You are here
Recurrent implantation failure: definition and management
Reproductive BioMedicine Online, Volume 28, Issue 1 , Pages 14-38, January 2014
Recurrent implantation failure refers to failure to achieve a clinical pregnancy after transfer of at least four good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years. The failure to implant may be a consequence of embryo or uterine factors. Thorough investigations should be carried out to ascertain whether there is any underlying cause of the condition. Ovarian function should be assessed by measurement of antral follicle count, FSH and anti-Müllerian hormone. Increased sperm DNA fragmentation may be a contributory cause. Various uterine pathology including fibroids, endometrial polyps, congenital anomalies and intrauterine adhesions should be excluded by ultrasonography and hysteroscopy. Hydrosalpinges are a recognized cause of implantation failure and should be excluded by hysterosalpingogram; if necessary, laparoscopy should be performed to confirm or refute the diagnosis. Treatment offered should be evidence based, aimed at improving embryo quality or endometrial receptivity. Gamete donation or surrogacy may be necessary if there is no realistic chance of success with further IVF attempts.
Recurrent implantation failure is an important cause of repeated IVF failure. It is estimated that approximately 10% of women seeking IVF treatment will experience this particular problem. It is a distressing condition for patients and frustrating for clinicians and scientists. In this review, we have discussed the definition and management of the possible underlying causes of recurrent implantation failure.
Keywords: failure, implantation, IVF, fibroids, hysterosalpingogram, embryo.
Implantation is a process whereby the embryo attaches itself to the luminal surface of the endometrium followed by migration via the luminal epithelium and invasion into the deep layer of the endometrium to become embedded into the deeper layer ( Figure 1 ). Traditionally, implantation has been considered as a process involving only the embryo and the endometrium, but recent studies show that cumulus cell competency may also contribute to the process ( Benkhalifa et al., 2012 ). While implantation is a process with a well-defined starting point, it is a gradual process which lasts for several weeks with no universal agreement on when the process is completed.
In clinical practice, implantation is often considered to be successful when there is ultrasonographic evidence of an intrauterine gestational sac. Conversely, implantation failure is considered to have occurred if there is a lack of ultrasonographic evidence of an intrauterine gestational sac. Implantation failure may occur very early on during the attachment or migration stages, with the result that there is no objective evidence of a pregnancy, i.e. negative urine or blood pregnancy test (human chorionic gonadotrophin, HCG). It may also occur later on, following successful migration of the embryo through the luminal surface of the endometrium, when HCG produced by the embryo may be detected in the blood or urine, but the process becomes disrupted prior to the formation of an intrauterine gestational sac. In this situation, it is clinically referred to as a biochemical pregnancy. In assisted conception treatment, implantation is considered to be successful when an embryo has produced an intrauterine gestational sac, detectable by ultrasonography, usually about 3 weeks after oocyte retrieval or about 5 weeks of gestation.
The implantation rate is defined as the number of embryos which have produced ultrasonographic evidence of an intrauterine gestational sac per the total number of embryos transferred into the uterine cavity ( Zegers-Hochschild et al., 2009 ). In IVF–embryo transfer cycles, the implantation rate when day-2 or -3 embryos are transferred is about 25%, but the implantation rate when day-5 or -6 embryos are transferred is usually higher, about 40%.
Implantation failure refers to the failure of the embryo to reach a stage when an intrauterine gestational sac is recognized by ultrasonography. From the clinical point of view, it is worthy to note that the term ‘implantation failure’ refers to two different types of situation, those in whom there has never been evidence of implantation (no detectable HCG production) and those who have evidence of implantation (detectable HCG production) but it did not proceed to beyond the formation of a gestational sac visible on ultrasonography. Implantation failure may be a consequence of embryo or endometrial factors.
Definition of recurrent implantation failure
Recurrent implantation failure (RIF) is a clinical entity which refers to a situation when implantation has repeatedly failed to reach a stage recognizable by pelvic ultrasonography. There is as yet no universally accepted definition for RIF, despite many publications on this topic (Das and Holzer, 2012, Laufer and Simon, 2012, Penzias, 2012, Simon and Laufer, 2012a, Simon and Laufer, 2012b, and Urman et al, 2005).
Because the probability for an embryo to successfully implant is only approximately 30%, the probability of it failing to implant is approximately 70%. However, following transfer of two embryos, the probability of both embryos failing to implant is 0.702 = 0.49. Following the replacement of 3, 4, 5 or 6 embryos, the probabilities of all embryos failing to implant becomes 0.703 = 0.34, 0.704 = 0.24, 0.705 = 0.17 and 0.706 = 0.12, respectively. In a clinical setting, one has to decide when it becomes unusual for all transferred embryos to fail to implant. And then ask the question: why do all transferred embryos not implant?
One important variable is clearly the quality of the embryo. If the quality of the embryo is poor, and assuming that the probability of successful implantation is reduced only to 0.10, following the transfer of 2, 3, 4, 5, 6 and 7 embryos, the probabilities of all embryos failing to implant is 0.81, 0.73, 0.66, 0.59, 0.53 and 0.48, respectively. In other words, there is still a 48% chance that all seven embryos will fail to implant. Hence, in arriving at a clinically useful definition, some investigators specified that good-quality embryos had been transferred ( Margalioth et al., 2006 ). A good-quality embryo was defined as having the correct number of cells corresponding to the day of its development and day-5 embryos (blastocysts) were graded according to expansion and quality of the inner cell mass and trophoectoderm Cutting et al. (2008) . Other criteria included blastomeres of equal size and regular in distribution, even distribution of cytoplasm without granularity and less than 10% fragmentation ( Cutting et al., 2008 ).
As well as the definition of a good-quality embryo, one needs to consider the current methods of embryo assessment, which are by no means perfect ( Racowsky et al., 2000 ).
Some previous investigators proposed that RIF should be referred to as failure to achieve a clinical pregnancy after a total of 10 or more embryos had been transferred to the uterus ( Stern et al., 2003 ). This might have been appropriate when the implantation rate was rather lower than what most IVF centres can now achieve, partly because the culture environments and the quality of culture media used are now improved. Moreover, the increasing use of blastocyst transfer has further improved implantation rates to approximately 40%. In this situation, the likelihoods of all 2, 3 or 4 embryos failing to implant (for 1 embryo being 0.60) is 0.36, 0.22 and 0.13, respectively. It seems appropriate, given the improved implantation rate achieved nowadays, to base the definition on the transfer of 4 or more embryos.
Stage of development
The implantation potential of a blastocyst is well recognized to be greater than that of the day-2 or -3 embryo, mainly because of natural selection of better quality embryos for further development.
Some investigators believed that frozen embryo transfer cycles be excluded from the definition of RIF ( Tan et al., 2005 ), almost certainly based on earlier data that the implantation rate of frozen–thawed embryos was inferior to that of fresh embryos. However, there is good evidence that the implantation rate of frozen–thawed embryos is similar to that of fresh embryos (Horne et al, 1997 and Lieberman et al, 1992). Hence, the number of embryos transferred should include both fresh and frozen cycles in considering the diagnosis of RIF.
It is a matter of debate whether the diagnosis of RIF be based entirely on the number of embryos transferred or on the number of embryo transfer cycles. Many investigators prefer to base it on the failure to achieve a clinical pregnancy after three transfer cycles (Margalioth et al, 2006 and Tan et al, 2005), whereas others proposed to use the number of embryos transferred ( Stern et al., 2003 ). There are pros and cons of each approach. The definition based on the number of embryos transferred is more scientific and logical, but the definition based on the number of transfer cycles is more pragmatic and easily understood by patients. At the Royal Hallamshire Hospital, both factors are considered and a diagnosis of RIF is based on the transfer of at least 4 embryos in a minimum of three transfer cycles.
Distinction from recurrent IVF failure
RIF is not the same as recurrent IVF failure. The latter condition merely refers to the failure to achieve a pregnancy after several IVF attempts, a common cause being poor response to ovarian stimulation ( Ferraretti et al., 2011 ). Suboptimal embryo quality, advanced maternal age and uterine factors are also relatively common causes for recurrent IVF failure. The term ‘recurrent implantation failure’ is a subgroup of recurrent IVF failure and should not be used to replace the latter.
Based on the above considerations, this review proposes that RIF be defined as the failure to achieve a clinical pregnancy after transfer of at least 4 good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years. However, an internationally agreed consensus on the definition should be reached following further discussion, analogous to that of polycystic ovarian syndrome ( Rotterdam ESHRE/ASRM – Sponsored PCOS Consensus Workshop Group, 2004 ).
Causes of recurrent implantation failure
Based on the definition proposed above, RIF is primarily due to uterine factors. However, as discussed, given that current methods used to assess embryo quality are subjective and not always accurate, there will inevitably be a proportion of cases due to gamete or embryo factors.
Compromised oocyte quality as a cause of RIF is often suspected when there is a poor response to ovarian stimulation ( Ferraretti et al., 2011 ), with fewer numbers of oocytes retrieved, a high proportion of immature oocytes, a reduced fertilization rate and low embryo utilization rate. When the above features are associated with low antral follicle counts, high FSH and low anti-Müllerian hormone, it can be assumed that the underlying cause of RIF relates to poor oocyte quality. Age-related decline in oocyte quality is associated with increased chromosomal nondysjunction, resulting in aneuploid embryos, decrease in mitochondrial membrane potential and increase of mitochondrial DNA damage ( Wang et al., 2009 ). There is evidence to suggest that aggressive ovarian stimulation protocols may lead to the production of poor-quality oocytes and a higher rate of fertilization failure (Baart et al, 2007, Collins, 2009, and Verberg et al, 2009).
It is now recognized that not only the oocyte but the cumulus cells play an important role in the implantation process. The cumulus oophorus is a mass of granulosa cells associated with the oocyte from the antral follicle stage to fertilization and until early embryo development (Hernandez-Gonzalez et al, 2006, Motta et al, 1995a, Motta et al, 1995b, and Nottola et al, 1991). Cumulus cells are a source of prostaglandins and express angiogenic factors (vascular endothelial growth factor) that may play a role in angiogenesis at the implantation site. Cumulus cell gene expression appears to correlate with oocyte quality, embryo competence and pregnancy outcome ( Assou et al., 2010 ).
A recent prospective randomized trial showed that co-culture of embryos with cumulus cells produced improved implantation and pregnancy in women with repeated implantation failure compared with conventional culture without cumulus cells ( Benkhalifa et al., 2012 ).
Just as poor-quality oocytes produce poor-quality embryos, it is also possible that poor-quality spermatozoa may lead to the production of poor-quality embryos. It is widely accepted that conventional semen analysis parameters do not accurately reflect sperm quality. Genetic tests are more likely to be useful as genome and epigenome integrity is essential for fertilization, normal embryo development and successful implantation.
Several factors contribute to sperm DNA damage, including cigarette smoking, genital tract infection and previous chemotherapy or radiotherapy (Erenpreiss et al, 2002, Morris, 2002, and Potts et al, 1999).
Sperm DNA damage is associated with poor embryo development ( Fernandez-Gonzalez et al., 2008 ) and both animal and human studies have shown that it is associated with failure to achieve spontaneous ( Evenson and Wixon, 2008 ) and assisted conception (Bungum et al, 2007, Duran et al, 2002, and Muriel et al, 2006). A recent meta-analysis suggested that sperm DNA damage has a modest impact on pregnancy rates following IVF treatment ( Collins et al., 2008 ). Consequently, there is increasing recent interest in the use of sperm DNA integrity testing in the evaluation of reproductive failure. DNA fragmentation may be associated with an increased risk of miscarriage (Absalan et al, 2012 and Brahem et al, 2011) but its association with RIF has not yet been established.
Parental chromosomal anomalies
It is known that individuals with balanced translocations often produce gametes with chromosomal aberrations which may in turn result in various forms of reproductive failure, ranging from defective gametogenesis ( Crosignani and Rubin, 1982 ) to recurrent spontaneous miscarriage ( Campana et al., 1986 ). Stern et al. (1999) conducted a study to test the hypothesis that couples with a history of IVF failure, similar to those with recurrent miscarriage, have a higher than expected prevalence of translocations and found that couples with otherwise unexplained repeated IVF failures had a 2.5% chance of carrying a balanced chromosomal translocation, which was higher than that of the control population. A further study ( Raziel et al., 2002 ) identified a high frequency of chromosomal aberrations in a selected group of couples with high-order implantation failures and recommended karyotyping as part of the work up for repeated implantation failure in assisted reproduction. The genetics and epigenetics of reproductive failure including RIF is attracting increasing scientific interest and is worthy of a separate review.
Congenital uterine anomalies
Congenital uterine anomalies may affect endometrial receptivity manifesting as either infertility or recurrent pregnancy loss ( Taylor and Gomel, 2008 ). The majority of uterine anomalies occur as a result of a defect in the development or fusion of the paired Müllerian ducts during embryogenesis. It is now recognized that Hox genes play a role in the regulation of Müllerian duct development ( Du and Taylor, 2004 ). Nevertheless, a case–control study carried out in Thessaloniki found not one out of 30 women with Müllerian duct malformation had a plausible causative mutation in Hox A10 or Hox A11 genes ( Liatsikos et al., 2010 ). In addition to their role in the development of the Müllerian tract in the embryonic period, two particular HOX genes,Hoxa10andHoxa11, have been suggested as regulators of endometrial development in preparation for implantation (Daftary and Taylor, 2000 and Taylor, 2000).
The septate uterus is the most common structural uterine anomaly. It has long been recognized that uterine septae are associated with adverse reproductive outcomes such as first- and mid-trimester miscarriages but also possibly infertility (Fedele et al, 1993, Pabuccu and Gomel, 2004, and Raga et al, 1997). These poor outcomes are attributed not only to the disturbance of the uterine cavity but also to the inadequate blood supply to the septum ( Fedele et al., 1996 ). There is preliminary evidence that the septate uterus may also contribute to RIF. In a study involving women with a septate uterus undergoing IVF treatment, untreated septate uteri had a poor outcome following IVF treatment in comparison to women who had undergone hysteroscopic metroplasty prior to IVF ( Lavergne et al., 1996 ). Another study by Ban-Frangez et al. (2009) on the outcome of singleton pregnancy after IVF/intracytoplasmic sperm injection (ICSI) showed that the presence of a septum, whether large or small, was associated with a miscarriage rate of about 80%, which was reduced to 30% or so after surgical removal of the septum ( Ban-Frangez et al., 2009 ).
The same does not apply to bicornuate uteri, which rarely require surgical treatment. This is a relatively common anomaly and most women have no difficulty conceiving ( Grimbizis et al., 2001 ). The main risk for the woman with a bicornuate uterus is mid-trimester pregnancy loss and preterm birth ( Grimbizis et al., 2001 ).
Acquired intracavity conditions
A number of acquired intracavity uterine pathologies, including submucous fibroids, endometrial polyps and intrauterine adhesions, may contribute to RIF. The frequency of unrecognized intrauterine pathologies in patients with RIF varies between 25% and 50% ( Makrakis and Pantos, 2010 ).
There are several mechanisms by which fibroids can adversely affect implantation, including increased uterine contractility, deranged cytokine profile, abnormal vascularization and chronic endometrial inflammation (Buttram and Reiter, 1981, Donnez and Jadoul, 2002, Hunt and Wallach, 1974, and Taylor and Gomel, 2008).
There is evidence to suggest that submucosal and intramural fibroids that distort the endometrial cavity are associated with decreased pregnancy and implantation rates in women who attempt to conceive spontaneously or who are proceeding with IVF treatment (Bernard et al, 2000, Farhi et al, 1995, Narayan and Goswamy, 1994, and Varasteh et al, 1999). Several studies suggest that pregnancy rates improve following the resection of fibroids distorting the uterine cavity (Fernandez et al, 2001, Garcia and Tureck, 1984, Goldenberg et al, 1995, and Pritts et al, 2009). Pritts et al. (2009) conducted a systematic literature review and meta-analysis of existing controlled studies and concluded that women with submucosal fibroids have decreased clinical pregnancy and implantation rates compared with infertile control subjects ( Pritts et al., 2009 ). The authors concluded that removal of submucous myomas appeared to improve outcome ( Pritts et al., 2009 ). Since then, one further randomized controlled trial investigated the effect of hysteroscopic resection of submucous fibroids in women with unexplained primary infertility. This study revealed that hysteroscopic resection of submucous fibroids alone appeared to double cumulative clinical pregnancy rates ( Shokeir et al., 2010 ).
There is controversy as to whether or not non-cavity-distorting intramural fibroids adversely affect IVF outcome. Some studies suggest an adverse effect of non-cavity-distorting fibroids on implantation and pregnancy rates in women undergoing IVF, particularly with large fibroids >4 cm, whereas others fail to demonstrate such an association (Eldar-Geva et al, 1998, Gianaroli et al, 2005, Hart et al, 2001, Klatsky et al, 2007, Oliveira et al, 2004, Stovall et al, 1998, Surrey et al, 2001, Wang and Check, 2004, and Yarali and Bukulmez, 2002). There are three recent meta-analyses published on this particular subject (Metwally et al, 2011, Pritts et al, 2009, and Sunkara et al, 2010). All three analyses concur that women with intramural fibroids appear to have reduced implantation rates compared with women without intramural fibroids. However, myomectomy did not appear to significantly increase the clinical pregnancy and live birth rates ( Pritts et al., 2009 ) and the most recent meta-analysis cautioned that the available evidence is rather weak because of significant heterogeneity and methodological issues ( Metwally et al., 2011 ).
Endometrial polyps may also interfere with embryo implantation ( Richlin et al., 2002 ). The removal of endometrial polyps has been found to result in improved spontaneous pregnancy rates in three nonrandomized studies (Shokeir et al, 2004, Spiewankiewicz et al, 2003, and Varasteh et al, 1999). A more recent systematic review found that hysteroscopic removal of endometrial polyps resulted in doubling of the clinical pregnancy rate in women undergoing intrauterine insemination treatment ( Bosteels et al., 2010 ). It seems likely that endometrial polyps contribute to RIF.
The presence of adhesions within the uterine cavity may interfere with successful implantation at an early stage by preventing the embryos from attaching to the luminal surface of the endometrium. Intrauterine adhesions often occur following curettage of the gravid uterus to terminate an unwanted pregnancy or in cases of retained products of conception after a pregnancy or miscarriage. Intrauterine surgery or intrauterine infection of the nongravid uterus may also lead to the formation of intrauterine adhesions. Demirol and Gurgan (2004b) found that intrauterine adhesions occurred in 8.5% of women with RIF. The evidence available so far suggests that hysteroscopic removal of intrauterine adhesions improves fertility outcomes (Dawood et al, 2010, Katz et al, 1996, Pace et al, 2003, Yasmin et al, 2007, and Zikopoulos et al, 2004).
