139A
  • Achache et al., 2010b H. Achache, A. Tsafrir, D. Prus, R. Reich, A. Revel. Defective endometrial prostaglandin synthesis identified in patients with repeated implantation failure undergoing in vitro fertilization. Fertil. Steril.. 2010;94:1271-1278
  • Adamson, 2005 G. Adamson. Laparoscopy, in vitro fertilization, and endometriosis: an enigma. Fertil. Steril.. 2005;84:1582-1584
  • Aletebi, 2010 F. Aletebi. Hysteroscopy in women with implantation failures after in vitro fertilization: findings and effect on subsequent pregnancy rates. Middle East Fertil. Soc. J.. 2010;15:288-291
  • Alsalili et al., 1995 M. Alsalili, A. Yuzpe, I. Tummon, J. Parker, J. Martin, S. Daniel, M. Rebel, J. Nisker. Cumulative pregnancy rates and pregnancy outcome after in-vitro fertilization: >5000 cycles at one centre. Hum. Reprod.. 1995;10:470-474
  • Arefi et al., 2008 S. Arefi, H. Soltanghorace, A. Hassan, A.S. Tabaei, G. Novin, H. Zeraati, P. Ebadi. Repeated IVF/ICSI-ETs failures and impact of hysteroscopy. Iran. J. Reprod. Med.. 2008;6:19-24
  • Balaban et al., 2000 B. Balaban, B. Urman, A. Sertac, C. Alatas, S. Aksoy, R. Mercan. Blastocyst quality affects the success of blastocyst-stage embryo transfer. Fertil. Steril.. 2000;74:282-287
  • Berker et al., 2011 B. Berker, S. Taskin, K. Kahraman, E.A. Taskn, C. Atabekoglu, M. Sonmezer. The role of low-molecular-weight heparin in recurrent implantation failure: a prospective, quasi-randomized, controlled study. Fertil. Steril.. 2011;95:2499-2502
  • Blake et al., 2007 D.A. Blake, C.M. Farquhar, N. Johnson, M. Proctor. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst. Rev.. 2007;:CD002118
  • Blockeel et al., 2008 C. Blockeel, V. Schutyser, A. de Vos, W. Verpoest, M. de Vos, C. Staessen, P. Haentiens, J. van der Elst, P. Devroey. Prospectively randomized controlled trial of PGS in IVF/ICSI patients with poor implantation. Reprod. Biomed. Online. 2008;17:848-854
  • Brinsden et al., 2009 P.R. Brinsden, V. Alam, B. de Moustier, P. Engrand. Recombinant human leukemia inhibitory factor does not improve implantation and pregnancy outcomes after assisted reproductive techniques in women with recurrent unexplained implantation failure. Fertil. Steril.. 2009;91:1445-1447
  • Brosens et al., 2009 J.J. Brosens, A. Hodgetts, F. Feroze-Zaidi, J.R.A. Sherwin, L. Fusi, M.S. Salker, J. Higham, G.L. Rose, T. Kajihara, S.L. Young, B.A. Lessey, P. Henriet, P.R. Langford, A.T. Fazleabas. Proteomic analysis of endometrium from fertile and infertile patients suggests a role for apolipoprotein A–I in embryo implantation failure and endometriosis. Mol. Hum. Reprod.. 2009;16:273-285
  • Brown et al., 2010 J. Brown, K. Buckingham, A. Abou-Setta, W. Buckett. Ultrasound versus ‘clinical touch’ for catheter guidance during embryo transfer in women. Cochrane Database Syst. Rev.. 2010;:CD006107
  • Carp et al., 1994 H.J.A. Carp, V. Toder, S. Mashiach, J. Rabinovici. Effect of paternal leukocyte immunization on implantation after biochemical pregnancies and repeated failure of embryo transfer. Am. J. Reprod. Immunol.. 1994;31:112-115
  • Castelo-Branco et al., 2004 A. Castelo-Branco, N. Frydman, J. Kadoch, A. le Du, H. Fernandez, R. Fanchin, R. Frydman. The role of the semi natural cycle as option of treatment of patients with a poor prognosis for successful in vitro fertilization. J. Gynecol. Obstet. Biol. Reprod.. 2004;33:518-524
  • CDC, 2009 CDC, C. F. D. C. A. P. R. H., November 2009. Assisted reproductive technology. National Summary and Fertility Clinic Reports. Available from: < http://www.cdc.gov/art/ART2007/index.htm >.
