Should patients be screened for chronic endometritis before assisted reproductive technology?

Abstract

PRO: Patients should be screened for chronic endometritis before assisted reproductive technologyTesting for Chronic Endometritis before Assisted Reproductive TechnologyDefinition of chronic endometritisBy definition, chronic endometritis (CE) is a chronic inflammation of the lining of the uterine cavity. However, because anatomically the upper genital tract is a continuum, inflammatory process frequently involves both endocervical and endosalpingeal mucosa.EtiologyIn most cases, CE is caused by an alteration of the normal endometrial microbiome by bacterial pathogens. An infectious origin of CE may be inferred by considering that antibiotic therapy normalizes the endometrium and improve clinical outcomes (1Cicinelli E. Resta L. Loizzi V. Pinto V. Santarsiero C. Cicinelli R. et al.Antibiotic therapy versus no treatment for chronic endometritis: a case-control study.Fertil Steril. 2021; 115: 1541-1548Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). Yet, some noninfectious forms of CE may also exist.Clinical consequencesIn analogy with chronic inflammatory pathologies of different organs, CE is clinically silent or pauci-symptomatic in most cases, which makes its diagnosis challenging. Symptoms are generally mild and unspecific with typically abnormal uterine bleeding, pelvic pain, and dyspareunia. Moreover, recent studies from different investigators have demonstrated that CE interferes with spontaneous as well as assisted reproductive technology (ART)-induced pregnancies (2Cicinelli E. Matteo M. Trojano G. Mitola P.C. Tinelli R. Vitagliano A. et al.Chronic endometritis in patients with unexplained infertility: prevalence and effects of antibiotic treatment on spontaneous conception.Am J Reprod Immunol. 2018; 79Crossref PubMed Scopus (101) Google Scholar, 3McQueen D.B. Bernardi L.A. Stephenson M.D. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise.Fertil Steril. 2014; 101: 1026-1030Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar, 4Kitaya K. Matsubayashi H. Takaya Y. Nishiyama R. Yamaguchi K. Takeuchi T. et al.Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure.Am J Reprod Immunol. 2017; 78Crossref PubMed Scopus (99) Google Scholar) thus, causing infertility, ART failures, miscarriages, and other obstetrical complications (5Kitaya K. Matsubayashi H. Yamaguchi K. Nishiyama R. Takaya Y. Ishikawa T. et al.Chronic endometritis: potential cause of infertility and obstetric and neonatal complications.Am J Reprod Immunol. 2016; 75: 13-22Crossref PubMed Scopus (97) Google Scholar, 6Pirtea P. Cicinelli E. De Nola R. de Ziegler D. Ayoubi J.M. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis.Fertil Steril. 2021; 115: 546-560Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar).Pathophysiology mechanismsData in literature suggest that CE may impair reproduction by altering the endometrial receptivity and by interfering with spontaneous fertilization. In case of CE, impaired endometrial receptivity results from multiple alterations, namely:•Structural transformation of the endometrial surface and mucosal architecture. The endometrial surface seen on hysteroscopy shows abnormal features like micropolyps, hyperemia, polypoid aspect, and frequently displays an irregular or distorted anatomy, as displayed in Figure 1 (7Cicinelli E. Vitagliano A. Kumar A. Lasmar R.B. Bettocchi S. Haimovich S. et al.Unified diagnostic criteria for chronic endometritis at fluid hysteroscopy: proposal and reliability evaluation through an international randomized-controlled observer study.Fertil Steril. 