Clinical Relevance of Diagnostic Hysteroscopy with Concurrent Endometrial Biopsy in the Accurate Assessment of Intrauterine Alterations

Arch Gynecol Obstet DOI 10.1007/s00404-015-3634-0

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 Conclusions Our results show that diagnostic hysteros- Purpose The aim of this retrospective observational study copy demonstrated intrauterine alterations in half of was to evaluate the reliability of diagnostic hysteroscopy, infertile patients; histopathological endometrial alterations routinely performed along with endometrial biopsy, by suggest high rate of false-negative outcomes. Therefore, analyzing and comparing both hysteroscopic and histopa- diagnostic hysteroscopy and concurrent endometrial biopsy thological outcomes in asymptomatic infertile patients, should be used as complementary diagnostic and thera- previously to their IVF cycle. peutic approach, especially for patients with previous IVF Methods The study included 84 consecutive infertile failures. patients who underwent diagnostic hysteroscopy followed by endometrial biopsy. Four-micrometer sections were Keywords Hysteroscopy Á Endometrial biopsy Á Uterine stained with hematoxylin and eosin and examined micro- alterations Á Infertility Á In vitro fertilization scopically. The data evaluated the frequency and characteristics of endometrial abnormalities found in the biopsies of patients with normal hysteroscopy outcome. Descriptive Introduction data are presented as percentages, and the sensitivity, specificity, positive predictive value (PPV) and negative Infertility is a disease defined by the American Society for predictive value (NPV) of hysteroscopy for diagnosis of Reproductive Medicine as the failure to achieve a suc- endometrial alterations were calculated on the basis of cessful pregnancy after 12 months or more of regular pathologic reports. unprotected intercourse [1]. There are numerous etiologic Results The hysteroscopy evaluation showed 50.0 % of factors that contribute to female infertility, such as endo- patients with a normal uterine cavity, 40.5 % with endo- metriosis, polycystic ovarian syndrome, ovarian failure, metrial polyps, 6.0 % with endometrial hyperemia, and uterine abnormalities, and around 10 % of patients present 3.5 % with other endometrial abnormalities. Among the 42 idiopathic infertility. patients with a normal uterine cavity at hysteroscopic Unsuspected intrauterine abnormalities have been examination, 60.0 % also had a normal biopsy outcome, recorded to be up to 45 % of gynecological diagnoses, but in other 40.0 % of patients at least one histopatholo- which may play an important role in subfertility, implan- gical abnormal aspect was diagnosed at biopsy. The sen- tation failure or miscarriage [2–5]. Transvaginal ultraso- sitivity (67.3 %), specificity (80.6 %), PPV (85.4 %) and nography can be used to diagnose some endometrial NPV (59.5 %) of diagnostic hysteroscopy were calculated abnormalities; however, it has been proven to present on the basis of histopathological findings. certain drawbacks, and the best method of diagnosis is hysteroscopy. Hysteroscopy enables the direct visualiza- tion of the cervical canal and uterine cavity, and allows a & J. Ueno ( ) Á R. M. Salgado Á R. B. Tomioka Á more accurate assessment of intrauterine alterations, such J. A. Colucci Á E. Schor Á F. M. Carvalho GERA-Institute of Reproductive Medicine, Sao Paulo, SP, Brazil as endometrial polyps and hyperplasia, intrauterine syn- e-mail: [email protected] echiae and septum, myoma and endometritis [6, 7]. 123 Arch Gynecol Obstet