There is literature evidence available to suggest that adenomyosis has an adverse effect on female fertility (Maheshwari et al, 2012 and Sunkara and Khan, 2012). Transvaginal ultrasonography is useful for the detection of adenomyosis but is operator dependent. The prevalence of adenomyosis in women with RIF is likely to be underestimated as it may not always be detected by transvaginal ultrasonography. Magnetic resonance imaging provides superior soft tissue resolution and is probably the most accurate noninvasive diagnostic technique available (Ascher et al, 1994, Atzori et al, 1996, Bazot et al, 2002, Bromley et al, 2000, and Reinhold et al, 1996). The condition may appear in two forms, diffuse and focal, and the posterior uterine wall appears to be predominantly affected (Atzori et al, 1996, Bazot et al, 2002, Fedele et al, 1992, and Vercellini et al, 1998). Adenomyosis almost always affects the junctional zone of the uterus which is just beneath the endometrium and so may have a greater impact on implantation than intramural fibroids which are some distance away from the endometrium. Nevertheless, surgical intervention in the case of adenomyosis is technically more challenging than fibroids because there is no defined capsule, and the excision of adenomyosis often necessitates removal of part of the uterine wall.
Hydrosalpinx is a Greek word meaning a Fallopian tube filled with water or fluid ( Bloechle, 1999 ). It is now recognized that the live birth rate of patients with hydrosalpinges undergoing IVF is only one-half that of women who do not have hydrosalpinges (Camus et al, 1999, Strandell et al, 1999, and Zeyneloglu et al, 1998). Moreover, in a prospective, randomized multicentre trial in Scandinavia ( Strandell et al., 1999 ), it was shown that in women who had hydrosalpinges and were randomized to have no intervention prior to IVF, the pregnancy rate was 23.9%, miscarriage rate was 26.3% and live birth rate was only 16.3%; however, in women who were randomized to have salpingectomy prior to IVF, the corresponding results were 36.6%, 16.2% and 28.6%, respectively. The live birth rate was significantly (P < 0.05) higher than the no-treatment group. In a subgroup of women in whom the hydrosalpinges were visible by ultrasonography, the difference in results appeared more significant ( Strandell et al., 1999 ). There is, therefore, good evidence that salpingectomy prior to IVF in women with hydrosalpinges improves outcome.
The adverse impact of hydrosalpinges on implantation may be attributed to a direct embryotoxic effect, a mechanical effect whereby the accumulated fluid may flush the embryo out of the uterus, as well as a negative effect on endometrial receptivity. A study by Seli et al. (2005) showed that the expression of leukaemia inhibitory factor, a cytokine essential for successful implantation, was reduced in the presence of hydrosalpinges, but the expression was restored to normal after salpingectomy ( Seli et al., 2005 ). A further study showed that removal of hydrosalpinges may improve endometrial receptivity by restoring normal αvβ3 integrin expression ( Bildirici et al., 2001 ).
The molecular and immunological aspects of implantation failure is an interesting area and is worthy of a separate in-depth review (Koot et al, 2012 and Makrigiannakis et al, 2011). Of particular interest is the differentiation of endometrial stromal cells, a process called decidualization, which is considered critical for the establishment and maintenance of pregnancy. The decidualized stromal cells acquire the ability to regulate trophoblast invasion and to dampen local maternal immune responses (Blois et al, 2011 and Gellersen et al, 2007). There is much conflicting evidence in the literature on the value of various immunological investigations and treatments in women with RIF (Clark and Stricker, 2006 and Stephenson and Fluker, 2000). There is no consensus on whether or not immunological investigations are useful and whether immunological treatment is of benefit.
Many clinicians are attracted to the hypothesis that thrombophilic conditions contribute to the cause of RIF, mainly because antiphospholipid syndrome has been shown to be an important cause of recurrent pregnancy loss and that treatment of this condition with aspirin and heparin significantly improves the outcome. However, there is controversy regarding the association between antiphospholipid antibodies and IVF failure, with some studies describing a significant association (Birkenfeld et al, 1994, Coulam et al, 1997, Kaider et al, 1996, Qublan et al, 2006, and Stern et al, 1998), whereas others could not confirm it (Hill and Scott, 2000, Hornstein et al, 2000, and Kowalik et al, 1997). In addition, unlike the situation with recurrent miscarriage, the value of treatment in women with RIF and tested positive for the antibodies has not been confirmed. Similarly, in the case of heritable thrombophilia, while several studies have observed increased prevalence of conditions in women with RIF (Azem et al, 2004, Grandone et al, 2001, and Qublan et al, 2006), a relatively large case–control study of 468 women undergoing IVF did not show any association between maternal thrombophilia and IVF failure; however, the study population did not refer specifically to recurrent IVF failure ( Martinelli et al., 2003 ). A further study investigated thrombophilia and its relationship with repeated IVF failure ( Simur et al., 2009 ), which concluded that factor V Leiden, methylene tetrahydrofolate reductase mutations and prothrombin gene mutations do not have a significant role in IVF–embryo transfer implantation failure. Overall, it remains to be determined whether thrombophilic conditions are a cause of RIF.
Gamete and embryo factors
Ovarian function tests
Women with RIF should be offered ovarian reserve tests such as basal FSH, anti-Müllerian hormone and antral follicle counts to exclude any significant compromise of ovarian function associated with RIF, which may help in the counselling process.
Sperm DNA integrity testing
Several laboratory tests are available to measure sperm DNA fragmentation. They include TdT (terminal deoxynucleotidyl transferase)-mediated dUDP nick-end labelling (TUNEL; Gorczyca et al., 1993 ), Comet ( Hughes et al., 1996 ), CMA3 ( Manicardi et al., 1995 ), in-situ nick translation ( Tomlinson et al., 2001 ), DNA breakage detection fluorescence in-situ hybridization ( Fernandez et al., 2000 ) and sperm chromatin dispersion ( Fernandez et al., 2003 ). The most extensively studied, sperm chromatin structure assay, measures the stability of sperm chromatin in acid media by measuring DNA susceptibility to denaturation following exposure to mild acid with acridine orange (Erenpreiss et al, 2006, Evenson, 1990, and Evenson et al, 2002). Flow cytometric analysis determines the proportion of spermatozoa with fragmented DNA and is expressed as a DNA fragmentation index ( Sakkas and Alvarez, 2010 ). Earlier studies indicate that an index value of >27% is associated with pregnancy failure in assisted reproductive technology (Larson et al, 2000 and Larson-Cook et al, 2003), although, recent studies have questioned the predictive value of this test (Bungum et al, 2004, Bungum et al, 2007, and Gandini et al, 2004). Some clinics have already introduced sperm DNA integrity testing in the partners of women with RIF, which may well be premature. At present, sperm DNA integrity testing should only be offered to couples with RIF as part of a research programme.
Although only a small proportion of couples with RIF have abnormal karyotype results (2.5%; Stern et al., 1999 ), the rate is higher than that of the general population, suggesting an association between the two conditions. The test should be considered in couples with RIF.
In women with RIF, thorough investigations must be carried out to exclude any uterine pathology contributing to the clinical problem.
Pelvic ultrasonography is an integral part of IVF treatment as a means to monitor follicle growth and endometrial development. It is often assumed that significant uterine pathology such as large intramural fibroids would have been detected during the course of IVF treatment. Transvaginal ultrasonography may also detect some cases of hydrosalpinges, especially if they are large and persistent. However, it is necessary to confirm whether careful evaluation of the uterine anatomy has ever been carried out by an experienced ultrasonographer, and if not, it ought to be arranged.
Hysterosalpingography (HSG) is a useful test in RIF mainly because of its usefulness in the detection of hydrosalpinges. Its value in the detection of intrauterine pathology is limited. It is not a particularly sensitive test as some subtle lesions such as adhesions may be missed from time to time. Moreover, HSG has a high rate of false-positive results as air bubbles, mucus and debris may all mimic filling defects.
Sonohysterography (SHG) involves the use of contrast media, for example saline, along with transvaginal ultrasonography and is thought to improve the visualization of the uterine cavity ( Ayida et al., 1997 ). It has clear advantages over the use of HSG in that the use of radiation and iodine contrast is avoided and it is less invasive than hysteroscopy. A recently published study involving 64 patients investigated the use of SHG as a first-line evaluation for uterine abnormalities in women with RIF ( Shokeir and Abdelshaheed, 2009 ). A radiologist performed transvaginal ultrasound, SHG and then HSG prior to hysteroscopy, which was performed by a surgeon. All patients had a minimum of two unsuccessful IVF cycles in which two or more reasonable embryos were transferred per procedure. This study found that there was no statistically significant difference between the radiological methods in terms of diagnostic accuracy. In this particular study, SHG detected all uterine abnormalities except for a single, small endometrial polyp. The authors concluded that compared with hysteroscopy, SHG offered similar diagnostic capabilities, was less invasive and incurred less costs ( Shokeir and Abdelshaheed, 2009 ). However, as in the case of ultrasound and HSG, subtle small intrauterine lesions may not always be detected ( Soares et al., 2000 ). A recent prospective study compared transvaginal ultrasound, SHG and diagnostic hysteroscopy in the evaluation of endometrial pathology and concluded that diagnostic hysteroscopy was significantly more accurate in the diagnosis of intracavitary lesions than SHG and transvaginal ultrasound ( Grimbizis et al., 2010 ).
Hysteroscopy is one of the most important investigations in women with RIF. It allows reliable visual assessment of the cervical canal and uterine cavity. It is considered to be the gold standard to diagnose intrauterine pathology and has minimal intraoperative and post-operative morbidity.
Two prospective, randomized controlled studies confirmed the value of hysteroscopy in women with RIF demonstrating significantly increased clinical pregnancy rates (Demirol and Gurgan, 2004a and Rama Raju et al, 2006). It is concluded that, in women with RIF, even if the hysterosalpingogram was normal, hysteroscopic evaluation should be offered. Current evidence suggests that the incidence of abnormal hysteroscopic findings in women with recurrent IVF failures varies between 25 and 50% ( Makrakis and Pantos, 2010 ). From time to time, women with RIF may already have had a hysteroscopy in the past, often prior to the commencement of infertility treatment. The question may then be: should it be repeated? It should be repeated if the hysteroscopic assessment was conducted more than 2 years ago or if the patient has since had a further intrauterine surgery (e.g. removal of products of conception after miscarriage).
Hysteroscopy is not only a diagnostic tool; it also allows therapeutic procedures to be carried out at the time of diagnosis. It is useful to time the hysteroscopy to take place in the luteal phase of the cycle preceding IVF treatment as hysteroscopic-directed endometrial biopsy (scratch) may also be performed at the same time to improve the implantation rate ( Coughlan et al., in press ). However, when hysteroscopy is performed in the mid-luteal phase, the possibility of disturbing a spontaneously occurring pregnancy should be explained and women advised to consider protected sexual intercourse in the treatment cycle. On the other hand, hysteroscopy performed in the follicular phase has an advantage that the endometrium is thinner and the visibility is better.
Combined laparoscopy and hysteroscopy
In women suspected to have a congenital uterine anomaly on the basis of ultrasonography or HSG, further investigation is required to confirm the diagnosis. These tests include three-dimensional ultrasonography, magnetic resonance imaging or combined hysteroscopy and laparoscopy. The latter is considered to be the gold standard as it allows for direct visualization of the internal and external contour of the uterus and enables the clinician to diagnose and treat concurrently.
It is advisable to exclude hydrosalpinges as a cause of RIF, regardless of the initial infertility diagnosis leading to IVF treatment. A HSG should be arranged unless one has been performed recently. Ultrasound examination should not be relied upon to rule out hydrosalpinges as it may not always be visualized by ultrasonography. If the HSG is inconclusive, laparoscopic examination should confirm or refute the diagnosis beyond doubt.
A multidisciplinary approach should be adopted in the management of a couple with RIF. It should involve not only an experienced fertility specialist but also a senior embryologist and, where appropriate, a reproductive surgeon or a counsellor.
Couples with RIF should be reviewed by an experienced fertility specialist as there are inevitably many questions to be answered and important clinical decisions to be made. Patients need to be reassured that treatment is under the supervision of an experienced clinician. The couple should be offered ample time for their questions to be addressed and a clear treatment plan agreed. The appointment should not be just another ‘routine’ review. It ought to be a thorough review of the diagnosis of the underlying cause of infertility, the investigation results, the treatment protocol, the response to ovarian stimulation, the quality of the oocyte and embryos and possible explanation as to why they have not produced a successful pregnancy. The couple should have explained to them that any treatment plan recommended would be discussed and confirmed in a multidisciplinary team meeting and the final decision confirmed in writing.
Secondly, there ought to be an agreed local protocol as to how couples with RIF should be further investigated and managed. This is particularly important as there is still no universally agreed protocol for the investigation and management of this condition. The protocol ought to be updated regularly to take into consideration the findings of recent studies. The protocol should contain sufficient details to ensure that patients and staff clearly understand the plan of action and the rationale behind any decisions made.
Appropriate counselling of the couple with RIF is of the utmost importance prior to proceeding with further treatment. The couple should be advised as to the likelihood of success in future cycles and advised not to pursue further treatment if their prognosis is poor (i.e. <5%). The service of an independent counsellor should be offered at these difficult times. If it is deemed reasonable to pursue further treatment, it is beneficial to instigate appropriate investigations and review previous unsuccessful IVF treatment cycles with a view to modifying or changing the treatment protocol if indicated.
In addition to a review of investigations and treatment to date, clinicians should discuss and advise as to lifestyle changes which could improve the likelihood of treatment success.
Women who smoke should be advised to stop as there is evidence that smoking is associated with an increased gonadotrophin requirement for ovarian stimulation, fewer oocytes retrieved, higher numbers of cancelled cycles, lower implantation rates and more cycles with failed fertilization in those undergoing IVF treatment (Cooper et al, 1995, Feichtinger et al, 1997, Hughes and Brennan, 1996, Klonoff-Cohen et al, 2001, Sterzik et al, 1996, and Van Voorhis et al, 1996).
Male partners of women with RIF should also be advised to abstain from smoking due to its adverse effect on sperm counts and motility, increase in abnormal sperm morphology and sperm DNA damage ( Potts et al., 1999 ).
Body mass index
Underweight women (body mass index <19 kg/m2) should be encouraged to gain weight and obese women (body mass index >29 kg/m2) should be advised to lose weight prior to further attempts at IVF treatment.
For obese women, the first-line treatment is diet modification and regular exercise. A multidisciplinary approach is often necessary. It has been shown that women participating in structured weight-loss programmes involving a behavioural modification component are more successful than those who attempt weight loss on their own ( Wadden and Foster, 2000 ). In addition to lifestyle changes, pharmacotherapy such as orlistat may also be beneficial. In women with morbid obesity refractory to conventional measures, bariatric surgery may be considered but pregnancy is not recommended in the first year following the surgery as this is the time when the majority of weight loss occurs ( ASRM, 2008b ). Studies have shown that previous bariatric surgery is not associated with an increased risk of adverse perinatal outcomes (Marceau et al, 2004, Printen and Scott, 1982, and Sheiner et al, 2004), but the incidence of anaemia due to iron, folate, vitamin B12 and nutritional deficiencies may be increased ( ASRM, 2008b ).
It is recognized that alcohol consumption in pregnancy is associated with increased risks of spontaneous miscarriage, premature birth and low birthweight (Mukherjee et al, 2005 and Netherlands, 2007, 2007/19E; Windham et al., 1992 ). Women with RIF should be advised to reduce consumption to one or two units once or twice a week when trying to become pregnant ( NICE guideline, 2004 ) or abstain from alcohol altogether.
Ovarian stimulation protocol
The ovarian response to gonadotrophin stimulation should be reviewed. If the response is deemed satisfactory, it is not necessary to change the stimulation protocol.
In a small proportion of women who are deemed to have suboptimal response to ovarian stimulation, the dose of gonadotrophin may be increased. There is no firm evidence that antagonist protocol is better than agonist protocol or vice versa. There is some evidence to suggest that poor responders to FSH stimulation in down-regulated cycles may benefit from the addition of LH (Phelps et al, 1999 and Surrey and Schoolcraft, 2000). Evidence also points to a possible benefit from the addition of LH to the cycles of women older than 35 years of age (Balasch et al, 2001, Marrs et al, 2004, and Phelps et al, 1999).
In women with endometriosis and adenomyosis, the use of ultra-long protocol involving the administration of gonadotrophin-releasing hormone (GnRH) agonists for a few months prior to IVF or ICSI may increase the pregnancy rate (Sallam et al, 2006a, Sallam et al, 2006b, and Tremellen and Russell, 2011).
Sperm DNA fragmentation
In recent years, there has been increasing interest in sperm DNA fragmentation and its effect on fertility. Sperm DNA integrity testing has been proposed as a test with promising potential as compared with the standard semen analysis (Aitken and De Iuliis, 2007 and Barratt et al, 2010).
When suboptimal spermatozoa are considered to be a contributory cause of RIF, supported by an increased amount of sperm DNA fragmentation, several treatment options may be considered. First, medical treatment may be used to improve sperm quality ( Isidori et al., 2006 ). In particular, oral antioxidant treatment has been shown to reduce the incidence of sperm DNA fragmentation ( Greco et al., 2005b ).
Secondly, it is possible to select spermatozoa with low levels of DNA damage from the ejaculated semen samples ( Sakkas and Alvarez, 2010 ). A number of techniques have been proposed, including the use of annexin-V columns which has been shown to significantly reduce the percentage of spermatozoa with DNA fragmentation as measured by the TUNEL test and a sperm selection method incorporating sperm hyaluronic acid binding (Jakab et al, 2005, Said et al, 2005, and Said et al, 2006). Other techniques proposed include the use of confocal light absorption scattering spectroscopy (CLASS) technology and the use of high-magnification ICSI to identify spermatozoa devoid of surface vacuoles ( Bartoov et al., 2003 ). Intracytoplasmic morphologically selected sperm injection (IMSI) is considered to be a refined form of ICSI as it utilizes spermatozoa selected under high-power magnification with a defined set of morphological criteria. A recent meta-analysis comparing ICSI and IMSI outcome demonstrated a statistically significant improvement in implantation and pregnancy rates and a significant decrease in miscarriage rates with use of IMSI ( Souza Setti et al., 2010 ). However, a further study involving 200 couples with a minimum of two prior unsuccessful ICSI cycles demonstrated no statistically significant difference between the two groups in terms of fertilization, implantation and pregnancy rate ( Oliveira et al., 2011 ). Further randomized controlled studies are required to confirm the superiority of IMSI over ICSI.
Thirdly, based on the observation that sperm DNA damage is lower in the seminiferous tubules as compared with the cauda epididymis and ejaculated spermatozoa (Greco et al, 2005b, Steele et al, 1999, and Suganuma et al, 2005), it has been proposed that men with high levels of DNA damage in ejaculated spermatozoa have spermatozoa removed surgically from the testis for ICSI ( Greco et al., 2005a ). The use of testicular spermatozoa in couples with repeated implantation failure associated with high sperm DNA fragmentation in semen has been reported to result in a significant increase in pregnancy rate (Greco et al, 2005b and Weissman et al, 2008) and reduction of miscarriage rate ( Borini et al., 2006 ), but further studies are required to confirm the benefit.
