SYSTEMATIC REVIEW WITHOUT META-ANALYSIS

Recurrent implantation failure:

reality or a statistical mirage?
Consensus statement from the July 1, 2022
Lugano Workshop on recurrent
implantation failure
(The writing group) for the participants to the 2022 Lugano RIF Workshop, Paul Pirtea, M.D.,a
Marcelle I. Cedars, M.D.,b Kate Devine, M.D.,c Baris Ata, M.D., M.Sc.,d,e Jason Franasiak, M.D.,f
Catherine Racowsky, Ph.D.,a Jim Toner, M.D., Ph.D.,g Richard T. Scott, M.D.,f Dominique de Ziegler, M.D.,a
and Kurt T. Barnhart, M.D., M.S.C.E.h
a
Gynecology, Obstetrics and ART Department, Hospital FOCH, Paris, France; b UCSF Center for Reproductive Health, San
Francisco, California; c US Fertility, Washington, D.C.; d Koc University School of Medicine, Koç University, Istanbul,
Turkey; e ART Fertility Clinics, Dubai, UAE; f IVI RMA New Jersey, Bernards Township, New Jersey; g Emory University,
Atlanta, Georgia; and h Penn Medicine, Philadelphia, Pennsylvania

Importance: To date, recurrent implantation failure (RIF) has no clear definition and no clearly identified impaired function. Hence, the
term RIF is currently used somewhat haphazardly, on the basis of clinicians’ judgment.
Objective: International experts in reproductive medicine met on July 1, 2022, in Lugano, Switzerland, to review the different facets of
RIF and define the diagnosis and its appropriate management.
Evidence Review: A systematic review without meta-analysis of studies published in English from January 2015 to May 2022.
Findings: Data indicated that RIF has been largely overevaluated, overdiagnosed, and overtreated without sufficient critical assess-
ment of its true nature. Our analyses show that true RIF is extremely uncommon—occurring in <5% of couples with infertility—and
that reassurance and continued conventional therapies are warranted in most cases of assisted reproductive technology (ART) failure.
Although the true biologic determinants of RIF may exist in a small subset of people with infertility, they elude the currently available
tools for assessment. Without identification of the true underlying etiology(ies), it is reasonable not to assign this diagnosis to a patient
until she has failed at least 3 euploid blastocyst transfers (or the equivalent number of unscreened embryo transfers, adjusted to the
patient’s age and corresponding euploidy rate). In addition, other factors should be ruled out that may contribute to her reduced
odds of sustained implantation. In such cases, implantation failure should not be the only issue considered in case of ART failure
because this may result from multiple other factors that are not necessarily repetitive or persistent. In reality, RIF impacting the prob-
ability of further ART success is a very rare occurrence.
Conclusion: True RIF is extremely uncommon, occurring in <5% of couples with infertility. Reassurance and continued conventional
therapies are warranted in most cases. It would seem reasonable not to assign this diagnosis to a patient until she has failed at least 3
euploid embryo transfers (or the equivalent number of unscreened embryos, adjusted to her age).
Relevance: Given the number of internationally recognized experts in the field present at the Lugano meeting 2022, our publication
constitutes a consensus statement. (Fertil SterilÒ 2023;-:-–-. Ó2023 by American Society for Reproductive Medicine.)
Key Words: Recurrent implantation failure (RIF), endometrial receptivity, IVF failure, FET, frozen embryo transfer, PGT-A,
preimplantation genetic testing for aneuploidy

Received December 2, 2022; revised February 13, 2023; accepted February 14, 2023.
Participants of the 2022 Lugano RIF Workshop: Paul Pirtea, M.D., Marelle I. Cedars, M.D., Kate Devine, M.D., Baris Ata, M.D., M.Sc., Jason Franasiak, M.D., Jim
Toner, M.D., Ph.D., Shari Mackens, Elena Labarta, M.D., Ph.D., Catherine Racowsky, Ph.D., Carol Coughlan, M.D., Richard Anderson, M.D., Ph.D., Eric
Forman, M.D., Christophe Blockeel, M.D., Ph.D., Ettore Cicinelli , M.D., Richard Paulson, M.D., Ernesto Bosch, M.D., Nick Macklon, M.D., Ph.D., Emre Seli,
M.D., Ph.D., Peter Humaidan, M.D., Jared Robins, M.D., M.B.A., Somigliana Edgardo, M.D., Juan Garcia Velasco, M.D., Jim Hotaling, M.D., Antonio La
Marca, M.D., Dagan Wells, Ph.D., Richard T. Scott, M.D., Dominique de Ziegler, M.D., Kurt Barnhart, M.D., M.S.C.E.
P.P. has nothing to disclose. M.I . has nothing to disclose. K.D. has nothing to disclose. B.A. reports consulting fees from Organon Turkey; consulting fees
from Merck, Organon, and Abbott; President of the Turkish Society of Reproductive Medicine; and Executive Committee Member of the European
Society of Human Reproduction and Embryology. J.F. has nothing to disclose. C.R. reports support from IBSA (paid the hotel fees) for attending
the workshop. J.T. reports support for travel and lodging to attend the Lugano meeting before the ESHRE 2022 and American Society for Reproductive
Medicine, Secretary/Treasurer (unpaid). R.T.S. has nothing to disclose. D.d.Z. has nothing to disclose. K.T.B. has nothing to disclose.
Correspondence: Paul Pirtea, M.D., Hospital FOCH, 131 avenue de Malakoff, 75116, Paris, France (E-mail: [email protected]).