Interestingly, it has been reported that it is possible to hysteroscopy-guided endometrial biopsies, previous to the remove endometrial polyps by hysteroscopy, using the IVF cycle [16–18]. In fact, a recent retrospective study mini-resectoscope, in an office setting [8]. demonstrated that chronic endometritis is frequently found Even though office hysteroscopy as a first-line investi- in routine office hysteroscopy and suggests the procedure is gation in all subfertile women is not a consensus in the efficient in assessing or ruling out endometrial factor for literature, in patients with recurrent implantation failure, female infertility [19]. However, for the diagnosis of endo- with at least two failed IVF attempts, a simple diagnostic or metritis and endometrial hyperplasia, the validity of hys- operative hysteroscopy previous to a subsequent IVF teroscopy may be limited, and the biopsy of the endometrium treatment is known to improve positive pregnancy results is considered to be the gold standard procedure [17, 20]. [5, 7]. On the other hand, hysteroscopy has been increas- The hysteroscopy examination has been used as part of ingly recommended in the first-line infertility investigation, the infertility investigation in order to assess endometrium as it offers great assistance for the interpretation of previous to IVF cycle. Nevertheless, the literature needs to uncertain findings from other diagnostic methods and be enriched of studies around the agreement in diagnosing allows a directed biopsy and therapeutic intervention for benign intrauterine abnormalities by hysteroscopy and correction of most of these abnormalities [4, 6]. concurrent endometrial biopsies. Therefore, the aim of this In a previous work, the authors analyzed 2,500 diag- retrospective observational study was to evaluate the reli- nostic hysteroscopies performed in infertile patients prior ability of diagnostic hysteroscopy, routinely performed to IVF, and demonstrated endometrial pathology at hys- along with endometrial biopsy, by analyzing and compar- teroscopy from 22.9 % of patients [9]. These findings ing the hysteroscopic with the concurrent histopathological suggest a significant percentage of patients that may have outcomes in asymptomatic infertile patients, previously to impaired IVF success, due to lack of a proper diagnosis and their IVF cycle. infertility assessment. Interestingly, the most prevalent intrauterine alteration was endometrial polyps. A meta-analysis study evaluated the impact of diag- Materials and methods nostic hysteroscopy on the outcome of subsequent IVF cycle of 1,691 participants. Although the quality of these This is a retrospective descriptive study conducted at Gera studies was considerably variable, the results showed Reproductive Medicine Institute, a private assisted repro- strong evidence of the benefits of hysteroscopy in duction and education center in Sao Paulo, Brazil. Insti- improving pregnancy rates in the subsequent IVF cycle tutional review board approval was not required, as all of [10]. Later, the same group published another systematic the procedures are routinely performed, and a written review and meta-analysis (n = 901 participants), evi- informed consent was previously obtained from all dencing a statistically significant augment in clinical patients, in which they agreed to share the data of the pregnancy rates after local endometrial injury [11]. How- procedures for research purposes. In the informed consent, ever, more robust randomized trials are necessary to a detailed explanation of all the procedures involved was strengthen the benefits of hysteroscopy and endometrial given, thus all patients were able to understand the scope of biopsy in women undergoing assisted reproduction tech- the study in which they were participating [21]. niques. A recent clinical trial conducted a randomized controlled study in which the intervention group was sub- Patients mitted to two consecutive endometrial biopsies, one in the follicular phase and another in the luteal phase of the cycle All patients were undergoing infertility investigation, con- preceding the embryo transfer cycle. They showed a sig- sisting of medical history, physical examination, hormone nificant increase in implantation, clinical pregnancy and status, transvaginal ultrasonography, hysterosalpingography live birth rates, when comparing to the control group (no for tubal evaluation, hysteroscopy and endometrial biopsy. intervention) [12]. The data was collected in a period of 24 months. The study Concerning endometrial alterations, a randomized trial included 84 consecutive patients who underwent diagnostic [13] evidenced higher pregnancy rates after polypectomy in hysteroscopy and endometrial biopsy at the proliferative women undergoing intrauterine insemination compared with phase (days 7–12 of the menstrual cycle). Patients with those who had routine hysteroscopy and biopsy without hysteroscopy on secretory phase ware not included. treatment or surgery. Other retrospective studies, however, did not observe benefits of polypectomy of small polyps in Hysteroscopy procedures patients undergoing IVF cycles [14, 15]. Another common intrauterine abnormality is chronic endometritis, which is All of the hysteroscopy procedures were performed by the diagnosed in up to 45 % of patients undergoing clinical director in an ambulatory setting without 123 Arch Gynecol Obstet anesthesia, using the standard 30° forward-oblique lens and Results a 2.9-mm single-channel sheath with a 300-W light source (Storz). Saline solution was used for distention of the At the anamnesis, patients were scheduled for routine uterine cavity. All of the procedures were performed diagnostic hysteroscopy and concurrent endometrial between days 7 and 12 of the menstrual cycle. biopsy. Investigation of the uterine cavity was adequately Uterine abnormalities were defined as endometrial pol- completed in all cases, and no complications occurred. yps, endometrial hyperemia, uterine adhesions, uterine Detailed data on the patients included in the study are septa, myomas, endometrial irregularities, and endometrial shown in Table 1. atrophy. Alterations in the cervical canal were also observed, but were not considered in this study. Hysteroscopy findings