Improving embryo quality and selection
Even though RIF refers to those who fail to achieve a clinical pregnancy despite the transfer of good-quality embryos, embryo factors still play a part because the currently used methods of embryo selection are not always reliable. A careful review of recent investigations including age of the woman, antral follicle count, basal FSH measurement, anti-Müllerian hormone concentration, number of follicles produced in response to stimulation, number of oocytes retrieved, the proportion of immature oocytes, fertilization rate, the proportion of good-quality embryos and the total number of good-quality embryos transferred should be noted.
Several studies have suggested that extending embryo culture to day 5 or 6 in order to transfer the embryo at the blastocyst stage increases the implantation rate (Cruz et al, 1999, Gardner et al, 2000, Gardner et al, 2004, Guerif et al, 2004, Levitas et al, 2004, Machtinger et al, 2006, and Marek et al, 1999). A recent Cochrane review by Blake et al. (2007) , supported the rationale that blastocyst transfer improves implantation rates by enabling better selection of embryos and with better synchronicity between the embryo and endometrium ( Blake et al., 2007 ). Since the meta-analysis, a further report demonstrated significantly improved live birth rates after blastocyst transfer ( Papanikolaou et al., 2008 ). In women with RIF, blastocyst transfer ought to be considered if not performed in previous treatment cycles.
Hatching of the blastocyst plays an integral role in the implantation process. Failure to hatch (due to intrinsic abnormalities in either the blastocyst or zona pellucida is a possible cause of implantation failure. Assisted hatching involves the artificial thinning or breaching of the zona pellucida and has been proposed as one technique to improve implantation and pregnancy rates following IVF ( ASRM, 2008a ). The assisted hatching process itself is not without complications, including damage to individual blastomeres or to the embryo and as a result may compromise embryo viability. Studies have suggested that artificial manipulation of the zona pellucida is associated with an increased risk of monozygotic twinning (Hershlag et al, 1999 and Schieve et al, 2000).
A comprehensive review and meta-analysis identified 23 randomized controlled trials involving 2572 women undergoing assisted hatching during assisted reproduction treatment ( Edi-Osagie et al., 2003 ). Clinical pregnancy rates were evaluated in 19 trials (722 clinical pregnancies, 2175 women). An improvement in clinical pregnancy rates following assisted hatching was identified (OR 1.63, 95% CI 1.27–2.09), although significant heterogeneity was noted. Subgroups of patients who demonstrated the greatest improvement in clinical pregnancy rates were those with prior failed cycles (OR 2.33, 95% CI 1.63–3.34) and older women. It is an inherent weakness in this review and meta-analysis that only six of the studies included in the analysis (involving 523 women) reported live birth rates with and without assisted hatching. Taking into account that the study populations were heterogeneous, the live birth rates in the two groups were not different (OR 1.26, 95% CI 0.82–1.78).
Two further meta-analyses also confirmed that the live birth rates were not significantly higher than control subjects (Das et al, 2009 and Seif et al, 2005) and a third systematic review and meta-analysis of randomized controlled trials could not draw a proper conclusion regarding miscarriage and live birth due to the small sample evaluated by the pool of included studies ( Martins et al., 2011 ). There are two possible explanations for these observations. First, it may be that assisted hatching facilitates the production of suboptimal embryos, which subsequently miscarried. Secondly, the total number of cases available for analysis was relatively small, which does not produce sufficient power to detect a small difference. Interestingly, the miscarriage rate was not higher in the assisted hatching group, suggesting that the production of suboptimal embryos by assisted hatching is a less likely possibility ( Seif et al., 2005 ).
It is possible that the beneficial effect of assisted hatching depends on the selection of subjects. In a study by Petersen et al. (2005) , it was found that assisted hatching produced significantly higher implantation rates in women with repeated implantation failure, but not in women with only one previous implantation failure. A further study reported that the beneficial effect of assisted hatching in RIF was more significant in women younger than 38 years of age ( Ghobara et al., 2006 ).
The American Society of Reproductive Medicine published recommendations regarding assisted hatching in 2008 ( ASRM, 2008a ). The Practice Committee suggested that available evidence does not support the routine application of assisted hatching in all IVF cycles. However, it proposed that assisted hatching may be clinically useful in patients with a poor prognosis, including those with a history of two or more unsuccessful IVF cycles, poor embryo quality and older women (⩾38 years of age) Mansour et al., (2000) . In summary, it does seem that assisted hatching is worth considering in women with RIF.
Preimplantation genetic diagnosis
The value of preimplantation genetic diagnosis (PGD) in RIF is controversial. There is no evidence to suggest that the embryos produced by women with RIF are more likely to be abnormal. The frequency of aneuploidy (67%) in embryos from women with RIF ( Pehlivan et al., 2003 ) was rather similar to the frequency (64%) in women without the condition ( Baart et al., 2006 ).
Two randomized trials on the value of PGD for aneuploidy screening in women with RIF showed no evidence of benefit (Gianaroli et al, 1999 and Werlin et al, 2003). A recent review by Donoso et al. (2007) also concluded that PGD should not be implemented in women with RIF on a routine basis and highlighted mosaicism of blastomeres as the major source of misdiagnosis in PGD. Chromosomal mosaicism, in which different blastomeres have a different chromosomal complement, is well documented (Harper et al, 1995, Munné et al, 1997, and Voullaire et al, 2000) and affects up to 50% of early human embryos. This means that the blastomere biopsied for PGD may not be representative of the remainder of the embryo. Mosaicism exists in embryos, cannot be corrected and is an inherent limitation when a single blastomere is analysed ( Wilton et al., 2009 ). In an effort to detect mosaicism, some laboratories analyse 2 cells from each embryo. However, removal of 2 cells from the early embryo may pose a threat to its viability (Cohen et al, 2007 and Goossens et al, 2008).
In recent years, there is increasing interest in providing a more detailed characterization of blastocyst cytogenetics using methods such as comparative genomic hybridization (CGH) and single-nucleotide polymorphism microarrays (Fragouli et al, 2008 and Northrop et al, 2010) with a view to detecting and preferentially transferring euploid normal embryos. Early studies suggest that an approach combining blastocyst biopsy and comprehensive chromosome screening using CGH or microarray CGH may represent the optimal approach for PGD (Fragouli et al, 2010 and Schoolcraft et al, 2010). A recent study evaluated the accuracy and efficiency of CGH and microarray CGH for trophectoderm analysis using 52 blastocysts ( Fragouli et al., 2011 ). This study found both CGH and microarray CGH trophectoderm analyses to be accurate aneuploidy detection tools ( Fragouli et al., 2011 ). A further study examined comprehensive chromosome screening of polar bodies and blastocysts from couples experiencing repeated implantation failure and identified higher implantation and pregnancy rates in those patients receiving blastocyst analysis, suggesting that comprehensive chromosome screening may assist patients with RIF capable of producing blastocysts in achieving successful pregnancies ( Fragouli et al., 2010 ). Further studies are required to confirm whether or not routine PGD using microarray CGH is beneficial in women with RIF.
For many years, the selection of embryos for transfer into the uterine cavity is based on the visual assessment and scoring of the embryos at various stages of development. To improve the selection, metabolomic changes in the culture medium of embryos and oocytes (exometabolomics) may be measured determining what the embryo consumes or secretes (e.g. amino acids, proteins and oxygen consumption) and these parameters have been shown to correlate with embryo viability (Brison et al, 2004, Conaghan et al, 1993, Gardner et al, 2001, Gott et al, 1990, Hardy et al, 1989, Houghton et al, 2002, Lopes et al, 2007, Sakkas and Gardner, 2005, Sallam et al, 2006a, Sallam et al, 2006b, and Scott et al, 2008). It may improve the embryo selection process, thereby improving the implantation rate. Its application in women with RIF has yet to be confirmed.
Embryo implantation has been found to be dependent on embryo quality, endometrial receptivity and transfer efficiency ( Paulson et al., 1990 ). In women with RIF, the details of previous embryo transfers should be reviewed, paying particular attention to any technical difficulties encountered. In the absence of any particular difficulty encountered in previous attempts, there is no evidence that a change of embryo transfer technique will improve the implantation rate. However, if there had been difficulty with previous embryo transfers, identified as a procedure taking longer than usual, causing significant pain or requiring change of catheter, cervical dilatation or use of a tenaculum, it is accepted that the pregnancy rate would be lower (Mains and Van Voorhis, 2010, Sallam et al, 2003, and Tomas et al, 2002). Difficult embryo transfer may be due to cervical stenosis or acute anteversion/retroversion or acute anteflexion/retroflexion of the uterus. Several techniques may be considered in women with a history of difficult embryo transfer.
The transfer should be performed under ultrasound guidance ( Brown et al., 2010 ). A systematic review and meta-analysis of prospective, randomized, controlled trials comparing ultrasound with clinical touch methods of embryo catheter guidance concluded that ultrasound-guided embryo transfer significantly increases the chance of live birth and ongoing and clinical pregnancy rates ( Abou-Setta et al., 2007 ).
Trial embryo transfer
A trial embryo transfer should be considered where a prior embryo transfer has been described as difficult or where difficulty may be anticipated ,such as previous LLETZ.
Filling the bladder in women with acute anteversion or anteflexion is a simple measure which may sometimes be useful, but will not be helpful in cases of acute retroversion or retroflexion where an empty bladder is preferable ( Sharif et al., 1995 ). The application of a tenaculum to the anterior lip of the cervix and applying traction gently downwards may help to straighten an acutely flexed uterus but may compromise pregnancy rates by inducing uterine contractions (Lesny et al, 1999, Mains and Van Voorhis, 2010, and Wood et al, 1985). The use of a rigid catheter may help to negotiate the cervix if difficulty is encountered with the use of a soft catheter ( Abou-Setta et al., 2005 ).
Irrigation and aspiration of cervical mucus
Irrigation and aspiration of cervical mucus has been proposed to improve pregnancy rates but not all studies concur with this hypothesis (Glass et al, 2000 and McNamee et al, 1997). The removal of cervical mucus is thought to improve pregnancy rates by preventing or minimizing bacteriologic contamination of the endometrial cavity and preventing cervical mucus occluding the catheter tip but it remains to be determined as to whether this practice improves pregnancy rates ( Letterie et al., 2003 ). There is insufficient evidence to show that bed rest after transfer improves outcome ( Bar-Hava et al., 2005 ).
Sequential embryo transfer
Sequential embryo transfer has been proposed as a means of improving implantation rates ( Goto et al., 2003 ). The concept behind this strategy is to overcome the problem of embryo–endometrium asynchronicity as a potential cause of implantation failure.
However, a case–control study ( Ashkenazi et al., 2000 ), which evaluated the consecutive transfer approach of early embryos and blastocysts, did not show any clinical benefit; the authors proposed that a second transfer may have an adverse effect on the implantation process because a second insertion of a catheter through the cervix may cause trauma to the endometrium or stimulate the secretion of prostaglandins that could produce uterine contractions. It might also introduce more mucus or additional microbial contamination to the uterine cavity and both these factors may disturb the implantation process and decrease the pregnancy rate ( Egbase et al., 1996 ).
In contrast, Almog et al. (2008) demonstrated that interval double transfer did improve the outcome in women with repeated IVF–embryo transfer failures and postulated that the reinsertion of the catheter may affect the endometrial cavity in a positive manner by inducing factors which enhance implantation, a view supported by Barash et al. (2003) . Loutradis et al. (2004) also found that double-embryo transfer for women who had had three or more implantation failures with the transfer of good-quality embryos had a beneficial effect.
Overall, there appears to be preliminary evidence to suggest that double-embryo transfer may be of benefit but carefully designed randomized controlled trials are required to confirm its value, if any, in women with RIF.
Transfer into the Fallopian tube
During natural conception, zygotes come in contact with numerous growth factors and cytokines in the tubal fluid and, as a result, are thought to attain to the uterus with greater synchronization, which is thought to contribute to the development of the early embryo and enhance implantation potential ( Jansen, 1984 ).
Zygote intra-Fallopian transfer (ZIFT) as a method of treatment for patients with repeated IVF failure was reported by Levran et al. (1998) in a case–control study. The pregnancy and implantation rates in the ZIFT group were found to be significantly higher than in the control group: 34.2% (24/70) and 8.7% (29/333) versus 17.1% (12/70) and 4.4% (13/289), respectively. The authors speculated that ZIFT allowed early embryonal growth in the natural tubal environment rather than the uterine cavity. The initial enthusiasm regarding ZIFT was later curtailed by the results of a series of prospective, randomized studies that failed to demonstrate any difference in implantation rates in IVF–ZIFT as compared with standard IVF–embryo transfer (Fluker et al, 1993, Toth et al, 1992, and Tournaye et al, 1992). A meta-analysis reported similar pregnancy and implantation rates in ZIFT and IVF–embryo transfer groups (36.5% versus 31.4% and 15% versus 12%, respectively; Habana and Palter, 2001 ). The authors of this meta-analysis concluded that, with the advent of improvements in culture techniques in the IVF laboratory, intrauterine transfer remains the technique of choice.
Moreover, there are a number of disadvantages to the use of either zygote or embryo intra-Fallopian tubal transfer. These include the need for general anaesthetic, laparoscopy, theatre time and surgical equipment. From the financial viewpoint, it is also an expensive procedure. Furthermore, it has been reported to be associated with the increased risk of ectopic gestation ( Habana and Palter, 2001 ).
Nevertheless, several recent studies have renewed the interest in ZIFT as it seems to be of particular value in couples with RIF (Levran et al, 2002, Weissman et al, 2007, and Weissman et al, 2013). Further, large, prospective, randomized studies are required to further evaluate the role of ZIFT in RIF.
There is convincing evidence that hysteroscopy improves the outcome of women with RIF ( Demirol and Gurgan, 2004b ). It may be performed as an outpatient procedure and small lesions may be removed at the same time, but more significant pathology may need to be dealt with later under general anaesthesia.
A recent meta-analysis showed that submucous fibroids significantly reduced the implantation rate, clinical pregnancy rate and live birth rate and significantly increased the miscarriage rate ( Pritts et al., 2009 ). The presence of a submucous fibroid in women with RIF, regardless of the size, should be removed as it was shown in the meta-analysis that removal of submucous fibroids improves clinical pregnancy rates ( Pritts et al., 2009 ).
Prior to the surgery, the size and number of fibroids and the depth of intramural extension should be carefully assessed. Resection of a solitary submucous fibroid less than 5 cm in diameter and with little intramural extension should not pose significant difficulties. However, a submucous fibroid more than 5 cm in diameter or more than 50% embedded in the intramural part of the uterus may require removal in two stages. In the case of multiple submucosal fibroids, there is an increased risk of intrauterine adhesion formation after the procedure. Some surgeons advocate the removal of the anterior wall and posterior wall fibroids on separate occasions to reduce the risk of intrauterine adhesions.
Similarly, endometrial polyps in women with RIF ought to be removed. It has been shown that the removal of endometrial polyps in women undergoing intrauterine insemination resulted in doubling of the clinical pregnancy rate ( Bosteels et al., 2010 ). In women with multiple endometrial polyps, as in the case of multiple submucous fibroids, the possibility of the procedure being complicated by intrauterine adhesions should also be borne in mind.
In women with RIF, uterine septae should be removed, regardless of the size. Ban-Frangez et al. (2009) found that small and large septae had similar adverse impact, with significant increase in miscarriage rate in women undergoing IVF/ICSI treatment and that removal of these septae produced similar improvement in results ( Ban-Frangez et al., 2009 ). The various techniques used to remove uterine septae have been reviewed ( Homer et al., 2000 ).
It is accepted that intrauterine adhesions would interfere with the implantation process and adversely affect the implantation rate and so, if present in women with RIF, should be removed ( March, 2011 ). Nevertheless, there are as yet no firm literature data to confirm that removal of intrauterine adhesions improves the implantation rate. Furthermore, intrauterine adhesions often recur after surgical removal and there is a high rate of complication (10% or more) in cases of severe intrauterine adhesions resulting in partial or complete obliteration of the cavity.
The procedure should be carried out by an experienced reproductive surgeon under ultrasound guidance with a view to minimize complications. Special measures including the use of anti-adhesion barrier, intrauterine balloon, antibiotic therapy and high-dose oestrogen in the post-operative period to promote regeneration of the endometrium should be considered. The various surgical techniques used to remove intrauterine adhesions and to prevent reoccurrence of adhesions have been reviewed (March, 2011 and Yu et al, 2008).
While women with RIF should have submucous fibroids removed, the possible contribution of intramural fibroids which are not distorting the uterine cavity to RIF is far from clear. There is no consensus on whether or not intramural fibroids in women with RIF should be removed. Many clinicians would recommend removal of intramural fibroids if they are more than 4 cm in diameter. There is a lower threshold to removing an intramural fibroid if it is situated in the anterior lower uterine segment as it may pose problems in delivery of the fetus, especially if Caesarean section is required. The pros and cons of myomectomy should be carefully explained in each case.
Couples should be aware of the possible complications of myomectomy, including the likelihood of blood transfusion, a small risk (1%) of hysterectomy and a relatively high risk of adhesion formation over the uterine scar as well as a small but serious risk of scar rupture during the ensuing pregnancy. On the other hand, the couples should also understand that intramural fibroids may not only cause implantation failure but also a number of other problems including miscarriage (both first and second trimester), red degeneration, preterm delivery, placental abruption, fetal growth restriction, malpresentation, difficulty with delivery and intrapartum and post-partum haemorrhage.
In the authors’ view, the final decision must be individualized, and the involvement of a reproductive surgeon in the decision-making process is recommended. The techniques of myomectomy have recently been reviewed ( McIlveen and Li, 2005 ). Uterine artery embolization is a possible alternative to myomectomy but is not preferred because of a small but worrying risk of compromise to the ovarian blood supply and because there is only a modest reduction in size, but not complete resolution of the fibroid. A recent study suggested that magnetic resonance-guided focused ultrasound surgery is a possible noninvasive therapy for intramural fibroids as the pregnancy outcome after the treatment appeared encouraging ( Rabinovici et al., 2010 ).
The role played by adenomyosis in reproductive failure is receiving increasing attention and is now recognized to be a cause of RIF ( Tremellen and Russell, 2011 ). Unlike intramural fibroids, adenomyosis is not usually amenable to surgical treatment, but Tremellen and Russell (2011) , reported on four cases of RIF associated with adenomyosis, all successfully treated with an ultra-long pituitary downregulation protocol.
RIF may sometimes be associated with a thin endometrium (<7 mm) noted at the time of ultrasound examination on the day of HCG administration or embryo transfer. The observation suggests that the endometrium is not optimally responding to oestrogenic stimulation. There are several possible underlying causes. It may be congenital, associated with Turner’s syndrome or a T-shape uterus. It may also be acquired, as a consequence of previous radiotherapy to the pelvis or iatrogenic damage to the endometrium following intrauterine surgery or infection. From time to time, the underlying cause may not be obvious.
In this particular clinical situation, hysteroscopic examination of the uterine cavity is recommended to rule out intrauterine adhesions or Asherman’s syndrome. Any intrauterine adhesion should be carefully removed with minimal thermal injury, under ultrasound guidance, by an experienced reproductive surgeon. The main challenge of intrauterine adhesiolysis is the prevention of recurrence of the adhesions. The various methods available to prevent recurrence have been recently reviewed ( Yu et al., 2008 ).
