Clinical relevance of diagnostic hysteroscopy with concurrent endometrial biopsy in the accurate assessment of intrauterine alterations

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1 DOI /s GENERAL GYNECOLOGY Clinical relevance of diagnostic hysteroscopy with concurrent endometrial biopsy in the accurate assessment of intrauterine alterations Joji Ueno Renato M. Salgado Renato B. Tomioka Juliana A. Colucci Eduardo Schor Filomena M. Carvalho Received: 5 November 2014 / Accepted: 22 January 2015 Ó Springer-Verlag Berlin Heidelberg 2015 Abstract Purpose The aim of this retrospective observational study was to evaluate the reliability of diagnostic hysteroscopy, routinely performed along with endometrial biopsy, by analyzing and comparing both hysteroscopic and histopathological outcomes in asymptomatic infertile patients, previously to their IVF cycle. Methods The study included 84 consecutive infertile patients who underwent diagnostic hysteroscopy followed by endometrial biopsy. Four-micrometer sections were stained with hematoxylin and eosin and examined microscopically. The data evaluated the frequency and characteristics of endometrial abnormalities found in the biopsies of patients with normal hysteroscopy outcome. Descriptive data are presented as percentages, and the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of hysteroscopy for diagnosis of endometrial alterations were calculated on the basis of pathologic reports. Results The hysteroscopy evaluation showed 50.0 % of patients with a normal uterine cavity, 40.5 % with endometrial polyps, 6.0 % with endometrial hyperemia, and 3.5 % with other endometrial abnormalities. Among the 42 patients with a normal uterine cavity at hysteroscopic examination, 60.0 % also had a normal biopsy outcome, but in other 40.0 % of patients at least one histopathological abnormal aspect was diagnosed at biopsy. The sensitivity (67.3 %), specificity (80.6 %), PPV (85.4 %) and NPV (59.5 %) of diagnostic hysteroscopy were calculated on the basis of histopathological findings. J. Ueno (&) R. M. Salgado R. B. Tomioka J. A. Colucci E. Schor F. M. Carvalho GERA-Institute of Reproductive Medicine, Sao Paulo, SP, Brazil jojiueno@uol.com.br Conclusions Our results show that diagnostic hysteroscopy demonstrated intrauterine alterations in half of infertile patients; histopathological endometrial alterations suggest high rate of false-negative outcomes. Therefore, diagnostic hysteroscopy and concurrent endometrial biopsy should be used as complementary diagnostic and therapeutic approach, especially for patients with previous IVF failures. Keywords Hysteroscopy Endometrial biopsy Uterine alterations Infertility In vitro fertilization Introduction Infertility is a disease defined by the American Society for Reproductive Medicine as the failure to achieve a successful pregnancy after 12 months or more of regular unprotected intercourse [1]. There are numerous etiologic factors that contribute to female infertility, such as endometriosis, polycystic ovarian syndrome, ovarian failure, uterine abnormalities, and around 10 % of patients present idiopathic infertility. Unsuspected intrauterine abnormalities have been recorded to be up to 45 % of gynecological diagnoses, which may play an important role in subfertility, implantation failure or miscarriage [2 5]. Transvaginal ultrasonography can be used to diagnose some endometrial abnormalities; however, it has been proven to present certain drawbacks, and the best method of diagnosis is hysteroscopy. Hysteroscopy enables the direct visualization of the cervical canal and uterine cavity, and allows a more accurate assessment of intrauterine alterations, such as endometrial polyps and hyperplasia, intrauterine synechiae and septum, myoma and endometritis [6, 7].

