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Individualized ovarian stimulation: a groundbreaking practice to improve efficacy and efficiency in IVF treatment IVF treatment

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Individualized ovarian stimulation: a groundbreaking practice to improve efficacy and efficiency in IVF treatment IVF treatment

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Ji-Hyang Kim, South Korea

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Alberto Vaiarelli, Italy

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Endometriosis: Impact on the fertility maze and treatment roads

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Endometriosis: Impact on the fertility maze and treatment roads

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Aerul Chakra, Indonesia

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Luteal Phase Support Personalization: Why, When and How

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APHRODITE criteria and gonadotropin treatment unveil the intricate patterns of male infertility

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Alex Polyakov, Australia

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Surgical options for male infertility in IVF

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Surgical options for male infertility in IVF

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Tomomoto Ishikawa, Japan

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Rajesh Hemashree, Singapore

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Patients with expected High Ovarian Response: Tailored Strategies for Better Outcomes

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Vuong Thi Ngoc Lan, Vietnam

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New biological strategies in a Modern IVF lab: From fertilization to blastocyst culture

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New biological strategies in a Modern IVF lab: From fertilization to blastocyst culture

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Cecilia Sjoblom, Australia

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Faizal Ahmad, Malaysia

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'Fertility Counts - Progress and Future Directions'

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'Health Economics - Unlocking the Value of Fertility Medicines'

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'Health Economics - Unlocking the Value of Fertility Medicines'

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Somjate Manipalviratn, Thailand

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LH and HCG activity: from real word evidence to cost-effectiveness data

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LH and HCG activity: from real word evidence to cost-effectiveness data

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Rui-Jun Chang, Taiwan

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Endometriosis shows no impact on the euploid blastocyst rate per cohort of inseminated metaphase-II oocytes: A case-control study - PubMed

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Endometriosis might not impair oocyte developmental and reproductive competence, although its potential impact on the number of metaphase-II oocytes retrieved cannot be ignored. This information is critical for clinicians during counseling to outline an effective strategy to treat infertile patients …

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Opening the black box: why do euploid blastocysts fail to implant? A systematic review and meta-analysis

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AbstractBACKGROUND. A normal chromosomal constitution defined through PGT-A assessing all chromosomes on trophectoderm (TE) biopsies represents the stronge

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Abstract

Introduction

ART provides treatment options for heterosexual couples having difficulties conceiving naturally, single people, and same-sex couples. Despite advances in treatment approaches and laboratory technologies, many people fail to conceive with these technologies. When failure arises after serial attempts at IVF, the term 'recurrent implantation failure' (RIF) is often used. However, while this broadly descriptive term is often employed to focus discussions of clinical therapeutic options, it is evident that providing a name to unexplained IVF failure has not led to significant advances in its effective management. In contrast, RIF has become associated with accusations of poor and even exploitative practices, that have coloured the ongoing 'add-ons' debate. However, apparently unexplained repeated failure of IVF treatment is a frequently encountered, distressing, and difficult-to-manage clinical problem.

The ESHRE Working Group on Recurrent Implantation Failure recognized that there is a need to look afresh at how RIF should be identified, defined, and managed. While there is an evidence base to scrutinize, it is the view of the RIF working group (WG) that the available literature has not generated clinical data of sufficient quality around an agreed and consistent definition of RIF to permit a didactic guideline to be distilled. However, there is still a need for an evidence-supported document describing what represents 'Good Practice' in this challenging area of reproductive medicine. This document aims to meet that need through a systematic search for and synthesis of published studies on the topic, a survey among professionals on current clinical practice in RIF and considering the practical expertise of selected clinicians and embryologists.

Materials and methods

A WG tasked with drafting a document for review was composed of representatives of the relevant ESHRE Special Interest Groups (SIGs), notably the SIGs Implantation and Early Pregnancy, Reproductive Endocrinology, and Embryology, and further completed with an independent chair (N.M.), an expert in statistics (D.J.M.) and support for literature searches and project management. In the first meetings, the ESHRE Working Group on Recurrent Implantation Failure discussed the topics to be covered and divided to work in subgroups with defined tasks. Progress with the different tasks and issues arising was discussed in regular online meetings.

A literature search through PUBMED and Cochrane databases was performed using the key terms 'recurrent reproductive failure' OR 'recurrent implantation failure' OR 'repeated implantation failure'. Studies were included from inception to August 2022, with addition of more recent references where available. All titles and abstracts were screened to identify relevant studies, for which full-text papers were collected and summarized. While the literature search was focused on specific studies in RIF patients (defined as such by the authors) and the main outcomes live birth rate (LBR), pregnancy rate (PR), and side effects, in the absence of studies specifically addressing cases of RIF, the impact on implantation after ART, in general, was considered.

Recommendations for clinical practice were stated based on studies collected through the systematic search of the literature, and recommendations in other guidelines ( Coughlan et al., 2014a; Shaulov et al., 2020; Mascarenhas et al., 2022; Sociedad Española de Fertilidad; Grupo de Trabajo de Fracaso Reproductivo), a previously performed survey providing details on current clinical practice ( Cimadomo et al., 2021), assessment of biological rationale, and the expert opinion of the WG. While the WG was aware that for most investigations or interventions there may be specific patient groups that may be shown to benefit, or indeed the opposite, in order to aid clinical decision-making, the recommendations were colour-coded to indicate three levels of advice: green, recommended for all patients with suspected RIF; orange, can be considered in RIF patients; red, not recommended. When 'not recommended' is the advice given, this implies that the investigation/intervention is not to be routinely offered, but that does not mean that it is recommended not to be used in any circumstances, since in most cases, the evidence base cannot support such a didactic statement.

While key available evidence was summarized for all investigations and interventions, an exclusively evidence-based approach was not considered possible for the current topic, owing to the lack of consistency in the definition of RIF and the sparse direct and high-quality evidence available for most interventions, including those already established in clinical practice. The recommendations are, therefore, derived from expert interpretation of the available data, their biological rationale, and opinion rather than from the data alone. The evidence assessed and other factors considered for drafting each recommendation are tabulated in Supplementary Data S1 (investigations) and Supplementary Data S2 (interventions).

Specifically concerning the definition of RIF and to define a threshold for considering RIF, an exercise was performed among 10 members of the participating SIGs. In the exercise, three RIF cases were presented and the implications of three different thresholds (70%, 60%, and 50%) for the cumulative success of implantation leading to pregnancy were to be considered. Following the feedback from this exercise, the threshold of 60% was proposed and presented as part of the first draft of the recommendations for investigations and interventions in RIF.

The first draft of the recommendations for good practice was sent for review by the 14 ESHRE SIGs. Feedback was collected on the proposed definition of RIF, criteria for identifying it in an individual patient and on the relevance of diagnostic and treatment options. The feedback was discussed in an in-person WG meeting and adopted by agreement into a final draft of the paper, which was published on the ESHRE website between 1 November and 1 December 2022 for stakeholder review among the ESHRE membership. A total of 204 comments were received, considered by the WG, and incorporated by agreement. The report of the stakeholder review is available on www.eshre.eu/guidelines. The list of experts that contributed to the stakeholder review is included in Supplementary Data S3.

The current document adheres to the previously published definitions for ART, IVF, infertility, pregnancy, and live birth ( Zegers-Hochschild et al., 2017). Implantation rate is defined as the number of gestational sacs observed divided by the number of embryos transferred (usually expressed as a percentage) and is preferably calculated per ET procedure ( Griesinger, 2016). Implantation is taken to describe the attachment and subsequent penetration by a zona-free blastocyst into the endometrium ( Zegers-Hochschild et al., 2017). For the purpose of this document, successful implantation is taken to be the achievement of early pregnancy (i.e. detection of beta hCG in serum or urine indicative of a positive pregnancy test (precise levels will vary depending on the test used)) following an ET procedure.

In this document, in line with published research, the terminology and discussion focusses on men and women. The ESHRE Working Group on Recurrent Implantation Failure recognizes that there are individuals confronted with RIF who do not identify with the terms used in the literature. The terminology used in this document is not intended to isolate, exclude, or diminish any individual's experience or to discriminate against any group.

Defining RIF in ART: from population to individual

The ESHRE Working Group on Recurrent Implantation Failure recommends considering RIF as a secondary phenomenon of ART as it can only be observed in patients undergoing IVF. To address ambiguities in the definition to date, it is recommended that the following description of RIF be adopted:

RIF describes the scenario in which the transfer of embryos considered to be viable has failed to result in a positive pregnancy test sufficiently often in a specific patient to warrant consideration of further investigations and/or interventions.

Considering RIF as a distinct scenario confined to ICSI/IVF patients of heterogeneous cause and prognosis asks for an individualized approach that is not dependent on a 'one size fits all' criterion (e.g. a fixed number of embryos transferred) but accounts, at least in part, for factors known to impact the individual patient's chance of conception. Key to this concept is the need to identify how many embryos/ETs would be expected to be necessary in a specific patient to provide an 'acceptable' cumulative chance of successful implantation.

The task of defining RIF as a clinical entity is further complicated by the fact that ART patients represent a heterogeneous cohort with respect to the indication for treatment and the individual chances of achieving pregnancy. Treated patients range from subfertile couples who would be expected to conceive without treatment if they continue trying long enough to couples and individuals who will not conceive without ART. Similarly, among those undergoing ART, some might be expected to succeed if sufficient cycles are undertaken while others will fail regardless of the number and types of treatments; in the latter group, an identified pathology or advanced ovarian age may account for the poor prognosis. Focussing on couples that would be able to achieve a pregnancy through ART implies that a standardized range of investigations (the 'fertility workup') will have already been completed before the treatment process starts and that patients are deemed suitable for ART and for carrying a pregnancy. The recommended components of the fertility workup have been previously described by ESHRE ( Vlaisavljevic et al., 2021) ( Fig. 1). The present recommendations for good practice in RIF assume that this baseline fertility workup will already have been carried out before commencing ART, but acknowledge that in different regions and jurisdictions, other and/or additional tests and assessments are recommended ( National Institute for Health and Care Excellence, 2013; ACOG, 2019; Toth et al., 2019a, b) ( Supplementary Data S4). Furthermore, it is assumed that ART procedures are performed by fully trained and qualified personnel using state-of-the-art technology and procedures.

Defining RIF in the individual couple or patient for clinical purposes

Among ART patients, the chance of successful implantation will differ significantly. To identify RIF indicating further actions in a specific patient, it is necessary to determine what cumulative chance they have had to conceive thus far. If this is greater than an agreed threshold, but no positive pregnancy test has been achieved, then action may be indicated ( Fig. 2). Patients whose history indicates that their chance of conceiving thus far has not yet reached the threshold given their specific clinical context should be advised to simply proceed to another ART cycle. However, in patients whose failure to conceive thus far would be recognized as unusual, investigations of underlying contributing factors should be considered.