  • Chernyshov et al., 2010 V.P. Chernyshov, I.O. Sudoma, B.V. Dons’koi, A.A. Kostyuchyk, Y.V. Masliy. Elevated NK cell cytotoxicity, CD158a expression in NK cells and activated T lymphocytes in peripheral blood of women with IVF failures. Am. J. Reprod. Immunol.. 2010;64:58-67
  • Choi et al., 2011 Y. Choi, K. Kim, W. Lee, B. Lee, S. Kim. Endometrial expression of osteopontin, syndecan-1, Muc-1, MECA-79 and E-catherin in women with repeated implantation failure after IVF. Hum. Reprod.. 2011;26:i221
  • Chou et al., 2011 P.Y. Chou, M.H. Wu, H.A. Pan, K.H. Hung, F.M. Chang. Use of an oxytocin antagonist in in vitro fertilization-embryo transfer for women with repeated implantation failure: a retrospective study. Taiwan. J. Obstet. Gynecol.. 2011;50:136-140
  • Christiansen et al., 2006 O.B. Christiansen, H.S. Nielsen, A.M. Kolte. Future directions of failed implantation and recurrent miscarriage research. Reprod. Biomed. Online. 2006;13:71-83
  • Coulam and Roussev, 2002 C.B. Coulam, R. Roussev. Chemical pregnancies: immunologic and ultrasonographic studies. Am. J. Reprod. Immunol.. 2002;48:323-328
  • Coulam et al., 2006 C.B. Coulam, R.S. Jeyendran, L.A. Fishel, R. Roussev. Multiple thrombophilic gene mutations are risk factors for implantation failure. Reprod. Biomed. Online. 2006;12:322-327
  • Coulam et al., 2008 C.B. Coulam, R.S. Jeyendran, R. Roussev. Association of progesterone receptor polymorphisms with recurrent implantation failure after in vitro fertilization and embryo transfer. J. Assist. Reprod. Genet.. 2008;25:119-122
  • Creus et al., 1998 M. Creus, J. Balasch, F. Fabregues, J. Martorell, M. Boada, J. Penarrubia, P.N. Barri, J.A. Vanrell. Parental human leukocyte antigens and implantation failure after in-vitro fertilization. Hum. Reprod.. 1998;13:39-43
  • Croucher et al., 1998 C.A. Croucher, A. Lass, R. Margara, R.M. Winston. Predictive value of the results of a first in-vitro fertilization cycle on the outcome of subsequent cycles. Hum. Reprod.. 1998;13:403-408
  • Csokmay et al., 2011 J.M. Csokmay, M.J. Hill, R.J. Chason, S. Hennessy, A.N. James, J. Cohen, A.H. Decherney, J.H. Segars, M.D. Payson. Experience with a patient-friendly, mandatory, single-blastocyst transfer policy: the power of one. Fertil. Steril.. 2011;96:580-584
  • Das and Holzer, 2012 M. Das, H.E.G. Holzer. Recurrent implantation failure: gamete and embryo factors. Fertil. Steril.. 2012;97:1021-1027
  • de Mouzon et al., 2012 J. de Mouzon, V. Goossens, S. Bhattacharya, J.A. Castilla, A.P. Ferraretti, V. Korsak, M. Kupka, K.G. Nygren, A.N. Andersen. Assisted reproductive technology in Europe, 2007: results generated from European registers by ESHRE. Hum. Reprod.. 2012;27:954-966
  • de Placido et al., 1991 G. de Placido, F. Zullo, N. Colacurci, D. Perrone, A. Nazzaro, F. Paolillo, U. Montemagno. Immunological treatment of implantation failure. Ann. N. Y. Acad. Sci.. 1991;622:291-295
  • Debrock et al., 2009 S. Debrock, C. Spiessens, K. Peeraer, P. de Loecker, D. Willemen, T.M. D’Hooghe. Higher implantation rate using modified quarter laser-assisted zona thinning in repeated implantation failure. Gynecol. Obstet. Invest.. 2009;67:127-133
  • Demirol and Gurgan, 2004 A. Demirol, T. Gurgan. Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure. Reprod. Biomed. Online. 2004;8:590-594
  • Dokras et al., 1991 A. Dokras, I. Sargent, C. Ross, R. Gardner, D. Barlow. The human blastocyst: morphology and human chorionic gonadotrophin secretion in vitro. Hum. Reprod.. 1991;6:1143-1151
  • Dor et al., 1996 J. Dor, D. Seidman, I. Ben-Shlomo, D. Levran, Z. Ben-Rafael, S. Mashiach. Cumulative pregnancy rate following in-vitro fertilization: the significance of age and infertility aetiology. Hum. Reprod.. 1996;11:425-428
  • dos Santos et al., 2012 E. dos Santos, V. Serazin, C. Morvan, A. Torre, R. Wainer, P. de Mazancourt, M.N. Dieudonne. Adiponectin and leptin systems in human endometrium during window of implantation. Fertil. Steril.. 2012;97:e1
  • El-Toukhy and Taranissi, 2006 T. El-Toukhy, M. Taranissi. Towards better quality research in recurrent implantation failure: standardizing its definition is the first step. Reprod. Biomed. Online. 2006;12:383-385
  • Elram et al., 2005 T. Elram, A. Simon, S. Israel, A. Revel, D. Shveiky, N. Laufer. Treatment of recurrent IVF failure and human leukocyte antigen similarity by intravenous immunoglobulin. Reprod. Biomed. Online. 2005;11:745-749
  • Evers, 2002 J. Evers. Female subfertility. Lancet. 2002;360:151-159
  • Eyheremendy et al., 2010 V. Eyheremendy, F.G.E. Raffo, M. Papayannis, J. Barnes, C. Granados, J. Blaquier. Beneficial effect of autologous endometrial cell coculture in patients with repeated implantation failure. Fertil. Steril.. 2010;93:769-773
  • Farhi et al., 2000 J. Farhi, A. Weissman, H. Nahum, D. Levran. Zygote intrafallopian transfer in patients with tubal factor infertility after repeated failure of implantation with in vitro fertilization-embryo transfer. Fertil. Steril.. 2000;74:390-393
  • Farquharson et al., 2005 R. Farquharson, E. Jauniaux, N. Exalto. Updated and revised nomenclature for description of early pregnancy events. Hum. Reprod.. 2005;20:3008-3011
  • Fauque et al., 2007 P. Fauque, R. Leandri, F. Merlet, J.C. Juillard, S. Epelboin, J. Guibert, P. Jouannet, C. Patrat. Pregnancy outcome and live birth after IVF and ICSI according to embryo quality. J. Assist. Reprod. Genet.. 2007;24:159-165
