SIGNIFICANCE OF HYSTEROSCOPY IN DIAGNOSIS AND TREATMENT OF CONGENITAL UTERINE ANOMALIES ZNAČAJ HISTEROSKOPIJE U DIJAGNOSTICI I TRETMANU UROĐENIH ANOMALIJA MATERIČNE ŠUPLJINE Authors Šaranović Milena*, Matejić Suzana*, Matejić Nebojša †, Radić Ivan *, Trajković Goran ‡*, Vojnosanitetski pre

Background/Aim: Hysteroscopy is one of the important methods in the endoscopic diagnosis and treatment of infertility, particularly at the examination of the morphology and function of the uterus. Uterine factor is present at 10% of infertile women, in which changes of the uterus can be congenital or acquired. The aim of this study is to estimate the significance of hysteroscopy in the diagnosis and treatment of congenital anomalies of the uterine cavity in patients in whom there is a reasonable suspicion based on prior clinical, ultrasound and HSG findings. The significance of hysteroscopy is considered in relation to the number of pregnancies achieved depending on the malformations in the 12 months period after the completion of the diagnostic or operational hysteroscopy. Methods: The study included 176 patients with congenital uterine anomalies, which had undergone hysteroscopy, diagnostic or operative, in the period from Jan.1 st 2013 till Jan.1st 2016. Percentage of pregnancy was followed at all patients, during the first 12 months after surgery. Patients were divided in two groups; first group contained women that conceived a pregnancy and second group were those which did not. Their characteristics were compared, such as: age, duration of infertility, previous pregnancy and/or pregnancy loss, HSG and ultrasound findings, types of congenital anomalies, type of hysteroscopy, as well as the existence of associated pathology. Results: Mean age of patients tested in study was 35 years. The group of patients with primary infertility makes a total of 107 patients, while 69 patients were with secondary infertility. The average duration of infertility was 3 years in the studied patients. In the 12 months period, 39 examined women had begin pregnancy, which was in 33 women completed with term delivery. Chi-square test showed a statistical significance difference (p <0.05) between the groups of the patients (with or without pregnancy after hysteroscopy) in the presence of types of infertility, as well as in the number of previous miscarriages in the patients of both groups. Conclusion: From all congenital uterine malformations, the most common are subseptus and septus uteri. Very rare are uterus arquatus, uterus unicornis and uterus bicornis. In our study 1/5 of examined women have achieved pregnancy after hysteroscopy in the reporting period of 12 months, while the majority of these pregnancies ended with term delivery. The percentage of miscarriages in the examined women was reduced from 38% to 15% after hysteroscopy. In women who have achieved pregnancy mostly diagnosed are uterine septum and subseptum, at whome hysteroscopic resection was performed.


Introduction
The absence of pregnancy during one year of marital life and regular sexual relations, without the use of contraceptive means, is marked as infertility and represents a reversible condition.During intrauterine development and differentiation of organs, disorders as congenital malformation of the genital organs can occur.Their frequency according to literature data is 0.5-1% in the general population of women.The uterine factor is present at approximately 10% of infertile women.In female embryos, mesonephric channels caese to exist, while paramezonephric channels evolve, merging in the central part.The cranial horizontal parts of the Miller canal remain unbroken and evolve into the Falopian tube, while the middle and caudal parts merge and form an uterovaginal channel, from which the upper third of the vagina and the epithelium of the body and neck of the uterus are developed.Stroma of the uterus and myometrium originate from the splanchic mesoderm.Miller tuberculum of the urogenital sinus thickens, and forms 2 parts of the vaginal plate, which separate from it, with the lumen that forms the lower two thirds of the vagina.The occurrence of complete and incomplete longitudinal septum happens in 30-35%, which makes it most common among uterine anomalies.The septum is represented by poor vascular fibro muscular tissue and leads to spontaneous abortion.A complete longitudinal septum extends from the fundus to the inner cervix, dividing the cavum into 2 parts; and is commonly associated with the longitudinal septum in vagina.The incomplete septum does not reach the inner cervix and there is communication between the parts of the cavity.During the first trimester, the risk of spontaneous abortion in patients with uterine septum is elevated, and the cause is a poorer vascularization of the implantation site.