Two factors are essential for the individual approach for RIF: the model used to estimate the chance of implantation/pregnancy and the level at which the threshold to act is set.

Estimating the chance of implantation

The likelihood of successful implantation after ART is determined by a multitude of factors including, but not limited to, female-related factors such as age, hormonal levels, endometrial and uterine status and underlying conditions, embryo-related factors such as embryonic cleavage speed, euploidy, and previous implantations of sibling embryos, male factors like genetic disorders, and external factors such as the performance of the laboratory and clinic, transfer policies, and legal restrictions.

For RIF, the chosen model would be used to estimate the chance of pregnancy after each subsequent ET, which implies that a different calculation would be required. However, to limit complexity, the likelihood of achieving a positive pregnancy test following a defined number of cumulative ETs ( n) can be approximated by the following formula: [likelihood of implantation] = 1−[(1−PR)], where PR is pregnancy rate. If not a reported outcome, PR can be reasonably estimated by multiplying the live birth rate by 1.16 ( Arce et al., 2005; Kolibianakis et al., 2006).

Setting a threshold for the cumulative chance of successful implantation to signal action

Irrespective of the model used, a threshold needs to be defined to determine at what point failure to achieve successful implantation indicates an 'issue' rather than simply 'an event by chance'. The threshold will guide the clinical decision on whether the patient should simply proceed to a further ET or whether investigations for factors contributing to RIF should be explored ( Fig. 2).

The recommended threshold for the cumulative predicted chance of implantation to identify RIF for the purposes of initiating further investigation is 60%. When a couple have not had a successful implantation by a certain number of embryo transfers and the cumulative predicted chance of implantation associated with that number is greater than 60%, then they should be counselled on further investigation and/or treatment options. This term defines clinical recurrent implantation failure for which further actions should be considered.

Figure 3 summarizes how the individualized definition of RIF should be integrated into clinical pathways.

Investigations for RIF

While the management of RIF is often empirical and interventions are tried without any attempt to identify the underlying cause, many different investigations for RIF have been proposed. Recognizing the limitations imposed by the current evidence base, this section aims to provide a framework to assist clinicians and couples in decision-making regarding RIF investigations.

In the context of RIF, investigations aim to identify contributing or causative factors. As previously stated, it is assumed that a complete pre-ART fertility workup has already been carried out and that the results are available for consideration. Similarly, the patient's age and past medical history and treatment (e.g. for malignant disease) are assumed to have been accounted for before embarking on ART.

To place each investigation (and associated intervention) into context, data are provided (where available) both on the reported prevalence of their use in clinical practice and the biological rationale underpinning their use.

A summary of all investigations and whether they are recommended, to be considered or not recommended is provided in Fig. 4. Details on the justification for the recommendations are included below and summarized in Supplementary Data S1.

Investigating female factors

Lifestyle factors

In a large survey among 735 clinicians and 300 embryologists, more than two-thirds of clinicians reported taking female lifestyle factors into account, mainly drugs, smoking, and BMI, when managing RIF ( Cimadomo et al., 2021). Diet, stress, and caffeine intake were evaluated by about 50% of responding clinicians ( Cimadomo et al., 2021). Certain lifestyle behaviours, such as cigarette smoking, alcohol consumption or caffeine, have been associated with lower ART success rates ( Kinney et al., 2007; Hornstein, 2016; Ozbakir and Tulay, 2021). However, while association studies abound, evidence from well-designed intervention studies demonstrating an improvement in ART outcomes following short and/or long-term lifestyle changes remains scarce ( Freour et al., 2018; Kermack et al., 2020; Wang et al., 2021).

Based on the probable relevance of lifestyle factors on ART success rates, the WG considered re-evaluating these factors appropriately. For vitamin D, the value of measuring blood levels is not clear.

Screening for genetic factors: karyotyping of the female and male partner

In a survey of clinical practice, 67% of clinicians reported considering chromosomal disorders as a potential risk factor for RIF and most clinicians assess both the female and male karyotypes ( Cimadomo et al., 2021). Embryonic chromosomal disorders represent the major cause of (early) pregnancy loss in humans ( Papas and Kutteh, 2021). Aneuploid blastocysts have a significantly reduced developmental capacity during the preimplantation stage ( Rubio et al., 2007; Martín et al., 2021) and negligible implantation potential ( Grati et al., 2018; Capalbo et al., 2022). However, most embryonic chromosomal aneuploidies are of maternal meiotic origin.

Anatomical investigations

Assessment of the uterine cavity

Transvaginal ultrasound is considered to be performed as part of the fertility workup.

While assessment of the presence of adenomyosis, endometriosis, and submucosal fibroids should be carried out before ART, if there is renewed suspicion owing to emerging clinical signs or ultrasound features noted after RIF, then further investigations including MRI or diagnostic laparoscopy should be considered.

The use of hysteroscopy is often proposed when uterine pathology has been detected by transvaginal ultrasound and further diagnostics are indicated (e.g. submucous fibroids, uterine adhesions). A meta-analysis focussing on patients with RIF reported a significantly higher LBR after hysteroscopy compared to those that did not have hysteroscopy (Risk Ratio (RR) 1.29; 95% CI 1.03-1.62; 4 studies; n = 2247; P =0.046) ( Cao et al., 2018). The analysis by Cao et al. included a large randomized controlled trial (RCT) (the TROPHY study) that reported a similar LBR after ART in patients with RIF (two to four failed IVF cycles) without a previously recognized pathology ( n = 702) when comparing those undergoing hysteroscopy versus those proceeding to ART without hysteroscopy (29% versus 29%, RR 1.0; 95% CI 0.79-1.25; P = 0.96) ( El-Toukhy et al., 2016). Sonohysterography is another technique to diagnose uterine pathologies, but it is less well studied in RIF ( Negm et al., 2012; Reda et al., 2016).

Other uterine cavity anomalies can be treated by established interventions including endometrial polypectomy, surgical removal of submucous fibroids, uterine septum resection, or removal of intrauterine adhesions. While the interventions are established for the treatment of symptoms, their impact on pregnancy or LBRs has, to our knowledge, not been evaluated in patients with RIF. Similarly, the effect of treatment of adenomyosis on pregnancy or LBR in women with RIF has not been evaluated.

There is a lack of studies evaluating hysterosalpingography (HSG) in the context of RIF, but HSG or other means of imaging of the fallopian tubes can be considered if there is a doubt about hydrosalpinx after ultrasound.

Endometrial function and receptivity tests

A meta-analysis from 2022 included 11 studies and reported that the prevalence of displaced WOI, as detected through endometrial receptivity tests, was 34% (95% CI 24-43%) in RIF/poor prognosis patients ( Liu et al., 2022b). In patients with RIF, comparable ongoing pregnancy rates (OPR)/LBR were found between those with diagnosed non-receptive endometrium undergoing personalized ET (p-ET) and those with receptive endometrium undergoing routine ET (40.7% versus 49.6%; odds ratio (OR) 0.94; 95% CI 0.70-1.26; 6 studies; n = 2552) ( Liu et al., 2022b). In a more recent multicentre cohort study in patients with a single previous failed transfer, LBR and cumulative LBR were reported to be higher after unguided ET compared to p-ET, for both autologous and donor transfers ( Cozzolino et al., 2022).

Investigating chronic endometritis

Chronic endometritis (CE) has been described in patients with RIF with bacterial colonization, but also in women without clinical signs of infection and can lower the pregnancy rate ( Johnston-MacAnanny et al., 2010; Kitaya et al., 2014, 2019; Cicinelli et al., 2015; Bouet et al., 2016; Kushnir et al., 2016; Song et al., 2018; Li et al., 2020; Saxtorph et al., 2020; Zargar et al., 2020). It can be diagnosed by hysteroscopy, haematoxylin and eosin staining, and CD138-labelling ( Kitaya et al., 2014, 2019). Other diagnostic tests for endometritis include chromohysteroscopy (methylene blue dying of endometrium during hysteroscopy), bacterial culture, and molecular techniques such as PCR, RT-PCR, and next-generation sequencing (NGS) ( Küçük and Safali, 2008; Moreno et al., 2018). Nowadays, CE (and vaginal infection) seems to be routinely investigated in clinical practice (85% of clinicians) ( Cimadomo et al., 2021), even if there are limitations to histology in general, a lack of standardization of the concentration of plasma cells that should be regarded as a threshold (e.g. >1 or >5 plasma cells per high power field), and available studies often include only small numbers of patients or lack controls.

Antibiotics can be considered for the treatment of CE. Recent reviews on the topic, with different inclusion criteria and overlap in the studies included, reported conflicting results. Based on data from four studies, one systematic review reported significantly higher LBR/OPR (OR 5.33; 95% CI 2.41-11.79; I ² = 0%) in patients with cured CE (treated with antibiotics) compared to those with persistent CE ( Vitagliano et al., 2022). Another review calculated the LBR/OPR was not significantly higher in RIF patients with cured CE (after oral antibiotics) compared to those with persistent CE (OR 2.90; 95% CI 0.65-12.98; I ² = 77%; 4 studies) ( Cheng et al., 2022). The reviewers did report higher CPR in cured compared to persistent CE. A third review concluded oral antibiotic treatment for CE did not improve PR or LBR ( Kato et al., 2022).

At present, conclusions regarding the value of the diagnosis and treatment of endometritis are significantly hampered by the lack of standardization. However, the investigation and treatment of CE can be considered in RIF. Revision of this recommendation may be indicated should studies using more standardized diagnostic techniques, including the emerging DNA-based tests, reveal a clearer benefit.

Re-assessment of endometrial thickness

If the endometrium remains thin despite adjustment of the endometrial preparation regimen, hysteroscopy can be considered to rule out adhesions or Asherman's syndrome.