Fertility and Sterility® Vol. -, No. -, - 2023 0015-0282

Copyright ©2023 The Authors. Published by Elsevier Inc. on behalf of the American Society for Reproductive Medicine. This is an open access article under
the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
https://doi.org/10.1016/j.fertnstert.2023.02.014

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SYSTEMATIC REVIEW WITHOUT META-ANALYSIS

T
he success rates of assisted reproductive technologies searches to be covered. Topics included the definition(s) of
(ARTs) have improved steadily since the first live birth RIF, its clinical characteristics, correct uterine assessment
(LB) from in vitro fertilization (IVF) in 1978. The im- before ART, and the soundness of diagnostic means and ther-
plantation rates (IRs) of <10% in the early years have now apeutic measures, commonly proposed after 1 or several ART
increased to as high as 65% in several IVF programs with failures.
transfer of euploid blastocysts (1). However, 35% of euploid
embryos transferred to an anatomically normal uterus still Literature Search and Consensus Building
fail to implant, leaving patients worried that something has
been overlooked in the management of their infertility. A literature search through PubMed and Cochrane was per-
Defining failure after multiple ART cycles—commonly formed using the following key terms: ‘‘recurrent embryo im-
referred to as recurrent implantation failure (RIF)—has been plantation failure,’’ ‘‘recurrent reproductive failure,’’ ‘‘RIF,’’
estimated on the basis of cumulative ART results (2). In the ‘‘successive euploid embryo transfer,’’ and ‘‘euploid embryo
absence of consensus on the diagnostic criteria for RIF, this transfer.’’ All titles and abstracts, written in English and pub-
presumptive diagnosis is used somewhat haphazardly, on lished from January 2015 to May 2022, were screened to iden-
the basis of an individual clinician’s judgment (3). Compli- tify relevant studies, for which full-text articles were collected
cating the assessment of implantation failure is the recogni- and summarized. Scientific data were reviewed regarding the
tion that there are several factors that contribute to the success rates for serial transfers with euploid embryos, and
establishment of a successful pregnancy after ART. More the success rates and mathematical models were derived on
confusion stems from the fact ART failure is defined in a the basis of age (with and without genetic evaluation of the
multitude of ways, including by the absence of an LB, lack embryo). To assess implantation failure, our working group
of sustained implantation with fetal heart activity (4) or no started with an assumption of good-quality embryos to limit
detectable beta-human chorionic gonadotropin in the serum the impact of the many factors that affect the quality of gam-
after embryo transfer (ET) (5). The lack of consensus on the etes and embryos.
definition of RIF leads to the risk of overdiagnosing and over- Consensus conclusions were stated on the basis of this
treating the condition (3). The uncertainties and confusion literature search and the expert opinions of the working
regarding the diagnosis of RIF, an important clinical topic, group. At the end of the meeting, key points were established,
were the primary motivation for organizing the Lugano and conclusions were reached.
Workshop. The members of the Lugano Workshop decided
to study RIF as being the repeated failure to establish a sus- Preparation of the Manuscript
tained implantation after ART. To limit, as much as possible, The writing group prepared successive drafts of recommenda-
the role of the embryo in implantation failures, this group also tions that were shared among the work group experts for
decided to primarily focus on the outcome of euploid blasto- feedback and suggestions. The feedback received was dis-
cyst transfers conducted in hormone replacement–primed cy- cussed online. The list of experts who contributed to the
cles using intramuscular (IM) progesterone. consensus is included at the beginning of the manuscript.
A particular feature of the Lugano RIF Workshop was that
it included representative specialists practicing reproductive
medicine in both the United States and Europe. Hence, the Lu- COMMENTARY WITH RESULTS
gano Workshop aimed to merge any transatlantic variation in Defining RIF
the clinical concept and management of RIF. Given the num- A recent Views and Reviews in Fertility and Sterility on RIF
ber of recognized experts in the field present in this meeting was summarized by Hill (6) with the following comment: ‘‘ev-
and their broad origin, we believe that this publication consti- idence based medicine is wanted for the evidence component
tutes a consensus statement. that so vitally informs its practice.’’ Evidence is certainly lack-
ing to inform us regarding what constitutes a diagnosis of RIF.
The definition, which has drifted enormously over the last
MATERIALS AND METHODS several decades, has been complicated by improvements in
The Workshop and the Working Group sustained IRs and by changes in ART practice, especially by
The 2022 Lugano RIF Workshop received an unconditional decreasing the number of embryos transferred.
grant from IBSA for covering the cost of this meeting. The consensus reached by our group was that consider-
Although the financial support was an unconditional grant, ation of an RIF diagnosis should focus on failure to achieve
it is worth mentioning that one of IBSA’s products, a subcu- ‘‘sustained’’ implantation (defined as a gestational sac identi-
taneous progesterone preparation (Prolutex; IBSA, Lugano, fied on ultrasound [US]). This definition does not literally
Switzerland), is mentioned in the discussion of this manu- follow the concept of ‘‘implantation failure,’’ but neither clini-
script. However, this is just one of the progesterone prepara- cians nor patients consider a biochemical pregnancy an ART
tions available. success. Furthermore, this definition allows differentiation
The members of the workshop comprised a panel of inter- from recurrent pregnancy loss.
national experts (n ¼ 27) who met in Lugano, Switzerland, on Today’s high IRs result from a variety of factors that are
July 1, 2022. Experts were selected on the basis of their overall now routine in IVF: improved embryo culture; blastocyst trans-
research activities and their publications on the subject. Each fer; US-guided ET; and, in several cases, preimplantation ge-
member of the working group received a defined topic and the netic testing for aneuploidy. Therefore, RIF refers to the lack