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

123 Arch Gynecol Obstet 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 throm- bosis. 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 Fig. 2 Intense accumulation of inflammatory cells around epithelia When diagnostic hysteroscopy and biopsy outcomes were and blood vessels, indicating the presence of endometritis evaluated together, we noted a positive correlation between them (Pearson Correlation: r = 0.464, p \ 0.001). Among 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

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 gyne- cologist’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 Fig. 1 a Outcome parameters of diagnostic hysteroscopy. Polyps are a first line of infertility investigation, and the evaluation of the major alterations observed, followed by hyperemia. b Outcome the uterine cavity by routine office hysteroscopy prior to parameters of endometrial biopsy. Endometritis and polyps are the major alterations observed, followed by vessel alterations and the IVF is gaining an increasing value in the management inflammatory infiltrate of infertile patients [27]. The present study corroborates 123 Arch Gynecol Obstet

Fig. 3 a Hysteroscopic general outcome of all patients. Half of the diagnostic hysteroscopy. The data demonstrates that 40 % of these patients showed no alterations at diagnostic hysteroscopy. b Endome- patients had alterations at the histopathology analysis trial biopsy outcome of those patients who showed no alteration at with this approach, as the prevalence of uterine abnor- shown in the present study, even if the hysteroscopy out- malities diagnosed at hysteroscopy was 50.0 %, which is in come is classified as normal, a concurrent endometrial accordance with the overall prevalence of hysteroscopy biopsy should be performed to ratify the presence of alterations described in the literature (20–45 %) [3–5, 28, endometrial intrauterine alterations. 29]. In spite of clear advantages of office hysteroscopy for A systematic review evaluated the impact of hysteros- the diagnosis of intrauterine abnormalities, some authors copy following failed IVF, and evidenced the benefit from have suggested that hysteroscopy without endometrial hysteroscopy in increasing the chance of pregnancy in the biopsy has a low positive predictive value in the detec- subsequent IVF cycle [9]. In fact, implantation failure tion of intrauterine inflammatory status, such as chronic events may be associated with intrauterine alterations, as endometritis [20]. In opposition, Zolghadri and col- the number of previously failed IVF/ICSI cycles with leagues [32] investigated the importance of hysteroscopy transfer of good-quality embryos may be predictive of in the diagnosis of chronic endometritis in patients with intrauterine abnormalities. Also, these data suggest that unexplained recurrent spontaneous miscarriage, and sug- each unsuccessful IVF/ICSI cycle increases the chance of gested that hysteroscopy has high sensitivity and finding intrauterine abnormalities at hysteroscopy by 70 % acceptable specificity. Recently, Yang et al. [33] showed (p = 0.038, OR 1.70), adjusted for woman’s age and the the value of hysteroscopy with concurrent endometrial day of the menstrual cycle at hysteroscopy. biopsy for the diagnosis and treatment of chronic Other authors also observed more frequent abnormal endometritis in patients with recurrent implantation findings at hysteroscopy in patients with previous IVF failure. failure and/or miscarriage [29, 30]. An interesting study by In our study, the main alteration observed in the endo- Bohlmann et al. [31] analyzed through hysteroscopy the metrial biopsies was chronic endometritis, which is in presence of intrauterine anomalies in groups of patients accordance with previous studies from our group that with exactly two consecutive miscarriages and three or evidenced endometritis, polyps and/or vascular alterations more consecutive miscarriages. Although there were no in circa 40 % of the infertile patients undergoing IVF [22, significant differences among groups, the incidence of 34]. In spite of the fact that diagnostic hysteroscopy pre- abnormalities was high (36.8 vs. 42.9 %). Uterine abnor- sents a positive predictive value of 85.4 % for the diagnosis malities are estimated to play a relevant role in infertility, of various benign uterine alterations, endometritis was not for over 30 % of infertile patients suffer from abnormal diagnosed in various hysteroscopic assessments, but it was intrauterine findings. Thus, it is possible to infer that office observed in 19.0 % of the biopsies, confirming that hys- hysteroscopy is a valuable tool for the treatment of patients teroscopy alone may not be a suitable diagnostic method presenting recurrent pregnancy loss. Nevertheless, as for endometritis. This is probably due to the microscopic

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