Microbiome profiling

In recent years, the Human Microbiome Project has highlighted the importance of micro-organisms and their genomes in human health and disease ( Human Microbiome Project Consortium, 2012). Almost 10% of the bacterial population present in the body resides in the female genital tract and Lactobacillus species are part of the physiologic flora ( Moreno and Simon, 2019). Whether microbial dysbiosis is among the determining factors of implantation failure remains under study, but in clinical practice, 47% of clinicians consider this a relevant factor ( Cimadomo et al., 2021). Microbiome testing in the context of fertility treatment is attracting much attention and has been indicated to offer promise as a potentially treatable factor in embryo implantation. A small study failed to demonstrate a correlation between the presence of Lactobacillus strains and ongoing pregnancy after analyzing the embryo catheter tips ( Franasiak et al., 2016). However, a recent meta-analysis of six cohort studies, including a total of 1095 women, and several other studies have reported an association between dysbiotic microbiota and impaired reproductive outcomes ( Moreno et al., 2016, 2022; Koedooder et al., 2019; Kyono et al., 2019; Singer et al., 2019). In RIF, a case-control study comparing the vaginal and endometrial microbial configuration through 16S rRNA gene sequencing in 145 women with RIF and 21 healthy women with male factor infertility showed lower levels of Lactobacillus in vaginal samples but not in the endometrium of patients with RIF ( Ichiyama et al., 2021).

Based on the currently available data, and considering there are several unanswered questions on the relevance of microbiome testing in the context of RIF, uterine and vaginal microbiome profiling is not currently recommended.

Metabolic and endocrinologic factors

Thyroid function

Progesterone

Another topic is the assessment of mid-luteal progesterone levels to evaluate exogenous progesterone therapy. A Cochrane meta-analysis reported a higher LBR/OPR with progesterone compared to placebo/no treatment for luteal phase support in women undergoing ART (OR 1.77; 95% CI 1.09-2.86; I ² = 5%; 5 RCTs; n = 642) ( van der Linden et al., 2015). Consistent with the possibility that absorption from the vagina may be variable between women, there is increasing evidence linking low blood progesterone levels on the day of ET to poorer outcomes after fresh ET ( Thomsen et al., 2018) and after frozen ET ( Alsbjerg et al., 2018; Lawrenz et al., 2018; Labarta et al., 2021). A recent matched cohort study showed low mid-luteal progesterone levels to be more prevalent in women with a history of RIF versus controls ( Saxtorph et al., 2020). Individualized progesterone administration has been shown to restore implantation rates in cohort studies ( Álvarez et al., 2021; Labarta et al., 2021).

With regards to both late follicular and mid-luteal progesterone level assessment, questions remain about the validity of published cut-off levels for individual centres as assays can vary. Local validation of cut-off progesterone levels is recommended.

Immunological screening

A full assessment of the biological basis of immunological screening in RIF is beyond the scope of this article, but the more commonly employed approaches used are addressed below.

Uterine and peripheral natural killer cells

Uterine natural killer cells (uNK cells) are known to be key players at the feto-maternal interface, where they represent around 70% of immune cells ( Lédée-Bataille et al., 2004; Tuckerman et al., 2010; Lash and Bulmer, 2011; Moffett and Colucci, 2014; Seshadri and Sunkara, 2014; Vomstein et al., 2020). However, compared to peripheral NK cells (pNK cells), uNK cells are not cytotoxic. Both NK cell types act as immunomodulators but demonstrate a different profile of secreted cytokines and receptor/gene expression ( Tang et al., 2011; Seshadri and Sunkara, 2014; Vomstein et al., 2020). Besides functional differences, measured numbers of pNK and uNK cells do not correlate in an individual and therefore should be regarded as two individual markers ( Kuon et al., 2017a; Woon et al., 2022). uNK cell concentrations undergo tremendous changes during the menstrual cycle, showing hormone-dependent changes in phenotype and high levels in the luteal phase, underlining the need for defining strict criteria when analyzing uNK cell counts and functions ( Fraser and Zenclussen, 2022). Some studies have reported that finding higher than normal uNK cell counts is associated with a less favourable implantation milieu ( Chen et al., 2017; Kuon et al., 2017b; Odendaal and Quenby, 2021) and in a recent systematic review, including eight studies with patients with RIF, a significant difference in total CD56+ uNK cells was shown in women with RIF compared with controls (standardized mean difference 0.49; 95% CI −0.01-0.98; P = 0.046; 604 women) ( Woon et al., 2022). However, other studies have not shown an association of either uNK cells ( Donoghue et al., 2019) or pNK cells with RIF ( Seshadri and Sunkara, 2014; Salazar et al., 2022).

Recent studies have further elucidated the roles of uNK cells in the endometrium, including that in the biosensor function of the decidualized endometrium ( Kong et al., 2021). It has also been proposed that inadequate activation of uNK cells might be a cause of RIF ( Donoghue et al., 2019; Alecsandru et al., 2020) and the same is true for pNK cells in RIF ( Seshadri and Sunkara, 2014; Salazar et al., 2022).

T lymphocytes

Peripheral blood cytokine levels

During implantation, cytokines in the peripheral blood have been described as changing from a proinflammatory (Th1 type) to an anti-inflammatory (Th2 type) profile ( Zhao et al., 2021). While this may represent an over-simplification, some studies with small study populations showed that a pro-inflammatory state persists in women with RIF, which might disturb implantation ( Inagaki et al., 2003; Liang et al., 2015a, b; Marron and Harrity, 2019). However, as the assessment of cytokine levels is time-consuming and expensive, it is not applied in clinical practice.

HLA-C compatibility

Thrombophilia screening

Inherited thrombophilia

Inherited thrombophilia comprises conditions in which a genetic mutation affects the amount or the function of a protein in the coagulation pathway. Mutations in several genes have been shown to be involved: G1619A (factor V Leiden), R2 H1299R (factor V Leiden polymorphism), A1298C (methylenetetrahydrofolate reductase (MTHFR) enzyme mutation), C677T (MTHFR polymorphism), V34L (factor XIII polymorphism), G20210A (mutation of the prothrombin gene), a/b L33P (ribosomal polymorphism of MTHFR enzyme), and 4G/5G (plasminogen activator inhibitor-1 (PAI-1)) ( Neamţu et al., 2021).

Acquired thrombophilia

A recent review summarized studies evaluating the prevalence of antiphospholipid antibodies (APA) in women with RIF ( Papadimitriou et al., 2022). The RR for the presence of any type of APA was 3.06 (95% CI 1.97-4.77; I ² = 15%; 5 studies; n = 864) in women with RIF compared to women having at least one successful IVF-ET. In women experiencing at least two implantation failures, the presence of anti-cardiolipin antibodies only or lupus anticoagulant was associated with a significant RR of, respectively, 5.06 and 5.81 for impaired implantation. A recent study evaluated the prevalence of APS (meeting all clinical and laboratory criteria) in 185 patients with RIF and showed APS in only 2.88% of patients, with <5% having APA ( Vomstein et al., 2020).

Investigating factors related to the embryo

Mitochondrial DNA content

The mitochondrial DNA (mtDNA) content of human embryos has been proposed as a possible indicator of embryo viability and implantation potential. Several studies have reached contradictory results on mtDNA content-often expressed as the mitochondrial score or the ratio of mitochondrial/nuclear DNA copy number-according to embryo developmental day, embryo quality, maternal age, and implantation capacity. On the clinical significance of mtDNA content or the mitochondrial score for predicting the embryo's ability to implant, the study results are highly conflicting, finding a positive, negative, or no correlation with implantation rate ( Tan et al., 2014; Diez-Juan et al., 2015; Fragouli et al., 2015, 2017; Ravichandran et al., 2017; Treff et al., 2017; Victor et al., 2017; de los Santos et al., 2018; Klimczak et al., 2018; Podolak et al., 2022). It could be considered that only extreme values for mtDNA content may be correlated with clinical outcomes ( Podolak et al., 2022). Given the experimental nature of the test, the small sample size, and the small number of studies, further studies are required to reach a conclusion.

Artificial intelligence-powered tools for embryo/blastocyst quality assessment

Similarly, omics analyses of IVF spent media are currently subject to intense academic, pre-clinical, and clinical investigations. Nevertheless, the data are still preliminary, and they have not been studied in the context of RIF, therefore they cannot be considered for the time being.

Investigating male factors

Semen analysis, spermiogram, sperm fluorescent in situ hybridization, and sperm DNA-fragmentation

Semen analysis is part of the routine fertility workup before ART ( Fig. 1) ( ASRM, 2015; Vlaisavljevic et al., 2021). Deviations in sperm concentration, motility, and morphology seem to be associated with lower conception rates ( Jouannet et al., 1988; WHO, 2021), but also low fertilization and poor embryo development. In a study comparing patients with RIF to controls, significantly better sperm motility and morphology were detected in the couples with RIF, indicating a lack of robustness of data to link sperm parameters with RIF ( Ocal et al., 2012).

Sperm fluorescent in situ hybridization (FISH) is a cytogenetic clinical diagnostic assay that assesses the frequencies of chromosomal abnormalities, considered useful in counselling RPL patients with previously failed ART ( WHO, 2021). A retrospective case-control study showed no correlation of sperm aneuploidy FISH with RIF as an independent factor. However, around 24% of males with RIF having an abnormal FISH result were normozoospermic ( Rodrigo et al., 2019). Others reported aberrant FISH results in only 14.8% (4/27) of RIF patients without impact on implantation or pregnancy rates ( Sarrate et al., 2019).

There are several different sperm DNA-fragmentation (SDF) tests, and currently there is no standardization on the methodologies and threshold for normal values. In addition, there are conflicting data regarding SDF testing results and clinical pregnancy following ART ( Evenson and Wixon, 2006; Cissen et al., 2016; Simon et al., 2017). A recent large retrospective cohort study including 1339 women undergoing 2759 IVF/ICSI cycles reported that there was no significant difference in LBR per first ET between ≤15% and >15% SDF groups: 38.2% (95% CI 34.5-41.9; n = 665) versus 41.9% (95% CI 34.2-49.7; n = 155; OR 1.2; 95% CI 0.8-1.7; P = 0.4). Similarly, cumulative LBR was not significantly different between groups with high or low SDF ( Hervás et al., 2022). While SDF is suggested to be a contributing factor to RPL and unexplained infertility, data specifically in patients with RIF are scarce. Furthermore, there is no consensus on the cost-effectiveness of the test in general or in couples with RIF ( Minhas et al., 2021; Hervás et al., 2022).

Different treatments have been suggested as viable options for male partners of patients with RIF. These include improving semen quality, such as antioxidant use, and techniques to select functional sperm, such as magnetic-activated cell sorting (MACS), intracytoplasmic morphologically selected sperm injection and other sperm selection techniques, and surgical sperm retrieval (e.g. testicular sperm extraction (TESE)). However, so far, there are no studies that have evaluated these interventions in couples with RIF which were of sufficient quality to support any recommendations.