This study has aims to: 1. Evaluate the importance of hysteroscopy in the diagnosis and treatment of congenital anomalies of the uterine cavity, in patients with diagnosed infertility.2. Determine the types and frequency of congenital anomalies in the investigated groups of patients.3. Estimate the prevalence of previous pregnancies and their outcome in patients with diagnosed anomalies.4. Determine type of hysteroscopy treatment and its safety (existence of complications or reintervention).5. Determine the number of pregnancies achieved, depending on the diagnosed anomaly, for a period of 12 months, after the performed hysteroscopy for diagnostic or surgical purposes.

Methods
The cross section study covered 176 infertile patients with congenital uterine anomalies in which a hysteroscopy was performed in the period from 01.01.2011.till01.01.2016.Indications for hysteroscopy in all patients were based on anamnestic data, previous clinical examination, ultrasound examination, and additional methods such as three/dimensional ultrasound and/or HSG.All patients had indication for hysteroscopy.They all were fully laboratory, bacteriologically, internist and anesthetically treated, and then a hysteroscopy was performed according to all rules of asepsis.Hysteroscopy was performed by 5 doctors, which have adequate professional training for endoscopic methods in gynecology and years of experience.Hysteroscopy was performed in early proliferative phase of cycle, with the use of 0,9 % NaCl solution as distension media and after the dilatation of cervix to 10,5mm, hysteroscope with diameter of 10mm was inserted in the uterus (Karl Storz, Germany).Mechanical instruments (scissors) and versa-point electrode were used in resection on septum and sub septum, and removing polyps.In patients with suspected severe congenital anomalies, a laparoscopic intervention was performed along with hysteroscopy in order to establish the exact diagnosis of congenital anomaly, at approximately 30% of patients.In the case of patients with septum and sub septum in hysteroscopy, a septum was resected.Septum was classified as a longitudinal septum with the length more than 15 mm from the fundus, which divided uterus inside in half.The safety of hysteroscopy, which was assessed on the basis of complications and the need for re-intervention, was observed.The percentage of pregnancies was observed during the first 12 months after surgery in all patients.Thus, two groups of patients were formed, one that conceived pregnancy and those who did not.Both groups had characteristics that were compared: previous pregnancy, ultrasound and HSG findings, types of congenital anomalies, types of hysteroscopy treatment, and the existence of associated pathology.The following parameters were monitored for all patients: age, professional capacity, type of infertility, duration of infertility, the existence of earlier delivery or abortion, ultrasound findings, findings at hysteroscopy and type of hysteroscopy surgery performed.The obtained data were processed using the descriptive and analytical statistics methods.Data processing was done using the statistical packages Med Calc 15.8 and SPSS 20.0.From the descriptive statistics method, the arithmetic mean, the standard deviation, the range, the grouping and the tabulation of the data are determined.Analytical methods used the t-test for numerical data and the hi-square test for attribute data.The obtained data were analyzed and compared with the results available in domestic and foreign literature.On the basis of the obtained results, the conclusions were brought out in the paper.The study procedure was conducted in accordance with the Helsinki Declaration.

Limitations of study
This study has some limitations.The study included women who were diagnosed with infertility according to valid criteria.The study has a relatively small number of subjects in one of the reference centers for hysteroscopy treatment of uterine anomalies.Since hysteroscopy was conducted only on the basis of indications, some women were admitted after one or more miscarriages and one or more unsuccessful processes of IVF.Some of the patients after hysteroscopy treatment and 12 months period of control at Clinic, had back to their hometowns, and didn't get back to Clinic in the next pregnancy and we don't know exactly how much of them had pregnancy and its outcomes after the 12 month period.Data of the husband/partners male infertility was not followed at all patients, so they have been excluded from study.It is recommended that center makes some follow up program of the patients which had been diagnosed in congenital uterine anomalies and had laparoscopic, hysteroscopy or non endoscopic operative treatment, so that doctors can follow them during pregnancy and its outcome.