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FIGURE 1

The most effective way to estimate the number of patients with recurrent implantation failure (RIF) in a typical assisted reproductive technology
population was to model the decline in the pregnancy rates over successive euploid embryo transfers (ETs). This model could then be compared
with the actual clinical data to determine whether the estimated prevalence was similar. Given a population with a 10% prevalence of RIF
undergoing euploid ET, at the first transfer, 100 had RIF, and 900 had some chance at implantation. If the RIF was 70%, a total of 630 (63%)
would deliver. At the second transfer, a total of 370 patients would remain undelivered—100 with RIF and 270 without. Applying the 70%
sustained implantation rates for euploid ET to the receptive patients, 189 would deliver. At third transfer, 100 still had RIF, and 81 normal
patients remain. This provided a live birth rate of 31% (57 of 181) for the third ET. The population of patients with RIF was enriched with each
successive ET. *Undelivered unknown—all those patients without RIF who did not deliver after the ET including the following: no pregnancy;
biochemical pregnancies; and miscarriage.
Recurrent implantation failure. Fertil Steril 2023.

of sustained implantation after the transfer of good-quality Perhaps, the first task in defining RIF is to ask what it
embryos in a uterus that is morphologically normal (as per would look like clinically. When performing clinical ART,
US, saline infusion sonography, and/or hysteroscopy). Impor- the population would consist of 2 groups: those patients
tantly, there are many sporadic reasons why a good-quality with a realistic probability to conceive and deliver and those
embryo may not implant. Not every ET is identical because with RIF, who have a biologic resistance to sustained implan-
some may be technically difficult because of anatomical chal- tation, and are, therefore, unlikely to conceive and deliver.
lenges, which could affect the success rates. These technical dif- Some have proposed that RIF is likely very rare because
ficulties in performing ET may not necessarily be encountered the chance of implantation is high with the first ET and re-
on every occasion. Moreover, implantation failure of the mains relatively high with successive ETs (6). Indeed, Pirtea
approximately 35% of euploid blastocysts may be due to 1 or et al. (4) demonstrated that the initial sustained IR was
multiple factors and not necessarily the same factor each time. 69.9% and remained high at 59.8% and 60.3% with the sec-
Several definitions of RIF have been proposed, and most ond and third euploid frozen ETs (FETs), respectively. The
have focused on the number of ET failures. Historically, RIF cumulative sustained IR was 95.5% with 3 consecutive
was defined as the transfer of >10 embryos of high quality euploid single ETs. This suggests that the upper limit of the
(by morphology) (7–9). Today, the various proposed RIF group is 4.5% because 95.5% were successful by the third
definitions rather refer to the number of failed ETs a patient transfer (4). It is notable as well that the sample size was not
has had, with a common number being 3 (10). Still, others sufficient to evaluate the success of a fourth euploid ET,
count the cumulative number of high-quality embryos that begging the following questions: after how many ETs does
have been transferred along with female age, the primary fac- the odds of success per transfer go down, and is there even
tor of aneuploidy risk (11), as reviewed by Macklon (12). such a number?
In a survey including a total of 735 clinicians and 300
ART biologists, more than two thirds of the participants also
took lifestyle factors into account (e.g., medications, smoking, ESTIMATING THE SIZE OF THE RIF COHORT
and body mass index [BMI]), and overall, the study found a (SUSTAINED IMPLANTATION FAILURE
profound lack of agreement on the definition of RIF (13). DECLINE OVER SUCCESSIVE ETS)
These investigators concluded that the definition of RIF is Estimating the true size of the RIF group can be assessed by
blurred by a ‘‘profusion of confusion and may, in their eyes, the rate at which sustained IRs decline over successive ETs.
simply be an illusion’’ (14). Because, conceptually, patients with true RIF would be

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SYSTEMATIC REVIEW WITHOUT META-ANALYSIS

FIGURE 2

Calculated implantation rates (IRs) assuming IRs of 70% and recurrent implantation failure (RIF) prevalence rates of 1%, 2%, and 5% in the initial
group, compared with the rates observed in the study by Pirtea et al. (4), suggesting a true incidence of RIF of between 1% and 5%. Using this
model, the estimated prevalence would be <1%.
Recurrent implantation failure. Fertil Steril 2023.