2019; 112: 162-173.e2Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). Looking at Figure 1, one is led to proffer that this is not an “optimal endometrium” for embryo implantation.Figure 1Endometrial surface at fluid hysteroscopy. The aspect of surface appears to be completely distorted by micropolyps, little endometrial outgrowths with vascular axis floating in the distention medium.View Large Image Figure ViewerDownload Hi-res image Download (PPT)•Regarding histologic findings, CE is characterized by altered quantity and quality of leucocyte infiltration. Leucocytes often organize in nodular aggregates that infiltrate glands and vessels resulting in structural disruptions. Moreover, abnormal leucocyte subpopulations (increase in B cells and plasma cells [PCs], reduction in NK cells) cause alterations in the expression of inflammatory mediators and cytokines. Inflammatory milieu may alter the expression of genes involved in the cell replication, implantation process, and also the immune tolerance of the endometrium meant to improve embryo implantation (8Di Pietro C. Cicinelli E. Guglielmino M.R. Ragusa M. Farina M. Palumbo M.A. et al.Altered transcriptional regulation of cytokines, growth factors, and apoptotic proteins in the endometrium of infertile women with chronic endometritis.Am J Reprod Immunol. 2013; 69: 509-517Crossref PubMed Scopus (80) Google Scholar). Finally, an alteration of autophagy seen in CE may affect the endometrial cell function and impair endometrial decidualization (9Buzzaccarini G. Vitagliano A. Andrisani A. Santarsiero C.M. Cicinelli R. Nardelli C. et al.Chronic endometritis and altered embryo implantation: a unified pathophysiological theory from a literature systematic review.J Assist Reprod Genet. 2020; 37: 2897-2911Crossref PubMed Scopus (26) Google Scholar).Moreover, CE may interfere with the fertilization and inhibit the transport of gametes. Inflammatory mediators may alter uterine contractility during the midluteal phase impeding in vivo fertilization and transuterine migration of the embryo before implantation (10Pinto V. Matteo M. Tinelli R. Mitola P.C. De Ziegler D. Cicinelli E. Altered uterine contractility in women with chronic endometritis.Fertil Steril. 2015; 103: 1049-1052Abstract Full Text Full Text PDF PubMed Scopus (45) Google Scholar).Impaired reproductive outcomes in women with CE undergoing ART and efficacy of antibiotic therapyTo date, many studies have concurred to report a detrimental effect of CE on implantation and early embryo development in naturally developing and ART-induced pregnancies. The evidence for such effects was primarily based on the observation that antibiotic treatments improve reproductive outcome.First, studies have shown a high prevalence of CE among women with repeated miscarriages, whereas successful pregnancies were seen after treatment with antibiotics. In 2014, a retrospective study including 360 women with unexplained repeated miscarriages showed that CE was present in 208 women (57.8%). One year after antibiotic treatment, women cured for CE showed a significantly high number of pregnancies (78.4%) compared with women with persistent CE after therapy (15.3%; p =.005) (11Cicinelli E. Matteo M. Tinelli R. Pinto V. Marinaccio M. Indraccolo U. et al.Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment.Reprod Sci. 2014; 21: 640-647Crossref PubMed Scopus (139) Google Scholar). Similar results have been reported by a recent study by Mitter et al. (12Mitter V.R. Meier S. Rau T.T. Gillon T. Mueller M.D. Zwahlen M. et al.Treatment following hysteroscopy and endometrial diagnostic biopsy increases the chance for live birth in women with chronic endometritis.Am J Reprod Immunol. 2021; 86e13482Crossref PubMed Scopus (6) Google Scholar) that included 108 women with repeated implantation failure or without known pathologies but infertile. Forty-one women underwent only a hysteroscopy (reference group); the remaining 67 women underwent an endometrial biopsy with immunohistochemically staining for CD138 in addition to hysteroscopy to detect PCs (biopsy group) and were treated with antibiotics if positive. The biopsy group had higher chances of pregnancy (hazard ratio, 2.28; 95% confidence interval, 1.23–4.24; P=.009) and of live birth (hazard ratio, 2.76; 95% confidence interval, 1.30–5.87; P=.008) compared with the reference group (12Mitter V.R. Meier S. Rau T.T. Gillon T. Mueller M.D. Zwahlen M. et al.Treatment following hysteroscopy and endometrial diagnostic biopsy increases the chance for live birth in women with chronic endometritis.Am J Reprod Immunol. 