  • Fiedler and Wurfel, 2004 K. Fiedler, W. Wurfel. Effectivity of Heparin in Assisted Reproduction Germany. Eur. J. Med. Res.. 2004;9:207-214
  • Firouzabadi et al., 2009 R.D. Firouzabadi, N. Ghasemi, M.A. Rozbahani, N. Tabibnejad. Association of p53 polymorphism with ICSI/IVF failure and recurrent pregnancy loss. Aust. N. Z. J. Obstet. Gynaecol.. 2009;49:216-219
  • Foulk et al., 2007 R.A. Foulk, T. Zdravkovic, O. Genbacev, A. Prakobphol. Expression of L-selectin ligand MECA-79 as a predictive marker of human uterine receptivity. J. Assist. Reprod. Genet.. 2007;24:316-321
  • Fragouli et al., 2010 E. Fragouli, M. Katz-Jaffe, S. Alfarawati, J. Stevens, P. Colls, N.N. Goodall, S. Tormasi, C. Gutierrez-Mateo, R. Prates, W.B. Schoolcraft, S. Munne, D. Wells. Comprehensive chromosome screening of polar bodies and blastocysts from couples experiencing repeated implantation failure. Fertil. Steril.. 2010;94:875-887
  • Friedler et al., 2007 S. Friedler, M. Schachter, D. Strassburger, K. Esther, R.R. El, A. Raziel. A randomized clinical trial comparing recombinant hyaluronan/recombinant albumin versus human tubal fluid for cleavage stage embryo transfer in patients with multiple IVF-embryo transfer failure. Hum. Reprod.. 2007;22:2444-2448
  • Fukui et al., 2006 A. Fukui, E. Ntrivalas, A. Gilman-Sachs, J. Kwak-Kim, S.K. Lee, R. Levine, K. Beaman. Expression of natural cytotoxicity receptors and a2V-ATPase on peripheral blood NK cell subsets in women with recurrent spontaneous abortions and implantation failures. Am. J. Reprod. Immunol.. 2006;56:312-320
  • Fukui et al., 2008 A. Fukui, J. Kwak-Kim, E. Ntrivalas, A. Gilman-Sachs, S.K. Lee, K. Beaman. Intracellular cytokine expression of peripheral blood natural killer cell subsets in women with recurrent spontaneous abortions and implantation failures. Fertil. Steril.. 2008;89:157-165
  • Gardner et al., 1998 D.K. Gardner, P. Vella, M. Lane, L. Wagley, T. Schlenker, W.B. Schoolcraft. Culture and transfer of human blastocysts increases implantation rates and reduces the need for multiple embryo transfers. Fertil. Steril.. 1998;69:84-88
  • Gardner et al., 2004 D.K. Gardner, E. Surrey, D. Minjarez, A. Leitz, J. Stevens, W.B. Schoolcraft. Single blastocyst transfer: a prospective randomized trial. Fertil. Steril.. 2004;81:551-555
  • Gardner et al., 2005 D.K. Gardner, L. Reed, D. Linck, C. Sheehan, M. Lane. Quality control in human in vitro fertilization. Semin. Reprod. Med.. 2005;23:319-324
  • Genbacev et al., 2003 O. Genbacev, A. Prakobphol, R. Foulk, A. Krtolica, D. Ilic, M. Singer, Z.Q. Yang, L. Kiessling, S. Rosen, S. Fisher. Trophoblast L-selectin-mediated adhesion at the maternal–fetal interface. Science. 2003;299:405-408
  • Germeyer et al., 2010 A. Germeyer, M. von Wolff, J. Jauckus, T. Strowitzki, T. Sharma, A.T. Grazul-Bilska. Changes in cell proliferation, but not in vascularisation are characteristic for human endometrium in different reproductive failures – a pilot study. Reprod. Biol. Endocrinol.. 2010;8:67
  • Ghobara et al., 2006 T.S. Ghobara, D.J. Cahill, W.C.L. Ford, H.M. Collyer, P.E. Wilson, L. Al-Nuaim, J.M. Jenkins. Effects of assisted hatching method and age on implantation rates of IVF and ICSI. Reprod. Biomed. Online. 2006;13:261-267
  • Gianaroli et al., 1997 L. Gianaroli, M.C. Magli, S. Munne, A. Fiorentino, N. Montanaro, A.P. Ferraretti. Will preimplantation genetic diagnosis assist patients with a poor prognosis to achieve pregnancy?. Hum. Reprod.. 1997;12:1762-1767
  • Goodman et al., 2008 C. Goodman, R.S. Jeyendran, C.B. Coulam. Vascular endothelial growth factor gene polymorphism and implantation failure. Reprod. Biomed. Online. 2008;16:720-723
  • Goodman et al., 2009 C. Goodman, R.S. Jeyendran, C.B. Coulam. P53 tumor suppressor factor, plasminogen activator inhibitor, and vascular endothelial growth factor gene polymorphisms and recurrent implantation failure. Fertil. Steril.. 2009;92:494-498
  • Guan-Gui et al., 2011 L. Guan-Gui, L. Peiyan, M. Meilan, W. Lijuan, Y. Biao, Z. Yong, C. Jing, W. Tonghua. Immunohistochemical evidence for increased numbers of CD57+ cells in the endometrium of women suffering repeated implantation failure after IVF-ET. J. Reprod. Immunol.. 2011;90:178
  • Guzick et al., 1986 D.S. Guzick, C. Wilkes, H.W. Jones. Cumulative pregnancy rates for in vitro fertilization. Fertil. Steril.. 1986;46:663-667
  • Hapangama et al., 2008 D.K. Hapangama, M.A. Turner, J.A. Drury, C. Martin-Ruiz, T. von Zglinicki, R.G. Farquharson, S. Quenby. Endometrial telomerase shows specific expression patterns in different types of reproductive failure. Reprod. Biomed. Online. 2008;17:416-424
  • Hiraoka et al., 2008 K. Hiraoka, M. Fuchiwaki, K. Hiraoka, T. Horiuchi, T. Murakami, M. Kinutani, K. Kinutani. Effect of the size of zona pellucida opening by laser assisted hatching on clinical outcome of frozen cleaved embryos that were cultured to blastocyst after thawing in women with multiple implantation failures of embryo transfer: a retrospective study. J. Assist. Reprod. Genet.. 2008;25:129-135
  • Huang et al., 1999 C.C. Huang, T.C. Cheng, H.H. Chang, C.C. Chang, C.I. Chen, J. Liu, M.S. Lee. Birth after the injection of sperm and the cytoplasm of tripronucleate zygotes into metaphase II oocytes in patients with repeated implantation failure after assisted fertilization procedures. Fertil. Steril.. 1999;72:702-706