2 Interestingly, it has been reported that it is possible to remove endometrial polyps by hysteroscopy, using the mini-resectoscope, in an office setting [8]. Even though office hysteroscopy as a first-line investigation in all subfertile women is not a consensus in the literature, in patients with recurrent implantation failure, with at least two failed IVF attempts, a simple diagnostic or operative hysteroscopy previous to a subsequent IVF treatment is known to improve positive pregnancy results [5, 7]. On the other hand, hysteroscopy has been increasingly recommended in the first-line infertility investigation, as it offers great assistance for the interpretation of uncertain findings from other diagnostic methods and allows a directed biopsy and therapeutic intervention for correction of most of these abnormalities [4, 6]. In a previous work, the authors analyzed 2,500 diagnostic hysteroscopies performed in infertile patients prior to IVF, and demonstrated endometrial pathology at hysteroscopy from 22.9 % of patients [9]. These findings suggest a significant percentage of patients that may have impaired IVF success, due to lack of a proper diagnosis and infertility assessment. Interestingly, the most prevalent intrauterine alteration was endometrial polyps. A meta-analysis study evaluated the impact of diagnostic hysteroscopy on the outcome of subsequent IVF cycle of 1,691 participants. Although the quality of these studies was considerably variable, the results showed strong evidence of the benefits of hysteroscopy in improving pregnancy rates in the subsequent IVF cycle [10]. Later, the same group published another systematic review and meta-analysis (n = 901 participants), evidencing a statistically significant augment in clinical pregnancy rates after local endometrial injury [11]. However, more robust randomized trials are necessary to strengthen the benefits of hysteroscopy and endometrial biopsy in women undergoing assisted reproduction techniques. A recent clinical trial conducted a randomized controlled study in which the intervention group was submitted to two consecutive endometrial biopsies, one in the follicular phase and another in the luteal phase of the cycle preceding the embryo transfer cycle. They showed a significant increase in implantation, clinical pregnancy and live birth rates, when comparing to the control group (no intervention) [12]. Concerning endometrial alterations, a randomized trial [13] evidenced higher pregnancy rates after polypectomy in women undergoing intrauterine insemination compared with those who had routine hysteroscopy and biopsy without treatment or surgery. Other retrospective studies, however, did not observe benefits of polypectomy of small polyps in patients undergoing IVF cycles [14, 15]. Another common intrauterine abnormality is chronic endometritis, which is diagnosed in up to 45 % of patients undergoing hysteroscopy-guided endometrial biopsies, previous to the IVF cycle [16 18]. In fact, a recent retrospective study demonstrated that chronic endometritis is frequently found in routine office hysteroscopy and suggests the procedure is efficient in assessing or ruling out endometrial factor for female infertility [19]. However, for the diagnosis of endometritis and endometrial hyperplasia, the validity of hysteroscopy may be limited, and the biopsy of the endometrium is considered to be the gold standard procedure [17, 20]. The hysteroscopy examination has been used as part of the infertility investigation in order to assess endometrium previous to IVF cycle. Nevertheless, the literature needs to be enriched of studies around the agreement in diagnosing benign intrauterine abnormalities by hysteroscopy and concurrent endometrial biopsies. Therefore, the aim of this retrospective observational study was to evaluate the reliability of diagnostic hysteroscopy, routinely performed along with endometrial biopsy, by analyzing and comparing the hysteroscopic with the concurrent histopathological outcomes in asymptomatic infertile patients, previously to their IVF cycle. Materials and methods This is a retrospective descriptive study conducted at Gera Reproductive Medicine Institute, a private assisted reproduction and education center in Sao Paulo, Brazil. Institutional review board approval was not required, as all of the procedures are routinely performed, and a written informed consent was previously obtained from all patients, in which they agreed to share the data of the procedures for research purposes. In the informed consent, a detailed