expected to very rarely achieve sustained implantation, they FETs and 90.0% among fresh ETs (17), implying that the
will remain in the group who fail after multiple transfers, size of the RIF group would be 9.2%. However, notably, this
thereby ‘‘enriching’’ the pool in later ETs. Figure 1 illustrates, study did not control for ploidy status (17).
in detail, this concept. If 10% of routine ART patients were to Taken together, a decline in the IRs of between 7% and
experience RIF, they would constitute 10% of the first trans- 10% would occur when an RIF subgroup of 2%–5% exists
fers but 27% and 55% of the second and third ETs, respec- in the initial cohort. We, therefore, estimate that 2%–5% of
tively. This level of enrichment (as would be evidenced by patients pursuing ART treatment may have RIF.
rapidly dropping sustained IRs with successive ETs) is not
observed in clinical practice. Figure 2 illustrates, in detail,
the variable rates of RIF in the population who would be Defining RIF by Assessing Success After Transfer of
anticipated to impact sustained IRs in successive high- Euploid Embryos
quality ETs. Comparing these curves to the Pirtea dataset (4) The consensus of the group was to assess ART results observed
suggests that the true rate of RIF is likely to be in the range after transfers of genetically tested embryos conducted in
of 1%–5% (15). hormonally controlled conditions, using FET in hormone
Other datasets corroborate this estimate. The Society for replacement treatment (HRT) regimens to minimize con-
Reproductive Technology (SART) (16) publishes annual na- founding factors from other causes of failure. Indeed, the
tional data on most US ART programs. On the basis of the risk of implantation failure increases with age (19) in parallel
SART 2020 data, among women aged <35 years having a sin- with the age-related increase in the aneuploidy rates (20),
gle euploid blastocyst transferred, a total of 62.5% of the first indicating that embryo aneuploidy is a primary cause of
ETs implant (n ¼ 17,890), and 55.5% of the second or subse- age-related ART failure. Conversely, the effect of maternal
quent ETs implant (n ¼ 9,474), reporting only a 7.0% decline. age on implantation of euploid blastocysts appears small
Pirtea et al. (4) reported results—for sustained IRs and live (21), and paternal age has limited impact (22). Moreover,
birth rates (LBRs)—after successive euploid FETs. In case of the chances of obtaining euploid blastocysts are not affected
euploid FETs, implantation chances are high with the first by prior ART cycles yielding only aneuploid embryos (23).
euploid transfer (69.9%) and remain relatively high with the Finally, trophectoderm biopsy has limited adverse impact
second (59.8%) and third (60.3%) ETs (4). The cumulative on sustained implantation (24). This suggests that the 35%
sustained IR was 95.5% after 3 consecutive single euploid of cases in which a euploid embryo does not implant fail for
FETs (4). reasons other than aneuploidy (25). Although some see a
A study using the National Assisted Reproductive Tech- possible cause in the cytoplasmic properties of the embryo—
nology Surveillance System data (17) of 44,750 women mitochondria (23)—this issue remains puzzling, may be multi-
aged 20–35 years who have R4 embryos cryopreserved factorial, and awaits data from further research.
used a novel modified dynamical model (18) to assess the Given that embryo aneuploidy is the primary cause of
change in IRs over successive transfers to calculate the size ART failure (20), Pagidas et al. (19) investigated the outcome
of the ‘‘inherent fertility.’’ Estimates were 91.7% among of euploid ET conducted in patients clinically diagnosed with

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TABLE 1

Sustained implantation rate after embryo transfer with or without preimplantation genetic testing for aneuploidy by age in the 2020 Society for
Reproductive Technology national outcomes report (18).
Type of ART cycle <35y 35–37y 38–40y 41–42 y ‡43y
PGT-A cycles 62.5% 60.8% 58.7% 53.7% 48.3%
Non-PGT-A cycles 46.8% 41.1% 34.7% 25.5% 16.7%

PGT-A ¼ preimplantation genetic testing for aneuploidy.

Recurrent implantation failure. Fertil Steril 2023.

RIF. According to their findings, the availability of euploid confidence interval may be taken as the cutoff value. If a pa-
embryos in a patient with a history of RIF was associated tient’s value is greater than this cutoff value, it may be consid-
with high ongoing pregnancy rates and IRs (19). In a retro- ered positive (diseased). This approach may carry a chance of
spective study, Cimadomo et al. (26) analyzed the factors declaring some false-positive cases, thus lowering its negative
that affect euploidy and implantation in 2,676 patients un- predictive value. Yet, the use of a 95% threshold for defining
dergoing 8,151 euploid blastocysts transfers. As shown by RIF has benefits when no diagnostic test exists for the entity.
others (25), these investigators observed that the euploidy Notably, using a 5% cutoff is also similar to the rate of failure
rates sharply decreased with increasing maternal age (26). of 3 euploid FETs (4).
However, this age-related decrease in the euploidy rate was Definitions on the basis of normal distributions have lim-
not affected by previous LB (1 or >1), miscarriage (1, 2, or itations. There is always someone whose outcomes will fall
>2) or past ART cycles with no euploid blastocysts (26). The outside of 2 standard deviations or 3. If the definition of
fact that a prior lack of obtaining euploid embryos does not RIF is not based on pathology, it will not predict diminished
impact the further chances of having euploid embryos has outcomes in future attempts. A probabilistic definition of
also been shown by others (23). Together, these findings indi- RIF may lead to overdiagnosis with the potential to generate
cate that studying the outcome of euploid ET is most likely the incorrect diagnoses, unnecessary testing, and altered clinical
best method for analyzing the prevalence of RIF. management without evidence of benefit.
Assessing sustained IRs of euploid blastocysts for study-
ing RIF is supported by Ata et al. (27). Indeed, these investiga-
tors proffer that one should not talk of RIF until after one can PUTATIVE CAUSES UNDERLYING RIF
ascertain that implantation failure is reasonably likely caused Oocyte Cohort Effect
by factors other than embryo aneuploidy, the leading cause of
implantation failure. Therefore, these investigators propose One question regarding RIF is the possibility of variation due
that the definition of RIF should consider the anticipated blas- to a cohort effect in oocyte/embryo quality on the basis of
tocyst euploidy rates across categories of female age to predict ovarian stimulation and oocyte harvests between cycles.
cumulative probability of implantation (27). The expected Several aspects of laboratory performance suggest that this
sustained IRs after euploid and nontested embryos as in the is the case. One of the earliest factors to be identified to
SART age groups reported in US 2020 national outcome vary from cycle-to-cycle in the same couple was fertilization.
report are depicted in Table 1. An estimation model of the In the days before intracytoplasmic sperm injection (ICSI),
number of unscreened embryos needed to be equivalent to 3 excluding severe male factor, failed fertilization in a single
euploid ETs and achieve a 95% chance of a sustained implan- cycle was associated with a <30% risk of recurrence in a sub-
tation is presented in Table 2. sequent cycle (28). Although this may be thought to be due to
sperm quality, a suggestion that the oocyte equally contrib-
utes to this is supported by the observation that the fertiliza-
Defining RIF on the Basis of Defining a Statistical tion rate (with either ICSI or conventional IVF) is correlated
Outlier with the IR (29). Additionally, abnormal fertilization (triploidy
A commonly used method to establish diagnostic criteria for a with ICSI) lowers the IRs of the entire normally fertilized
given clinical entity is the application of the 95% confidence cohort, again suggesting an oocyte issue in the cohort (30).
interval (i.e., 2 standard deviations) of the mean. This method Another aspect of the cohort is the presence of excess embryos
may be used in 1 of 2 ways: first, it can be in a sample of for freezing and whether transfer was at the cleavage (31) or
adequate size of diagnosed cases of a particular entity from blastocyst stage (32, 33). Availability of excess embryos was
which the mean and 2 standard deviations are calculated. associated with higher IRs even with equivalent embryo grade
This method may carry the chance of declaring some false- at transfer. Thus, the definition of RIF should not be consid-
negative cases, thereby lowering its positive predictive value. ered on the basis of only 1 cohort of embryos but rather on
Second, this method may be performed on a sample of known the basis of the number of euploid blastocyst transferred or
negative cases. In this case, the upper limit of its 95% the number of transfers adjusted to patients’ age.