2021; 86e13482Crossref PubMed Scopus (6) Google Scholar).In recent years, the interest on CE has also greatly increased in ART. Numerous studies have reported the effects of CE and antibiotic therapy on in vitro fertilization (IVF) outcomes. Table 1 shows the results observed in women with either ≥3 previous embryo transfers (ETs) and implantation failures who were either treated or not treated for CE (12Mitter V.R. Meier S. Rau T.T. Gillon T. Mueller M.D. Zwahlen M. et al.Treatment following hysteroscopy and endometrial diagnostic biopsy increases the chance for live birth in women with chronic endometritis.Am J Reprod Immunol. 2021; 86e13482Crossref PubMed Scopus (6) Google Scholar, 13Johnston-MacAnanny E.B. Hartnett J. Engmann L.L. Nulsen J.C. Sanders M.M. Benadiva C.A. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization.Fertil Steril. 2010; 93: 437-441Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar, 14Zolghadri J. Momtahan M. Aminian K. Ghaffarpasand F. Tavana Z. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion.Eur J Obstet Gynecol Reprod Biol. 2011; 155: 217-220Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar, 15Hirata K. Kimura F. Nakamura A. Kitazawa J. Morimune A. Hanada T. et al.Histological diagnostic criterion for chronic endometritis based on the clinical outcome.BMC Womens Health. 2021; 21: 94Crossref PubMed Scopus (6) Google Scholar, 16Xiong Y. Chen Q. Chen C. Tan J. Wang Z. Gu F. et al.Impact of oral antibiotic treatment for chronic endometritis on pregnancy outcomes in the following frozen-thawed embryo transfer cycles of infertile women: a cohort study of 640 embryo transfer cycles.Fertil Steril. 2021; 116: 413-421Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 17Cicinelli E. Matteo M. Tinelli R. Lepera A. Alfonso R. Indraccolo U. et al.Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy.Hum Reprod. 2015; 30: 323-330Crossref PubMed Scopus (229) Google Scholar). As shown, the reproductive outcomes (expressed as ongoing and live birth rates) were high among women cured for CE as compared with those diagnosed with CE who were not cured. In women with >3 failed ETs, these results were 53.2% vs. 24.3 and 70.2% vs. 34.3%, respectively.Table 1Studies in literature in women undergoing in vitro fertilization with undefined number of repeated implantation failures and >3 embryo transfers (recurrent implantation failure).StudyDesignDiagnosisType of cycleOngoing pregnancy rate/live birth rateNon chronic endometritis (CE) Events/TotalPercentageChronic endometritisEvents/TotalPercentageUndefined no. of previous embryo transfersFan et al., Fertil Steril 2019 (63Fan X. Li X. Li Y. Liao J. Chen H. Li Y. et al.Endometrial CD138 count appears to be a negative prognostic indicator for patients who have experienced previous embryo transfer failure.Fertil Steril. 2019; 112: 1103-1111Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar)RetrospectiveCD138Fresh78/9780.423/4452.3Johnston-MacAnanny et al. Fertil Steril 2010 (13Johnston-MacAnanny E.B. Hartnett J. Engmann L.L. Nulsen J.C. Sanders M.M. Benadiva C.A. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization.Fertil Steril. 2010; 93: 437-441Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar)RetrospectiveCD138Fresh12/2352.22/1020Kitaya et al., AJRM 2017 (4Kitaya K. Matsubayashi H. Takaya Y. Nishiyama R. Yamaguchi K. Takeuchi T. et al.Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure.Am J Reprod Immunol. 2017; 78Crossref PubMed Scopus (99) Google Scholar)ProspectiveCD138Fresh/Frozen and thawed61/22648.40/40Zhang et al., Am J Reprod Immunol 2019 (14Zolghadri J. Momtahan M. Aminian K. Ghaffarpasand F. Tavana Z. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion.Eur J Obstet Gynecol Reprod Biol. 2011; 155: 217-220Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar)ProspectiveHysteroscopy, H & E, CD138Fresh40/12631.76/2425Total (mean)53.224.3RIF (>3 embryo transfers)Kuroda et al., Immun Infiamm Dis 2020 (64Kuroda K. Horikawa T. Moriyama A. Nakao K. Juen H. Takamizawa S. et al.Impact of chronic endometritis on endometrial receptivity analysis results and pregnancy outcomes.Immun Inflamm Dis. 2020; 8: 650-658Crossref PubMed Scopus (17) Google Scholar)Cross-sectionalCD138Fresh21/2777.84/1822.2Hirata et al., BMC Women’s Health 2021 (15Hirata K. Kimura F. Nakamura A. Kitazawa J. Morimune A. Hanada T. et al.Histological diagnostic criterion for chronic endometritis based on the clinical outcome.BMC Womens Health. 2021; 21: 94Crossref PubMed Scopus (6) Google Scholar)ProspectiveCD138Fresh17/2763.08/2630.8Li et al., Am J Reprod Immunol 2021RetrospectiveCD138Fresh283/44363.9172/27363.0Xiong et al., Fertil Steril 2021 (16Xiong Y. Chen Q. Chen C. Tan J. Wang Z. Gu F. et al.Impact of oral antibiotic treatment for chronic endometritis on pregnancy outcomes in the following frozen-thawed embryo transfer cycles of infertile women: a cohort study of 640 embryo transfer cycles.Fertil Steril. 2021; 116: 413-421Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar)RetrospectiveHysteroscopyCD138Frozen-thawed58/8866.011/2642.3Cicinelli et al., Hum Reprod 2015 (17Cicinelli E. Matteo M. Tinelli R. Lepera A. Alfonso R. Indraccolo U. et al.Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy.Hum Reprod. 2015; 30: 323-330Crossref PubMed Scopus (229) Google Scholar)RetrospectiveCD138,Hysteroscopy, Cultures, H&E,Fresh28/4680.42/1513.3Mitter et al., Am J Reprod Immunol 2021 (12Mitter V.R. Meier S. Rau T.T. Gillon T. Mueller M.D. Zwahlen M. et al.Treatment following hysteroscopy and endometrial diagnostic biopsy increases the chance for live birth in women with chronic endometritis.Am J Reprod Immunol. 2021; 86e13482Crossref PubMed Scopus (6) Google Scholar)RetrospectiveHysteroscopyCD138Fresh70.234.3Total (mean)70.234.3Note: Events are calculated and ongoing pregnancy rate and live birth rate. H & E = hematoxylin and eosin. Open table in a new tab Many protocols of antibiotic treatment have been proposed. Basically, antibiotic choice may be guided based on the antibiogram (endometrial cultures required) (1Cicinelli E. Resta L. Loizzi V. Pinto V. Santarsiero C. Cicinelli R. et al.Antibiotic therapy versus no treatment for chronic endometritis: a case-control study.Fertil Steril. 2021; 115: 1541-1548Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar, 2Cicinelli E. Matteo M. Trojano G. Mitola P.C. Tinelli R. Vitagliano A. et al.Chronic endometritis in patients with unexplained infertility: prevalence and effects of antibiotic treatment on spontaneous conception.Am J Reprod Immunol. 2018; 79Crossref PubMed Scopus (101) Google Scholar) or empirically chosen (standard protocol). The most commonly employed standard protocol consists of oral levofloxacin 500 mg and tinidazole 1,000 mg daily for 14 days (18Song D. He Y. Wang Y. Liu Z. Xia E. Huang X. et al.Impact of antibiotic therapy on the rate of negative test results for chronic endometritis: a prospective randomized control trial.Fertil Steril. 2021; 115: 1549-1556Abstract Full Text Full Text PDF PubMed Scopus (14) Google Scholar). Alternatively, it has been proposed a first course with oral doxycycline 100 mg twice daily for 14 days. In case of persistence, a second treatment with oral levofloxacin 200 mg administered twice daily plus oral metronidazole 500 mg thrice daily for 14 days. If the endometrial culture was still positive, a third and last treatment course with oral levofloxacin 200 mg twice daily plus oral metronidazole 500 mg thrice daily for another 14 days (16Xiong Y. Chen Q. Chen C. Tan J. Wang Z. Gu F. et al.Impact of oral antibiotic treatment for chronic endometritis on pregnancy outcomes in the following frozen-thawed embryo transfer cycles of infertile women: a cohort study of 640 embryo transfer cycles.Fertil Steril. 