  • Huang et al., 2011 S.Y. Huang, C.J. Wang, Y.K. Soong, H.S. Wang, M.L. Wang, C.Y. Lin, C.L. Chang. Site-specific endometrial injury improves implantation and pregnancy in patients with repeated implantation failures. Reprod. Biol. Endocrinol.. 2011;9:140
  • Inagaki et al., 2003 N. Inagaki, C. Stern, J. McBain, A. Lopata, L. Kornman, D. Wilkinson. Analysis of intra-uterine cytokine concentration and matrix-metalloproteinase activity in women with recurrent failed embryo transfer. Hum. Reprod.. 2003;18:608-615
  • Ivanov et al., 2012 P. Ivanov, E. Konova, N. Ajvazova, T. Tsvyatkovska, M. Geogieva, K. Kovacheva, R. Roussev, R. Komsa-Penkova, M. Simeonova. Prothrormbin gene mutation 20210 G>A and IVF implantation failure. Am. J. Reprod. Immunol.. 2012;67:19
  • Jee et al., 2009 B.C. Jee, C.S. Suh, K.C. Kim, W.D. Lee, H. Kim, S.H. Kim. Expression of vascular endothelial growth factor-A and its receptor-1 in a luteal endometrium in patients with repeated in vitro fertilization failure. Fertil. Steril.. 2009;91:528-534
  • Johnson et al., 2004 N. Johnson, W. Mak, M. Sowter. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst. Rev.. 2004;:CD002125
  • Johnston-Macananny et al., 2010 E.B. Johnston-Macananny, J. Hartnett, L.L. Engmann, J.C. Nulsen, M.M. Sanders, C.A. Benadiva. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization. Fertil. Steril.. 2010;93:437-441
  • Kahraman et al., 2000 S. Kahraman, M. Bahce, H. Samli, N. Imirzalioglu, K. Yakisn, G. Cengiz, E. Donmez. Healthy births and ongoing pregnancies obtained by preimplantation genetic diagnosis in patients with advanced maternal age and recurrent implantation failure. Hum. Reprod.. 2000;15:2003-2007
  • Kahraman et al., 2004 S. Kahraman, M. Benkhalifa, E. Donmez, A. Biricik, S. Sertyel, N. Findikli, H. Berkil. The results of aneuploidy screening in 276 couples undergoing assisted reproductive techniques. Prenat. Diagn.. 2004;24:307-311
  • Kalu et al., 2008 E. Kalu, S. Bhaskaran, M.Y. Thum, R. Vishwanatha, C. Croucher, E. Sherriff, B. Ford, A.S. Bansal. Serial estimation of Th1:Th2 cytokines profile in women undergoing in-vitro fertilization-embryo transfer. Am. J. Reprod. Immunol.. 2008;59:206-211
  • Karimzadeh et al., 2009 M.A. Karimzadeh, M. Ayazi Rozbahani, N. Tabibnejad. Endometrial local injury improves the pregnancy rate among recurrent implantation failure patients undergoing in vitro fertilisation/intra cytoplasmic sperm injection: a randomised clinical trial. Aust. N. Z. J. Obstet. Gynaecol.. 2009;49:677-680
  • Kim et al., 2011 C.H. Kim, R.M. You, H.Y. Nah, H.J. Kang, S. Kim, H.D. Chae, B.M. Kang. Effect of granulocyte colony-stimulating factor on pregnancy outcome following IVF/ICSI in patients with repeated implantation failure. Hum. Reprod.. 2011;26:i244
  • Kling et al., 2008a C. Kling, A. Schmutzler, G. Wilke, J. Hedderich, D. Kabelitz. IVF prognosis after recurrent implantation failure: experience of German centers. Geburtshilfe Frauenheilkd.. 2008;68:505-511
  • Kling et al., 2008b C. Kling, A. Schmutzler, G. Wilke, J. Hedderich, D. Kabelitz. Two-year outcome after recurrent implantation failure: prognostic factors and additional interventions. Arch. Gynecol. Obstet.. 2008;278:135-142
  • Koler et al., 2009 M. Koler, H. Achache, A. Tsafrir, Y. Smith, A. Revel, R. Reich. Disrupted gene pattern in patients with repeated in vitro fertilization (IVF) failure. Hum. Reprod.. 2009;24:2541-2548
  • Koscinski et al., 2006 I. Koscinski, S. Viville, N. Porchet, A. Bernigaud, F. Escande, A. Defossez, M.P. Buisine. MUC4 gene polymorphism and expression in women with implantation failure. Hum. Reprod.. 2006;21:2238-2245
  • Kremenska et al., 2010 Y. Kremenska, Y. Masliy, Y. Goncharova, M. Kremenskoy, V. Veselovskyy, V. Zukin, I. Sudoma. Cytokines and hormone receptors gene expression in peripheral blood mononuclear cells of women with multiple implantation failures in ART cycles. Hum. Reprod.. 2010;25:i219-i220
  • Kwak-Kim et al., 2003 J.Y.H. Kwak-Kim, H.S. Chung-Bang, S.C. Ng, E.I. Ntrivalas, C.P. Mangubat, K.D. Beaman, A.E. Beer, A. Gilman-Sachs. Increased T helper 1 cytokine responses by circulating T cells are present in women with recurrent pregnancy losses and in infertile women with multiple implantation failures after IVF. Hum. Reprod.. 2003;18:767-773
  • Ledee et al., 2008 N. Ledee, G. Chaouat, V. Serazin, R. Lombroso, S. Dubanchet, P. Oger, N. Louafi, Y. Ville. Endometrial vascularity by three-dimensional power Doppler ultrasound and cytokines: a complementary approach to assess uterine receptivity. J. Reprod. Immunol.. 2008;77:57-62
  • Ledee-Bataille et al., 2004a N. Ledee-Bataille, S. Dubanchet, A. Coulomb-L’hermine, I. Durand-Gasselin, R. Frydman, G. Chaouat. A new role for natural killer cells, interleukin (IL)-12, and IL-18 in repeated implantation failure after in vitro fertilization. Fertil. Steril.. 2004;81:59-65
  • Ledee-Bataille et al., 2004b N. Ledee-Bataille, S. Dubanchet, J. Kadoch, A. Castelo-Branco, R. Frydman, G. Chaouat. Controlled natural in vitro fertilization may be an alternative for patients with repeated unexplained implantation failure and a high uterine natural killer cell count. Fertil. Steril.. 2004;82:234-236