Lifestyle factors

Obesity, especially when accompanied by metabolic syndrome, correlates with poor semen quality ( Ma et al., 2019; McPherson and Tremellen, 2020; Tremellen and Pearce, 2020). Likewise, lifestyle habits in men, such as smoking, high caffeine intake or alcohol consumption and drug abuse, seem to not only negatively alter conventional semen parameters, but also other molecular aspects such as sperm DNA integrity or redox status ( Rahban and Nef, 2020).

Interventions for RIF

The offer of a considerable range of interventions is not guided by evidence of efficacy but by a perceived need to act. Given this challenging landscape, this good practice document aims to support clinical practice by providing the evidence in a summary of the most relevant studies. The results of these studies should be interpreted with caution for several reasons. First, the definition of RIF applied varies, and consequently, the study cohort of one study may differ significantly from that of another. Variations in what constituted the fertility workup before ART add to the heterogeneity, as do differences in ET strategy. Moreover, sample sizes tend to be small and, in most cases, interventions are evaluated without any attempt to diagnose the cause of RIF or irrespective of the results of the diagnostic investigations.

A summary of all interventions and whether they are recommended, to be considered or are not recommended is provided in Fig. 5. Details on the justification for the recommendations are included below and in Supplementary Data S2.

Intentional endometrial injury

Endometrial injury or endometrial scratch is performed to improve the receptivity of the endometrium towards the transferred embryo. The biological mechanism of action is not fully understood.

A meta-analysis by Busnelli et al. (2021) reported that, based on three RCTs, there was no significantly increased chance of pregnancy and LBR in women who underwent intentional endometrial injury (random effects model, RR 1.43; 95% CI 0.79-2.61; P = 0.24; I ² = 52% and RR 1.55; 95% CI 0.81-2.94; P = 0.18; I ² = 46%, respectively). A consistent positive effect of endometrial injury on clinical PR (CPR) was reported in two observational studies ( Raziel et al., 2007; Matsumoto et al., 2017). A more recent RCT including 211 women also reported no significant difference in clinical pregnancy (foetal heartbeat), pregnancy loss, or multiple pregnancies between patients with RIF who underwent hysteroscopy and intentional endometrial injury versus hysteroscopy only ( Zahiri et al., 2021). A Cochrane review on endometrial injury in women undergoing IVF reported similar data from a sub-analysis on RIF ( Lensen et al., 2021). To date, studies of the efficacy of endometrial scratching have been empirical, as tests that would define a cause of RIF for which endometrial injury could represent a relevant therapy are not yet established.

Granulocyte colony-stimulating factor administration

G-CSF plays a role in embryo implantation and the continuation of pregnancy by temporarily suppressing immune response through its effects on lymphocytes, macrophages, and T helper-2 cells ( Moldenhauer et al., 2010). Its use may be associated with recruiting dendritic cells, promoting Th-2 cytokine secretion, activating Tregs, favouring the local immune responses, vascular remodelling of the endometrium, and cellular adhesion pathways ( Rahmati et al., 2014). When administered systemically, G-CSF has been reported to play a role in embryonic development, implantation, and trophoblastic growth ( Würfel, 2015), while local intrauterine administration could improve endometrial receptivity ( Rahmati et al., 2014).

Few studies, summarized in two meta-analyses including some of the same RCTs, evaluated the effect of subcutaneous or intrauterine G-CSF administration in patients with RIF ( Busnelli et al., 2021; Hou et al., 2021). Subcutaneous G-CSF administration was associated with an increased chance of clinical pregnancy compared with no treatment in both meta-analyses (RR 2.29; 95% CI 1.58-3.31; 4 RCTs; n = 333) ( Busnelli et al., 2021) (RR 1.73; 95% CI 1.33-2.23; 6 RCTs; n = 497) ( Hou et al., 2021). Intrauterine administration had no impact on CPR in the review by Busnelli et al. (2021) (RR 1.53; 95% CI 1.00-2.33; 2 RCTs; n = 257), while the other review reported an increased chance of clinical pregnancy with intrauterine G-CSF (RR 1.39; 95% CI 1.09-1.78; 4 RCTs; n = 479) ( Hou et al., 2021). The analysis for LBR failed to show a benefit (RR 1.43; 95% CI 0.86-2.36; 3 RCTs; n = 372) ( Hou et al., 2021). Two more recent RCTs on intrauterine G-CSF administration in patients with RIF confirmed conflicting results ( Karimi et al., 2020; Torky et al., 2021).

Side-effects or adverse events for G-CSF administration include mucositis, splenic enlargement, hepatomegaly, transient hypotension, epistaxis, urinary abnormalities, osteoporosis, exacerbation of rheumatoid arthritis, anaemia, and pseudogout ( Moffett and Shreeve, 2015).

Overall, there is conflicting evidence on whether intrauterine G-CSF administration improves LBR in patients with RIF. For subcutaneous G-CSF administration, it was considered that prior to a possible recommendation for clinical practice, the suggested positive impact on pregnancy rates in RIF patients needs further corroboration, both in terms of follow-up to live birth and safety aspects.

Intravenous intralipid infusion

Intravenous intralipid infusion has been proposed to have a role in immune modulation through the reduction of platelet aggregation, a decrease of IL-2, tumour necrosis factor-α, and IL-1β production as well as suppression of NK cell levels and activity.

Few RCTs have evaluated the effectiveness of intravenous intralipid during ART in patients with RIF. A systematic review and meta-analysis reported a higher CPR (172/417 versus 119/426; RR 1.55; 95% CI 1.16-2.07; 5 RCTs; I ² = 44.2%) and LBR (132/417 versus 73/426; RR 1.83; 95% CI 1.42-2.35; 5 RCTs; I ² = 0%) with the intervention but concluded there is limited evidence to support the use of intravenous intralipid at the time of ET in women with a history of RIF ( Rimmer et al., 2021).

In a multicentre study evaluating intravenous intralipid and prednisone in 64 patients with RIF, higher CPRs were found in treated patients (44% versus 9%; P < 0.001) with OR at 8.13 (95% CI 4.49-14.72; P < 0.0001) ( Kolanska et al., 2021). Most studies to date have evaluated intravenous intralipid as an empirical intervention without targeting any diagnosed underlying pathology. In a cohort study that evaluated lipid infusions in 94 patients with RIF with an immune profile of endometrial over-immune activation, a LBR of 54% following the next ET was observed ( Lédée et al., 2018). However, larger controlled studies are required to confirm this.

Balanced against the possible benefits of intra-lipid infusions are side effects or adverse events, and these have been reported to include hepatomegaly, jaundice, cholestasis, splenomegaly, thrombocytopenia, leukopenia, and fat overload syndrome ( Moffett and Shreeve, 2015). Taken together, intravenous lipid infusions are, therefore, not recommended.

Intravenous immunoglobulin

The intravenous injection of IgG (IVIG) is suggested to have immunomodulatory actions by neutralizing autoantibodies, downregulation of B-cell and T-cell function, and blockage of Fc receptors.

The review of Abdolmohammadi-Vahid et al. (2019) included two cohort studies and two cross-sectional studies focussing on IVIG in RIF and showed a significant difference in the IVIG group compared to controls in LBR (cohort studies: OR 2.17; 95% CI 1.30-3.61; P = 0.003 and cross-sectional studies: OR 7.57; 95% CI 4.53-12.64; P < 0.00001) and PR (cohort studies: OR 1.82; 95% CI 1.14-2.89; P = 0.01 and cross-sectional studies: OR 11.12; 95% CI 6.43-19.23; P < 0.00001). One more recent observational study reported significantly increased LBR and CPR in treated women (OR 1.76; 95% CI 1.08-2.89; P = 0.02 and OR 2.08; 95% CI 1.28-3.36; P = 0.003, respectively) ( Ho et al., 2019; Busnelli et al., 2021). While the studies report a benefit for IVIG, study populations are small and RCTs are lacking.

Side effects or adverse events of IVIG include aseptic meningitis, renal failure, thromboembolism, haemolytic reactions, anaphylactic reactions, lung disease, enteritis, dermatologic disorders, and infectious diseases. An additional ethical concern that has been raised is the diversion of IVIG from patients with serious conditions, necessitating strict allocation of the limited supplies available ( Moffett and Shreeve, 2015).

Intrauterine autologous peripheral blood mononuclear cells infusion

A meta-analysis of studies with RIF patients experiencing ≥3 failed ETs showed a beneficial effect of intrauterine PBMCs infusion with regard to LBR and PR (RR 1.93; 95% CI 1.35-2.76; P < 0.001; 1 RCT + 3 studies and RR 1.92; 95% CI 1.48-2.49; P < 0.001; 2 RCTs and 6 quasi-experimental studies) ( Maleki-Hajiagha et al., 2019). Two more recent RCTs and one study confirmed these findings ( Chakrabarti et al., 2019; Nobijari et al., 2019; Pourmoghadam et al., 2020). Other meta-analyses including the same dataset have been published, but in all studies and RCTs, the study populations are small and the definitions for RIF are inconsistent. Furthermore, techniques to prepare PBMCs differed substantially between studies (co-cultured in the presence of hCG, corticotrophin-releasing hormone, HMG, a mixture of fresh and co-cultured PBMCs).

Intrauterine platelet-rich plasma infusion

Busnelli et al. reported a significantly increased chance of clinical pregnancy after intrauterine PRP administration (fixed effects model: RR 2.45; 95% CI 1.55-3.86; P = 0.0001; I ² = 0%; 2 RCTs; n = 195) ( Nazari et al., 2019; Zamaniyan et al., 2020; Busnelli et al., 2021). A more recent RCT from the same group confirmed these findings ( Nazari et al., 2022). Women included in the trials were not selected for thin endometrium.

A previous meta-analysis, which did not include the most recent RCT and employed less stringent inclusion criteria, included three RCTs and four cohort studies and reported a significantly higher probability of clinical pregnancy in the PRP group (RR 1.79; 95% CI 1.37-2.32; P < 0.001; I ² = 16%; n = 625) ( Maleki-Hajiagha et al., 2020). From a network meta-analysis of 16 studies, it was concluded that among different immunomodulatory therapies evaluated in RIF, PRP was the most effective treatment towards improving LBR ( Liu et al., 2022a). The authors did add a caveat that additional high-quality studies are necessary to verify the conclusions from their analysis owing to the restricted number of included studies.

Overall, the evidence available is not considered sufficient to support the use of PRP infusions.

Intrauterine hCG injection

Based on two observational studies, the effect of intrauterine hCG injection in women with RIF (≥3 failed ET) and normal EMT (8-16 mm) was reported to significantly increase LBR (OR 1.78; 95% CI 1.02-3.09; n = 303; P = 0.04) and CPR (fixed effects model: OR 1.81; 95% CI 1.23-2.65; n = 482; P = 0.002; I ² = 0%) ( Huang et al., 2018; Liu et al., 2019; Busnelli et al., 2021). Liu et al. (2019) showed a beneficial effect of intrauterine hCG injection on implantation rate (OR 1.71; 95% CI 1.08-2.71; P  = 0.02).