Modified long protocol with exogenous oestrogen therapy
In the absence of any surgically correctable underlying pathology, there ought to be a strategy to improve endometrial growth by increasing the duration of oestrogenic priming prior to HCG trigger. The Royal Hallamshire Hospital employs a modified long protocol, which as yet has not been subjected to clinical trials. In essence, GnRH agonist is commenced in the mid-luteal phase of the cycle preceding IVF treatment. Two days after menstruation has started, usually a week after the initiation of GnRH therapy, high-dose oestrogen therapy in the form of oestradiol valerate 6–8 mg/day or oestradiol transdermal patch 400 μg/day is commenced. Endometrial thickness is monitored with serial ultrasonography after 7 days of oestrogen therapy and thereafter every 3 or 4 days until the endometrium has grown to more than 5 mm. At this stage, gonadotrophin may be commenced to stimulate the ovary to grow follicles, while the oestrogen therapy continues to ensure ongoing growth of the endometrium. The oestrogen therapy may stop on the day of HCG administration, when endogenous oestrogen concentration is often well over 5000 pmol/l.
In women who fail to respond to the treatment outlined above or fail to achieve implantation again, the Hospital’s policy is to repeat the treatment protocol in a further cycle, collect the oocytes, but not transfer any embryo. Luteal support should be started after oocyte retrieval as usual. An endometrial biopsy should then be obtained 7 days after oocyte retrieval for histological evaluation. If there is evidence of satisfactory secretory transformation, embryo transfer may proceed in a subsequent artificial cycle with high-dose oestrogen therapy. If, however, there is no evidence of secretory transformation, this suggests that the endometrium is unable to support implantation and the couple should be advised to consider surrogacy.
Sildenafil citrate has also been proposed in the treatment of women with RIF associated with a thin endometrium. Sildenafil, a phosphodiesterase-5 inhibitor, augments the vasodilatory effects of nitric oxide. The hypothesis behind the use of sildenafil is that it increases endometrial blood flow, which then leads to an increase in endometrial function. There have been two small observational studies on the use of sildenafil (Viagra): one involving four women with RIF ( Sher and Fisch, 2000 ) and the other involving two women with Asherman’s syndrome ( Zinger et al., 2006 ). In addition, there has been a cohort study involving 105 infertile women with at least two consecutive prior IVF failures attributed to inadequate endometrial development ( Sher and Fisch, 2002 ). Sildenafil was administered as a vaginal suppository at a dose of 25 mg four times a day for 3–10 days. Among the 73 subjects who attained an endometrial thickness of 9 mm or more, the implantation rate (29%) and pregnancy rate (45%) were significantly higher than the those observed among 32 subjects whose endometrial thickness was less than 9 mm (implantation 2%, pregnancy 0%, respectively) ( Sher and Fisch, 2002 ). While the authors concluded that sildenafil appeared to benefit about 70% of subjects with inadequate endometrial development, the observation has not yet been confirmed by any randomized controlled trial.
Luteal support with GnRHa
In a recent randomized, placebo–control study involving 120 women with thin (7 mm or less) endometrium, women who received GnRHa on day of oocyte recovery, on the day of embryo transfer and 3 days later appeared to have significantly higher oestradiol and progesterone concentrations, thicker endometrium and higher implantation and pregnancy rates than those who received placebo ( Qublan et al., 2008 ). However, it is unclear whether GnRHa has any significant benefit over other commonly used forms of luteal support such as progesterone or HCG.
Endometrial perfusion with granulocyte colony-stimulating factor
A recent study reported on the successful use of endometrial perfusion with granulocyte colony-stimulating factor in four women with inadequate development previously resistant to the use of oestrogen and vasodilators ( Gleicher et al., 2011 ). The novel approach requires further investigation to confirm its usefulness.
Removal of hydrosalpinges
There is now good evidence that the removal of hydrosalpinges improves the implantation and live birth rates in women undergoing IVF. However, as salpingectomy is a surgical procedure which incurs extra cost, it opens up a debate on whether or not it is cost-effective to routinely remove all hydrosalpinges prior to IVF. Strandell et al. (2005) , analysed the cost-effectiveness of salpingectomy prior to IVF, for up to three IVF cycles ( Strandell et al., 2005 ). They found that the cost per live birth in the salpingectomy group was 22,823 Euros, which was significantly lower than the cost per live birth in the control (no salpingectomy) group (29,517 Euros). The observation suggests that it is more cost-effective to routinely remove hydrosalpinges prior to IVF treatment. There are conflicting reports on whether or not salpingectomy compromises ovarian response to stimulation during subsequent IVF treatment. It is prudent, when carrying out salpingectomy, to diathermize and incise as close to the Fallopian tube as possible and as far away from the ovary as possible to avoid disruption to the ovarian blood supply ( Figure 2 ).
Salpingectomy is not the only surgical treatment option for women with hydrosalpinges contemplating IVF treatment. Salpingostomy may be a possible alternative as it not only ‘removes’ the hydrosalpinges but also produces the possibility of natural conception. The intrauterine pregnancy rate following salpingostomy has been reported by a number of investigators to be over 30% (Canis et al, 1991, Dubuisson et al, 1994, McComb and Paleologou, 1991, Mettler et al, 1990, and Singhal et al, 1991). The results are likely to be higher if the damage to the Fallopian tubes is minimal ( Winston and Margara, 1991 ).
It seems logical, therefore, to recommend that in women with hydrosalpinges and Fallopian tubes with minimal damage salpingostomy should be considered whereas tubes which are severely damaged (especially for those with intraluminal adhesions) ought to be removed (salpingectomy). The drawback of this approach is the possible recurrence of hydrosalpinges after salpingostomy, which than necessitates a further procedure to remove the tube, further delaying the treatment and incurring extra cost.
Ultrasound-guided surgical drainage of hydrosalpinx has also been examined as a possible alternative to salpingostomy and salpingectomy. In a retrospective analysis, Sowter et al. (1997) showed that drainage of a hydrosalpinx did not improve the live birth rate. In a more recent randomized controlled trial, Hammadieh et al. (2008) found that ultrasound-guided hydrosalpinx aspiration increased the biochemical pregnancy rate but not the clinical pregnancy rate.
Transvaginal aspiration of hydrosalpinges is not recommended for a number of reasons. First, the fluid may rapidly reaccumulate as the underlying pathology has not been altered. Secondly, there is a risk of introducing infection. In addition, the efficacy of such a treatment modality has not been proven.
Alternatively, occlusion of the proximal part of the tube to prevent the hydrosalpingeal fluid from discharging into the uterine cavity has been proposed ( Sagoskin et al., 2003 ). It has the possible advantages of being a simpler operation and less likely to disturb ovarian blood supply and hence compromise ovarian response to stimulation by gonadotrophins during IVF treatment. A recent trial showed indirectly that proximal tubal occlusion and salpingectomy result in similar improvement in IVF outcome in patients with hydrosalpinges ( Kontoravdis et al., 2006 ). A further review provides evidence that laparoscopic tubal occlusion is an alternative to laparoscopic salpingectomy in improving IVF pregnancy rates in women with hydrosalpinges ( Johnson et al., 2010 ).
However, occlusion of the proximal part of the tube leaves behind tubes blocked at both proximal and distal ends, with fluid trapped within, thereby increasing the risk of future infection (pyosalpinx) and persistent pain and the likelihood of a further surgical procedure to remove the diseased tube. For those patients with severe pelvic adhesions in whom surgery is expected to incur increased risks such as bowel injury, the use of Essure may be considered. It involves the occlusion of the Fallopian tubes hysteroscopically and avoids the need for either laparoscopic or open surgery. A number of studies have reviewed the use of Essure in the treatment of hydrosalpinges prior to IVF (Galen et al, 2011, Mijatovic et al, 2010, Mijatovic et al, 2012, and Thebault et al, 2012), but its use should be reserved for cases with extensive pelvic adhesions.
For now, therefore, the treatment of hydrosalpinges in women with RIF should be either salpingectomy or salpingostomy, with proximal tubal occlusion reserved for cases with severe/dense tubo-ovarian adhesions when the surgical morbidity in such cases is significantly increased.
Barash et al. (2003) explored the possibility that local injury of the endometrium in the cycle preceding IVF treatment increases the success rate of implantation in a prospective study involving 130 patients who failed to conceive after one or more IVF treatment cycles. Forty-five out of 134 subjects were randomized by consent to have repeated endometrial biopsy on days 8, 12, 21 and 26 of the cycle immediately before the IVF treatment cycle. They found that the treatment resulted in a significant improvement (approximately double) in the rates of implantation, clinical pregnancy and live births (27.7%, 66.7% and 48.9%, respectively), compared with control subjects who did not have endometrial biopsies (14.2%, 30.3% and 22.5%, respectively).
It is not exactly clear why the endometrial biopsies helped the implantation rate. Barash et al. (2003) speculated that the healing process following endometrial biopsy may release cytokines and growth factors which facilitate the process of implantation. However, it is not certain whether four endometrial biopsies are required or only one is necessary to produce the observed beneficial results. Similarly, a further study identified a favourable influence of local injury to the endometrium in ICSI patients with high-order implantation failure ( Raziel et al., 2007 ).
Subsequently, there have been two randomized controlled trials which examined the value of endometrial biopsy or endometrial scratch in the luteal phase on IVF outcome in women who have repeated failures (Karimzadeh et al, 2009 and Narvekar et al, 2010). The pooled live birth rate in these two randomized controlled trials was significantly higher, more than double that of the control subjects. On the other hand, the pooled data from two randomized controlled trials on endometrial scratch carried out in the follicular phase of the index cycle showed no convincing evidence of benefit (Karimzade et al, 2010 and Zhou et al, 2008).
The overall conclusion of these studies suggests that endometrial scratch is of benefit in women with RIF but it should be carried out approximately 7 days prior to the onset of menstruation, immediately before the start of ovarian stimulation for IVF treatment. However, all couples should be advised regarding the importance of protected intercourse in the month of the endometrial scratch because, when carried out in the luteal phase of the cycle, there is the risk of performing the procedure in the presence of an early pregnancy.
Endometrial injury or scratch could simply be performed by the use of a pipelle endometrial biopsy sampler (Laboratoire CCD, Paris; Figure 3 ). After the pipelle sampler is introduced into the endometrial cavity, the inner shaft is withdrawn to create a negative suction after which the pipelle sampler is gradually rotated as it is moved up and down the endometrial cavity several times to produce the ‘scratching’ action. In some centres, mock embryo transfers are routinely carried out prior to IVF treatment. In this situation, endometrial scratch and mock embryo transfer may be carried out at the same time.
Apart from the use of a pipelle endometrial sampler, endometrial biopsy may also be carried out at the time of hysteroscopy. Two randomized controlled trials also showed evidence of benefit when endometrial biopsy and hysteroscopy were carried out in the luteal phase of the cycle preceding IVF treatment (Demirol and Gurgan, 2004b and Rama Raju et al, 2006).
Taken together, these trials on endometrial scratch suggest that it may be performed either with the use of a pipelle sampler or during hysteroscopy. Two recent systematic reviews and meta-analyses of the available literature showed a beneficial effect of local endometrial injury in RIF but advised that further robust randomized trials are required (El-Toukhy et al, 2012 and Potdar et al, 2012).
Some centres offer empirical use of aspirin or heparin in women with RIF. A recent systematic review and meta-analysis on the use of low-dose aspirin showed no benefit of its use in IVF programmes ( Gelbaya et al., 2007 ). A subsequent prospective, randomized, double-blind, placebo-controlled trial involving 201 couples concurred with the conclusion of the earlier meta-analysis ( Dirckx et al., 2009 ). There is good evidence to suggest that aspirin should not be used in women with RIF.
A recent randomized, double-blind, placebo-controlled trial of heparin and aspirin in women who had RIF (defined in study as ⩾10 embryos transferred without achieving a pregnancy) and who were tested positive for either antiphospholipids or antinuclear or β2-glycoprotein I antibodies, showed that the treatment did not improve implantation or pregnancy rate ( Stern et al., 2003 ). The Practice Committee of the American Society for Reproductive Medicine advises that the assessment of antiphospholipid antibodies is not indicated among couples undergoing IVF and therapy is not justified on the basis of existing data (Practice Committee of the American Society of Reproductive Medicine, 2008).
Women with RIF are desperate to seek a treatment which will lead to a successful outcome. Many of them would have been browsing the internet looking for a ‘new’ treatment on the horizon. They may not be able to judge for themselves the scientific credibility of such claims and they often seek the advice of their specialist to confirm whether certain treatments are worth trying. Clinicians should be able to judge whether a certain treatment has been proven to be of value. If not, treatment should not be initiated or the treatment should be offered only as part of a clinical trial. In this situation, prior ethics approval for the trial should have been obtained and national research governance guidelines followed. Written consent from each patient should be obtained.
Gamete donation and surrogacy
Couples with RIF need guidance on the appropriateness of proceeding with further IVF attempts. If implantation fails to occur despite repeated treatment attempts or if the prognosis of further IVF treatment is considered poor, alternative treatment options ought to be explored. If the likely source of the problem lies with the embryo, gamete donation should be advised. On the other hand, if the problem lies in the uterus, for example multiple small fibroids or Asherman’s syndrome which has failed to respond to surgical treatment, surrogacy ought to be discussed.
To conclude, RIF should be defined as the failure to achieve a clinical pregnancy after transfer of at least 4 good-quality embryos in a minimum of three fresh or frozen cycles in a woman under the age of 40 years. Women with RIF should be offered appropriate investigations to rule out an underlying cause for the repeated failure ( Table 1 ). The main treatment strategy in couples with RIF is to improve the quality of the embryos transferred and the receptivity of the endometrium.
|Recommended investigations||Investigations of research value|
|Hysterosalpingography||Sperm DNA fragmentation|
|Ovarian reserve and function: FSH, anti-Müllerian hormone, antral follicle count|
The following recommendations should be considered in the management of couples with RIF. The levels of evidence available in the literature to support each recommendation are given in accordance with the guidelines published by the Royal College of Obstetricians and Gynaecologists ( www.rcog.org.uk/guidelines ; Table 2 ).
|Evidence level||Type of evidence|
|1++||High-quality meta-analyses, systematic reviews of randomized controlled trials or randomized controlled trials with a very low risk of bias|
|1+||Well-conducted meta-analyses, systematic reviews of randomized controlled trials or randomized controlled trials with a low risk of bias|
|1−||Meta-analyses, systematic reviews of randomized controlled trials or randomized controlled trials with a high risk of bias|
|2++||High-quality systematic reviews of case–control or cohort studies or high-quality case–control or cohort studies with a very low risk of confounding, bias or chance and a high probability that the relationship is causal|
|2+||Well-conducted case–control or cohort studies with a low risk of confounding, bias or chance and a moderate probability that the relationship is causal|
|2−||Case–control or cohort studies with a high risk of confounding, bias or chance and a significant risk that the relationship is not causal|
|3||Non-analytical studies: e.g. case reports, case series|
Source: www.rcog.org.uk/guidelines .
Hysteroscopy should be carried out to exclude any intracavity uterine pathology; it has been shown to improve outcome (evidence level 1+).
Appropriate investigations should be carried out to exclude hydrosalpinx as it has been shown to reduce implantation rate, increase miscarriage rate and reduce live birth rate; removal of hydrosalpinges has been shown to improve the outcome (evidence level 1++).
Submucosal fibroids have been shown to reduce implantation, pregnancy and live birth rates; removal of submucosal fibroids improves implantation rate (evidence level 1+).
Endometrial polyps should be removed; although there is no data on its impact on women undergoing IVF, it has been shown to improve outcome in women undergoing intrauterine insemination (evidence level 1−).
Endometrial scratch should be considered in the luteal phase of the cycle immediately preceding IVF treatment; it improves implantation rate and outcome in women with unexplained RIF (evidence level 1−).
Uterine septum increases miscarriage rate; its removal improves outcome (evidence level 2+).
The use of ultra-long protocol may improve outcome in women with endometriosis and adenomyosis (evidence level 3).
Intramural fibroid of more than 5 cm should be removed (evidence level 3).
Intrauterine adhesions are a recognized cause of thin endometrium not responding to ovarian steroid stimulation; if present, intrauterine adhesions should be removed (evidence level 4).
A multidisciplinary approach should be adopted in the management of RIF (evidence level 4).
Empirical therapies should, whenever possible, be considered only in the setting of carefully conducted clinical trials (evidence level 4).
The authors would like to thank Patrick Elliott who kindly provided the figures for this manuscript.