2021; 116: 413-421Abstract Full Text Full Text PDF PubMed Scopus (13) Google Scholar). To this date, no studies demonstrated the superiority of one approach over the other.ConclusionsTo conclude, CE has an infectious origin. It causes a hostile uterine environment for the development and maintenance of pregnancy. Although there is a lack of randomized controlled trials looking at pregnancy outcomes in treated vs. untreated cohorts, the existing evidence suggests that CE is highly prevalent among women with failed ART outcome (up to 60%). Moreover, it appears that it is possible to diagnose and treat CE and thereby improve reproductive outcome. Hysteroscopy and/or endometrial biopsy are low-cost office procedures that are effective for diagnosing CE and evaluating the effects of treatment. We strongly suggest investigating all women for CE before ART.Pro 2: Dana B. McQueen, M.D.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Pro 3: Bridget Huepfel, B.S.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Patients with Recurrent Pregnancy Loss Should be Screened for CE Before ARTIn the past decade, increased attention has been paid to the connection between CE and recurrent pregnancy loss (RPL), and rightly so. As it stands right now, RPL remains unexplained in approximately 50% of women who present for assessment (19Stephenson M.D. Frequency of factors associated with habitual abortion in 197 couples.Fertil Steril. 1996; 66: 24-29Abstract Full Text PDF PubMed Google Scholar). The innocuity of the symptoms associated with CE and the relative difficulty of its diagnosis have led clinicians to overlook it during the workup of patients with RPL. Although in recent years, countries such as Germany, Austria, and Switzerland have added the diagnosis and treatment of CE to their guidelines for the management of recurrent miscarriages, the United States medical community has refrained from doing so (20Hennessy M. Dennehy R. Meaney S. Linehan L. Devane D. Rice R. et al.Clinical practice guidelines for recurrent miscarriage in high-income countries: a systematic review.Reprod Biomed Online. 2021; 42: 1146-1171Abstract Full Text Full Text PDF PubMed Scopus (10) Google Scholar). The preponderance of evidence now demonstrates that CE is common among women with RPL; highly amenable to treatment; and negatively impacts the reproductive outcomes.Chronic endometritis is common among women with RPLIt has been established that women with RPL have a high prevalence of CE compared with controls. In 2011, Zolghadri et al. (14Zolghadri J. Momtahan M. Aminian K. Ghaffarpasand F. Tavana Z. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion.Eur J Obstet Gynecol Reprod Biol. 2011; 155: 217-220Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar) compared CE rates between 142 women with a history of ≥3 pregnancy losses and 154 fertile controls. The cohort with RPL had a CE rate of 42.9%, significantly higher than the 18.2% CE rate found in the control group (14Zolghadri J. Momtahan M. Aminian K. Ghaffarpasand F. Tavana Z. The value of hysteroscopy in diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous abortion.Eur J Obstet Gynecol Reprod Biol. 2011; 155: 217-220Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). The high prevalence of CE among women with a history of RPL was confirmed in a 2014 study in which we evaluated 395 women with a history of ≥2 pregnancy losses at ≤10 weeks and/or a history of 1 fetal death at ≥10 weeks (3McQueen D.B. Bernardi L.A. Stephenson M.D. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise.Fertil Steril. 2014; 101: 1026-1030Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). A 2015 study of 107 patients with RPL found a CE rate as high as 57% when CD138 immunohistochemical (IHC) staining for PCs was used as the method of diagnosis (21McQueen D.B. Perfetto C.O. Hazard F.K. Lathi R.B. Pregnancy outcomes in women with chronic endometritis and recurrent pregnancy loss.Fertil Steril. 