  • Ledee-Bataille et al., 2005 N. Ledee-Bataille, K. Bonnet-Chea, G. Hosny, S. Dubanchet, R. Frydman, G. Chaouat. Role of the endometrial tripod interleukin-18, -15, and -12 in inadequate uterine receptivity in patients with a history of repeated in vitro fertilization-embryo transfer failure. Fertil. Steril.. 2005;83:598-605
  • Levran et al., 2002 D. Levran, J. Farhi, H. Nahum, M. Royburt, M. Glezerman, A. Weissman. Prospective evaluation of blastocyst stage transfer vs. zygote intrafallopian tube transfer in patients with repeated implantation failure. Fertil. Steril.. 2002;77:971-977
  • Li, 2012 T. Li. Recurrent implantation failure. Hum. Fertil.. 2012;15:2
  • Lodigiani et al., 2011 C. Lodigiani, P. di Micco, P. Ferrazzi, L. Libre, V. Arfuso, F. Polatti, B. Michela, R. Rossini, E. Morenghi, L. Rota, B. Brenner, E.L.S. Paolo. Low-molecular-weight heparin in women with repeated implantation failure. Women’s Health. 2011;7:425-431
  • Loutradis et al., 2004 D. Loutradis, P. Drakakis, K. Dallianidis, S.R. Bletsa, S. Milingos, N. Doumplis, N. Sofikitis, A. Asteriou-Dionyssiou, L. Michalas, S. Michalas. A double embryo transfer on days 2 and 4 or 5 improves pregnancy outcome in patients with good embryos but repeated failures in IVF or ICSI. Clin. Exp. Obstet. Gynecol.. 2004;31:63-66
  • Mantzouratou et al., 2007 A. Mantzouratou, A. Mania, E. Fragouli, L. Xanthopoulou, S. Tashkandi, K. Fordham, D.M. Ranieri, A. Doshi, S. Nuttall, J.C. Harper, P. Serhal, J.D.A. Delhanty. Variable aneuploidy mechanisms in embryos from couples with poor reproductive histories undergoing preimplantation genetic screening. Hum. Reprod.. 2007;22:1844-1853
  • Margalioth et al., 2006 E.J. Margalioth, A. Ben-Chetrit, M. Gal, T. Eldar-Geva. Investigation and treatment of repeated implantation failure following IVF-ET. Hum. Reprod.. 2006;21:3036-3043
  • Maritnez-Zamora et al., 2011 M.A. Maritnez-Zamora, M. Creus, D. Tassies, J.C. Reverter, S. Civico, F. Carmona, J. Balasch. Reduced plasma fibrinolytic potential in patients with recurrent implantation failure after IVF and embryo transfer. Hum. Reprod.. 2011;26:510-516
  • Marshall et al., 1968 J.R. Marshall, C.B. Hammond, G.T. Ross, A. Jacobson, P. Rayford, W.D. Odell. Plasma and urinary chorionic gonadotropin during early human pregnancy. Obstet. Gynecol.. 1968;32:760-764
  • Martinuzzo et al., 2005 M. Martinuzzo, M.L. Iglesias Varela, Y. Adamczuk, G.J. Broze, R. Forastiero. Antiphospholipid antibodies and antibodies to tissue factor pathway inhibitor in women with implantation failures or early and late pregnancy losses [6]. J. Thromb. Haemost.. 2005;3:2587-2589
  • Matsubayashi et al., 2001 H. Matsubayashi, T. Arai, S.I. Izumi, T. Sugi, J.A. McIntyre, T. Makino. Anti-annexin V antibodies in patients with early pregnancy loss or implantation failures. Fertil. Steril.. 2001;76:694-699
  • Matsubayashi et al., 2007 H. Matsubayashi, T. Sugi, T. Arai, M. Shida, A. Kondo, T. Suzuki, S.I. Izumi, J.A. McIntyre. Antiphospholipid antibodies in serum and follicular fluid: is there a correlation with IVF implantation failure?. Hum. Reprod.. 2007;22:3043-3044
  • Matteo et al., 2007 M.G. Matteo, P. Greco, P. Rosenberg, A. Mestice, D. Baldini, T. Falagario, V. Martino, M. Santodirocco, F. Massenzio, L. Castellana, G. Specchia, A. Liso. Normal percentage of CD56bright natural killer cells in young patients with a history of repeated unexplained implantation failure after in vitro fertilization cycles. Fertil. Steril.. 2007;88:990-993
  • Nastri et al., 2012 C.O. Nastri, A. Gibreel, N. Raine-Fenning, A. Maheshwari, R.A. Ferriani, S. Bhattacharya, W.P. Martins. Endometrial injury in women undergoing assisted reproductive techniques. Cochrane Database Syst. Rev.. 2012;7:CD009517
  • Oliveira et al., 2011 J.B.A. Oliveira, M. Cavagna, C.G. Petersen, A.L. Mauri, F.C. Massaro, L.F.I. Silva, R.L.R. Baruffi, J.G. Franco Jr. Pregnancy outcomes in women with repeated implantation failures after intracytoplasmic morphologically selected sperm injection (IMSI). Reprod. Biol. Endocrinol.. 2011;9
  • Osmanagaoglu et al., 1999 K. Osmanagaoglu, H. Tournaye, M. Camus, M. Vandervorst, A. van Steirteghem, P. Devroey. Cumulative delivery rates after intracytoplasmic sperm injection: 5 year follow-up of 498 patients. Hum. Reprod.. 1999;14:2651-2655
  • Pagidas et al., 2008 K. Pagidas, Y. Ying, D. Keefe. Predictive value of preimplantation genetic diagnosis for aneuploidy screening in repeated IVF-ET cycles among women with recurrent implantation failure. J. Assist. Reprod. Genet.. 2008;25:103-106
  • Pantos et al., 2004 K. Pantos, G. Nikas, E. Makrakis, D. Stavrou, P. Karantzis, M. Grammatis. Clinical value of endometrial pinopodes detection in artificial donation cycles. Reprod. Biomed. Online. 2004;9:86-90
  • Pehlivan et al., 2003 T. Pehlivan, C. Rubio, L. Rodrigo, J. Romero, J. Remohi, C. Simon, A. Pellicer. Impact of preimplantation genetic diagnosis on IVF outcome in implantation failure patients. Reprod. Biomed. Online. 2003;6:232-237
  • Pelinck et al., 2010 M.J. Pelinck, A. Hoek, A.H. Simons, M.J. Heineman, J. Van Echten-Arends, E.G. Arts. Embryo quality and impact of specific embryo characteristics on ongoing implantation in unselected embryos derived from modified natural cycle in vitro fertilization. Fertil. Steril.. 2010;94:527-534