- American Society Reproductive Medicine, 2008a American Society Reproductive Medicine. The role of assisted hatching in in vitro fertilization: a review of the literature. Fertil. Steril.. 2008;90
- American Society Reproductive Medicine, 2008b American Society Reproductive Medicine. Obesity and reproduction: an educational bulletin. Fertil. Steril.. 2008;90:S21-S29
- Abou-Setta et al., 2005 A.M. Abou-Setta, H.G. Al-Inany, R.T. Mansour, G.I. Serour, M.A. Aboulghar. Soft versus firm embryo transfer catheters for assisted reproduction: a systematic review and meta-analysis. Hum. Reprod.. 2005;20:3114-3121 Crossref
- Abou-Setta et al., 2007 A.M. Abou-Setta, R.T. Mansour, H.G. Al-Inany, M.M. Aboulghar, M.A. Aboulghar, G.I. Serour. Among women undergoing embryo transfer, is the probability of pregnancy and live birth improved with ultrasound guidance over clinical touch alone? A systemic review and meta-analysis of prospective randomized trials. Fertil. Steril.. 2007;88:333-341 Crossref
- Absalan et al., 2012 F. Absalan, A. Ghannadi, M. Kazerooni, R. Parifar, F. Jamalzadeh, S. Amiri. Value of sperm chromatin dispersion test in couples with unexplained recurrent abortion. J. Assist. Reprod. Genet.. 2012;29:11-14 Crossref
- Aitken and De Iuliis, 2007 R.J. Aitken, G.N. De Iuliis. Origins and consequences of DNA damage in male germ cells. Reprod. Biomed. Online. 2007;14:727-733 Crossref
- Almog et al., 2008 B. Almog, I. Levin, I. Wagman, R. Kapustiansky, T. Schwartz, N. Mey-Raz, A. Amit, F. Azem. Interval double transfer improves treatment success in patients with repeated IVF/ET failures. J. Assist. Reprod. Genet.. 2008;25:353-357 Crossref
- Ascher et al., 1994 S.M. Ascher, L.L. Arnold, R.H. Patt, J.J. Schruefer, A.S. Bagley, R.C. Semelka, R.K. Zeman, J.A. Simon. Adenomyosis: prospective comparison of MR imaging and transvaginal sonography. Radiology. 1994;190:803-806
- Ashkenazi et al., 2000 J. Ashkenazi, R. Yoeli, R. Orvieto, J. Shalev, Z. Ben-Rafael, I. Bar-Hava. Double (consecutive) transfer of early embryos and blastocysts: aims and results. Fertil. Steril.. 2000;74:936-940 Crossref
- Assou et al., 2010 S. Assou, D. Haouzi, J. De Vos, S. Hamamah. Human cumulus cells as biomarkers for embryo and pregnancy outcomes. Mol. Hum. Reprod.. 2010;16:531-538 Crossref
- Atzori et al., 1996 E. Atzori, C. Tronci, L. Sionis. Transvaginal ultrasound in the diagnosis of diffuse adenomyosis. Gynecol. Obstet. Invest.. 1996;42:39-41 Crossref
- Ayida et al., 1997 G. Ayida, P. Chamberlain, D. Barlow, S. Kennedy. Uterine cavity assessment prior to in-vitro fertilization: comparison of transvaginal scanning, saline contrast hysterosonography and hysteroscopy. Ultrasound Obstet. Gynecol.. 1997;10:59-62
- Azem et al., 2004 F. Azem, A. Many, I. Ben Ami, I. Yovel, A. Amit, J.B. Lessing, M.J. Kupferminc. Increased rates of thrombophilia in women with repeated IVF failures. Hum. Reprod.. 2004;19:368-370 Crossref
- Baart et al., 2006 E.B. Baart, E. Martini, I. van den Berg, N.S. Macklon, R.J. Galjaard, B.C. Fauser, D. Van Opstal. Preimplantation genetic screening reveals a high incidence of aneuploidy and mosaicism in embryos from young women undergoing IVF. Hum. Reprod.. 2006;21:223-233
- Baart et al., 2007 E.B. Baart, E. Martini, M.J. Eijkemans, D. Van Opstal, N.G. Beckers, A. Verhoeff, N.S. Macklon, B.C. Fauser. Milder ovarian stimulation for in-vitro fertilization reduces aneuploidy in the human preimplantation embryo: a randomized controlled trial. Hum. Reprod.. 2007;22:980-988 Crossref
- Balasch et al., 2001 J. Balasch, E. Vidal, J. Penarrubia, R. Casamitjana, F. Carmona, M. Creus, F. Fabreques, J.A. Vanrell. Suppression of LH during ovarian stimulation: analysing threshold values and effects on ovarian response and the outcome of assisted reproduction in down-regulated women stimulated with recombinant FSH. Hum. Reprod.. 2001;16:1636-1643 Crossref
- Ban-Frangez et al., 2009 H. Ban-Frangez, T. Tomazevic, I. Virant-Klun, I. Verdenik, M. Ribic-Pucelj, E.V. Bokal. The outcome of singleton pregnancies after IVF/ICSI in women before and after hysteroscopic resection of a uterine septum compared to normal controls. Eur. J. Obstet. Gynecol. Reprod. Biol.. 2009;146:184-187 Crossref
- Bar-Hava et al., 2005 I. Bar-Hava, R. Kerner, R. Yoeli, J. Ashkenazi, Y. Shalev, R. Orvieto. Immediate ambulation after embryo transfer: a prospective study. Fertil. Steril.. 2005;83:594-597 Crossref
- Barash et al., 2003 A. Barash, N. Dekel, S. Fieldust, I. Segal, E. Schechtman, I. Granot. Local injury to the endometrium doubles the incidence of successful pregnancies in patients undergoing in vitro fertilisation. Fertil. Steril.. 2003;79:1317-1322 Crossref
- Barratt et al., 2010 C.L. Barratt, R.J. Aitken, L. Bjorndahl, D.T. Carrell, P. de Boer, U. Kvist, S.E. Lewis, S.D. Perreault, M.J. Perry, L. Ramos, B. Robaire, S. Ward, A. Zini. Sperm DNA: organization, protection and vulnerability: from basic science to clinical applications – a position report. Hum. Reprod.. 2010;25:824-838 Crossref
- Bartoov et al., 2003 B. Bartoov, A. Berkovitz, F. Eltes, A. Kogosovsky, A. Yagoda, H. Lederman, S. Artzi, M. Gross, Y. Barak. Pregnancy rates are higher with intracytoplasmic morphologically selected sperm injection than with conventional intracytoplasmic injection. Fertil. Steril.. 2003;80:1413-1419 Crossref
- Bazot et al., 2002 M. Bazot, E. Darai, J. Rouger, R. Detchev, A. Cortez, S. Uzan. Limitations of transvaginal sonography for the diagnosis of adenomyosis, with histopathological correlation. Ultrasound Obstet. Gynecol.. 2002;20:605-611 Crossref
- Benkhalifa et al., 2012 M. Benkhalifa, A. Demirol, T. Sari, E. Balashova, M. Tsouroupaki, Y. Giakoumakis, T. Gurgan. Autologous embryo-cumulus cells co-culture and blastocyst transfer in repeated implantation failures: a collaborative prospective randomized study. Zygote. 2012;20:173-180 Crossref
- Bernard et al., 2000 G. Bernard, E. Darai, C. Poncelet, J.L. Benifla, P. Madelenat. Fertility after hysteroscopic myomectomy: effect of intramural myomas associated. Eur. J. Obstet. Gynecol. Reprod. Biol.. 2000;88:85-90 Crossref
- Bildirici et al., 2001 I. Bildirici, O. Bukulmez, A. Ensari, H. Yarali, T. Gurgan. A prospective evaluation of the effect of salpingectomy on endometrial receptivity in cases of women with communicating hydrosalpinges. Hum. Reprod.. 2001;16:2422-2426
- Birkenfeld et al., 1994 A. Birkenfeld, T. Mukaida, L. Minichiello, M. Jackson, N.G. Kase, M. Yemini. Incidence of autoimmune antibodies in failed embryo transfer cycles. Am. J. Reprod. Immunol.. 1994;31:65-68 Crossref
- Blake et al., 2007 D. Blake, C. Farquhar, N. Johnson, M. Proctor. Cleavage stage versus blastocyst stage embryo transfer in assisted conception. Cochrane Database Syst. Rev.. 2007;:CD002118
- Bloechle, 1999 M. Bloechle. What is a hydrosalpinx? A plea for the use of a proper terminology in scientific discussion. Hum. Reprod.. 1999;14:578 Crossref
- Blois et al., 2011 S.M. Blois, B.F. Klapp, G. Barrientos. Decidualisation and angiogenesis in early pregnancy: unravelling the functions of DC and NK cells. J. Reprod. Immunol.. 2011;88:86-92 Crossref
- Borini et al., 2006 A. Borini, N. Tarozzi, D. Bizzaro, M.A. Bonu, L. Fava, C. Flamigni, G. Coticchio. Sperm DNA fragmentation: paternal effect on early post-implantation embryo development in ART. Hum. Reprod.. 2006;21:2876-2881 Crossref
- Bosteels et al., 2010 J. Bosteels, S. Weyers, P. Puttemans, C. Panayotidis, B. Van Herendael, V. Gomel, B.W. Mol, C. Mathieu, T. D’Hooghe. The effectiveness of hysteroscopy in improving pregnancy rates in subfertile women without other gynaecological symptoms: a systematic review. Hum. Reprod. Update. 2010;16:1-11 Crossref
- Brahem et al., 2011 S. Brahem, M. Mehdi, H. Landolsi, S. Mougou, H. Elghezal, A. Saad. Semen parameters and sperm DNA fragmentation as causes of recurrent pregnancy loss. Urology. 2011;78:792-796 Crossref
- Brison et al., 2004 D.R. Brison, F. Houghton, D. Falconer, S.A. Roberts, J. Hawkhead, P.G. Humpherson, B.A. Lieberman, H.J. Leese. Identification of viable embryos in IVF by non-invasive measurement of amino acid turnover. Hum. Reprod.. 2004;19:2319-2324 Crossref
- Bromley et al., 2000 B. Bromley, T. Shipp, B. Benacerraf. Adenomyosis: sonographic findings and diagnostic accuracy. J. Ultrasound Med.. 2000;19:529-534
- Brown et al., 2010 J. Brown, K. Buckingham, A.M. Abou-Setta, W. Buckett. Ultrasound versus ‘clinical touch’ for catheter guidance during embryo transfer in women. Cochrane Database Syst. Rev.. 2010;20:CD006107
- Bungum et al., 2004 M. Bungum, P. Humaidan, M. Spano, K. Jepson, L. Bungum, A. Giwercman. The predictive value of sperm chromatin structure assay (SCSA) parameters for the outcome of intrauterine insemination, IVF and ICSI. Hum. Reprod.. 2004;19:1401-1408 Crossref
- Bungum et al., 2007 M. Bungum, P. Humaidan, A. Axmon, M. Spano, L. Bungum, J. Erenpreiss, A. Giwercman. Sperm DNA integrity assessment in prediction of assisted reproduction technology outcome. Hum. Reprod.. 2007;22:174-179
- Buttram and Reiter, 1981 V.C. Buttram Jr., R. Reiter. Uterine leiomyomata: etiology, symptomatology, and management. Fertil. Steril.. 1981;36:433-445
- Campana et al., 1986 M. Campana, A. Serra, G. Neri. Role of chromosome aberrations in recurrent abortion: a study of 269 balanced translocations. Am. J. Med. Genet.. 1986;24:341-356 Crossref
- Camus et al., 1999 E. Camus, C. Poncelet, F. Goffinet, B. Wainer, F. Merlet, I. Nisand, H.J. Philippe. Pregnancy rates after in-vitro fertilization in cases of tubal infertility with and without hydrosalpinx: a meta-analysis of published comparative studies. Hum. Reprod.. 1999;14:1243-1249 Crossref
- Canis et al., 1991 M. Canis, G. Mage, J.L. Pouly, H. Manhes, A. Wattiez, M.A. Bruhat. Laparoscopic distal tuboplasty: report of 87 cases and a 4-year experience. Fertil. Steril.. 1991;56:616-621
- Clark and Stricker, 2006 D.A. Clark, R.B. Stricker. Is intravenous immunoglobulins (IVIG) efficacious in early pregnancy failure? A critical review and meta-analysis for patients who fail in vitro fertilisation and embryo transfer (IVF). J. Assist. Reprod. Genet.. 2006;23:113 Crossref
- Cohen et al., 2007 J. Cohen, D. Wellis, S. Munné. Removal of 2 cells from cleavage stage embryos is likely to reduce the efficacy of chromosomal tests that are used to enhance implantation rates. Fertil. Steril.. 2007;87:496-503 Crossref
- Collins, 2009 J. Collins. Mild stimulation for in vitro fertilization: making progress downward. Hum. Reprod. Update. 2009;15:1-3
- Collins et al., 2008 J.A. Collins, K. Barnhart, P.N. Schlegel. Do sperm DNA integrity tests predict pregnancy with in vitro fertilization?. Fertil. Steril.. 2008;89:823-831 Crossref
- Conaghan et al., 1993 J. Conaghan, K. Hardy, A.H. Handyside, R.M. Winston, H.J. Leese. Selection criteria for human embryo transfer: a comparison of pyruvate uptake and morphology. J. Assist. Reprod. Genet.. 1993;10:21-30 Crossref
- Cooper et al., 1995 G.S. Cooper, D. Baird, B.S. Hulka, C.R. Weinberg, D.A. Savitz, C.L. Hughes Jr. Follicle-stimulating hormone concentrations in relation to active and passive smoking. Obstet. Gynecol.. 1995;85:407-411 Crossref
- Coughlan et al., in press Coughlan, C., Yuan, Xi, Demirol, A., Ledger, W., Li, T.C. Factors affecting the outcome of ‘Endometrial Scratch’ in women with recurrent implantation failure. J. Reprod. Med., in press.
- Coulam et al., 1997 C. Coulam, B. Kaider, A.S. Kaider, P. Janowicz, R.G. Roussev. Antiphospholipid antibodies associated with implantation failure after IVF.ET. J. Assist. Reprod. Genet.. 1997;14:603-606
- Crosignani and Rubin, 1982 Crosignani, Rubin. Genetic Control of Gamete Production and Function. (Academic Press, New York, 1982)
- Cruz et al., 1999 J.R. Cruz, A.K. Dubey, J. Patel, D. Peak, B. Hartog, P.R. Gindoff. Is blastocyst transfer useful as an alternative treatment for patients with multiple in vitro fertilization failures?. Fertil. Steril.. 1999;72:218-220 Crossref
- Cutting et al., 2008 R. Cutting, D. Morroll, S.A. Roberts, S. Pickering, A. Rutherford. Elective single embryo transfer: guidelines for practice British Fertility Society and Association of Clinical Embryologists. Hum. Fertil. (Camb.). 2008;11:131-146 Crossref
- Daftary and Taylor, 2000 G.S. Daftary, H.S. Taylor. Implantation in the human: the role of HOX genes. Semin. Reprod. Med.. 2000;18:311-320 Crossref
- Das and Holzer, 2012 M. Das, H.E. Holzer. Recurrent implantation failure: gamete and embryo factors. Fertil. Steril.. 2012;97:1021-1027
- Das et al., 2009 S. Das, D. Blake, C. Farquhar, M.M. Seif. Assisted hatching on assisted conception (IVF and ICSI). Cochrane Database Syst. Rev.. 2009;:CD001894
- Dawood et al., 2010 A. Dawood, A. Al-Talib, T. Tulandi. Predisposing factors and treatment outcome of different stages of intrauterine adhesions. J. Obstet. Gynaecol. Can.. 2010;32:767-770
- Demirol and Gurgan, 2004a A. Demirol, T. Gurgan. Effect of treatment of intrauterine pathologies with office hysteroscopy in patients with recurrent IVF failure. Reprod. Biomed. Online. 2004;:590-594 Crossref
- Demirol and Gurgan, 2004b 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 Crossref
- Devroey et al., 1996 P. Devroey, H. Godoy, J. Smitz, M. Camus, H. Tournaye, M.P. Derde, A. Van Steirteghem. Female age predicts embryonic implantation after ICSI: a case-controlled study. Hum. Reprod.. 1996;11:1324-1327 Crossref
- Dirckx et al., 2009 K. Dirckx, P. Cabri, A. Merien, L. Galajdova, J. Gerris, M. Dhont, P. De Sutter. Does low-dose aspirin improve pregnancy rate in IVF/ICSI? A randomized double-blind placebo controlled trial. Hum. Reprod.. 2009;24:856-860
- Donnez and Jadoul, 2002 J. Donnez, P. Jadoul. What are the implications of myomas on fertility? A need for a debate?. Hum. Reprod.. 2002;17:1424-1430 Crossref
- Donoso et al., 2007 P. Donoso, C. Staessen, B.C. Fauser, P. Devroey. Current value of preimplantation genetic aneuploidy screening in IVF. Hum. Reprod. Update. 2007;13:15-25
- Du and Taylor, 2004 H. Du, H.S. Taylor. Molecular regulation of Müllerian development by Hox genes. Ann. N. Y. Acad. Sci.. 2004;1034:152-165 Crossref
- Dubuisson et al., 1994 J.B. Dubuisson, C. Chapron, P. Morice, F.X. Aubriot, H. Foulot, J. Bouquet de Joliniere. Laparoscopic salpingostomy: fertility results according to the tubal mucosal appearance. Hum. Reprod.. 1994;9:334-339
- Duran et al., 2002 E.H. Duran, M. Morshedi, S. Taylor, S. Oehninger. Sperm DNA quality predicts intrauterine insemination outcome: a prospective cohort study. Hum. Reprod.. 2002;17:3122-3128 Crossref
- Edi-Osagie et al., 2003 E. Edi-Osagie, L. Hooper, M.W. Seif. The impact of assisted hatching on live birth rates and outcomes of assisted conception: a systematic review. Hum. Reprod.. 2003;18:1828-1835 Crossref
- Egbase et al., 1996 P.E. Egbase, M. al-Sharhan, S. al-Othman, M. al-Mutawa, E.E. Udo, J.G. Grudzinskas. Incidence of microbial growth from the tip of the embryo transfer catheter after embryo transfer in relation to clinical pregnancy rate following in-vitro fertilization and embryo transfer. Hum. Reprod.. 1996;11:1687-1689 Crossref
- Eldar-Geva et al., 1998 T. Eldar-Geva, S. Meagher, D.L. Healy, V. MacLachlan, S. Breheny, C. Wood. Effect of intramural, subserosal, and submucosal uterine fibroids on the outcome of assisted reproductive technology treatment. Fertil. Steril.. 1998;70:687-691 Crossref
- El-Toukhy et al., 2012 T. El-Toukhy, S. Sunkara, Y. Khalaf. Local endometrial injury and IVF outcome: a systematic review and meta-analysis. Reprod. Biomed. Online.. 2012;25:345-354 Crossref