A less stringent systematic review on intrauterine hCG administration in patients with RIF (≥2 failed ET) also showed increased LBR and CPR in the treatment group versus controls (27.8 versus 18.0%; RR 1.52; 95% CI 1.18-1.96; 3 studies; n = 870 and 41.8 versus 31.2%; RR 1.30; 95% CI 1.14-1.50; 6 studies; n = 1432, respectively) ( Xie et al., 2019). A recent RCT including 98 women compared intrauterine hCG injection with placebo and reported significantly higher CPR (23/49 (46.9%) versus 11/48 (22.9%)) and implantation rates (28/120 (23.3%) versus 16/118 (13.6%)) with hCG treatment ( Torky et al., 2021). The review of Conforti et al. (2022), while not focussed on women with RIF, concluded that the possible benefit of intrauterine hCG injection may be limited to cleavage-stage ET.

While the evidence is suggestive of a benefit, the data are mainly derived from (small, uncontrolled) studies rather than RCTs. Furthermore, there is significant heterogeneity between the studies concerning hCG dosage and timing of administration, the volume of perfusion fluid, and the type of transfer cycle (fresh or frozen). From this, it is concluded that there is insufficient evidence to support a recommendation for applying intrauterine hCG injection in clinical practice.

Low molecular weight heparin

Low molecular weight heparin (LMWH) was found to have a significant impact on LBR in women with acquired thrombophilia. It has been postulated that the anticoagulation effect of heparin prevents placental thrombosis and infarction, and promotes the establishment and continuation of pregnancy ( Nelson and Greer, 2008). Considering a possible association of thrombophilia with RPL and RIF, the use of LMWH has been expanded to these patients undergoing ART, even in the absence of acquired or inherited thrombophilia.

A meta-analysis investigated the use of LMWH in patients with RIF (≥3 failed ET) but failed to show an effect of LMWH on LBR (RR 1.38; 95% CI 0.64-2.96; 2 RCTs; n = 71) and CPR (RR1.39; 95% CI 0.87-2.23; 2 RCTs; n = 218) ( Busnelli et al., 2021). The observational study by Berker et al. (2011) also failed to show a difference in LBR or PR.

GnRH agonist and aromatase inhibitor pre-treatment

In an RCT, 67 women with at least two implantation failures were randomized to receive GnRH agonist (0.1 mg/day) from Day 21 of the cycle preceding frozen-thawed ET. The dose was reduced to 0.05 mg/day from Cycle Day 2. The control group received no GnRH agonist. No significant differences were found in CPR (25.8% versus 19.4%) or implantation rate (13.55% versus 10.52%) in the study versus the control group ( Davar et al., 2020). In a retrospective cohort study, infertile patients aged 36-43 years undergoing their third or more ET after autologous IVF or ICSI were included. The study group ( n = 290) received a single injection of 3.75 mg long-acting triptorelin acetate on Day 2 of the preceding cycle, followed by hormone replacement therapy (HRT). The control group ( n = 194) received HRT only. Clinical pregnancy rate (49.0% versus 35.1%), OPR (37.6% versus 22.7%), and LBR (36.6% versus 22.1%) were significantly higher in the study group compared to controls, respectively. Miscarriage rates did not differ between groups ( Pan et al., 2022).

In another retrospective cohort study, infertile women who failed two blastocyst transfers underwent a third frozen blastocyst transfer ( Steiner et al., 2019). Prior to the third ET, 143 women received 2 months of GnRH agonist (3.75 mg intramuscular leuprolide acetate monthly) only, 176 received GnRH agonist and aromatase inhibitor (5 mg oral letrozole daily for 60 days), and 204 received no pre-treatment. CPR and LBR were higher among women who received GnRH agonist plus letrozole compared with women who received GnRH agonist-only or women without pre-treatment (CPR: 63%, 42%, and 40%, respectively; P < 0.0001; LBR: 56%, 36%, and 34%, respectively; P  < 0.0001). However, there was no difference between no pre-treatment and GnRH agonist-only pre-treatment.

Taken together, while a role for GnRH agonist and aromatase inhibitor pre-treatment in specific patients with RIF might be identified, at present, their empirical use is not recommended.

Preimplantation genetic testing for aneuploidies

Busnelli et al. included two RCTs ( Blockeel et al., 2008; Rubio et al., 2013) and three observational studies ( Yakin et al., 2008; Greco et al., 2014; Sato et al., 2020) investigating the potential role of PGT-A in improving IVF outcomes in women with RIF. The meta-analysis of RCTs failed to show an improvement in both clinical pregnancy and LBR (random effects model: RR 1.07; 95% CI 0.36-3.15; P = 0.90; I ² = 89% and RR 0.98; 95% CI 0.32-2.94; P = 0.97; I ²  = 87%) in women who underwent PGT-A.

Non-invasive means of assessing embryo euploidy are the focus of much current research, but this approach is at too early a stage to yet be considered as an option in clinical practice.

Blastocyst-stage ET

Blastocyst-stage embryos may have a better chance of implantation owing to a lower risk of embryo aneuploidy, better synchronization with the endometrium, and fewer uterine contractions at the time of transfer. A systematic review of 27 studies in ART patients showed, with a low quality of evidence, that LBR after a fresh transfer was higher in the blastocyst transfer group compared to the cleavage-stage ET group (OR 1.27; 95% CI 1.06-1.51; I ² = 53%; 15 studies; n = 2219 women) ( Glujovsky et al., 2022).

Assisted hatching

The inability of the blastocyst to escape from its zona pellucida is considered one of the pathways leading to unsuccessful ART, including implantation failure. Assisted blastocyst hatching could, in that respect, be an option to facilitate implantation.

A systematic review, including one RCT and one observational study, evaluated assisted hatching on ART outcomes in patients with RIF after at least three failed ETs and exclusion of probable causes of RIF ( Busnelli et al., 2021). Assisted hatching did not increase CPR (RCT data: RR 0.78; 95% CI 0.48-1.27; P = 0.31; observational data: OR 1.42; 95% CI 0.45-4.48; P = 0.55) or LBR (observational data: OR 1.92; 95% CI 0.48-7.67; P = 0.36) ( Primi et al., 2004; Rufas-Sapir et al., 2004; Busnelli et al., 2021).

Other treatments

Other treatments have been suggested for RIF, including additional interventions in the laboratory (e.g. time-lapse imaging), medical treatments (sildenafil), adaptations in the ET procedure (e.g. ultrasound-guided ET, performing a trial ET, ensuring the catheter tip is >15 mm from the fundus, recommending a full bladder at ET, cervical dilatation, cervical mucus removal, use of fibrin sealant, use of antibiotics, bed rest following the procedure), and adaptations in the ET strategy (e.g. frozen ET). To our knowledge, there are no studies evaluating the effect of these interventions on the chances of LBR in patients with RIF.

With regards to hyaluronic acid (HA)-supplemented ET medium, meta-analyses support an improvement in the LBR in the general ART population (OR 1.33; 95% CI 1.11-1.60) ( Heymann et al., 2020; Holt-Kentwell et al., 2022). However, to our knowledge, the evidence specifically for women with RIF is limited to a single RCT showing a benefit of HA-enriched ET medium compared to routine ET medium in terms of clinical PR ( Friedler et al., 2007).

It should be added that couples diagnosed with RIF may benefit from moving to third-party donation for further ART cycles. While third-party donation brings a new set of challenges and requires support and stringent provision of information, it could bypass an underlying (unidentified) issue with the sperm, oocyte, or embryo. Studies are needed to confirm that resorting to ART with donated sperm or oocytes indeed improves the chances of pregnancy and live birth after RIF.

Treatment based on diagnostic findings

Few studies have evaluated interventions for RIF with an established underlying factor.

Some of these combinations of detected underlying factors and respective treatments have been covered in the previous section on investigations. The treatments covered include optimization of lifestyle factors following their re-assessment, review of estradiol treatment if the endometrium remains thin, hysteroscopy to rule out Asherman's syndrome, genetic counselling and where relevant PGT when a chromosomal abnormality is detected, and antibiotic treatment in case CE is detected. Any other abnormalities or dysfunctions identified (thyroid dysfunction, diagnosis of APS, uterine malformations, endometriosis, adenomyosis) should be followed-up in line with the respective applicable clinical guidelines.

Within the OPTIMUM trial, patients with RIF ( n = 116) were treated according to an identified possible risk factor (e.g. CE with antibiotics, aberrant high Th1/Th2 cell ratios with vitamin D and/or tacrolimus, overt/subclinical hypothyroidism with levothyroxine, and thrombophilia with low-dose aspirin) ( Kuroda et al., 2021). In the patients aged <40 years and ≥40 years, the OPR in the OPTIMUM group was significantly higher than that in the control group (57.4% and 30.3% versus 21.4% and 0% per ET, respectively; P  < 0.01). These data suggest that using diagnostics to assess the cause of RIF is likely to improve the efficacy of interventions, which would then be applied with more rationale than at present. At present few validated tests of value in the context of RIF are available, but this is likely to change in the future.

Patient care and counselling

Recognize the woman/couple as an individual.

Provide time for questions, information, repetition, and discussion, especially when the patient/couple is distressed or anxious.

Listen to the facts and the feelings of the patient/couple.

Show respect for the patient/couple and their wishes and choices.

Use clear and sensitive language: explain terminology, avoid insensitive terms, and mirror the patient's preferred terms.

Be honest about processes, likely outcomes, and prognoses, and avoid false reassurance. This includes being honest about the evidence and benefit (or lack of benefit) for the investigations and treatments that have been proposed for RIF and are being applied in clinical practice without solid ground. Patients/couples can further be reassured based on their individual estimation of the likelihood of implantation in the next cycle that simply continuing with ART treatment is a good option for them. Further support for this can be derived from a study showing that half of the patients with RIF achieve a live birth with ART within 5 years ( Koot et al., 2019).

Apply shared treatment planning in a partnership approach. It was recently suggested that a multi-cycle approach could be beneficial in this respect, as it would consider cycle failure and how to cope with it from the start of the treatment process ( Harrison et al., 2022).

Be kind, show concern, empathy, and compassion.