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experienced complete premature ovarian failure (63, 64).

TABLE 2
The remarkable successes of donor egg ART led to adopt a
Estimation model for of the number of unscreened good-quality
similar approach, using E2 and progesterone, for priming
embryos needed to be equivalent to 3 successive euploid embryo FETs (65). In women whose ovaries are functional, this was
transfers and achieve a 95% chance of sustained implantation on conducted with (65), and later without (66, 67), ovarian sup-
the basis of the observed aneuploidy rate (20). pression with a gonadotropin-releasing hormone agonist. The
No. of untested blastocysts to alternative is to perform FET in natural or modified natural
Observed achieve a 95% chance of
Age (y) aneuploidy rate sustained implantation
cycles. In an RCT, Groenewoud et al. (68) demonstrated that
ETs timed in natural, modified natural, or E2 and progester-
<35 20% 4 one programed cycles had similar outcomes. Although this
35–37 30% 5
38–40 50% 7 observation has been confirmed in meta-analyses (69–71),
41–42 70% 13 some investigators suggest that true natural cycles have
R43 85% 27 better results (72).
Recurrent implantation failure. Fertil Steril 2023. The WOR is controlled by the duration of progesterone
exposure after sufficient E2 priming, as clearly defined in
HRT cycles (64, 73). The exact duration of the WOR has
Uterine Factors been a matter of debate. Van de Vijver et al. (74, 75) have
studied this issue by conducting 2 RCTs in E2 and progester-
Uterine/endometrial factors can certainly cause infertility by one programed cycles. These investigators reported similar
impairing embryo implantation. However, these possible LBR after the transfer of cleavage-stage embryos on the third
causes of ART failure ought to be ruled out before undertaking or fifth day (74) and blastocysts on the fifth or seventh day of
ART, not after an unspecified number of ART failures. progesterone treatment (75).
Notably, it has been well demonstrated that communicating
hydrosalpinges significantly reduce the odds of sustained
IRs (34–38), as do various uterine cavity distorting Receptivity Assays
anatomical lesions (39–45), and that surgical management Over the last 2 decades, tests were developed for assessing
can improve success. Therefore, such possible uterine causes endometrial receptivity. The most widely used of these tests
should be ruled out before initial planned ET to a patient is the endometrial receptivity assay (ERA), which requires a
with infertility. Saline infusion sonohysterography paired biopsy performed in a cycle before the transfer cycle
with hysterosalpingo-contrast sonography can accomplish (76, 77). The results provided by ERA indicate whether the
both goals in experienced hands (46–49). Given its excellent endometrium is receptive, prereceptive, or postreceptive on
diagnostic accuracy and tolerability, saline infusion the anticipated WOR. The recommendation is to transfer on
sonography has emerged as the initial method of choice for the calculated, also known as personalized, period of recep-
evaluating the uterine cavity (50–54). Of note, randomized tivity, which can be either during, after, or before the antici-
clinical trial (RCT) data indicate that the routine use of pated WOR (78). The ERA test was heavily marketed well
diagnostic hysteroscopy either before the initial ET or after before any proof of validation was provided, and several
multiple ETs does not improve the odds of sustained IRs recent studies have shown that ‘‘personalized’’ ETs on the ba-
(55, 56). A hysterosalpingogram can be used to exclude the sis of ERA data do not improve outcomes (79–82) compared
presence of hydrosalpinx(ges) in settings where with ETs on the basis of conventional timing (83).
hysterosalpingo-contrast sonography with 3-dimensional Another functional endometrial assay investigated
rendering and high-frequency Doppler are not available possible overexpression of B-cell lymphoma 6 protein expres-
(57). Although plain transvaginal US without contrast instil- sion in the endometrium (84). This assay marketed under the
lation has high specificity for a diagnosis of hydrosalpinx, the name of Receptiva (85) is proposed as a marker of endometrial
test lacks sensitivity (58, 59). alterations encountered in endometriosis and notably, endo-
In the absence of abnormal uterine bleeding and with a metrial resistance to progesterone. Although the value of the
normal size uterus on US, further uterine examination in test as a diagnostic tool for endometriosis is not questioned
search of possible adenomyosis is not warranted. Indeed, here, its ability to predict endometrial receptivity was not
recent data indicate that the impact of asymptomatic adeno- properly validated in an appropriately designed study or an
myosis on implantation after FET is doubtful (60–62). RCT. Of note, the outcome of euploid FET in E2 and progester-
one programed cycles was not different between patients with
and without endometriosis (86). Klimczak et al. (87) reported
Endometrial Receptivity and Factors that the proportion of patients with B-cell lymphoma 6 posi-
The concept that the endometrium is receptive only during a tivity did not significantly differ between those who achieved
short-lasting window of receptivity (WOR) emanates from LB and those who did not. Finally, other endometrial recep-
early experience with donor oocyte ART. The early cycles tivity tests have been proposed for assessing endometrial
were conducted using estradiol (E2) and progesterone—IM in- receptivity; however, none of these have been properly vali-
jections—in programed or ‘‘HRT’’ cycles in women who dated in an RCT (88, 89).