  • Penzias, 2012 A. Penzias. Recurrent IVF failure: other factors. Fertil. Steril.. 2012;97:1033-1038
  • Petersen et al., 2005 C.G. Petersen, A.L. Mauri, R.L. Baruffi, J.B.A. Oliveira, F.C. Massaro, K. Elder, J.G. Franco Jr. Implantation failures: success of assisted hatching with quarter-laser zona thinning. Reprod. Biomed. Online. 2005;10:224-229
  • Phillips, 2013 J.A. Phillips, W.P. Martins, C.O. Nastri, N.J. Raine-Fenning. Difficult embryo transfers or blood on catheter and assisted reproductive outcomes: a systematic review and meta-analysis. Eur. J. Obstet. Gynecol. Reprod. Biol.. 2013;168:121-128
  • Platteau et al., 2006 P. Platteau, C. Staessen, A. Michiels, A. van Steirteghem, I. Liebaers, P. Devroey. Which patients with recurrent implantation failure after IVF benefit from PGD for aneuploidy screening?. Reprod. Biomed. Online. 2006;12:334-339
  • Prakash et al., 2008 A. Prakash, E. Tuckerman, S. Laird, B. Ola, T.C. Li, W.L. Ledger. A preliminary study comparing the endometrial expression of inhibin, activin and follistatin in women with a history of implantation failure after IVF treatment and a control group. BJOG. 2008;115:532-536
  • Primi et al., 2004 M.P. Primi, A. Senn, M. Montag, H. van der Ven, J. Mandelbaum, A. Veiga, P. Barri, M. Germond. A European multicentre prospective randomized study to assess the use of assisted hatching with a diode laser and the benefit of an immunosuppressive/antibiotic treatment in different patient populations. Hum. Reprod.. 2004;19:2325-2333
  • Qublan et al., 2006 H.S. Qublan, S.S. Eid, H.A. Ababneh, Z.O. Amarin, A.Z. Smadi, F.F. Al-Khafaji, Y.S. Khader. Acquired and inherited thrombophilia: implication in recurrent IVF and embryo transfer failure. Hum. Reprod.. 2006;21:2694-2698
  • Quenby et al., 2007 S. Quenby, M. Anim-Somuah, C. Kalumbi, R. Farquharson, J.D. Aplin. Different types of recurrent miscarriage are associated with varying patterns of adhesion molecule expression in endometrium. Reprod. Biomed. Online. 2007;14:224-234
  • Quenby et al., 2009 S. Quenby, H. Nik, B. Innes, G. Lash, M. Turner, J. Drury, J. Bulmer. Uterine natural killer cells and angiogenesis in recurrent reproductive failure. Hum. Reprod.. 2009;24:45-54
  • Rajaei et al., 2011 S. Rajaei, A. Zarnani, M. Jeddi-Tehrani, M. Tavakoli, A. Mohammadzadeh, A. Dabbagh, M. Mirahmadian. Cytokine profile in the endometrium of normal fertile and women with repeated implantation failure. Iran. J. Immunol.. 2011;8:201-208
  • Raziel et al., 2002 A. Raziel, S. Friedler, M. Schachter, E. Kasterstein, D. Strassburger, R. Ron-El. Increased frequency of female partner chromosomal abnormalities in patients with high-order implantation failure after in vitro fertilization. Fertil. Steril.. 2002;78:515-519
  • Raziel et al., 2007 A. Raziel, M. Schachter, D. Strassburger, O. Bern, R. Ron-El, S. Friedler. Favorable influence of local injury to the endometrium in intracytoplasmic sperm injection patients with high-order implantation failure. Fertil. Steril.. 2007;87:198-201
  • Rinehart, 2007 J. Rinehart. Recurrent implantation failure: definition. J. Assist. Reprod. Genet.. 2007;24:284-287
  • Roberts and Stylianou, 2012 S.A. Roberts, C. Stylianou. The non-independence of treatment outcomes from repeat IVF cycles: estimates and consequences. Hum. Reprod.. 2012;27:436-443
  • Roberts et al., 2010 S.A. Roberts, W.M. Hirst, D.R. Brison, A. Vail. Embryo and uterine influences on IVF outcomes: an analysis of a UK multi-centre cohort. Hum. Reprod.. 2010;25:2792-2802
  • Roberts et al., 2011 S.A. Roberts, L. McGowan, W. Mark Hirst, A. Vail, A. Rutherford, B.A. Lieberman, D.R. Brison. Reducing the incidence of twins from IVF treatments: predictive modelling from a retrospective cohort. Hum. Reprod.. 2011;26:569-575
  • Roest et al., 1998 J. Roest, A.M. van Heusden, G.H. Zeilmaker, A. Verhoeff. Cumulative pregnancy rates and selective drop-out of patients in in-vitro fertilization treatment. Hum. Reprod.. 1998;13:339-341
  • Rubio et al., 2001 C. Rubio, M. Gil-Salom, C. Simon, F. Vidal, L. Rodrigo, Y. Minguez, J. Remohi, A. Pellicer. Incidence of sperm chromosomal abnormalities in a risk population: relationship with sperm quality and ICSI outcome. Hum. Reprod.. 2001;16:2084-2092
  • Rufas-Sapir et al., 2004 O. Rufas-Sapir, A. Stein, R. Orvieto, O.M. Avrech, N. Kotler, H. Pinkas, J. Bar, B. Fisch. Is assisted hatching beneficial in patients with recurrent implantation failures?. Clin. Exp. Obstet. Gynecol.. 2004;31:110-112
  • Russell et al., 2011 P. Russell, L. Anderson, D. Lieberman, K. Tremellen, H. Yilmaz, B. Cheerala, G. Sacks. The distribution of immune cells and macrophages in the endometrium of women with recurrent reproductive failure. I: techniques. J. Reprod. Immunol.. 2011;91:90-102
  • Sacks et al., 2012 G. Sacks, Y. Yang, E. Gowen, S. Smith, L. Fay, M. Chapman. Detailed analysis of peripheral blood natural killer cells in women with repeated IVF failure. Am. J. Reprod. Immunol.. 2012;67:434-442
  • Sallam et al., 2006 H. Sallam, J. Garcia-Velasco, S. Dias, A. Arici. Long-term pituitary down-regulation before in vitro fertilization (IVF) for women with endometriosis. Cochrane Database Syst. Rev.. 2006;:CD004635