2015; 104: 927-931Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar). Finally, a 2021 meta-analysis of 12 studies estimated the incidence of CE in women with RPL to be 29.67% (6Pirtea P. Cicinelli E. De Nola R. de Ziegler D. Ayoubi J.M. Endometrial causes of recurrent pregnancy losses: endometriosis, adenomyosis, and chronic endometritis.Fertil Steril. 2021; 115: 546-560Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar). Several factors complicate the analysis of these studies, including differences among the method of diagnosis chosen by each study; differences in the populations from which study cohorts originated from; and the phase of the menstrual cycle in which CE was assessed. Standardized sample collection protocols and strict diagnostic criteria for CE are clearly needed to address these challenges. Toward this end, in a recently published study, we reported that when both endometrial stromal changes and PCs are required to diagnose CE, a clear association between RPL and CE exists. With the additional requirement of the presence of endometrial stromal changes, 30% (15/50) of the unexplained cohort with RPL were diagnosed opposed to none among the fertile controls (22McQueen D.B. Maniar K.P. Hutchinson A. Confino R. Bernardi L. Pavone M.E. Redefining chronic endometritis: the importance of endometrial stromal changes.Fertil Steril. 2021; 116: 855-861Abstract Full Text Full Text PDF PubMed Scopus (11) Google Scholar). We would propose that future research on CE should use these strict diagnostic criteria to minimize false positives.Treatment for chronic endometritis is effectiveAlthough CE is common among women with RPL, treatment with antibiotics is effective at achieving a cure. Johnston et al. (13Johnston-MacAnanny E.B. Hartnett J. Engmann L.L. Nulsen J.C. Sanders M.M. Benadiva C.A. Chronic endometritis is a frequent finding in women with recurrent implantation failure after in vitro fertilization.Fertil Steril. 2010; 93: 437-441Abstract Full Text Full Text PDF PubMed Scopus (217) Google Scholar) reported that the cure rate after a single course of antibiotics was 66% and increased to 100% after a second course. In 2014, we reported that the cure rate after a single course of antibiotics was 94%, which increased to 100% after a second course of antibiotics (3McQueen D.B. Bernardi L.A. Stephenson M.D. Chronic endometritis in women with recurrent early pregnancy loss and/or fetal demise.Fertil Steril. 2014; 101: 1026-1030Abstract Full Text Full Text PDF PubMed Scopus (113) Google Scholar). Finally, Duan et al. (23Duan H. Li X. Hao Y. Shi J. Cai H. Risk of spontaneous abortion after antibiotic therapy for chronic endometritis before in vitro fertilization and intracytoplasmic sperm injection stimulation.Fertil Steril. 2022; 118: 337-346Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar) in 2022, reported that the cure rate after a single course of antibiotics was 93.5% (316/338), and once again 100% (338/338) after a second course. In all the cases, a subsequent endometrial biopsy was performed as a test of cure. In addition to being effective, treatment with antibiotics is considered safe with minimal side effects.Treatment for chronic endometritis improves reproductive outcomesAfter treatment for CE, several studies report improved reproductive outcomes. Cicinelli et al. (11Cicinelli E. Matteo M. Tinelli R. Pinto V. Marinaccio M. Indraccolo U. et al.Chronic endometritis due to common bacteria is prevalent in women with recurrent miscarriage as confirmed by improved pregnancy outcome after antibiotic treatment.Reprod Sci. 2014; 21: 640-647Crossref PubMed Scopus (139) Google Scholar) reported that patients with unexplained RPL and CE whose hysteroscopic findings normalized 1 year after antibiotic treatment had significantly high clinical pregnancy rates compared with patients with CE and persistently abnormal hysteroscopic findings (78% vs. 24.4%). Yang et al. (24Yang R. Du X. Wang Y. Song X. Yang Y. Qiao J. The hysteroscopy and histological diagnosis and treatment value of chronic endometritis in recurrent implantation failure patients.Arch Gynecol Obstet. 