- Erenpreiss et al., 2002 J. Erenpreiss, S. Hlevicka, J. Zalkalns, J. Erenpreisa. Effect of leukocytospermia on sperm DNA integrity: a negative effect in abnormal semen samples. J. Androl.. 2002;23:717-723
- Erenpreiss et al., 2006 J. Erenpreiss, M. Bungum, M. Spano, S. Elzanaty, J. Orbidans, A. Giwercman. Intra-individual variation in sperm chromatin structure assay parameters in men from infertile couples: clinical implications. Hum. Reprod.. 2006;21:2061-2064 Crossref
- Evenson, 1990 D.P. Evenson. Flow cytometric analysis of male germ cell quality. Methods Cell Biol.. 1990;33:401-410 Crossref
- Evenson et al., 2002 D.P. Evenson, K.L. Larson, L.K. Jost. Sperm chromatin structure assay: its clinical use for detecting sperm DNA fragmentation in male infertility and comparisons with other techniques. J. Androl.. 2002;23:25-43
- Evenson and Wixon, 2008 D.P. Evenson, R. Wixon. Data analysis of two in vivo fertility studies using Sperm Chromatin Structure Assay-derived DNA fragmentation index vs. pregnancy outcome. Fertil. Steril.. 2008;90:1229-1231 Crossref
- Farhi et al., 1995 J. Farhi, J. Ashkenazi, D. Feldberg, D. Dicker, R. Orvieto, Z. Ben Rafael. Effect of uterine leiomyomata on the results of in-vitro fertilization treatment. Hum. Reprod.. 1995;10:2576-2578
- Fedele et al., 1992 L. Fedele, S. Bianchi, M. Dorta, L. Arcaini, F. Zanotti, S. Carinelli. Transvaginal ultrasonography in the diagnosis of diffuse adenomyosis. Fertil. Steril.. 1992;58:94-97
- Fedele et al., 1993 L. Fedele, L. Arcaini, F. Parazzini, P. Vercellini, G. Di Nola. Reproductive prognosis after hysteroscopic metroplasty in 102 women: life-table analysis. Fertil. Steril.. 1993;59:768-772
- Fedele et al., 1996 L. Fedele, S. Bianchi, B. Agnoli, L. Tozzi, M. Vignali. Urinary tract anomalies associated with unicornuate uterus. J. Urol.. 1996;155:847-848
- Feichtinger et al., 1997 W. Feichtinger, K. Papalambrou, M. Poehl, U. Krischker, K. Neumann. Smoking and in vitro fertilization: a meta-analysis. J. Assist. Reprod. Genet.. 1997;14:596-599 Crossref
- Fernandez et al., 2000 J.L. Fernandez, F. Vazquez-Gundin, A. Delgado, V.J. Goyanes, J. Ramiro-Diaz, J. de la Torre, J. Gosalvez. DNA breakage detection-FISH (DBD-FISH) in human spermatozoa: technical variants evidence different structural features. Mutat. Res.. 2000;453:77-82 Crossref
- Fernandez et al., 2001 H. Fernandez, O. Sefrioui, C. Virelizier, A. Gervaise, V. Gomel, R. Frydman. Hysteroscopic resection of submucosal myomas in patients with infertility. Hum. Reprod.. 2001;16:1489-1492 Crossref
- Fernandez et al., 2003 J.L. Fernandez, L. Muriel, M.T. Rivero, V. Goyanes, R. Vazquez, J.G. Alvarez. The sperm chromatin dispersion test: a simple method for the determination of sperm DNA fragmentation. J. Androl.. 2003;24:59-66
- Fernandez-Gonzalez et al., 2008 R. Fernandez-Gonzalez, P.N. Moreira, M. Perez-Crespo, M. Sanchez-Martin, M.A. Ramirez, E. Pericuesta, A. Bilbao, P. Bermejo-Alvarez, J. de Dios Hourcade, F.R. de Fonseca, A. Gutierrez-Adan. Long-term effects of mouse intracytoplasmic sperm injection with DNA-fragmented sperm on health and behavior of adult offspring. Biol. Reprod.. 2008;78:761-772 Crossref
- Ferraretti et al., 2011 A.P. Ferraretti, A. La Marca, B.C. Fauser, B. Tarlatzis, G. Nargund, L. Gianaroli. ESHRE consensus on the definition of ‘poor response’ to ovarian stimulation for in vitro fertilization: the Bologna criteria. Hum. Reprod.. 2011;26:1616-1624 Crossref
- Fluker et al., 1993 M.R. Fluker, C.G. Zouves, M.W. Bebbington. A prospective randomized comparison of zygote intrafallopian transfer and in vitro fertilisation – embryo transfer for nontubal factor infertility. Fertil. Steril.. 1993;60:519
- Fragouli et al., 2008 E. Fragouli, M. Lenzi, R. Ross, M. Katz-Jaffe, W.R. Schoolcraft, D. Wells. Comprehensive molecular cytogenetic analysis of the human blastocyst stage. Hum. Reprod.. 2008;2008:2596-2608 Crossref
- Fragouli et al., 2010 E. Fragouli, M. Katz-Jaffe, S. Alfarawati, J. Stevens, P. Colls, N. Goodall, S. Tormasi, C. Gutierrez-Mateo, R. Prates, W.B. Schoolcraft, S. Munné, D. Wells. Comprehensive chromosome screening of polar bodies and blastocysts from couples experiencing repeated implantation failure. Fertil. Steril.. 2010;94:875-887 Crossref
- Fragouli et al., 2011 E. Fragouli, S. Alfarawati, D. Daphnis, N. Goodall, A. Mania, T. Griffiths, A. Gordon, D. Wells. Cytogenetic analysis of human blastocysts with the use of FISH, CGH and aCGH: scientific data and technical evaluation. Hum. Reprod.. 2011;26:480-490 Crossref
- Galen et al., 2011 D.I. Galen, N. Khan, K.S. Richter. Essure multicentre off-label treatment for hydrosalpinx before in vitro fertilization. J. Minim. Invasive Gynecol.. 2011;18:338-342 Crossref
- Gandini et al., 2004 L. Gandini, F. Lombardo, D. Paoli, F. Caruso, P. Eleuteri, G. Leter, R. Ciriminna, F. Culasso, F. Dondero, A. Lenzi, M. Spano. Full-term pregnancies achieved with ICSI despite high levels of sperm chromatin damage. Hum. Reprod.. 2004;19:1409-1417 Crossref
- Garcia and Tureck, 1984 C.R. Garcia, R.W. Tureck. Submucosal leiomyomas and infertility. Fertil. Steril.. 1984;42:16-19
- Gardner et al., 2000 D.K. Gardner, M. Lane, J. Stevens, T. Schlenker, W.B. Schoolcraft. Blastocyst score affects implantation and pregnancy outcome: towards a single blastocyst transfer. Fertil. Steril.. 2000;73:1155-1158 Crossref
- Gardner et al., 2001 D.K. Gardner, M. Lane, J. Stevens, W.B. Schoolcraft. Noninvasive assessment of human embryo nutrient consumption as a measure of developmental potential. Fertil. Steril.. 2001;76:1175-1180 Crossref
- 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 Crossref
- Gelbaya et al., 2007 T.A. Gelbaya, M. Kyrgiou, T.C. Li, C. Stern, L.G. Nardo. Low-dose aspirin for in vitro fertilization: a systematic review and meta-analysis. Hum. Reprod. Update. 2007;13:357-364 Crossref
- Gellersen et al., 2007 B. Gellersen, I.A. Brosens, J.J. Brosens. Decidualisation of the human endometrium: mechanisms, functions and clinical perspectives. Semin. Reprod. Med.. 2007;25:445-453 Crossref
- Ghobara et al., 2006 T.S. Ghobara, D.J. Cahill, W.C. 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 Crossref
- Gianaroli et al., 1999 L. Gianaroli, M.C. Magli, A.P. Ferraretti, S. Munné. Preimplantation diagnosis for aneuploidies in patients undergoing in vitro fertilization with a poor prognosis: identification of the categories for which it should be proposed. Fertil. Steril.. 1999;72:837-844 Crossref
- Gianaroli et al., 2005 L. Gianaroli, S. Gordts, A. D’Angelo, M.C. Magli, I. Brosens, C. Cetera, R. Campo, A.P. Ferraretti. Effect of inner myometrium fibroid on reproductive outcome after IVF. Reprod. Biomed. Online. 2005;10:473-477 Crossref
- Glass et al., 2000 K.B. Glass, C. Green, M.R. Fluker, W.B. Schoolcraft, R.T. McNamee, D.R. Meldrum. Multicenter randomized controlled trial of cervical irrigation at the time of embryo transfer. Fertil. Steril.. 2000;73(Suppl. 1):S31 Crossref
- Gleicher et al., 2011 N. Gleicher, A. Vidali, D.H. Barad. Successful treatment of unresponsive thin endometrium. Fertil. Steril.. 2011;95:e2113-e2127
- Goldenberg et al., 1995 M. Goldenberg, E. Sivan, Z. Sharabi, D. Bider, J. Rabinovici, D.S. Seidman. Outcome of hysteroscopic resection of submucous myomas for infertility. Fertil. Steril.. 1995;64:714-716
- Goossens et al., 2008 V. Goossens, M. De Rycke, A. De Vos, C. Staessen, A. Michiels, W. Verpoest, A. Van Steirteghem, C. Bertrand, I. Liebaers, P. Devroey, K. Sermon. Diagnostic efficiency, embryonic development and clinical outcome after the biopsy of one or two blastomeres for preimplantation genetic diagnosis. Hum. Reprod.. 2008;23:481-492 Crossref
- Gorczyca et al., 1993 W. Gorczyca, F. Traganos, H. Jesionowska, Z. Darzynkiewicz. Presence of DNA strand breaks and increased sensitivity of DNA in situ to denaturation in abnormal human sperm cells: analogy to apoptosis of somatic cells. Exp. Cell Res.. 1993;207:202-205 Crossref
- Goto et al., 2003 S. Goto, K. Takebayashi, M. Shiotani, M. Fujiwara, M. Hirose, Y. Noda. Effectiveness of 2-step (consecutive) embryo transfer. Comparison with cleavage-stage transfer. J. Reprod. Med.. 2003;48:370-374
- Gott et al., 1990 A.L. Gott, K. Hardy, R.M. Winston, H.J. Leese. Non-invasive measurement of pyruvate and glucose uptake and lactate production by single human preimplantation embryos. Hum. Reprod.. 1990;5:104-108
- Grandone et al., 2001 E. Grandone, D. Colaizzo, A. Lo Bue, M.G. Checola, E. Cittadini, M. Margaglione. Inherited thrombophilia and in vitro fertilization implantation failure. Fertil. Steril.. 2001;76:201-202 Crossref
- Greco et al., 2005a E. Greco, M. Iacobelli, L. Rienzi, F. Ubaldi, S. Ferrero, J. Tesarik. Reduction of the incidence of sperm DNA fragmentation by oral antioxidant treatment. J. Androl.. 2005;26:349-353 Crossref
- Greco et al., 2005b E. Greco, F. Scarselli, M. Iacobelli, L. Rienzi, F. Ubaldi, S. Ferrero, G. Franco, N. Anniballo, C. Mendoza, J. Tesarik. Efficient treatment of infertility due to sperm DNA damage by ICSI with testicular spermatozoa. Hum. Reprod.. 2005;20:226-230
- Grimbizis et al., 2001 G.F. Grimbizis, M. Camus, B.C. Tarlatzis, J.N. Bontis, P. Devroey. Clinical implications of uterine malformations and hysteroscopic treatment results. Hum. Reprod. Update. 2001;7:161-174 Crossref
- Grimbizis et al., 2010 G.F. Grimbizis, D. Tsolakidis, T. Mikos, E. Anagnostou, E. Asimakopoulos, P. Stamatopoulos, B.C. Tarlatzis. A prospective comparison of transvaginal ultrasound, saline infusion sonohysterography, and diagnostic hysteroscopy in the evaluation of endometrial pathology. Fertil. Steril.. 2010;94:2720-2725 Crossref
- Guerif et al., 2004 F. Guerif, R. Bidault, O. Gasnier, M.L. Couet, O. Gervereau, J. Lansac, D. Royere. Efficacy of blastocyst transfer after implantation failure. Reprod. Biomed. Online. 2004;9:630-636 Crossref
- Habana and Palter, 2001 A. Habana, S.F. Palter. Is tubal embryo transfer of any value? A meta analysis and comparison with the society for assisted reproductive technology database. Fertil. Steril.. 2001;76:293
- Hammadieh et al., 2008 N. Hammadieh, A. Coomarasamy, B. Ola, S. Papaioannou, M. Afnan, K. Sharif. Ultrasound-guided hydrosalpinx aspiration during oocyte collection improves pregnancy outcome in IVF: a randomized controlled trial. Hum. Reprod.. 2008;23:1113-1117 Crossref
- Hardy et al., 1989 K. Hardy, M.A. Hooper, A.H. Handyside, A.J. Rutherford, R.M. Winston, H.J. Leese. Non-invasive measurement of glucose and pyruvate uptake by individual human oocytes and preimplantation embryos. Hum. Reprod.. 1989;4:188-191
- Harper et al., 1995 J.C. Harper, E. Coonen, A.H. Handyside, R.M. Winston, A.H. Hopman, J.D. Delhanty. Mosaicism of autosomes and sex chromosomes in morphologically normal, monospermic preimplantation human embryos. Prenat. Diagn.. 1995;15:41-49 Crossref
- Hart et al., 2001 R. Hart, Y. Khalaf, C.T. Yeong, P. Seed, A. Taylor, P. Braude. A prospective controlled study of the effect of intramural uterine fibroids on the outcome of assisted conception. Hum. Reprod.. 2001;16:2411-2417
- Hernandez-Gonzalez et al., 2006 I. Hernandez-Gonzalez, I. Gonzalez-Robayna, M. Shimada, C.M. Wayne, S.A. Ochsner, L. White, J.S. Richards. Gene expression profiles of cumulus cell oocyte complexes during ovulation reveal cumulus cells express neuronal and immune-related genes: does this expand their role in the ovulation process?. Mol. Endocrinol.. 2006;20:1300-1321 Crossref
- Hershlag et al., 1999 A. Hershlag, T. Paine, G.W. Cooper, G.M. Scholl, K. Rawlinson, G. Kvapil. Monozygotic twinning associated with mechanical assisted hatching. Fertil. Steril.. 1999;71:144-146 Crossref
- Hill and Scott, 2000 J.A. Hill, R.T. Scott. Immunologic tests and IVF: ‘Please, enough already’. Fertil. Steril.. 2000;74:439-442 Crossref
- Homer et al., 2000 H.A. Homer, T.C. Li, I.D. Cooke. The septate uterus: a review of management and reproductive outcome. Fertil. Steril.. 2000;73:1-14 Crossref
- Horne et al., 1997 G. Horne, J.D. Critchlow, M.C. Newman, L. Edozien, P.L. Matson, B.A. Lieberman. A prospective evaluation of cryopreservation strategies in a two-embryo transfer programme. Hum. Reprod.. 1997;12:542-547 Crossref
- Hornstein et al., 2000 M.D. Hornstein, O.K. Davis, J.B. Massey, R.J. Paulson, J.A. Collins. Antiphospholipid antibodies and in vitro fertilization success: a meta-analysis. Fertil. Steril.. 2000;73:330-333 Crossref
- Houghton et al., 2002 F.D. Houghton, J.A. Hawkhead, P.G. Humpherson, J.E. Hogg, A.H. Balen, A.J. Rutherford, H.J. Leese. Non-invasive amino acid turnover predicts human embryo developmental capacity. Hum. Reprod.. 2002;17:999-1005
- Hughes and Brennan, 1996 E.G. Hughes, B.G. Brennan. Does cigarette smoking impair natural or assisted fecundity?. Fertil. Steril.. 1996;66:679-689
- Hughes et al., 1996 C.M. Hughes, S.E. Lewis, V.J. McKelvey-Martin, W. Thompson. A comparison of baseline and induced DNA damage in human spermatozoa from fertile and infertile men, using a modified comet assay. Mol. Hum. Reprod.. 1996;2:613-619 Crossref
- Hunt and Wallach, 1974 J.E. Hunt, E.E. Wallach. Uterine factors in infertility – an overview. Clin. Obstet. Gynecol.. 1974;17:44-64 Crossref
- Isidori et al., 2006 A.M. Isidori, C. Pozza, D. Ganfrilli, A. Isidori. Medical treatment to improve sperm quality. Reprod. Biomed. Online. 2006;12:704-714 Crossref
- Jakab et al., 2005 A. Jakab, D. Sakkas, E. Delpiano, S. Cayli, E. Kovanci, D. Ward, A. Revelli, G. Huszar. Intracytoplasmic sperm injection: a novel selection method for sperm with normal frequency of chromosomal aneuploidies. Fertil. Steril.. 2005;84:1665-1673 Crossref
- Jansen, 1984 R. Jansen. Endocrine response in the fallopian tube. Endocr. Rev.. 1984;5:551
- Johnson et al., 2010 N. Johnson, S. van Voorst, M.C. Sowter, A. Strandell, B.W. Mol. Surgical treatment for tubal disease in women due to undergo in vitro fertilisation. Cochrane Database Syst Rev.. 2010;20:CD002125
- Kaider et al., 1996 B.D. Kaider, D.E. Price, R.G. Roussev, C.B. Coulam. Antiphospholipid antibody prevalence in patients with IVF failure. Am. J. Reprod. Immunol.. 1996;35:388-393 Crossref
- Karimzade et al., 2010 M.A. Karimzade, H. Oskouian, S. Ahmadi, L. Oskouian. Local injury to the endometrium on the day of oocyte retrieval has a negative impact on implantation in assisted reproductive cycles: a randomized controlled trial. Arch. Gynecol. Obstet.. 2010;281:499-503 Crossref
- 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 Crossref
- Katz et al., 1996 Z. Katz, A. Ben-Arie, S. Lurie, M. Manor, V. Insler. Reproductive outcome following hysteroscopic adhesiolysis in Asherman’s syndrome. Int. J. Fertil. Menopausal Stud.. 1996;41:462-465
- Klatsky et al., 2007 P.C. Klatsky, D.E. Lane, I.P. Ryan, V.Y. Fujimoto. The effect of fibroids without cavity involvement on ART outcomes independent of ovarian age. Hum. Reprod.. 2007;22:521-526
- Klonoff-Cohen et al., 2001 H. Klonoff-Cohen, L. Natarajan, R. Marrs, B. Yee. Effects of female and male smoking on success rates of IVF and gamete intra-Fallopian transfer. Hum. Reprod.. 2001;16:1382-1390 Crossref
- Kontoravdis et al., 2006 A. Kontoravdis, E. Makrakis, K. Pantos, D. Botsis, E. Deligeoroglou, G. Creatsas. Proximal tubal occlusion and salpingectomy result in similar improvement in in vitro fertilization outcome in patients with hydrosalpinx. Fertil. Steril.. 2006;86:1642-1649 Crossref
- Koot et al., 2012 Y. Koot, G. Teklenburg, M. Salker, J. Brosens, N. Macklon. Molecular aspects of implantation failure. Biochim. Biophys. Acta. 2012;1822:1943-1950 Crossref