Discussion

In these recommendations for good clinical practice, the ESHRE WG encourages the reconsideration of RIF from being a medical condition with fixed diagnostic criteria to a clinical secondary phenomenon of ART that can arise at different moments in different patients, and which requires a degree of empathy and pragmatism to manage well. The recommendations provided are based on this approach, with a clear acknowledgement of the lack of a robust evidence base to support them. However, it is the nature and requirement of clinical medicine to advise what is best for a patient given their individual clinical context, even when hard data are scarce. It is to be hoped that, in the coming years, studies will be published that can provide a firmer basis for clinical recommendations and allow a clear consensus for the optimal management of RIF to emerge. Ideally, all investigations used in patients with RIF will have proven clinical utility and relevance. Tests will be performed to detect an underlying problem or assess a contributing factor to the implantation failures and linked to a specific intervention that has been shown to improve the chances of live birth in the next cycle. Additional tests that do not have a linked intervention can be considered for patient counselling and to estimate the relevance of continuing ART treatment or resorting to other reproductive options.

The need for further research in RIF

In this respect, the herein proposed definition of RIF should be applied in future research studies as it will increase homogeneity both in the study population as well as across studies, which should be helpful towards meaningful study outcomes and feasible meta-analysis.

With regard to specific investigations and treatments, the following topics should be priorities for researchers:

The role of vitamin D determination and supplementation (in case of low levels) in patients with RIF.

The role of immunological factors as an underlying factor in RIF, methods to investigate these, and efficacy of targeted treatments.

The role of decidualization as a potential therapeutic target to overcome inappropriate rejection of the implanting embryo.

The relevance of endometrial receptivity tests, CE evaluation, and microbiome profiling in patients with RIF should be further evaluated.

The role of thin endometrium, as well as the relevance of specific treatments to increase the chance of pregnancy in patients with RIF and detected thin endometrium.

The clinical value of SDF tests

Possible genetic predispositions to extreme IVF outcomes ( Capalbo et al., 2021), such as RIF.

The value of treatments, such as intrauterine autologous PBMC infusion, intrauterine PRP infusion, and intrauterine hCG injection, to prevent implantation failure in a next cycle should be further evaluated.

The value of antioxidant treatments should be further evaluated.

Apart from the clinical aspect of RIF, more insight and data are needed on the impact of RIF on the stress, mental health, and well-being of patients, and on supportive treatment options that could minimize such impact and lead to better care.

While awaiting the results of further studies and trials, the ESHRE WG recommends the approach summarized in Figs 3, 4, and 5, which is to individualize the diagnosis of RIF based on the chance of successful implantation for the individual patient or couple, and to restrict investigations and treatments to those supported by a clear rationale and data on their benefit. The current recommendations will be updated 4 years after publication.

Supplementary data

Supplementary data are available at Human Reproduction Open online.

Data availability

The data underlying this article are available in the article and in its online supplementary material.

Acknowledgements

The authors would like to thank the 35 experts who contributed to the stakeholder review for their helpful comments and suggestions; the list of these reviewers is available in Supplementary Data S3.

Authors' roles

N.M. chaired the ESHRE Working Group on Recurrent Implantation Failure. N.V. and N.L.C. provided methodological support. All other authors contributed equally in writing the article, and all approved the final version for publication.

Funding

The meetings and technical support for this project were funded by ESHRE.

Conflict of interest

N.M. declared consulting fees from ArtPRED (The Netherlands) and Freya Biosciences (Denmark); honoraria for lectures from Gedeon Richter, Merck, Abbott, and IBSA; being co-founder of Verso Biosense. He is Co-Chief Editor of Reproductive Biomedicine Online (RBMO). D.C. declared being an Associate Editor of Human Reproduction Update, and declared honoraria for lectures from Merck, Organon, IBSA, and Fairtility; support for attending meetings from Cooper Surgical, Fujifilm Irvine Scientific. G.G. declared that he or his institution received financial or non-financial support for research, lectures, workshops, advisory roles or travelling from Ferring, Merck, Gedeon-Richter, PregLem, Abbott, Vifor, Organon, MSD, Coopersurgical, ObsEVA, and ReprodWissen. He is an Editor of the journals Archives of Obstetrics and Gynecology and Reproductive Biomedicine Online, and Editor in Chief of Journal Gynäkologische Endokrinologie. He is involved in guideline developments and quality control on national and international level. G.L. declared he or his institution received honoraria for lectures from Merck, Ferring, Vianex/Organon, and MSD. He is an Associate Editor of Human Reproduction Update, immediate past Co-ordinator of Special Interest Group for Reproductive Endocrinology of ESHRE and has been involved in Guideline Development Groups of ESHRE and national fertility authorities. D.J.M. declared being an Associate Editor for Human Reproduction Open and statistical Advisor for Reproductive Biomedicine Online. B.T. declared being shareholder of Reprognostics and she or her institution received financial or non-financial support for research, clinical trials, lectures, workshops, advisory roles or travelling from support for attending meetings from Ferring, MSD, Exeltis, Merck Serono, Bayer, Teva, Theramex and Novartis, Astropharm, Ferring. The other authors had nothing to disclose.

References

# data[].attributes.attachment_link.title
ESHRE good practice recommendations on recurrent implantation failure†

# data[].attributes.attachment_link.description
AbstractSTUDY QUESTION. How should recurrent implantation failure (RIF) in patients undergoing ART be defined and managed?SUMMARY ANSWER. This is the first

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doi: 10.1016/j.rbmo.2023.103737.

Affiliations

¹ IVIRMA Global Research Alliance, IVI Roma, Rome, Italy.; IVIRMA Global Research Alliance, IVI Foundation-IIS la Fe, Valencia, Spain.. Electronic address: mauro.cozzolino@ivirma.com.

² The Fertility Clinic, Skive Regional Hospital, Denmark and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

³ IVIRMA Global Research Alliance, IVI Roma, Rome, Italy.; IVIRMA Global Research Alliance, IVI Foundation-IIS la Fe, Valencia, Spain.

⁴ IVIRMA Global Research Alliance, IVI, Madrid, Spain.; Department of Obstetrics and Gynecology, Universidad Rey Juan Carlos, Madrid, Spain.

doi: 10.1016/j.rbmo.2023.103737.

Affiliations

¹ IVIRMA Global Research Alliance, IVI Roma, Rome, Italy.; IVIRMA Global Research Alliance, IVI Foundation-IIS la Fe, Valencia, Spain.. Electronic address: mauro.cozzolino@ivirma.com.

² The Fertility Clinic, Skive Regional Hospital, Denmark and Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

³ IVIRMA Global Research Alliance, IVI Roma, Rome, Italy.; IVIRMA Global Research Alliance, IVI Foundation-IIS la Fe, Valencia, Spain.

⁴ IVIRMA Global Research Alliance, IVI, Madrid, Spain.; Department of Obstetrics and Gynecology, Universidad Rey Juan Carlos, Madrid, Spain.

Abstract

Endometriosis and adenomyosis are distinct clinical conditions that carry the same pathophysiological features. In recent years the clinical focus on assisted reproductive technology patients with either condition (E/A) has increased, in the recognition that this subgroup of patients might need special attention to obtain reproductive success. Endometriosis and adenomyosis are characterized by a disruption of progesterone and oestrogen signalling pathways, resulting in local oestrogen dominance and progesterone resistance at the receptor level. Recent scientific evidence suggests that the endometrial progesterone receptor resistance encountered in E/A patients can be overcome by a freeze-all policy, followed by down-regulating circulating oestradiol concentrations prior to frozen embryo transfer (FET), in combination with an increase in exogenous luteal phase progesterone supplementation in hormonal replacement therapy (HRT) FET cycles. Specifically, for adenomyosis patients who do not respond to gonadotrophin-releasing hormone agonist down-regulation in terms of a decrease in circulating oestradiol concentrations, a small case series has suggested that the addition of an aromatase inhibitor for 21 days prior to HRT-FET is a valid option. Endometriosis and adenomyosis are hormonally active diseases, which need to be treated by controlling local hyperoestrogenism and progesterone resistance. Based on physiology and recent preliminary clinical data, the authors of this opinion paper wish to stimulate discussion and spark interest in research in E/A patients.

Keywords: Adenomyosis; Endometriosis; Oestradiol; Progesterone resistance.

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Progesterone levels do not differ between patients with or without endometriosis/adenomyosis both in those who conceive after hormone replacement therapy-frozen embryo transfer cycles and those who do not.

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Impact of adenomyosis and endometriosis on IVF/ICSI pregnancy outcome in patients undergoing gonadotropin-releasing hormone agonist treatment and frozen embryo transfer.

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Endometrial receptivity in adenomyosis and/or endometriosis.

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Long-term pituitary downregulation before frozen embryo transfer could improve pregnancy outcomes in women with adenomyosis.

Niu Z, Chen Q, Sun Y, Feng Y. Niu Z, et al. Gynecol Endocrinol. 2013 Dec;29(12):1026-30. doi: 10.3109/09513590.2013.824960. Epub 2013 Sep 5. Gynecol Endocrinol. 2013. PMID: 24006906

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national center for biotechnology information

# data[].attributes.attachment_link.title
The adenomyosis/endometriosis IVF patient - call for clinical focus - PubMed

# data[].attributes.attachment_link.description
Endometriosis and adenomyosis are distinct clinical conditions that carry the same pathophysiological features. In recent years the clinical focus on assisted reproductive technology patients with either condition (E/A) has increased, in the recognition that this subgroup of patients might need spec ...

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Affiliations

¹ Faculté de Médecine, Université de Paris Cité, Paris, France.

² Department of Gynecology Obstetrics II and Reproductive Medicine (Professor Chapron), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.

³ Department "Development, Reproduction and Cancer", Cochin Institute, INSERM U1016, Paris, France.

⁴ Department of Reproductive Biology-CECOS (Professor Patrat), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.

⁵ Department of Biological Endocrinology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.

Affiliations

¹ Faculté de Médecine, Université de Paris Cité, Paris, France.

² Department of Gynecology Obstetrics II and Reproductive Medicine (Professor Chapron), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.

³ Department "Development, Reproduction and Cancer", Cochin Institute, INSERM U1016, Paris, France.

⁴ Department of Reproductive Biology-CECOS (Professor Patrat), Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.

⁵ Department of Biological Endocrinology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre (HUPC), Centre Hospitalier Universitaire (CHU) Cochin, Paris, France.

Abstract

Study question: Is there a significant intra-individual variability of serum progesterone levels on the day of single blastocyst Hormone Replacement Therapy-Frozen Embryo Transfer (HRT-FET) between two consecutive cycles?

Summary answer: No significant intra-individual variability of serum progesterone (P) levels was noted between two consecutive HRT-FET cycles.