explanation of all the procedures involved was given, thus all patients were able to understand the scope of the study in which they were participating [21]. Patients All patients were undergoing infertility investigation, consisting of medical history, physical examination, hormone status, transvaginal ultrasonography, hysterosalpingography for tubal evaluation, hysteroscopy and endometrial biopsy. The data was collected in a period of 24 months. The study included 84 consecutive patients who underwent diagnostic hysteroscopy and endometrial biopsy at the proliferative phase (days 7 12 of the menstrual cycle). Patients with hysteroscopy on secretory phase ware not included. Hysteroscopy procedures All of the hysteroscopy procedures were performed by the clinical director in an ambulatory setting without

3 anesthesia, using the standard 30 forward-oblique lens and a 2.9-mm single-channel sheath with a 300-W light source (Storz). Saline solution was used for distention of the uterine cavity. All of the procedures were performed between days 7 and 12 of the menstrual cycle. Uterine abnormalities were defined as endometrial polyps, endometrial hyperemia, uterine adhesions, uterine septa, myomas, endometrial irregularities, and endometrial atrophy. Alterations in the cervical canal were also observed, but were not considered in this study. Endometrial biopsy Immediately after uterine cavity examination, the endometrial sample was collected with a silicone catheter number 8, and the tissue was formalin-fixed and embedded in paraffin. Four-micrometer histological sections were stained with hematoxylin and eosin, and all slides were blindly examined by the same pathologist (FMC). Detailed criteria for the diagnosis of endometritis are presented in the Results and Fig. 2. Criteria for polyps were the presence of thick-walled vessels, fibrous stroma and irregular gland architecture; at least two of these criteria were needed for polyp diagnosis. Thick-walled vessels without stromal and glandular/epithelial alterations were included with other vascular changes endothelial swelling, hyaline degeneration of the vessel wall, abnormal vascular proliferation and were generally analyzed as vascular alterations [22]. Statistical analysis Patient demographic data were evaluated by descriptive statistics, which included information on means and frequencies. The outcome analysis evaluated the frequency of endometrial abnormalities at hysteroscopy and biopsies. Continuous variables were given as mean ± standard deviation (SD) and compared using Student s t test; the nominal variables were tested by Chi-squared or Fisher s exact tests as appropriate; Pearson s correlation analysis was used to evaluate the relationship between variables. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of hysteroscopy for the diagnosis of endometrial alterations were calculated on the basis of pathologic reports. To evaluate the influence of patients characteristics observed on hysteroscopy or biopsy findings, we used binomial logistic regression using a multi-adjusted approach; the results were given as the odds ratio (OR), 95 % confidence interval (CI) and p value. The analyses were performed using Minitab 14 for Windows (Minitab, USA), and p B 0.05 were considered statistically significant. Results At the anamnesis, patients were scheduled for routine diagnostic hysteroscopy and concurrent endometrial biopsy. Investigation of the uterine cavity was adequately completed in all cases, and no complications occurred. Detailed data on the patients included in the study are shown in Table 1. Hysteroscopy findings The frequency of diagnostic hysteroscopy showing no endometrial alteration was 50.0 %. The most frequent abnormality found was the presence of polyps (40.5 %), followed by endometrial hyperemia (6.0 %) (Fig. 1a). Of all patients diagnosed with hyperemia, only 30 % showed pathologic signs of endometritis in the endometrial biopsy, which was not statistically significant (Chi-square test). The multivariate binary logistic regression analysis showed that the number of previous IVF/ICSI was predictive of occurrence of intrauterine abnormalities at diagnostic hysteroscopy, adjusted for female age and hysteroscopy cycle day (p = 0.038, OR 1.70). To further support these findings, we compared the percentage of patients presenting abnormalities at diagnostic hysteroscopy who had at least one previous IVF/ ICSI cycle (59.1 %) versus those who did not have previous IVF/ICSI cycles (46.8 %; p = 0.320). A higher percentage of alterations was observed in patients with previous IVF failure, in spite of non-statistically significant difference (data not shown). Biopsy findings The frequency of non-alterations at endometrial biopsy was 36.9 %. The most common alterations found were Table 1 Patient characteristics Variables Age (years) 36.3 ± 4.8 Body mass index (kg/m 2 ) 24.0 ± 3.8 Period of infertility (years) 3.0 ± 2.2 Hysteroscopy/biopsy cycle day 10.5 ± 2.3 Type of infertility Primary 90.5 % Secondary 9.5 % Previous infertility treatment None 53.6 % Timed intercourse (TI) or intrauterine insemination 20.2 % (IUI) IVF or ICSI 26.2 % Chi-square test, Fisher s exact test