- Kowalik et al., 1997 A. Kowalik, M. Vichnin, H.C. Liu, W. Branch, A.S. Berkeley. Midfollicular anticardiolipin and antiphosphatidylserine antibody titers do not correlate with in vitro fertilization outcome. Fertil. Steril.. 1997;68:298-304 Crossref
- Larson et al., 2000 K.L. Larson, C.J. DeJonge, A.M. Barnes, L.K. Jost, D.P. Evenson. Sperm chromatin structure assay parameters as predictors of failed pregnancy following assisted reproductive techniques. Hum. Reprod.. 2000;15:1717-1722 Crossref
- Larson-Cook et al., 2003 K.L. Larson-Cook, J.D. Brannian, K.A. Hansen, K.M. Kasperson, E.T. Aamold, D.P. Evenson. Relationship between the outcomes of assisted reproductive techniques and sperm DNA fragmentation as measured by the sperm chromatin structure assay. Fertil. Steril.. 2003;80:895-902 Crossref
- Laufer and Simon, 2012 N. Laufer, A. Simon. Recurrent implantation failure: current update and clinical approach to an ongoing challenge. Fertil. Steril.. 2012;97:1019-1020 Crossref
- Lavergne et al., 1996 N. Lavergne, J. Aristizabal, V. Zarka, R. Erny, B. Hedon. Uterine anomalies and in vitro fertilization: what are the results?. Eur. J. Obstet. Gynecol. Reprod. Biol.. 1996;68:29-34 Crossref
- Lesny et al., 1999 P. Lesny, S.R. Killick, J. Robinson, G. Raven, S.D. Maguiness. Junctional zone contractions and embryo transfer: is it safe to use a tenaculum?. Hum. Reprod.. 1999;14:2367-2370 Crossref
- Letterie et al., 2003 G. Letterie, L. Marshall, M. Angle. Intrauterine reflux of media during cervical irrigation at embryo transfer. Fertil. Steril.. 2003;79:1444-1445 Crossref
- Levitas et al., 2004 E. Levitas, E. Lunenfeld, I. Har-Vardi, S. Albotiano, Y. Sonin, R. Hackmon-Ram, G. Potashnik. Blastocyst–stage embryo transfer in patients who failed to conceive in three or more day 2–3 embryo transfer cycles: a prospective, randomized study. Fertil. Steril.. 2004;81:567-571 Crossref
- Levran et al., 1998 D. Levran, S. Mashiach, J. Dor, J. Levron, J. Farhi. Zygote intrafallopian transfer may imnprove pregnancy rate in patients with repeated failure of implantation. Fertil. Steril.. 1998;69:30
- 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 Crossref
- Liatsikos et al., 2010 S.A. Liatsikos, G.F. Grimbizis, I. Georgiou, N. Papadopoulos, L. Lazaros, J.N. Bontis, B.C. Tarlatzis. HOX A10 and HOX A11 mutation scan in congenital malformations of the female genital tract. Reprod. Biomed. Online. 2010;21:126-132 Crossref
- Lieberman et al., 1992 B.A. Lieberman, S.A. Troup, P.L. Matson. Cryopreservation of embryos and pregnancy rates after IVF. Lancet. 1992;340:116 Crossref
- Lopes et al., 2007 A.S. Lopes, T. Greve, H. Callesen. Quantification of embryo quality by respirometry. Theriogenology. 2007;67:21-31 Crossref
- 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
- Machtinger et al., 2006 R. Machtinger, J. Dor, M. Margolin, J. Levron, M. Baum, B. Ferber, A. Shulman, D. Bider, D.S. Seidman. Sequential transfer of day 3 embryos and blastocysts after previous IVF failures despite adequate ovarian response. Reprod. Biomed. Online. 2006;13:376-379 Crossref
- Maheshwari et al., 2012 A. Maheshwari, S. Gurunath, F. Fatima, S. Bhattacharya. Adenomyosis and subfertility: a systematic review of prevalence, diagnosis, treatment and fertility outcomes. Hum. Reprod. Update. 2012;18:374-392 Crossref
- Mains and Van Voorhis, 2010 L. Mains, B.J. Van Voorhis. Optimizing the technique of embryo transfer. Fertil. Steril.. 2010;94:785-790 Crossref
- Makrakis and Pantos, 2010 E. Makrakis, K. Pantos. The outcomes of hysteroscopy in women with implantation failures after in-vitro fertilization: findings and effect on subsequent pregnancy rates. Curr. Opin. Obstet. Gynecol.. 2010;22:339-343
- Makrigiannakis et al., 2011 A. Makrigiannakis, G. Petsas, B. Toth, K. Relakis, U. Jeschke. Recent advances in understanding immunology of reproductive failure. J. Reprod. Immunol.. 2011;90:96-104 Crossref
- Manicardi et al., 1995 G.C. Manicardi, P.G. Bianchi, S. Pantano, P. Azzoni, D. Bizzaro, U. Bianchi, D. Sakkas. Presence of endogenous nicks in DNA of ejaculated human spermatozoa and its relationship to chromomycin A3 accessibility. Biol. Reprod.. 1995;52:864-867 Crossref
- Mansour et al., 2000 R.T. Mansour, C.A. Rhodes, M.A. Aboulghar, G.I. Serour, A. Kamal. Transfer of zona-free embryos improves outcome in poor prognosis patients: a prospective randomized controlled study. Hum. Reprod.. 2000;15:1061-1064 Crossref
- Marceau et al., 2004 P. Marceau, D. Kaufman, S. Biron, F.S. Hould, S. Lebel, S. Marceau, J.G. Kral. Outcome of pregnancies after biliopancreatic diversion. Obes. Surg.. 2004;14:318-324 Crossref
- March, 2011 C.M. March. Management of Asherman’s syndrome. Reprod. Biomed. Online. 2011;23:63-76 Crossref
- Marek et al., 1999 D. Marek, M. Langley, D.K. Gardner, N. Confer, K.M. Doody, K.J. Doody. Introduction of blastocyst culture and transfer for all patients in an in vitro fertilization program. Fertil. Steril.. 1999;72:1035-1040 Crossref
- 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 Crossref
- Marrs et al., 2004 R. Marrs, D. Meldrum, S. Muasher, W. Schoolcraft, L. Werlin, E. Kelly. Randomized trial to compare the effect of recombinant human FSH (follitropin alfa) with or without recombinant human LH in women undergoing assisted reproduction treatment. Reprod. Biomed. Online. 2004;8:175-182 Crossref
- Martinelli et al., 2003 I. Martinelli, E. Taioli, G. Ragni, P. Levi-Setti, S.M. Passamonti, T. Battaglioli, C. Lodigiani, P.M. Mannucci. Embryo implantation after assisted reproductive procedures and maternal thrombophilia. Haematologica. 2003;88:789-793
- Martins et al., 2011 W.P. Martins, I.A. Rocha, R.A. Ferriani, C.O. Nastri. Assisted hatching of human embryos: a systematic review and meta-analysis of randomized controlled trials. Hum. Reprod. Update. 2011;17:438-453 Crossref
- McComb and Paleologou, 1991 P.F. McComb, A. Paleologou. The intussusception salpingostomy technique for the therapy of distal oviductal occlusion at laparoscopy. Obstet. Gynecol.. 1991;78:443-447
- McIlveen and Li, 2005 M. McIlveen, T.C. Li. Myomectomy: a review of surgical technique. Hum. Fertil. (Camb.). 2005;8:27-33 Crossref
- McNamee et al., 1997 P. McNamee, T. Huang, A. Carwile, B. Chun, T. Kosasa, C. Morton, F. Terada. Significant increase in pregnancy rate achieved by vigorous irrigation of endocervical mucus prior to embryo transfer with the Wallace catheter in an IVF-ET program. Fertil. Steril.. 1997;68(Suppl. 1):S208-S209
- Mettler et al., 1990 L. Mettler, S. Irani, A. Kapamadzija, K. Semm. Pelviscopic tubal surgery: the acceptable vogue. Hum. Reprod.. 1990;5:971-974
- Metwally et al., 2011 M. Metwally, C.M. Farquhar, T.C. Li. Is another meta-analysis on the effects of intramural fibroids on reproductive outcomes needed?. Reprod. Biomed. Online. 2011;23:2-14 Crossref
- Mijatovic et al., 2010 V. Mijatovic, S. Veersema, Mh. Emanuel, R. Schats, P.G. Hompes. Essure hysteroscopic tubal occlusion device for the treatment of hydrosalpinx prior to in-vitro fertilization -embryo transfer in patients with a contraindication for laparoscopy. Fertil. Steril.. 2010;93:1338-1342 Crossref
- Mijatovic et al., 2012 V. Mijatovic, K. Dreyer, M.H. Emanuel, R. Schats, P.G. Hompes. Essure hydrosalpinx occlusion prior to IVF-ET as an alternative to laparoscopic salpingectomy. Eur. J. Obstet. Gynecol. Reprod. Biol.. 2012;161:42-45 Crossref
- Morris, 2002 I.D. Morris. Sperm DNA damage and cancer treatment. Int. J. Androl.. 2002;25:255-261 Crossref
- Motta et al., 1995a P.M. Motta, S.A. Nottola, G. Familiari, G. Macchiarelli, E. Vizza, S. Correr. Ultrastructure of human reproduction from folliculogenesis to early embryo development. A review. Ital. J. Anat. Embryol.. 1995;100:9-72
- Motta et al., 1995b P.M. Motta, S.A. Nottola, J. Pereda, H.B. Croxatto, G. Familiari. Ultrastructure of human cumulus oophorus: a transmission electron microscopic study on oviductal oocytes and fertilized eggs. Hum. Reprod.. 1995;10:2361-2367 Crossref
- Mukherjee et al., 2005 R.A. Mukherjee, S. Hollins, M.T. Abou-Saleh, J. Turk. Low level alcohol consumption and the fetus. BMJ. 2005;330:375-376 Crossref
- Munné et al., 1997 S. Munné, C. Magli, A. Adler, G. Wright, K. de Boer, D. Mortimer, M. Tucker, J. Cohen, L. Gianaroli. Treatment-related chromosome abnormalities in human embryos. Hum. Reprod.. 1997;12:780-784
- Muriel et al., 2006 L. Muriel, M. Meseguer, J.L. Fernandez, J. Alvarez, J. Remohi, A. Pellicer, N. Garrido. Value of the sperm chromatin dispersion test in predicting pregnancy outcome in intrauterine insemination: a blind prospective study. Hum. Reprod.. 2006;21:738-744
- Narayan and Goswamy, 1994 R. Narayan, Rajat K. Goswamy. Treatment of submucous fibroids, and outcome of assisted conception. J. Am. Assoc. Gynecol. Laparosc.. 1994;1:307-311 Crossref
- Narvekar et al., 2010 S.A. Narvekar, N. Gupta, N. Shetty, A. Kottur, M. Srinivas, K.A. Rao. Does local endometrial injury in the nontransfer cycle improve the IVF-ET outcome in the subsequent cycle in patients with previous unsuccessful IVF? A randomized controlled pilot study. J. Hum. Reprod. Sci.. 2010;3:15-19 Crossref
- National Institute for Health and Care Excellence, 2013 National Institute for Health and Care Excellence, 2013. Fertility: assessment and treatment for people with fertility problems. Clinical Guidelines CG156.
- Netherlands, 2007 H.C.o.t. Netherlands. Preconception Care: A Good Beginning. (Health Council of the Netherlands, The Hague, 2007)
- Northrop et al., 2010 L.E. Northrop, N.R. Treff, B. Levy, R.T. Scott Jr. SNP microarray -based 24 chromosome aneuploidy screening demonstrates that cleavage stage FISH poorly predicts aneuploidy in embryos that develop to morphologically normal blastocysts. Mol. Hum. Reprod.. 2010;16:590-600 Crossref
- Nottola et al., 1991 S.A. Nottola, G. Familiari, G. Micara, C. Aragona, P.M. Motta. The ultrastructure of human cumulus-corona cells at the time of fertilization and early embryogenesis. A scanning and transmission electron microscopic study in an in vitro fertilization program. Arch. Histol. Cytol.. 1991;54:145-161 Crossref
- Oliveira et al., 2004 F.G. Oliveira, V.G. Abdelmassih, M.P. Diamond, D. Dozortsev, N.R. Melo, R. Abdelmassih. Impact of subserosal and intramural uterine fibroids that do not distort the endometrial cavity on the outcome of in vitro fertilization-intracytoplasmic sperm injection. Fertil. Steril.. 2004;81:582-587 Crossref
- Oliveira et al., 2011 J.B. Oliveira, M. Cavagna, C.G. Petersen, A.L. Mauri, F.C. Massaro, L.F. Silva, R.L. Baruffi, J.G. Franco Jr. Pregnancy outcomes in women with repeated implantation failures after intracytoplasmic morphologically selected sperm injection (IMSI). Reprod. Biol. Endocrinol.. 2011;9:99 Crossref
- Pabuccu and Gomel, 2004 R. Pabuccu, V. Gomel. Reproductive outcome after hysteroscopic metroplasty in women with septate uterus and otherwise unexplained infertility. Fertil. Steril.. 2004;81:1675-1678 Crossref
- Pace et al., 2003 S. Pace, P. Stentella, R. Catania, P.L. Palazzetti, A. Frega. Endoscopic treatment of intrauterine adhesions. Clin. Exp. Obstet. Gynecol.. 2003;30:26-28
- Papanikolaou et al., 2008 E.G. Papanikolaou, E.M. Kolibianakis, H. Tournaye, C.A. Venetis, H. Fatemi, B. Tarlatzis, P. Devroey. Live birth rates after transfer of equal number of blastocysts or cleavage-stage embryos in IVF. A systematic review and meta-analysis. Hum. Reprod.. 2008;23:91-99
- Paulson et al., 1990 R.J. Paulson, M.V. Sauer, R.A. Lobo. Factors affecting embryo implantation after human in vitro fertilization: a hypothesis. Am. J. Obstet. Gynecol.. 1990;163:2020-2023 Crossref
- 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 Crossref
- Penzias, 2012 A.S. 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. 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 Crossref
- Phelps et al., 1999 J.Y. Phelps, L. Figueira-Armada, A.S. Levine, N.P. Vlahos, D. Roshanfekr, H.A. Zacur, J.E. Garcia. Exogenous luteinizing hormone (LH) increases estradiol response patterns in poor responders with low serum LH concentrations. J. Assist. Reprod. Genet.. 1999;16:363-368 Crossref
- Potdar et al., 2012 N. Potdar, T. Gelbaya, L.G. Nardo. Endometrial injury to overcome recurrent embryo implantation failure: a systematic review and meta-analysis. Reprod. Biomed. Online.. 2012;25:561-571 Crossref
- Potts et al., 1999 R.J. Potts, C.J. Newbury, G. Smith, L.J. Notarianni, T.M. Jefferies. Sperm chromatin damage associated with male smoking. Mutat. Res.. 1999;423:103-111 Crossref
- Printen and Scott, 1982 K.J. Printen, D. Scott. Pregnancy following gastric bypass for the treatment of morbid obesity. Am. Surg.. 1982;48:363-365
- Pritts et al., 2009 E.A. Pritts, W.H. Parker, D.L. Olive. Fibroids and infertility: an updated systematic review of the evidence. Fertil. Steril.. 2009;91:1215-1223 Crossref
- 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 Crossref
- Qublan et al., 2008 H. Qublan, Z. Amarin, M. Al-Qudah, F. Diab, M. Nawasreh, S. Malkawi, M. Balawneh. Luteal phase support with GnRH-a improves implantation and pregnancy rates in IVF cycles with endometrium of < or = 7 mm on day of egg retrieval. Hum. Fertil. (Camb.). 2008;11:43-47 Crossref
- Rabinovici et al., 2010 J. Rabinovici, M. David, H. Fukunishi, Y. Morita, B.S. Gostout, E.A. Stewart, MRgFUS Study Group. Pregnancy outcome after magnetic resonance-guided focused ultrasound surgery (MRgFUS) for conservative treatment of uterine fibroids. Fertil. Steril.. 2010;93:199-209 Crossref
- Racowsky et al., 2000 C. Racowsky, K.V. Jackson, N.A. Cekleniak, J.H. Fox, M.D. Hornstein, E.S. Ginsburg. The number of eight-cell embryos is a key determinant for selecting day 3 or day 5 transfer. Fertil. Steril.. 2000;73:558-564 Crossref
- Raga et al., 1997 F. Raga, C. Bauset, J. Remohi, F. Bonilla-Musoles, C. Simon, A. Pellicer. Reproductive impact of congenital Müllerian anomalies. Hum. Reprod.. 1997;12:2277-2281 Crossref
- Rama Raju et al., 2006 G.A. Rama Raju, G. Shashi Kumari, K.M. Krishna, G.J. Prakash, K. Madan. Assessment of uterine cavity by hysteroscopy in assisted reproduction programme and its influence on pregnancy outcome. Arch. Gynecol. Obstet.. 2006;:160-164 Crossref
- Raziel et al., 2002 A. Raziel, S. Friedler, M. Schachter, E. Kasterstein, D. Strassburger, R. Ron-EI. Increased frequency of female partner chromosomal abnormalities in patients with high-order implantation failure after in vitro fertilization. Fertil. Steril.. 2002;78:515-519 Crossref
- Raziel et al., 2007 A. Raziel, M. Schachter, D. Strassburger, O. Bern, R. Ron-EI, 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 Crossref
- Reinhold et al., 1996 C. Reinhold, S. McCarthy, P.M. Bret, A. Mehio, M. Atri, R. Zakarian, Y. Glaude, L. Liang, R.J. Seymour. Diffuse adenomyosis: comparison of endovaginal US and MR imaging with histopathologic correlation. Radiology. 1996;199:151-158
- Richlin et al., 2002 S.S. Richlin, S. Ramachandran, A. Shanti, A.A. Murphy, S. Parthasarathy. Glycodelin levels in uterine flushings and in plasma of patients with leiomyomas and polyps: implications for implantation. Hum. Reprod.. 2002;17:2742-2747 Crossref
- Royal College of Obstetricians, 0000 Royal College of Obstetricians and Gynaecologists. Greentop Guidelines. Classification of Evidence Levels. www.rcog.org.uk/guidelines .
- Rotterdam ESHRE/ASRM–Sponsored PCOS Consensus Workshop Group, 2004 Rotterdam ESHRE/ASRM–Sponsored PCOS Consensus Workshop Group, 2004. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS).