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In summary, the current tests of endometrial receptively the nature of the endometrial microbiome impacts endome-
should not be used to characterize or justify treatment of trial receptivity (105, 106), whereas others have not found
women with suspected RIF. such a correlation (107). The most common vaginal dysbiosis
is bacterial vaginosis. A recent systematic review including 17
studies did not report a significant decline in ART outcome in
Endometrial Thickness women with bacterial vaginosis (105). A recent study em-
Large registry and retrospective studies suggest decreased ployed ribonucleic acid sequencing, rather than the previ-
pregnancy rates and LBRs in case of a ‘‘thin’’ endometrium ously used deoxyribonucleic acid sequencing, to identify
at the time of ET (90), and the existence of a threshold below live active microbiota in the endometrial cavity from 7
which results start to compromise is an ongoing discussion healthy women (108). With this methodology change, the in-
(91). vestigators reported that the lactobacillus represented only
A negative association between endometrial thickness/ <1% of the ‘‘live’’ endometrial microbiota (108), whereas its
pattern and pregnancy rates has also been reported in FETs presence was taken as a sign of receptive endometrium by
and natural cycles (92, 93). However, numerous studies, those claiming that the endometrial microbiome affects endo-
with or without stratification according to somewhat arbi- metrial receptivity (105, 106). In view of the existing diver-
trarily chosen cutoff values, for example, <6, <7, and <8 gence of results and new methodological issues (108),
mm, have provided contradictory conclusions (90, 94–98). further study is needed to define whether the microbiome
Interestingly, however, prospective and retrospective studies plays a role in the probability of implantation.
in which transfers were performed irrespective of
endometrial thickness suggested that endometrial thickness
does not impact ART outcome (91, 94–96, 98). Women with Endometrial Inflammatory Factors
an endometrial thickness of <5 mm after E2 preparation are Numerous publications have highlighted the presence of
rare, and it is difficult to draw definitive conclusions. endometrial alterations within the eutopic endometrium,
However, whether endometrial thickness per se affects notably in women with endometriosis. The characteristic
implantation once an intracavitary pathology has been feature of these effects is an endometrial resistance to proges-
ruled out is controversial. Conversely, a hyperechogenic terone (109, 110). The impact of these endometrial changes is
appearance of the endometrium reflects premature minimized by ovarian suppression using either a
progesterone exposure, which shifts the WOR and can affect gonadotropin-releasing hormone agonist (111) or the oral
sustained IRs (94, 95, 99). Finally, it is important to contraceptive pill (112). Recently, normal IRs have been re-
underscore that the study on repeated euploid blastocyst ported after FETs in E2 and progesterone (IM) replacement cy-
transfers quoted earlier was conducted in women whose cles (88). In a large donor oocyte study, the success rates were
endometrial thickness was R7 mm (4). not altered in recipients affected by endometriosis (113).
Certain studies have emphasized the importance of the Recent data indicate that when embryos are transferred to pa-
timing of endometrial thickness measurement. Haas et al. tients with endometriosis in HRT cycles, serum progesterone
(100) and Zilberberg et al. (101) reported that a decrease in mattered (114) with higher LBRs when the serum progesterone
endometrial thickness after exposure to progesterone—a phe- levels were >37.1 ng/mL. Moreover, endometriosis does not
nomenon identified as ‘‘compaction’’—was associated with affect oocyte quality, as evidenced by unaltered fertilization,
optimal outcome. Conversely, Bu et al. (102) reported opposite blastulation, and blastocyst euploidy rates (115, 116). Adeno-
findings with optimal results achieved when the endometrial myosis has been claimed to affect IRs (60) but not in the
thickness on the day of ET increased or remained unchanged morphologically normal uterus (61).
compared with that on the first day of progesterone adminis- Chronic endometritis (CE) is a persistent inflammatory
tration. An additional study indicated that endometrial condition of the endometrium. Contrary to acute forms of
compaction did not predict ART outcome (103). Taken endometritis, CE is characterized by a paucity of symptoms
together, available evidence indicates that a clear role of that may include abnormal uterine bleeding and some degree
endometrial compaction in response to progesterone treat- of pelvic pain (117). The diagnostic criteria of CE have been
ment and its association with outcome awaits further data. debated. Commonly, the diagnosis is made using hysterosco-
It is crucial to mention that most prior studies on endome- py with identification of micropolyps (118) or the presence of
trial thickness did not account for embryo ploidy status or immune-stained plasmocytes either on endometrial biopsies
morphologic grade of embryos, another major determinant (119) or in endometrial cultures (120). Interestingly, the inci-
of implantation potential (90, 95, 98). Thus, it would be fair dence of CE is increased in patients with endometriosis, a fac-
to suggest that more studies that control for embryo ploidy tor which may play a role in the genesis of this disease (121).
status are needed to bring further light on this issue. Unfortunately, the diagnosis of CE is said to lack clarity and
specificity (122, 123), and given the inconsistencies in avail-
able evidence, the issue on CE diagnosis is still far from being
Endometrial Microbiome resolved, and the role of this disease in reproductive failure
Recent interest has been focused on the endometrial micro- deserves further investigation (124, 125). The most common
biome. Numerous publications have demonstrated that the therapy proposed is antibiotic treatment (126). Recent data
endometrial cavity is not sterile but rather the resident site indicate that CE does not impair ART outcome after euploid
of various microorganisms (104). Some have claimed that FET. Indeed, Herlihy et al. (127) who investigated the