What is known already: In HRT-FET cycles, a minimum P level on the day of embryo transfer is necessary to optimise reproductive outcomes. In a previous study by our team, a threshold of 9.8 ng/ml serum P was identified as significantly associated with the live birth rates in single autologous blastocyst transfers under HRT using micronized vaginal progesterone (MVP). Such patients may benefit from an intensive luteal phase support (LPS) using other routes of P administration in addition to MVP. A crucial question in the way towards individualising LPS is whether serum P measurements are reproducible for a given patient in consecutive HRT-FET cycles, using the same LPS.

Study design, size, duration: We conducted an observational cohort study at the university-based reproductive medicine centre of our institution focusing on women who underwent at least two consecutive single autologous blastocyst HRT-FET cycles between January 2019 and March 2020.

Participants/materials, setting, methods: Patients undergoing two consecutive single autologous blastocyst HRT-FET cycles using exogenous oestradiol and vaginal micronized progesterone for endometrial preparation were included. Serum progesterone levels were measured on the morning of the Frozen Embryo Transfer (FET), by a single laboratory. The two measurements of progesterone levels performed on the day of the first (FET1) and the second FET (FET2) were compared to evaluate the intra-individual variability of serum P levels. Paired statistical analyses were performed, as appropriate.

Main results and the role of chance: Two hundred and sixty-four patients undergoing two consecutive single autologous blastocyst HRT-FET were included. The mean age of the included women was 35.0 ± 4.2 years. No significant intra-individual variability was observed between FET1 and FET2 (mean progesterone level after FET1: 13.4 ± 5.1 ng/ml vs after FET2: 13.9 ± 5.0; P = 0.08). The characteristics of the embryo transfers were similar between the first and the second FET. Forty-nine patients (18.6%) had discordant progesterone levels (defined as one progesterone measurement > and one ≤ to the threshold of 9.8 ng/ml) between FET1 and FET2. There were 37/264 women (14.0%) who had high intra-individual variability (defined as a difference in serum progesterone values >75th percentile (6.0 ng/ml)) between FET1 and FET2. No specific clinical parameter was associated with a high intra-individual variability nor a discordant P measurement.

Limitations, reasons for caution: This study is limited by its retrospective design. Moreover, only women undergoing autologous blastocyst HRT-FET with MVP were included, thereby limiting the extrapolation of the study findings to other routes of P administration and other kinds of endometrial preparation for FET.

Wider implications of the findings: No significant intra-individual variability was noted. The serum progesterone level appeared to be reproducible in >80% of cases. These findings suggest that the serum progesterone level measured on the day of the first transfer can be used to individualize luteal phase support in subsequent cycles.

Study funding/competing interest(s): No funding or competing interests.

Trial registration number: N/A.

Keywords: frozen embryo transfer; hormonal replacement therapy; intra-individual variability; micronized vaginal progesterone; serum progesterone level.

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Rectal progesterone administration secures a high ongoing pregnancy rate in a personalized Hormone Replacement Therapy Frozen Embryo Transfer (HRT-FET) protocol: a prospective interventional study.

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Clinical factors associated with low serum progesterone levels on the day of frozen blastocyst transfer in hormonal replacement therapy cycles.

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Frozen embryo transfer: a review on the optimal endometrial preparation and timing.

Mackens S, Santos-Ribeiro S, van de Vijver A, Racca A, Van Landuyt L, Tournaye H, Blockeel C. Mackens S, et al. Hum Reprod. 2017 Nov 1;32(11):2234-2242. doi: 10.1093/humrep/dex285. Hum Reprod. 2017. PMID: 29025055 Review.

Natural Micronized Progesterone Sustained Release (SR) and Luteal Phase: Role Redefined!!

Malik S, Krishnaprasad K. Malik S, et al. J Clin Diagn Res. 2016 Feb;10(2):QE01-4. doi: 10.7860/JCDR/2016/17278.7212. Epub 2016 Feb 1. J Clin Diagn Res. 2016. PMID: 27042538 Free PMC article. Review.

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# data[].attributes.attachment_link.title
Intra-individual variability of serum progesterone levels on the day of frozen blastocyst transfer in hormonal replacement therapy cycles - PubMed

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doi: 10.3389/fendo.2021.688237.

Affiliations

¹ Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey.

² Anatolia IVF and Women Health Centre, Ankara, Turkey.

³ Nature IVF Unit, Thessaloniki, Greece.

⁴ Androfert, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Campinas, Brazil.

⁵ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

⁶ The Fertility Clinic, Skive Regional Hospital Resenvej 25, Skive, Denmark.

Sezcan Mumusoglu et al. Front Endocrinol (Lausanne).

doi: 10.3389/fendo.2021.688237.

Affiliations

¹ Department of Obstetrics and Gynecology, Hacettepe University School of Medicine, Ankara, Turkey.

² Anatolia IVF and Women Health Centre, Ankara, Turkey.

³ Nature IVF Unit, Thessaloniki, Greece.

⁴ Androfert, Andrology and Human Reproduction Clinic, Referral Center for Male Reproduction, Campinas, Brazil.

⁵ Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.

⁶ The Fertility Clinic, Skive Regional Hospital Resenvej 25, Skive, Denmark.

Abstract

Despite the worldwide increase in frozen embryo transfer, the search for the best protocol to prime endometrium continues. Well-designed trials comparing various frozen embryo transfer protocols in terms of live birth rates, maternal, obstetric and neonatal outcome are urgently required. Currently, low-quality evidence indicates that, natural cycle, either true natural cycle or modified natural cycle, is superior to hormone replacement treatment protocol. Regarding warmed blastocyst transfer and frozen embryo transfer timing, the evidence suggests the 6 th day of progesterone start, LH surge+6 day and hCG+7 day in hormone replacement treatment, true natural cycle and modified natural cycle protocols, respectively. Time corrections, due to inter-personal differences in the window of implantation or day of vitrification (day 5 or 6), should be explored further. Recently available evidence clearly indicates that, in hormone replacement treatment and natural cycles, there might be marked inter-personal variation in serum progesterone levels with an impact on reproductive outcomes, despite the use of the same dose and route of progesterone administration. The place of progesterone rescue protocols in patients with low serum progesterone levels one day prior to warmed blastocyst transfer in hormone replacement treatment and natural cycles is likely to be intensively explored in near future.

Keywords: frozen embryo transfer; hormone replacement treatment cycle; individualized approach; modified natural cycle; natural cycle; true natural cycle.

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Conflict of interest statement

HY, EP, and GB declare receipt of honorarium for lectures from Merck and research grants from Merck and Ferring. SE declares receipt of unrestricted research grants from Merck and lecture fees from Merck and Med.E.A. PH has received unrestricted research grants from MSD and Merck, as well as honoraria for lectures from MSD, Merck, Gedeon-Richter, Theramex, and IBSA. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

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References

De Geyter C, Wyns C, Calhaz-Jorge C, de Mouzon J, Ferraretti AP, Kupka M, et al. . 20 Years of the European IVF-Monitoring Consortium Registry: What Have We Learned? A Comparison With Registries From Two Other Regions. Hum Reprod (2020) 35(12):2832-49. 10.1093/humrep/deaa250 - DOI - PMC - PubMed

Prevention. CfDCa . 2018, Assisted Reproductive Technology Fertility Clinic Success Rates Report. Atlanta GA: US Dept of Health and Human Services; (2020).

European IVFMC. European Society of Human R. Embryology. Kupka MS, D'Hooghe T, Ferraretti AP, et al. . Assisted Reproductive Technology in Europe, 2011: Results Generated From European Registers by ESHRE. Hum Reprod (2016) 31(2):233-48. 10.1093/humrep/dev319 - DOI - PubMed

Kupka MS, Ferraretti AP, de Mouzon J, Erb K, D'Hooghe T, Castilla JA, et al. . Assisted Reproductive Technology in Europe, 2010: Results Generated From European Registers by ESHREdagger. Hum Reprod (2014) 29(10):2099-113. 10.1093/humrep/deu175 - DOI - PubMed

Glujovsky D, Pesce R, Sueldo C, Quinteiro Retamar AM, Hart RJ, Ciapponi A. Endometrial Preparation for Women Undergoing Embryo Transfer With Frozen Embryos or Embryos Derived From Donor Oocytes. Cochrane Database Syst Rev (2020) 10:CD006359. 10.1002/14651858.CD006359.pub3 - DOI - PMC - PubMed

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national center for biotechnology information

# data[].attributes.attachment_link.title
Preparation of the Endometrium for Frozen Embryo Transfer: A Systematic Review - PubMed

# data[].attributes.attachment_link.description
Despite the worldwide increase in frozen embryo transfer, the search for the best protocol to prime endometrium continues. Well-designed trials comparing various frozen embryo transfer protocols in terms of live birth rates, maternal, obstetric and neonatal outcome are urgently required. Currently, ...

# data[].attributes.attachment_link.readable_text
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Affiliations

¹ Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, Pakistan.

² Nishter Hospital, Multan, Pakistan.

³ Department of Urology, Hamad Medical Corporation, Doha, Qatar.

⁴ Weill Cornell Medicine- Qatar, Doha, Qatar.

⁵ ANDROFERT, Andrology and Human Reproduction Clinic, Av. Dr. Heitor Penteado, 1464, Campinas, São Paulo, 13075-460, Brazil. s.esteves@androfert.com.br.

⁶ Department of Surgery (Division of Urology), University of Campinas (UNICAMP), Campinas, Brazil. s.esteves@androfert.com.br.

⁷ Faculty of Health, Department of Clinical Sciences, Aarhus University, Aarhus, Denmark. s.esteves@androfert.com.br.

Affiliations

¹ Fatima Memorial Hospital College of Medicine and Dentistry, Lahore, Pakistan.

² Nishter Hospital, Multan, Pakistan.

³ Department of Urology, Hamad Medical Corporation, Doha, Qatar.

⁴ Weill Cornell Medicine- Qatar, Doha, Qatar.

⁵ ANDROFERT, Andrology and Human Reproduction Clinic, Av. Dr. Heitor Penteado, 1464, Campinas, São Paulo, 13075-460, Brazil. s.esteves@androfert.com.br.

⁶ Department of Surgery (Division of Urology), University of Campinas (UNICAMP), Campinas, Brazil. s.esteves@androfert.com.br.

⁷ Faculty of Health, Department of Clinical Sciences, Aarhus University, Aarhus, Denmark. s.esteves@androfert.com.br.