- Sagoskin et al., 2003 A.W. Sagoskin, B.A. Lessey, G.L. Mottla, K.S. Richter, R.J. Chetkowski, A.S. Chang, M.J. Levy, R.J. Stillman. Salpingectomy or proximal tubal occlusion of unilateral hydrosalpinx increases the potential for spontaneous pregnancy. Hum. Reprod.. 2003;18:2634-2637 Crossref
- Said et al., 2006 T. Said, A. Agarwal, S. Grunewald, M. Rasch, T. Baumann, C. Kriegel, L. Li, H.J. Glander, A.J. Thomas Jr., U. Paasch. Selection of nonapoptotic spermatozoa as a new tool for enhancing assisted reproduction outcomes: an in vitro model. Biol. Reprod.. 2006;74:530-537 Crossref
- Said et al., 2005 T.M. Said, S. Grunewald, U. Paasch, H.J. Glander, T. Baumann, C. Kriegel, L. Li, A. Agarwal. Advantage of combining magnetic cell separation with sperm preparation techniques. Reprod. Biomed. Online. 2005;10:740-746 Crossref
- Sakkas and Alvarez, 2010 D. Sakkas, J.G. Alvarez. Sperm DNA fragmentation: mechanisms of origin, impact on reproductive outcome, and analysis. Fertil. Steril.. 2010;93:1027-1036 Crossref
- Sakkas and Gardner, 2005 D. Sakkas, D.K. Gardner. Noninvasive methods to assess embryo quality. Curr. Opin. Obstet. Gynecol.. 2005;17:283-288
- Sallam et al., 2003 H.N. Sallam, A.F. Agameya, A.F. Rahman, F. Ezzeldin, A.N. Sallam. Impact of technical difficulties, choice of catheter, and the presence of blood on the success of embryo transfer – experience from a single provider. J. Assist. Reprod. Genet.. 2003;20:135-142 Crossref
- Sallam et al., 2006a H.N. Sallam, Y. El-Kassar, A. Hany Abdel-Rahman, A. Agameya, A. Farraq, A. Shams. Glucose consumption and total protein production by preimplantation embryos in women with the polycystic ovary syndrome. Fertil. Steril.. 2006;86(Suppl. 3):S462-S463 Crossref
- Sallam et al., 2006b H.N. Sallam, J.A. 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
- Schieve et al., 2000 L.A. Schieve, S.F. Meikle, H.B. Peterson, G. Jeng, N.M. Burnett, L.S. Wilcox. Does assisted hatching pose a risk for monozygotic twinning in pregnancies conceived through in vitro fertilization?. Fertil. Steril.. 2000;74:288-294 Crossref
- Schoolcraft et al., 2010 W.R. Schoolcraft, E. Fragouli, I. Stevens, S. Munné, M. Katz-Jaffe, D. Wells. Clinical application of comprehensive chromosomal screening at the blastocyst stage. Fertil. Steril.. 2010;94:1700-1706 Crossref
- Scott et al., 2008 L. Scott, J. Berntsen, D. Davies, J. Gundersen, J. Hill, N. Ramsing. Symposium: innovative techniques in human embryo viability assessment. Human oocyte respiration-rate measurement – potential to improve oocyte and embryo selection?. Reprod. Biomed. Online. 2008;17:461-469 Crossref
- Seif et al., 2005 M.M. Seif, E.C. Edi-Osagie, C. Farquhar, L. Hooper, D. Blake, P. McGinlay. Assisted hatching on assisted conception (IVF and ICSI). Cochrane Database Syst. Rev.. 2005;:CD001894
- Seli et al., 2005 E. Seli, U.A. Kayisli, H. Cakmak, O. Bukulmez, I. Bildirici, O. Guzeloglu-Kayisli, A. Arici. Removal of hydrosalpinges increases endometrial leukaemia inhibitory factor (LIF) expression at the time of the implantation window. Hum. Reprod.. 2005;20:3012-3017 Crossref
- Sharif et al., 1995 K. Sharif, M. Afnan, W. Lenton. Mock embryo transfer with a full bladder immediately before the real transfer for in-vitro fertilization treatment: the Birmingham experience of 113 cases. Hum. Reprod.. 1995;10:1715-1718
- Sharif et al., 1996 K. Sharif, M. Afnan, W. Lenton, D. Bilalis, M. Hunjan, Y. Khalaf. Transmyometrial embryo transfer after difficult immediate mock transcervical transfer. Fertil. Steril.. 1996;65:1071-1074
- Sheiner et al., 2004 E. Sheiner, A. Levy, D. Silverberg, T.S. Menes, I. Levy, M. Katz, M. Mazor. Pregnancy after bariatric surgery is not associated with adverse perinatal outcome. Am. J. Obstet. Gynecol.. 2004;190:1335-1340 Crossref
- Sher and Fisch, 2000 G. Sher, J.D. Fisch. Vaginal sildenafil (Viagra): a preliminary report of a novel method to improve uterine artery blood flow and endometrial development in patients undergoing IVF. Hum. Reprod.. 2000;15:806-809 Crossref
- Sher and Fisch, 2002 G. Sher, J.D. Fisch. Effect of vaginal sildenafil on the outcome of in vitro fertilization (IVF) after multiple IVF failures attributed to poor endometrial development. Fertil. Steril.. 2002;78:1073-1076 Crossref
- Shokeir and Abdelshaheed, 2009 T. Shokeir, M. Abdelshaheed. Sonohysterography as a first-line evaluation for uterine abnormalities in women with recurrent failed in vitro fertilization-embryo transfer. Fertil. Steril.. 2009;91:1321-1322 Crossref
- Shokeir et al., 2004 T.A. Shokeir, H.M. Shalan, M.M. El-Shafei. Significance of endometrial polyps detected hysteroscopically in eumenorrheic infertile women. J. Obstet. Gynaecol. Res.. 2004;30:84-89 Crossref
- Shokeir et al., 2010 T. Shokeir, M. El-Shafei, H. Yousef, A.F. Allam, E. Sadek. Submucous myomas and their implications in the pregnancy rates of patients with otherwise unexplained primary infertility undergoing hysteroscopic myomectomy: a randomized matched control study. Fertil. Steril.. 2010;94:724-729 Crossref
- Simon and Laufer, 2012a A. Simon, N. Laufer. Assessment and treatment of repeated implantation failure (RIF). J. Assist. Reprod. Genet.. 2012;29:1227-1239 Crossref
- Simon and Laufer, 2012b A. Simon, N. Laufer. Repeated implantation failure: clinical approach. Fertil. Steril.. 2012;97:1039-1043
- 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 Crossref
- Singhal et al., 1991 V. Singhal, T.C. Li, I.D. Cooke. An analysis of factors influencing the outcome of 232 consecutive tubal microsurgery cases. Br. J. Obstet. Gynaecol.. 1991;98:628-636 Crossref
- Soares et al., 2000 S.R. Soares, M.M. Barbosa dos Reis, A.F. Camargos. Diagnostic accuracy of sonohysterography, transvaginal sonography, and hysterosalpingography in patients with uterine cavity diseases. Fertil. Steril.. 2000;73:406-411 Crossref
- Souza Setti et al., 2010 A. Souza Setti, R.C. Ferreira, D. Paes de Almeida Ferreira Braga, R. de Cassia Savio Figueira, A. Iaconelli Jr., E. Borges Jr. Intracytoplasmic sperm injection outcome versus intracytoplasmic morphologically selected sperm injection outcome: a meta-analysis. Reprod. Biomed. Online. 2010;21:450-455 Crossref
- Sowter et al., 1997 M.C. Sowter, V.A. Akande, J.A. Williams, M.G. Hull. Is the outcome of in-vitro fertilization and embryo transfer treatment improved by spontaneous or surgical drainage of a hydrosalpinx?. Hum. Reprod.. 1997;12:2147-2150 Crossref
- Spandorfer et al., 2000 S.D. Spandorfer, P.H. Chung, I. Kligman, H.C. Liu, O.K. Davis, Z. Rosenwaks. An analysis of the effect of age on implantation rates. J. Assist. Reprod. Genet.. 2000;17:303-306 Crossref
- Spiewankiewicz et al., 2003 B. Spiewankiewicz, J. Stelmachow, W. Sawicki, K. Cendrowski, P. Wypych, K. Swiderska. The effectiveness of hysteroscopic polypectomy in cases of female infertility. Clin. Exp. Obstet. Gynecol.. 2003;30:23-25
- Steele et al., 1999 E.K. Steele, N. McClure, R.J. Maxwell, S.E. Lewis. A comparison of DNA damage in testicular and proximal epididymal spermatozoa in obstructive azoospermia. Mol. Hum. Reprod.. 1999;5:831-835 Crossref
- Stephenson and Fluker, 2000 M.D. Stephenson, M.R. Fluker. Treatment of repeated unexplained in vitro fertilization failure with intravenous immunoglobulin: a randomized, placebo-controlled Canadian trial. Fertil. Steril.. 2000;74:1108-1113 Crossref
- Stern et al., 1998 C. Stern, L. Chamley, L. Hale, M. Kloss, A. Speirs, H.W. Baker. Antibodies to beta2 glycoprotein I are associated with in vitro fertilization implantation failure as well as recurrent miscarriage: results of a prevalence study. Fertil. Steril.. 1998;70:938-944 Crossref
- Stern et al., 1999 C. Stern, M. Pertile, H. Norris, L. Hale, H.W. Baker. Chromosome translocations in couples with in-vitro fertilization implantation failure. Hum. Reprod.. 1999;14:2097-2101 Crossref
- Stern et al., 2003 C. Stern, L. Chamley, H. Norris, L. Hale, H.W. Baker. A randomized, double-blind, placebo-controlled trial of heparin and aspirin for women with in vitro fertilization implantation failure and antiphospholipid or antinuclear antibodies. Fertil. Steril.. 2003;80:376-383 Crossref
- Sterzik et al., 1996 K. Sterzik, E. Strehler, M. De Santo, N. Trumpp, M. Abt, B. Rosenbusch, A. Schneider. Influence of smoking on fertility in women attending an in vitro fertilization program. Fertil. Steril.. 1996;65:810-814
- Stovall et al., 1998 D.W. Stovall, S.B. Parrish, B.J. Van Voorhis, S.J. Hahn, A.E. Sparks, C.H. Syrop. Uterine leiomyomas reduce the efficacy of assisted reproduction cycles: results of a matched follow-up study. Hum. Reprod.. 1998;13:192-197 Crossref
- Strandell et al., 1999 A. Strandell, A. Lindhard, U. Waldenstrom, J. Thorburn, P.O. Janson, L. Hamberger. Hydrosalpinx and IVF outcome: a prospective, randomized multicentre trial in Scandinavia on salpingectomy prior to IVF. Hum. Reprod.. 1999;14:2762-2769 Crossref
- Strandell et al., 2005 A. Strandell, A. Lindhard, I. Eckerlund. Cost – effectiveness analysis of salpingectomy prior to IVF, based on a randomized controlled trial. Hum. Reprod.. 2005;20:3284-3292 Crossref
- Suganuma et al., 2005 R. Suganuma, R. Yanagimachi, M.L. Meistrich. Decline in fertility of mouse sperm with abnormal chromatin during epididymal passage as revealed by ICSI. Hum. Reprod.. 2005;20:3101-3108 Crossref
- Sunkara and Khan, 2012 S.K. Sunkara, K.S. Khan. Adenomyosis and female fertility: a critical review of the evidence. J. Obstet. Gynaecol.. 2012;32:113-116 Crossref
- Sunkara et al., 2010 S.K. Sunkara, M. Khairy, T. El-Toukhy, Y. Khalaf, A. Coomarasamy. The effect of intramural fibroids without uterine cavity involvement on the outcome of IVF treatment: a systematic review and meta-analysis. Hum. Reprod.. 2010;25:418-429 Crossref
- Surrey and Schoolcraft, 2000 E.S. Surrey, W.B. Schoolcraft. Evaluating strategies for improving ovarian response of the poor responder undergoing assisted reproductive techniques. Fertil. Steril.. 2000;73:667-676 Crossref
- Surrey et al., 2001 E.S. Surrey, A.K. Lietz, W.B. Schoolcraft. Impact of intramural leiomyomata in patients with a normal endometrial cavity on in vitro fertilization-embryo transfer cycle outcome. Fertil. Steril.. 2001;75:405-410 Crossref
- 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 Crossref
- Taylor, 2000 H. Taylor. The role of HOX genes in human implantation. Hum. Reprod. Update. 2000;6:75-79 Crossref
- Taylor and Gomel, 2008 E. Taylor, V. Gomel. The uterus and fertility. Fertil. Steril.. 2008;89:1-16 Crossref
- Thebault et al., 2012 N. Thebault, P.L. Broux, L. Moy, J. Vialard. Utilization of Essure micro-insert for hydrosalpinx occlusion in infertile women. J. Gynecol. Obstet. Biol. Reprod.. 2012;41:145-150 Crossref
- Tomas et al., 2002 C. Tomas, K. Tikkinen, L. Tuomivaara, J.S. Tapanainen, H. Martikainen. The degree of difficulty of embryo transfer is an independent factor for predicting pregnancy. Hum. Reprod.. 2002;17:2632-2635 Crossref
- Tomlinson et al., 2001 M.J. Tomlinson, O. Moffatt, G.C. Manicardi, D. Bizzaro, M. Afnan, D. Sakkas. Interrelationships between seminal parameters and sperm nuclear DNA damage before and after density gradient centrifugation: implications for assisted conception. Hum. Reprod.. 2001;16:2160-2165 Crossref
- Toth et al., 1992 T.L. Toth, S. Oehninger, J.P. Toner, R.G. Brzyski, A.A. Acosta, S.J. Muasher. Embryo transfer to the uterus or the fallopian tube after in vitro fertilisation yields similar results. Fertil. Steril.. 1992;52:1113
- 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 Crossref
- Tournaye et al., 1992 H. Tournaye, P. Devroey, M. Camus, M. Valkenburg, N. Bollen, A.C. Van Steirteghem. Zygote intrafallopian transfer or in vitro fertilisation and embryo transfer for the treatment of male factor infertility: a prospective randomised trial. Fertil. Steril.. 1992;58:350
- Urman et al., 2005 B. Urman, K. Yakin, B. Balaban. Recurrent implantation failure in assisted reproduction: how to counsel and manage. B. Treatment options that have not been proven to benefit the couple. Reprod. Biomed. Online. 2005;11:382-391 Crossref
- Van Voorhis et al., 1996 B.J. Van Voorhis, J.D. Dawson, D.W. Stovall, A.E. Sparks, C.H. Syrop. The effects of smoking on ovarian function and fertility during assisted reproduction cycles. Obstet. Gynecol.. 1996;88:785-791 Crossref
- Varasteh et al., 1999 N.N. Varasteh, R.S. Neuwirth, B. Levin, M.D. Keltz. Pregnancy rates after hysteroscopic polypectomy and myomectomy in infertile women. Obstet. Gynecol.. 1999;94:168-171 Crossref
- Verberg et al., 2009 M.F. Verberg, M.J. Eijkemans, N.S. Macklon, E.M. Heijnen, E.B. Baart, F.P. Hohmann, B.C. Fauser, F.J. Broekmans. The clinical significance of the retrieval of a low number of oocytes following mild ovarian stimulation for IVF: a meta-analysis. Hum. Reprod. Update. 2009;15:5-12
- Vercellini et al., 1998 P. Vercellini, I. Cortesi, O. De Giorgi, D. Merlo, S.G. Carinelli, P.G. Crosignani. Transvaginal ultrasonography versus uterine needle biopsy in the diagnosis of diffuse adenomyosis. Hum. Reprod.. 1998;13:2884-2887 Crossref
- Voullaire et al., 2000 L. Voullaire, H. Slater, R. Williamson, L. Wilton. Chromosome analysis of blastomeres from human embryos by using comparative genomic hybridization. Hum. Genet.. 2000;106:210-217 Crossref
- Wadden and Foster, 2000 T.A. Wadden, G.D. Foster. Behavioral treatment of obesity. Med. Clin. North Am.. 2000;84:441-461 vii Crossref
- Wang and Check, 2004 W. Wang, J.H. Check. Effect of corporal fibroids on outcome following embryo transfer in donor-oocyte recipients. Clin. Exp. Obstet. Gynecol.. 2004;31:263-264
- Wang et al., 2009 L.Y. Wang, D.H. Wang, X.Y. Zou, C.M. Xu. Mitochondrial functions on oocytes and preimplantation embryos. J. Zhejiang Univ. Sci. B. 2009;10:483-492 Crossref
- 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 Crossref
- Weissman et al., 2008 A. Weissman, E. Horowitz, A. Ravhon, H. Nahum, A. Golan, D. Levran. Pregnancies and livebirths following ICSI with testicular spermatozoa after repeated implantation failure using ejaculated spermatozoa. Reprod. Biomed. Online. 2008;17:605-609 Crossref
- Weissman et al., 2013 A. Weissman, E. Horowitz, A. Ravhon, H. Nahum, A. Golan, D. Levran. Zygote intrafallopian transfer among patients with repeated implantation failure. Int. J. Gynaecol. Obstet.. 2013;120:70-73 Crossref
- Werlin et al., 2003 L. Werlin, I. Rodi, A. DeCherney, E. Marello, D. Hill, S. Munné. Preimplantation genetic diagnosis as both a therapeutic and diagnostic tool in assisted reproductive technology. Fertil. Steril.. 2003;80:467-468 Crossref
- Wilton et al., 2009 L. Wilton, A. Thornhill, J. Traeger-Synodinos, K.D. Sermon, J.C. Harper. The causes of misdiagnosis and adverse outcomes in PGD. Hum. Reprod.. 2009;24:1221-1228 Crossref
- Windham et al., 1992 G.C. Windham, L. Fenster, S.H. Swan. Moderate maternal and paternal alcohol consumption and the risk of spontaneous abortion. Epidemiology. 1992;3:364-370 Crossref
- Winston and Margara, 1991 R.M. Winston, R.A. Margara. Microsurgical salpingostomy is not an obsolete procedure. Br. J. Obstet. Gynaecol.. 1991;98:637-642 Crossref
- Wood et al., 1985 C. Wood, R. McMaster, G. Rennie, A. Trounson, J. Leeton. Factors influencing pregnancy rates following in vitro fertilization and embryo transfer. Fertil. Steril.. 1985;43:245-250
- Yang et al., 1992 Y.S. Yang, S. Melinda, H.N. Ho, J.L. Hwang, S.U. Chen, H.R. Lin, S.C. Huang, T.Y. Lee. Effect of the number and depth of embryos transferred and unilateral or bilateral transfer in tubal embryo transfer (TET). J. Assist. Reprod. Genet.. 1992;9:534-538 Crossref
- Yarali and Bukulmez, 2002 H. Yarali, O. Bukulmez. The effect of intramural and subserous uterine fibroids on implantation and clinical pregnancy rates in patients having intracytoplasmic sperm injection. Arch. Gynecol. Obstet.. 2002;266:30-33 Crossref
- Yasmin et al., 2007 H. Yasmin, A. Nasir, K.J. Noorani. Hystroscopic management of Ashermans syndrome. J. Pak. Med. Assoc.. 2007;57:553-555
- Yu et al., 2008 D. Yu, Y.M. Wong, Y. Cheong, E. Xia, T.C. Li. Asherman syndrome – one century later. Fertil. Steril.. 2008;89:759-779 Crossref
- Zegers-Hochschild et al., 2009 F. Zegers-Hochschild, G.D. Adamson, J. de Mouzon, O. Ishihara, R. Mansour, K. Nygren, E. Sullivan, S. Vanderpoel. International Committee for Monitoring Assisted Reproductive Technology (ICMART) and the World Health Organization (WHO) revised glossary of ART terminology. Fertil. Steril.. 2009;92:1520-1524 Crossref
- Zeyneloglu et al., 1998 H.B. Zeyneloglu, A. Arici, D.L. Olive. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization-embryo transfer. Fertil. Steril.. 1998;70:492-499 Crossref
- Zhou et al., 2008 L. Zhou, R. Li, R. Wang, H.X. Huang, K. Zhong. Local injury to the endometrium in controlled ovarian hyperstimulation cycles improves implantation rates. Fertil. Steril.. 2008;89:1166-1176 Crossref
- Zikopoulos et al., 2004 K.A. Zikopoulos, E.M. Kolibianakis, P. Platteau, L. de Munck, H. Tournaye, P. Devroey, M. Camus. Live delivery rates in subfertile women with Asherman’s syndrome after hysteroscopic adhesiolysis using the resectoscope or the Versapoint system. Reprod. Biomed. Online. 2004;8:720-725 Crossref
- Zinger et al., 2006 M. Zinger, J.H. Liu, M.A. Thomas. Successful use of vaginal sildenafil citrate in two infertility patients with Asherman’s syndrome. J. Womens Health (Larchmt). 2006;15:442-444 Crossref
a Department of Reproductive and Developmental Medicine, Jessop Wing, Royal Hallamshire Hospital, Sheffield, United Kingdom
b Department of Obstetrics and Gynaecology, Royal Hospital for Women, Sydney, Australia
c Reproductive Centre, First Affiliated Hospital of Sun Yat Sen University, Guangzhou, China
d The Women and Children Hospital of Guangdong Province, No. 13, Guangyuan Road West, Guangzhou 510010, China
e Women’s Health, Infertility and IVF Centre, Cankaya Caddesi, 20/3, Ankara, Turkey
f Monash IVF, Gold Coast, Australia
g Department of Obstetrics and Gynaecology, University of Alexandria and Suzanne Mubarak Regional Centre for Womens Health and Development, Alexandria, Egypt
Dr Carol Coughlan received her medical training in Ireland and obtained her MRCOG in 2003 and MRCPI in 2004. She completed subspecialist training in reproductive medicine and surgery at the Jessop Wing, Royal Hallamshire Hospital, Sheffield, UK. She is pursuing her research interests in recurrent implantation failure and recurrent miscarriage.
© 2013 Published by Elsevier B.V.