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SYSTEMATIC REVIEW WITHOUT META-ANALYSIS

sustained IRs of euploid FETs did not find the differences in a high-risk factor for reproductive health. Although obesity
the presence of CD138 cell in endometrial biopsies at any con- has long been known to exert various deleterious effects on
centration. These recent data, therefore, indicate that CE, female fertility, the underlying mechanisms, especially the
which likely plays a role in the pathophysiology of endome- roles of lipid metabolism in endometrial receptivity, remain
triosis, may fail to directly impact ART outcome, as assessed largely elusive (140). In addition, whether the association be-
by sustained IRs after euploid FET in E2 and progesterone cy- tween obesity and chronic inflammation and oxidative stress
cles (121). (141) decreases endometrial receptivity (by displacing the
WOR) (142, 143) remains to be clarified. Further studies
need to clarify these gaps in knowledge and help inform
Progesterone Effects how obesity may need to be factored into a definition of
Progesterone levels and implantation Labarta et al. (128) were RIF in this unique patient population (144).
first to report that in women receiving vaginal progesterone
in programed FET cycles, ART outcome was decreased in
women whose progesterone levels were low on the day of Male Factor
ET. These findings were later confirmed in a meta-analysis The possible contribution of male gametes in RIF remains
showing poorer outcome when serum progesterone levels incompletely understood. There are data suggesting that
were <10 to 20 ng/mL (129). These shortcomings encountered sperm quality—notably, the deoxyribonucleic acid fragmen-
in case of low progesterone levels on the day of transfer could tation level—contributes to ART failures and, possibly, to
be corrected by the addition of exogenous supplementation RIF (145). The mechanism whereby sperm may affect embryo
using subcutaneous progesterone 25 mg/day (Prolutex; implantation is still unclear, and results are controversial
IBSA) (130–132). This led some to propose individualizing (146–148). Likewise, sperm quality has been implicated as a
progesterone administration with supplementing women possible cause of miscarriage (149).
whose serum progesterone levels are <10 to 20 ng/mL
(133). However, others, opted for supplementing all women
receiving vaginal progesterone with subcutaneous Therapeutic Measures Commonly Proposed After
progesterone 25 mg/day for the sake of simplicity (134). Several ART Failures and Place of ART ‘‘Add-Ons’’
Subcutaneous progesterone alone was also effective at the
dose of 25 mg twice a day in FETs (135, 136). Hence, Couples who repeatedly fail to conceive after ART inevitably
assuring that proper progesterone supplementation is will look for possible explanations. Couples with infertility
achieved in HRT cycles for FET appears crucial to optimize become even more vulnerable and fall prey to accepting
ART outcome because inadequate progesterone and/or seeking all kinds of recipes, treatments, and various
supplementation is a possible cause of ART failure. The measures that they may hear about to increase their chances
reported ‘‘optimal’’ serum progesterone levels apply only to of conception. Possible therapeutic options are often pre-
vaginal progesterone (128), and it is difficult to extrapolate sented by word of mouth, the Internet, and other means. Cur-
to IM progesterone cycles. It is worth mentioning that rent evidence shows no known effective treatment for RIF.
vaginal progesterone use in HRT FET has been found Collectively, these therapeutic options proposed after failed
inferior to IM progesterone in a multicenter RCT by Devine ART attempts—or, sometimes, up front—are regrouped under
et al. (137). In this RCT including a total of 1,060 FETs, the the name of ART ‘‘add-ons.’’ Among these add-ons, we
LBR was significantly lower in women who received only notably highlight the following.
vaginal progesterone (27%) than in those who received IM Immunologic, thrombophilia testing and treatments.
progesterone (44%) or combination treatment (46%). Fifty Reports associating RIF with inherited thrombophilic condi-
percent of pregnancies in women who received only vaginal tions are multiple. A recent meta-analysis including 7
progesterone ended in miscarriage (137). articles reported no difference in ART outcome in case of
Progesterone supplementation in programed cycles Data factor V Leiden mutation, prothrombin gene, methylenete-
reported by Pirtea et al. (4) were obtained after euploid FET trahydrofolate reductase, and activated protein C resistance
in E2 primed cycles, which used IM progesterone (50 mg/ mutation (150, 151). Acquired thrombophilias, specifically
day). A prospective RCT reported lower LBRs when using antiphospholipid syndrome, are significantly associated
vaginal progesterone than when using IM progesterone in with recurrent pregnancy loss and obstetric complications
HRT-based FETs (138). Of note, IM progesterone has been re- (152). However, evidence is conflicting regarding their
ported recently as consistent practice by a comprehensive sur- association with RIF (153–155).
vey conducted in 13 high-performing US fertility clinics Consequently, testing for inherited or acquired thrombo-
(139). philia in patients with ART failures is not recommended
because of insufficient evidence regarding a positive associa-
tion with ART outcome (156).
Metabolic Factors The hypothetical role of cytokines and uterine natural
In a recent clinical practice survey, metabolic factors were lymphocyte killer cells led to proposals for the use of gluco-
related to RIF by 82 % of medical providers (13). Although corticoids (157, 158). However, several RCTs have shown no
diabetes was not addressed in specialized guidelines, BMI clinical improvements (159–162), and the American Society
was considered relevant to RIF and has been recognized as for Reproductive Medicine guidelines (157) currently