Abstract

Intracytoplasmic sperm injection (ICSI), combined with surgical sperm retrieval (SR) techniques, is the sole option for patients with non-obstructive azoospermia to achieve fertility; however, with suboptimal results. Given the variability in clinical presentation, the potential role of factors that can predict the likelihood of successful testicular SR needs to be clarified. This article summarizes the current evidence concerning the variables predicting SR success in non-obstructive azoospermic patients with spermatogenic failure. For this, we used 60 articles, including 46 original papers and six meta-analyses. Clinical and laboratory factors, as well as adjuvant therapies and surgical retrieval methods, were the factors most commonly investigated. We found that Klinefelter syndrome, Y chromosome microdeletions in regions AZFa/b, and Sertoli cell-only histopathology were associated with reduced SR success. By contrast, testis volume > 12.5 ml, history of cryptorchidism, use of micro-TESE as the sperm retrieval method, and adjuvant therapy were associated with improved SR success. None of the predictors, alone or combined, provide definitive information about the chances of harvesting sperm in men with non-obstructive azoospermia, except for Y chromosome microdeletions in regions AZFa/b. In the latter, SR success is virtually nil. We conclude that SR outcomes in men with non-obstructive azoospermia are difficult to predict based on the existing variables. Although several predictors can be used for patient counseling, their clinical value is limited to either ensure SR success or discourage reproductive urologists from recommending SR to men with non-obstructive azoospermia seeking fertility. A notable exception includes the deletions involving the regions AZFa and/or AZFb of the Y chromosome; the affected patients should be counseled against undergoing SR.

Keywords: Male infertility; Non-obstructive azoospermia; Outcome assessment; Review; Sperm retrieval; Testis.

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[Predictive factors of testicular sperm extraction in men with non-obstructive azoospermia].

Yang HL, Shao XJ, Zhu YY, Wu WL. Yang HL, et al. Zhonghua Nan Ke Xue. 2016 May;22(5):462-6. Zhonghua Nan Ke Xue. 2016. PMID: 27416674 Review. Chinese.

Prognostic factors for sperm retrieval in non-obstructive azoospermia.

Glina S, Vieira M. Glina S, et al. Clinics (Sao Paulo). 2013;68 Suppl 1(Suppl 1):121-4. doi: 10.6061/clinics/2013(sup01)13. Clinics (Sao Paulo). 2013. PMID: 23503961 Free PMC article. Review.

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Predictors of surgical sperm retrieval in non-obstructive azoospermia: summary of current literature - PubMed

# data[].attributes.attachment_link.description
Intracytoplasmic sperm injection (ICSI), combined with surgical sperm retrieval (SR) techniques, is the sole option for patients with non-obstructive azoospermia to achieve fertility; however, with suboptimal results. Given the variability in clinical presentation, the potential role of factors that ...

# data[].attributes.attachment_link.readable_text
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Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you're on a federal government site.

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Affiliations

¹ Global Andrology Forum, Ohio, USA.

² Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt.

³ Ajyal IVF Center, Ajyal Hospital, Sohag, Egypt.

⁴ Division of Andrology, Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India.

⁵ Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Affiliations

¹ Global Andrology Forum, Ohio, USA.

² Department of Dermatology, Venereology and Andrology, Faculty of Medicine, Sohag University, Sohag, Egypt.

³ Ajyal IVF Center, Ajyal Hospital, Sohag, Egypt.

⁴ Division of Andrology, Department of Urology, Lilavati Hospital and Research Centre, Mumbai, India.

⁵ Cleveland Clinic Foundation, Cleveland, Ohio, USA.

Abstract

Objectives: Sperm DNA fragmentation (SDF) is a molecular marker of sperm chromatin health. Elevated SDF is associated with male infertility, recurrent pregnancy loss, and failure of assisted reproductive technologies (ART). In 2021, the sixth edition of the World Health Organization (WHO) Manual for the Laboratory Examination and Processing of Human Semen has listed SDF as an extended test of semen that can be ordered under certain circumstances. However, the manual neither explained the indications for testing nor provided clear guidance on diagnostic thresholds.

Methods: This article summarizes the current body of knowledge regarding clinical applications of SDF, including the appropriate population to test, methods of testing, and management strategies.

Results: Several etiologic factors and pathophysiologic mechanisms for SDF have been described including poor lifestyle habits, noxious exposures, and varicocele. Four SDF assays are included in the WHO manual and may be utilized based on resources and expertise. Strategies to lower SDF levels in infertile men include addressing underlying causes, supplementation with antioxidants, shorter abstinence periods, and use of testicular sperm for intracytoplasmic sperm injection.

Conclusion: SDF testing can be implemented in the evaluation of infertile men and couples experiencing ART failure and appropriate management strategies can be offered to improve reproductive outcomes. There is vast potential for future research regarding the clinical utility of SDF in the evaluation and treatment of infertile couples.

Keywords: Male infertility; extended examination of semen; sperm DNA fragmentation.

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Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Similar articles

Role of sperm DNA fragmentation in male factor infertility: A systematic review.

Cho CL, Agarwal A. Cho CL, et al. Arab J Urol. 2017 Dec 6;16(1):21-34. doi: 10.1016/j.aju.2017.11.002. eCollection 2018 Mar. Arab J Urol. 2017. PMID: 29713533 Free PMC article.

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Sánchez V, Wistuba J, Mallidis C.. Semen analysis: update on clinical value, current needs and future perspectives. Reproduction. 2013 Oct 21;146(6):R249-58. doi: 10.1530/REP-13-0109 - DOI - PubMed

Evgeni E, Sabbaghian M, Saleh R, et al. Sperm DNA fragmentation test: usefulness in assessing male fertility and assisted reproductive technology outcomes. Panminerva Med. 2023. Jun;65(2):135-147. doi: 10.23736/S0031-0808.23.04836-X - DOI - PubMed

Baskaran S, Agarwal A, Panner Selvam MK, et al. Tracking research trends and hotspots in sperm DNA fragmentation testing for the evaluation of male infertility: a scientometric analysis. Reprod Biol Endocrinol. 2019 Dec 26; 17(1):110. doi: 10.1186/s12958-019-0550-3 - DOI - PMC - PubMed

Calogero AE, Cannarella R, Agarwal A, et al. The renaissance of male infertility management in the golden age of Andrology. World J Mens Health. 2023. Apr;41(2):237-254. doi: 10.5534/wjmh.220213 - DOI - PMC - PubMed

World Health Organization (WHO) . WHO laboratory manual for the examination and processing of human semen. 6th ed. Geneva: WHO; 2021.

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national center for biotechnology information

# data[].attributes.attachment_link.title
Sperm DNA fragmentation in male infertility: From bench to bedside - PubMed

# data[].attributes.attachment_link.description
SDF testing can be implemented in the evaluation of infertile men and couples experiencing ART failure and appropriate management strategies can be offered to improve reproductive outcomes. There is vast potential for future research regarding the clinical utility of SDF in the evaluation and treatm ...

# data[].attributes.attachment_link.keywords[]
national center for biotechnology information

# data[].attributes.attachment_link.title
Technical Aspects and Clinical Limitations of Sperm DNA Fragmentation Testing in Male Infertility: A Global Survey, Current Guidelines, and Expert Recommendations - PubMed

# data[].attributes.attachment_link.description
This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial.

# data[].attributes.attachment_link.readable_text
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Abstract

Growing evidence of successful outcomes achieved with the oocyte vitrification technique has greatly contributed to its application in the field of fertility preservation (FP). The population that can benefit from FP includes women at a risk of losing their ovarian function because of either iatrogenic causes or natural depletion of their ovarian reserve. Therefore, oncological patients and healthy women who wish to delay motherhood for various reasons-elective FP-are currently being offered this option. Satisfactory oocyte survival rates and clinical outcomes, including cumulative live birth rates, have been reported in recent years. These studies show that age at oocyte retrieval strongly affects reproductive prognosis after FP. Therefore, elective FP patients should be encouraged to decide before they reach the age of 35 years to significantly increase their chances of success. The effect of age has also been observed in patients with cancer and women diagnosed with endometriosis. The reproductive outcome after FP is worse in patients with cancer, but a direct association between the disease and reproductive outcome is yet to be proven. Young patients (≤35 years) with endometriosis who have undergone cystectomy before oocyte retrieval for FP have worse outcomes than nonoperated women in age-matched groups. In addition, the number of oocytes used per patient is closely related to success in all populations, with considerable improvement in the result with the addition of a few oocytes, especially in healthy young patients.

Keywords: Fertility preservation; endometriosis; oncological patients; oocyte survival; oocyte vitrification.

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Combining fertility preservation procedures to spread the eggs across different baskets: a feasibility study.

Delattre S, Segers I, Van Moer E, Drakopoulos P, Mateizel I, Enghels L, Tournaye H, De Vos M. Delattre S, et al. Hum Reprod. 2020 Nov 1;35(11):2524-2536. doi: 10.1093/humrep/deaa193. Hum Reprod. 2020. PMID: 32951035

Oocyte vitrification for fertility preservation in women with endometriosis: an observational study.

Cobo A, Giles J, Paolelli S, Pellicer A, Remohí J, García-Velasco JA. Cobo A, et al. Fertil Steril. 2020 Apr;113(4):836-844. doi: 10.1016/j.fertnstert.2019.11.017. Epub 2020 Mar 4. Fertil Steril. 2020. PMID: 32145929

Elective and Onco-fertility preservation: factors related to IVF outcomes.

Cobo A, García-Velasco J, Domingo J, Pellicer A, Remohí J. Cobo A, et al. Hum Reprod. 2018 Dec 1;33(12):2222-2231. doi: 10.1093/humrep/dey321. Hum Reprod. 2018. PMID: 30383235

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The Effect of Open and Closed Oocyte Vitrification Systems on Embryo Development: A Systematic Review and Network Meta-Analysis.

Pantos K, Maziotis E, Trypidi A, Grigoriadis S, Agapitou K, Pantou A, Nikolettos K, Kokkini G, Sfakianoudis K, Pomeroy KO, Simopoulou M. Pantos K, et al. J Clin Med. 2024 Apr 30;13(9):2651. doi: 10.3390/jcm13092651. J Clin Med. 2024. PMID: 38731179 Free PMC article. Review.

Overactivation or Apoptosis: Which Mechanisms Affect Chemotherapy-Induced Ovarian Reserve Depletion?

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national center for biotechnology information

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Oocyte vitrification for fertility preservation for both medical and nonmedical reasons - PubMed

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Growing evidence of successful outcomes achieved with the oocyte vitrification technique has greatly contributed to its application in the field of fertility preservation (FP). The population that can benefit from FP includes women at a risk of losing their ovarian function because of either iatroge ...

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