4 endometritis (19.0 %), polyps (17.9 %), and both (endometritis plus polyps 7.1 %) (Fig. 1b). For the purpose of statistical analysis, we grouped cases that fulfilled the criteria for endometritis with those that had highly suggestive findings under the designation signs of endometritis. The vascular changes that were qualitatively investigated were: high vascular density with endothelial proliferation and swelling, hyaline thickening of the vessel wall with luminal occlusion, fibrinoid degeneration of the vessel wall and small vessel thrombosis. Moreover, intense accumulation of plasma cells in the stroma and granular leukocytes around epithelia and blood vessels was also considered a feature of endometritis (Fig. 2) [22]. Correlated outcomes When diagnostic hysteroscopy and biopsy outcomes were evaluated together, we noted a positive correlation between them (Pearson Correlation: r = 0.464, p \ 0.001). Among Fig. 2 Intense accumulation of inflammatory cells around epithelia and blood vessels, indicating the presence of endometritis the 42 patients with a normal uterine cavity at hysteroscopy, 40.0 % showed abnormal biopsy outcome (Fig. 3). Moreover, on the basis of the pathologic findings from the biopsy analyses, we calculated the sensitivity (67.3 %), specificity (80.6 %), PPV (85.4 %) and NPV (59.5 %) of hysteroscopy for diagnosis of endometrial alterations. We observed that although the specificity and PPV were higher than 80 %, the sensitivity was lower than 70 % and NPV was around 60 %. Discussion Fig. 1 a Outcome parameters of diagnostic hysteroscopy. Polyps are the major alterations observed, followed by hyperemia. b Outcome parameters of endometrial biopsy. Endometritis and polyps are the major alterations observed, followed by vessel alterations and inflammatory infiltrate Hysterosalpingography (HSG) and transvaginal ultrasonography (TV-USG) are currently used to assess the uterine cavity, and when a suspect alteration is observed at HSG or TV-USG, hysteroscopy is highly indicated and employed [23]. On the other hand, although the association of benign intrauterine alterations and infertility has been established, the evaluation of the uterine cavity by hysteroscopy is still unconsidered for first-line infertility investigation [6]. Hysteroscopy is considered the gold standard for the diagnosis of uterine alterations and is gradually becoming a routine procedure in patients with repeated failure in IVF cycles [24]. The procedure can be performed in the gynecologist s office without patient discomfort and permits the resolution of most benign alterations [25, 26]. In fact, there is an ongoing debate regarding the value of hysteroscopy as a first line of infertility investigation, and the evaluation of the uterine cavity by routine office hysteroscopy prior to the IVF is gaining an increasing value in the management of infertile patients [27]. The present study corroborates

5 Fig. 3 a Hysteroscopic general outcome of all patients. Half of the patients showed no alterations at diagnostic hysteroscopy. b Endometrial biopsy outcome of those patients who showed no alteration at diagnostic hysteroscopy. The data demonstrates that 40 % of these patients had alterations at the histopathology analysis with this approach, as the prevalence of uterine abnormalities diagnosed at hysteroscopy was 50.0 %, which is in accordance with the overall prevalence of hysteroscopy alterations described in the literature (20 45 %) [3 5, 28, 29]. A systematic review evaluated the impact of hysteroscopy following failed IVF, and evidenced the benefit from hysteroscopy in increasing the chance of pregnancy in the subsequent IVF cycle [9]. In fact, implantation failure events may be associated with intrauterine alterations, as the number of previously failed IVF/ICSI cycles with transfer of good-quality embryos may be predictive of intrauterine abnormalities. Also, these data suggest that