2014; 289: 1363-1369Crossref PubMed Scopus (80) Google Scholar) reported improved implantation and ongoing pregnancy rates in IVF-ET after treatment of CE. Cicinelli et al. (17Cicinelli E. Matteo M. Tinelli R. Lepera A. Alfonso R. Indraccolo U. et al.Prevalence of chronic endometritis in repeated unexplained implantation failure and the IVF success rate after antibiotic therapy.Hum Reprod. 2015; 30: 323-330Crossref PubMed Scopus (229) Google Scholar) found significantly increased clinical pregnancy rates and live birth rates among patients with recurrent implantation failure after treatment of CE. A 2020 study compared pregnancy outcomes between 220 pregnant controls and 303 pregnant women with CE confirmed by histologic findings before the beginning of their pregnancy. Women with untreated CE had a 2.6-fold increased risk of miscarriage in their next pregnancy (25Taranovska O.O. Likhachov V.K. Dobrovolska L.M. Makarov O.G. Shymanska Y.V. The role of secreting function of decidua in the development of complications of gestation process in pregnant women with a past history of chronic endometritis.Wiad Lek. 2020; 73: 2416-2420Crossref PubMed Google Scholar). Taken together, these studies demonstrate that treatment for CE is warranted.The totality of the previously described evidence suggests that the presence of CE creates a suboptimal uterine environment for pregnancy. Although there is a lack of randomized controlled trials looking at pregnancy outcomes in treated and untreated cohorts, the evidence suggests that CE is common, treatable, and detrimental to reproductive outcomes. Given the minimal risk and low cost associated with an endometrial biopsy and antibiotic therapy, we suggest assessing all women with RPL for CE before ART.Pro 4: Amerigo Vitagliano, M.D., Ph.D.View Large Image Figure ViewerDownload Hi-res image Download (PPT)Testing for CE in Specific Subgroups of Women with Reproductive FailureThe offering of diagnostic endometrial “add-ons” in women with infertility, such as notably screening for CE, remains a thorny and hotly debated issue. In recent times, the demonstration that embryo selection with preimplantation genetic testing for aneuploidy improves success rates per ET has reinforced the “old belief” that the only needed element to reach a live birth is a good quality, chromosomally normal embryo.In line with this principle, a recent, well-conducted study demonstrated that only a minority of patients (7.4%) will fail to obtain a live birth after 3 consecutive euploid ETs (26Pirtea P. De Ziegler D. Tao X. Sun L. Zhan Y. Ayoubi J.M. et al.Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.Fertil Steril. 2021; 115: 45-53Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar), apparently proving that what we define as “true” recurrent implantation failure (RIF), i.e., repeated IVF failures not linked to embryo aneuploidy, is only a statistical deception. Therefore, it has been argued that the diagnosis of RIF represents just a virtual population on which we have been unnecessarily speculating for years, whose destiny is to be extinct after the extended application of preimplantation genetic testing for aneuploidy.As it is well known, misinterpretations of studies results have repeatedly occurred in biomedical research history. Yet, when scientists looked at the data with different eyes, new frontiers opened up for possible medical progress.The data reported by Pirtea et al. (26Pirtea P. De Ziegler D. Tao X. Sun L. Zhan Y. Ayoubi J.M. et al.Rate of true recurrent implantation failure is low: results of three successive frozen euploid single embryo transfers.Fertil Steril. 2021; 115: 45-53Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar) may not necessarily be extended to the whole general IVF population. Indeed, this data stem form a selection of patients with good prognosis, namely women without any uterine or endometrial pathology (as diagnosed by