  • Sauer et al., 2010 R. Sauer, R. Roussev, R.S. Jeyendran, C.B. Coulam. Prevalence of antiphospholipid antibodies among women experiencing unexplained infertility and recurrent implantation failure. Fertil. Steril.. 2010;93:2441-2443
  • Scarpellini and Sbracia, 2012 F. Scarpellini, M. Sbracia. G-CSF treatment improves IVF outcome in women with recurrent implantation failure in IVF. Am. J. Reprod. Immunol.. 2012;67:123-124
  • Schoolcraft et al., 2010 W.B. Schoolcraft, N.R. Treff, K. Ferry, J.M. Stevens, M.G. Katz-Jaffe, R.T. Scott. First clinical application of SNP microarray based 24 chromosome aneuploidy screening of human blastocysts. Fertil. Steril.. 2010;94:S23-S24
  • Schroder et al., 2004 A.K. Schroder, A. Katalinic, K. Diedrich, M. Ludwig. Cumulative pregnancy rates and drop-out rates in a German IVF programme: 4102 cycles in 2130 patients. Reprod. Biomed. Online. 2004;8:600-606
  • Sermondade et al., 2012 N. Sermondade, V. Delarouziere, C. Ravel, I. Berthaut, L. Verstraete, E. Mathieu, J.M. Antoine, J. Mandelbaum. Characterization of a recurrent poor-quality embryo morphology phenotype and zygote transfer as a rescue strategy. Reprod. Biomed. Online. 2012;24:403-409
  • Shapiro et al., 2001 B.S. Shapiro, K.S. Richter, D.C. Harris, S.T. Daneshmand. Dramatic declines in implantation and pregnancy rates in patients who undergo repeated cycles of in vitro fertilization with blastocyst transfer after one or more failed attempts. Fertil. Steril.. 2001;76:538-542
  • Sharif and Ghunaim, 2010 K.W. Sharif, S. Ghunaim. Management of 273 cases of recurrent implantation failure: results of a combined evidence-based protocol. Reprod. Biomed. Online. 2010;21:373-380
  • Sharma et al., 2002 V. Sharma, V. Allgar, M. Rajkhowa. Factors influencing the cumulative conception rate and discontinuation of in vitro fertilization treatment for infertility. Fertil. Steril.. 2002;78:40-46
  • Short, 1979 R. Short. When a conception fails to become a pregnancy. W. Julie (Ed.) Maternal Recognition of Pregnancy (Excerpta Medica, Amsterdam, 1979)
  • Shreeve and Sadek, 2012 N. Shreeve, K. Sadek. Intralipid therapy for recurrent implantation failure: new hope or false dawn?. J. Reprod. Immunol.. 2012;93:38-40
  • Silberstein et al., 2005 T. Silberstein, J.R. Trimarchi, L. Gonzalez, D.L. Keefe, A.S. Blazar. Pregnancy outcome in in vitro fertilization decreases to a plateau with repeated cycles. Fertil. Steril.. 2005;84:1043-1045
  • Simon et al., 1993 A. Simon, C. Ronit, A. Lewin, N. Mordel, G. Zajicek, N. Laufer. Conception rate after in vitro fertilization in patients who conceived in a previous cycle. Fertil. Steril.. 1993;59:343-347
  • Simur et al., 2009 A. Simur, S. Ozdemir, H. Acar, M.C. Colakoglu, H. Gorkemli, O. Balci, S. Nergis. Repeated in vitro fertilization failure and its relation with thrombophilia. Gynecol. Obstet. Invest.. 2009;67:109-112
  • Spandorfer et al., 2002 S.D. Spandorfer, L.I. Barmat, J. Navarro, H.C. Liu, L. Veeck, Z. Rosenwaks. Importance of the biopsy date in autologous endometrial cocultures for patients with multiple implantation failures. Fertil. Steril.. 2002;77:1209-1213
  • Stein et al., 1995 A. Stein, O. Rufas, S. Amit, O. Avrech, H. Pinkas, J. Ovadia, B. Fisch. Assisted hatching by partial zona dissection of human pre-embryos in patients with recurrent implantation failure after in vitro fertilization. Fertil. Steril.. 1995;63:838-841
  • Stephenson and Fluker, 2000 M. Stephenson, M. Fluker. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial. Fertil. Steril.. 2000;74:1108-1113
  • Stevens, 1997 V. Stevens. Some reproductive studies in the baboon. Hum. Reprod. Update. 1997;3:533-540
  • Sudoma et al., 2011 I. Sudoma, Y. Goncharova, V. Zukin. Optimization of cryocycles by using pinopode detection in patients with multiple implantation failure: preliminary report. Reprod. Biomed. Online. 2011;22:590-596
  • Takahashi et al., 2011 K. Takahashi, M. Nagaba, T. Mukaida. Long-term hypo-estrogenic treatment might enhance implantation in those who have failed to conceive after multiple embryo transfers. Hum. Reprod.. 2011;26:i353
  • Tan et al., 2005 B.K. Tan, P. Vandekerckhove, R. Kennedy, S.D. Keay. Investigation and current management of recurrent IVF treatment failure in the UK. BJOG. 2005;112:773-780
  • Taranissi et al., 2005 M. Taranissi, T. El-Toukhy, Y. Verlinsky. Influence of maternal age on the outcome of PGD for aneuploidy screening in patients with recurrent implantation failure. Reprod. Biomed. Online. 2005;10:628-632
  • Teklenburg et al., 2010 G. Teklenburg, M. Salker, C. Heijnen, N. Macklon, J. Brosens. The molecular basis of recurrent pregnancy loss: impaired natural embryo selection. Mol. Hum. Reprod.. 2010;16:886-895
  • Thum et al., 2008 M.Y. Thum, S. Bhaskaran, H.I. Abdalla, B. Ford, N. Sumar, A. Bansal. Prednisolone suppresses NK cell cytotoxicity in vitro in women with a history of infertility and elevated NK cell cytotoxicity. Am. J. Reprod. Immunol.. 2008;59:259-265
  • Tiboni et al., 2011 G. Tiboni, F. Giampietro, E. Gabriele, V. di Donato, G. Impicciatore. Impact of a single endometrial injury on assisted reproductive technology outcome; a preliminary observational study. J. Reprod. Med.. 2011;56:504-506
  • Tremellen and Russell, 2011 K. Tremellen, P. Russell. Adenomyosis is a potential cause of recurrent implantation failure during IVF treatment. Aust. N. Z. J. Obstet. Gynaecol.. 2011;51:280-283