Results
The conducted study included 176 patients, whose basic characteristics are shown in Table 1.The average age of the examined patients was 35 years; and the group included women from 29 to 47 years of age.A group of subjects with primary infertility includes a total of 107 patients (61%), while 69 patients (39%) make a group of subjects with secondary infertility.The average length of infertility in the patients tested was 3 years, while the range was 1-6 years.Only 3% of patients have previous successful pregnancies.4 patients with 1 miscarriage had previous IVF process; 8 patients with 2 miscarriages had previous IVF process and 2 patients with 3 miscarriage had previous IVF process.14 (8%) of all patients had previous 1 IVF and 2 IUI process.In 20% of subjects was observed presence of associated pathological changes, such as endometrial polyps, myom or longitudinal vaginal septum.Polyps were removed at hysteroscopy, myoms were small submucose and also removed during hysteroscopy, and longitudinal vaginal septum was resected.Complications in hysteroscopy were reported in 2% of subjects, mainly with complete uterine septum.Repeated hysteroscopy was needed in 5% of subjects, at resection of a complete septum.Chart 1 shows age-based respondents grouped in 6 age groups (in five-year intervals), which include the reproductive period of women.Most respondents (34%) were in the age group 30-35 years; the group of 35-40 years had 30% of respondents; the group of 40-45 years had 15%; the group of 25-30 years 12% and the group of 20-25 years had 4% of respondents.3% respondents were in the group of more than 45 years of age.Table 2 shows the characteristics of respondents who achieved pregnancy after hysteroscopy in observed 12 months period.39 subjects had pregnancy in a given test group; with spontaneous pregnancy at 64%. 36% of patients with pregnancy underwent the medically assisted fertilization process-15% patients had IUI and 21% patients had IVF.33 respondents successfully terminated pregnancy with child born in a term; out of which 28 women had spontaneous delivery and 5 had the Cesarean section.6 women (15%) had miscarriage in the first trimester after hysteroscopy.Chart 2 shows the type and frequency of uterine anomalies found in hysteroscopy.76% of subjects had sub-septum, 16% had a septum, while rarely presented were: uterus arquatus in 4%, uterus unicornis in 3%, and uterus bicornis at 1%. Chart 3 shows the types of congenital uterine anomalies of the examined women and their frequency in both groups.In the group of subjects who had pregnancy, 28 of them had sub septum, 10 had septum and 1 had uterus arquatus.In the group of subjects who did not get pregnant, the representation of anomalies was: the highest number of respondents 105 had subseptum; 19 had septum; 7 had uterus arquatus, 5 had uterus unicornis and only 1 had uterus bicornis.Table 3 shows the data of respondents who conceived after the hysteroscopy and those who did not.The first group consists of 39 women, only 22% of all respondents involved in study.Their average age was 33 years.44% of subjects were with primary infertility and 56% with secondary infertility.There were no previous deliveries of women in this group.21% of women in this group had 1 previous miscarriage; 28% had 2 miscarriages and 8% of subjects had 3 or more.The existence of septum and sub-septum was diagnosed and resection of changes was made at 97% of women.Diagnostic hysteroscopy was performed to verify uterus unicornis, associated with diagnostic laparoscopy, in 3% of women.HSG was performed prior to hysteroscopy at 28% of women and the findings indicated the presence of congenital uterine anomalies.The second group of respondents consists of 137 women, or 78% of all respondents.Their average age was 35 years.66% of women were with primary infertility and 34% with secondary infertility.4% of women in this group have previous deliveries.18% of women in this group had 1 previous miscarriage, 10% had 2 miscarriages and 4% had 3 or more.The septum and subseptum were diagnosed at 90% of women and resection of changes was made.Diagnostic hysteroscopy with laparoscopy was performed to verify the uterus unicornis, uterus bicornis or uterus arquatus, at 10% of women in this group.HSG was performed prior to hysteroscopy at 24% of women and the findings indicated the presence of congenital uterine anomalies.Comparative analysis of the t-test for numerical values and the hi-square test for attribute values gave the observed characteristics of the patients in both groups.Hi square test, statistical significance (p <0.05) was obtained between the observed groups in the representation of the type of infertility, as well as in the number of previous miscarriages in the subjects of both groups.In the group of respondents who had a pregnancy after hysteroscopy, 56% of subjects were with secondary infertility, and they had a higher percentage of previous miscarriages.In Chart 4, the type of infertility is presented in women of both groups, whose difference is statistically significant (p <0.05).The group of women who did not conceive in the 12 months period after hysteroscopy, 99 women had primary and 47 had secondary infertility.The group of women who conceived in the 12 months period after hysteroscopy, 17 respondents had primary and 22 had secondary infertility.