each unsuccessful IVF/ICSI cycle increases the chance of finding intrauterine abnormalities at hysteroscopy by 70 % (p = 0.038, OR 1.70), adjusted for woman s age and the day of the menstrual cycle at hysteroscopy. Other authors also observed more frequent abnormal findings at hysteroscopy in patients with previous IVF failure and/or miscarriage [29, 30]. An interesting study by Bohlmann et al. [31] analyzed through hysteroscopy the presence of intrauterine anomalies in groups of patients with exactly two consecutive miscarriages and three or more consecutive miscarriages. Although there were no significant differences among groups, the incidence of abnormalities was high (36.8 vs %). Uterine abnormalities are estimated to play a relevant role in infertility, for over 30 % of infertile patients suffer from abnormal intrauterine findings. Thus, it is possible to infer that office hysteroscopy is a valuable tool for the treatment of patients presenting recurrent pregnancy loss. Nevertheless, as shown in the present study, even if the hysteroscopy outcome is classified as normal, a concurrent endometrial biopsy should be performed to ratify the presence of endometrial intrauterine alterations. In spite of clear advantages of office hysteroscopy for the diagnosis of intrauterine abnormalities, some authors have suggested that hysteroscopy without endometrial biopsy has a low positive predictive value in the detection of intrauterine inflammatory status, such as chronic endometritis [20]. In opposition, Zolghadri and colleagues [32] investigated the importance of hysteroscopy in the diagnosis of chronic endometritis in patients with unexplained recurrent spontaneous miscarriage, and suggested that hysteroscopy has high sensitivity and acceptable specificity. Recently, Yang et al. [33] showed the value of hysteroscopy with concurrent endometrial biopsy for the diagnosis and treatment of chronic endometritis in patients with recurrent implantation failure. In our study, the main alteration observed in the endometrial biopsies was chronic endometritis, which is in accordance with previous studies from our group that evidenced endometritis, polyps and/or vascular alterations in circa 40 % of the infertile patients undergoing IVF [22, 34]. In spite of the fact that diagnostic hysteroscopy presents a positive predictive value of 85.4 % for the diagnosis of various benign uterine alterations, endometritis was not diagnosed in various hysteroscopic assessments, but it was observed in 19.0 % of the biopsies, confirming that hysteroscopy alone may not be a suitable diagnostic method for endometritis. This is probably due to the microscopic

6 characteristics of the condition, observed by experienced pathologists. It is known that chronic endometritis may cause uterine bleeding, pain and reproductive failures [34]. Interestingly, we demonstrated that 40.0 % of patients with normal hysteroscopy had abnormal biopsy findings, showing the importance of endometrial biopsy for the accurate diagnosis of uterine abnormalities and indicating it for routine investigation of uterine alterations in infertile patients. Moreover, it has been documented that endometrial scratching significantly improves endometrial receptivity and pregnancy rates prior to IVF cycles. The meta-analysis published by El-Toukhy et al. [10] measured the outcome from eight studies, two randomized and six non-randomized trials. In all of them, clinical pregnancy rates significantly increased in the group submitted to local endometrial injury. Our results showed a high percentage of unsuspected benign intrauterine abnormalities, supporting the routine use of office hysteroscopy in the diagnosis of functional diseases of the uterine cavity in the investigation of infertility. Considering the fact that there is a higher prevalence of alteration when endometrial biopsy is performed, even with normal hysteroscopic results, endometrial biopsy should be used as a complementary diagnostic and therapeutic approach, especially for patients with previous IVF failures. Acknowledgments The authors gratefully acknowledge the contribution of Gera Reproductive Medicine Institute s staff for the excellent patient care. Conflict of interest The authors declare no conflict of interest. The authors state that they have full control of all data and agree to allow the journal to review the data if requested. References 1. ASRM (2008) Definitions of infertility and recurrent pregnancy loss. Fertil Steril 90(5 Suppl):S60 2. 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