  • Tsoumpou et al., 2010 I. Tsoumpou, A.M.F. Mohamed, S. Roberts, A. Baker, C. Tower, L.G. Nardo. Repeated implantation failure and fetal growth restriction in patients undergoing IVF: a retrospective cohort study. Arch. Dis. Child. Fetal Neonatal Ed.. 2010;95:Fa93
  • Tuckerman et al., 2010 E. Tuckerman, N. Mariee, A. Prakash, T.C. Li, S. Laird. Uterine natural killer cells in peri-implantation endometrium from women with repeated implantation failure after IVF. J. Reprod. Immunol.. 2010;87:60-66
  • Urman et al., 2009 B. Urman, B. Ata, K. Yakin, C. Alatas, S. Aksoy, R. Mercan, B. Balaban. Luteal phase empirical low molecular weight heparin administration in patients with failed ICSI embryo transfer cycles: a randomized open-labelled pilot trial. Hum. Reprod.. 2009;24:1640-1647
  • Valojerdi et al., 2008 M.R. Valojerdi, P. Eftekhari-Yazdi, L. Karimian, S.K. Ashtiani. Effect of laser zona pellucida opening on clinical outcome of assisted reproduction technology in patients with advanced female age, recurrent implantation failure, or frozen-thawed embryos. Fertil. Steril.. 2008;90:84-91
  • van den Heuvel et al., 2007 M.J. van den Heuvel, C.G. Peralta, K. Hatta, V.K. Han, D.A. Clark. Decline in number of elevated blood CD3(+) CD56(+) NKT cells in response to intravenous immunoglobulin treatment correlates with successful pregnancy. Am. J. Reprod. Immunol.. 2007;58:447-459
  • Vaquero et al., 2006 E. Vaquero, N. Lazzarin, D. Caserta, H. Valensise, M. Baldi, M. Moscarini, D. Arduini. Diagnostic evaluation of women experiencing repeated in vitro fertilization failure. Eur. J. Obstet. Gynecol. Reprod. Biol.. 2006;125:79-84
  • Varla-Leftherioti et al., 2007 M. Varla-Leftherioti, T. Keramitsoglou, M. Spyropoulou-Vlachou, M. Papadimitropoulos, V. Kontopoulou-Antonopoulou, C. Tsekoura, U. Sankarkumar, N. Paparistidis, K. Ghosh, A. Pawar, V. Vrani, M. Daniilidis, E. Parapanissiou, A.S. Diler, M. Carin, C. Stavropoulos-Giokas. 14th International HLA and Immunogenetics Workshop: report from the reproductive immunology component. Tissue Antigens. 2007;69:297-303
  • Vialard et al., 2007 F. Vialard, R. Lombroso, M. Bergere, D.M. Gomes, I. Hammoud, M. Bailly, J. Selva. Oocyte aneuploidy mechanisms are different in two situations of increased chromosomal risk: older patients and patients with recurrent implantation failure after in vitro fertilization. Fertil. Steril.. 2007;87:1333-1339
  • Vialard et al., 2008 F. Vialard, D.M. Gomes, I. Hammoud, M. Bergere, R. Wainer, M. Bailly, R. Lombroso, J. Selva. Stability of aneuploidy rate in polar bodies in two cohorts from the same patient. Reprod. Biomed. Online. 2008;17:213-219
  • Voullaire et al., 2002 L. Voullaire, L. Wilton, J. McBain, T. Callaghan, R. Williamson. Chromosome abnormalities identified by comparative genomic hybridization in embryos from women with repeated implantation failure. Mol. Hum. Reprod.. 2002;8:1035-1041
  • Voullaire et al., 2007 L. Voullaire, V. Collins, T. Callaghan, J. McBain, R. Williamson, L. Wilton. High incidence of complex chromosome abnormality in cleavage embryos from patients with repeated implantation failure. Fertil. Steril.. 2007;87:1053-1058
  • Weissman et al., 2007 A. Weissman, I. Eldar, A. Ravhon, G. Biran, J. Farhi, H. Nahum, A. Golan, D. Levran. Timing intra-Fallopian transfer procedures. Reprod. Biomed. Online. 2007;15:445-450
  • Wilton et al., 2003 L. Wilton, L. Voullaire, P. Sargeant, R. Williamson, J. McBain. Preimplantation aneuploidy screening using comparative genomic hybridization or fluorescence in situ hybridization of embryos from patients with recurrent implantation failure. Fertil. Steril.. 2003;80:860-868
  • Woodward et al., 1993 B.J. Woodward, E.A. Lenton, K. Turner. Human chorionic gonadotropin: embryonic secretion is a time dependent phenomenon. Hum. Reprod.. 1993;8:1463-1468
  • Yakin et al., 2008 K. Yakin, B. Ata, N. Ercelen, B. Balaban, B. Urman. The effect of preimplantation genetic screening on the probability of live birth in young women with recurrent implantation failure; a nonrandomized parallel group trial. Eur. J. Obstet. Gynecol. Reprod. Biol.. 2008;140:224-229
  • Yang et al., 2010 K.M. Yang, E. Ntrivalas, H.J. Cho, N.Y. Kim, K. Beaman, A. Gilman-Sachs, J. Kwak-Kim. Women with multiple implantation failures and recurrent pregnancy losses have increased peripheral blood T cell activation. Am. J. Reprod. Immunol.. 2010;63:370-378
  • Zander-Fox et al., 2011 D.L. Zander-Fox, K. Tremellen, M. Lane. Single blastocyst embryo transfer maintains comparable pregnancy rates to double cleavage-stage embryo transfer but results in healthier pregnancy outcomes. Aust. N. Z. J. Obstet. Gynaecol.. 2011;51:406-410

Footnotes

a Nurture Fertility, Division of Obstetrics and Gynaecology, School of Clinical Sciences, University of Nottingham, United Kingdom

b University of Warwick, Coventry, United Kingdom

lowast Corresponding author.

fx1 Lukasz Polanski obtained his medical degree in 2007 from the Medical University of Lublin, Poland. He completed his foundation training in the East of England Deanery, UK, where he also commenced his core obstetrics and gynaecology specialty training. Currently, he is undertaking a PhD at the University of Nottingham. His interests lie in recurrent reproductive failure and early pregnancy development.