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recommend against the use of glucocorticoids to improve ART blastocyst transfers (or the equivalent number of nontested
outcome. embryos).
Similarly, other immunomodulators, such as intravenous In conclusion, despite significant advances in ART suc-
immunoglobulin and intralipids, have been considered but cess over the past decades, there are still couples who fail to
without proof of efficacy (157, 163, 164). conceive after multiple ART attempts. Some have proposed
Endometrial scratching. Intentional injury of the endome- that these patients are diagnosed with RIF. However, whether
trium, known as endometrial ‘‘scratching,’’ has been proposed these patients have an undetected biologic condition or have
but with no proven efficacy (138). A recent study was stopped just been ‘‘unlucky so far’’ is a critical distinction when guid-
when interim evaluation showed that endometrial scratching ing future care for these patients. Given the existing data, it
had harmful effects (165). would seem reasonable not to assign this diagnosis to a pa-
Other potential add-ons, such as intrauterine infusion of tient until she has failed at least 3 euploid FETs (or the
intravenous immunoglobulin (166, 167), granulocyte colony- equivalent number of untested embryos, adjusted to the pa-
stimulating factor, intrauterine perfusion of autologous tient’s age) and other factors have been ruled out that are
platelet-rich plasma (168, 169), intrauterine autologous pe- known, or believed, to result in reduced odds of sustained im-
ripheral blood mononuclear cell infusion (167, 170), or hu- plantation. Further diagnostic or therapeutic interventions
man chorionic gonadotropin (167, 171), have been reviewed should be limited to this group that comprises fewer than
and discussed; however, given the lack of comprehensive 5% of patients undergoing ART.
data and heterogeneity of the studies reported, the working Contrary to infertility, RIF is not an overt clinical entity.
group decided not to include them for recommendation. Currently, RIF has no clear-cut definition or impairment-
related function. Data on repeat euploid FET success after
further ART attempts do not drastically differ from similarly
characterized couples undertaking their first ART attempt
DISCUSSION (4). In women with an apparent anatomically and function-
A Way Forward ally normal uterus and with a normal BMI, RIF is a challenge
We acknowledge the limitations of this consensus document (4). Assessments of couples who fail repeated ART attempts
and the shortfall of a systematic review without meta- should involve the number of euploid transferred embryos
analysis. Nevertheless, a common definition of RIF is needed and, if embryos were not tested, the number of FETs adjusted
to harmonize and interpret ongoing and future research of to the patient age accordingly.
this condition. In addition, a stricter estimate of the preva- Therefore, the consensus reached by the participants to
lence of RIF offers the added benefit of avoiding overdia- the 2022 Lugano Workshop is that RIF has been overeval-
gnosis and, thereby, unnecessary treatments, such as ART uated, overdiagnosed, and overtreated without sufficient crit-
add-ons. ical evaluation of the presumed condition. In repeated euploid
It is possible that there are unidentifiable factors that blastocyst transfers in HRT cycles using IM progesterone,
contribute to RIF. However, this condition is rare and is likely RIF—not yet defined as a biologic entity—only occurs in
present in <5% of women. Currently, this condition can only <5% of cases. Our understanding of the determinants of im-
be identified by unexplained repetitive failure after transfer of plantation, both embryonic and uterine, remains limited, and
good-quality embryos, a definition on the basis of probability further improvements in that knowledge will underpin future
instead of biology. With RIF, the decline in future IRs with improvements in the success of modern ART.
each cycle fits more to an exponential decay curve rather
than as a linear decrease. However, after repeated failure, Acknowledgments: The organizers of the 2022 Lugano
the chance of having a biologic basis for failure becomes Workshop on recurrent implantation failure gratefully
more likely, and investigation may be justified, depending acknowledge having received an unconditional grant from
on quality and cost of the test and the efficacy of the treat- IBSA Switzerland, which permitted the organization of the
ment. When a woman is found to meet these criteria, all as- LUGANO RIF meeting.
pects of the IVF process should be evaluated, not solely a
focus on the endometrium.
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