Discussion
The data of the frequency of occurrence of congenital uterine anomalies as a result of the incorrect development of the Miller channels are different, depending on the population in study.In the literature, researchers report the incidence of congenital anomalies of the uterus in the general population of about 1%, and even 19% in the infertile patient population (1).The true prevalence of uterine anomalies is difficult to estimate because many of them are asymptomatic.The occurrence of a complete and incomplete longitudinal septum of the uterus occurs in 7-76%, depending on the investigated group, which makes it the most common of uterine anomalies.Other anomalies occur in a lower percentage of 1-10% and represent anomalies in which hysteroscopy and laparoscopy were performed for the purpose of diagnosis and treatment.The obtained data are similar to those available in the literature.In one of the studies (2), 188 women were examined, with a rate of anatomical anomalies of 42%, of which uterus septus had 12%, uterus bicornis 1% and uterus arquatus in 0,5 %.In the second study, the prevalence of septum in the test population was 7-16 %, depending on the classification, after the ultrasound examination (3).In the third study in infertile patients, the incidence of the sub-septum was 60% and 40% of the septum (4).In the fourth study, 287 subjects had diagnosed anomalies: uterus septus in 55%, uterus arquatus in 14%, uterus bicornis in 10%, uterus unicornis in 6%, and only 2% of the uterus septum with double cervix (5).In our study, the mean lifetime of the examined patients is 35 years; and the group includes respondents aged 29 to 49.The available studies are similar: the average age of subjects in a single study was 36 years (6); while in the second 33 years +/-3 years.(7).The average duration of infertility in the patients tested is 3 years, while the range is 1-6 years.In available data in other studies, the duration of infertility is more than 2 years (6).Only 3% of our respondents have previous successful pregnancies, while 38% of the respondents have previous miscarriages; of which 19% with 1 miscarriage, 14% with 2 miscarriages and 5% with three or more miscarriages.Similar data is available in the literature, and the percentage of births in the examined group before the hysteroscopic operation is 5% (8).During the first trimester, the risk of spontaneous abortion in patients with uterine septum is 28-45%, according to literature data (2,9,10), and the cause of weaker vascularization of the implant site is considered to be the cause.Today, we use routine resection of septum during hysteroscopy.Retrospective cohort studies performed on women who underwent hysteroscopic resection of the septum of the uterus indicate a significant reduction in the abortion rate from 67% to 13% (7,9) and an increase in the livebirth rate to 37% (7,11).According to literature data, the percentage of pregnancy was 43% after hysteroscopy (12) in some authors, while in the second study the percentage of pregnancies after hysteroscopic resection was 69% and the percentage of live births was 49% (13).In a similar study, a patient with an idiopathic infertility was diagnosed with a septum; 12 months after the hysteroscopic resection, 44% of the subjects achieved pregnancy, of which 37% were live-born (11).Some authors questioned the justification of hysteroscopy after 2 miscarriages (10).The scientific community carried out a reassessment of the clinical significance of hysteroscopy in the diagnosis and treatment of uterine factors and the role in the treatment of infertility, thanks to its potential for improving reproductive results and reducing time to pregnancy (14).Studies can also be found to investigate the possibility of diagnosing and treating septum uterus only on the basis of hysteroscopy, which implies that only the use of hysteroscopy is insufficient (7.15), without prior detailed preparation, previous clinical examination, ultrasound measurement and review additional methods such as 3D UZ, HSG or MR (15).Among the available data, the assessment of the performance in diagnosis of anomalies by threedimensional ultrasound technique (3D UZ) ranges from 96-100% (16,17), which makes this technique recommended for routine use as accurate and precise (18,19,20).Additional diagnostic methods (HSG) for the diagnosis of congenital anomalies, according to the data from our study, were applied in 30% of subjects.In 24% of patients, HSG diagnosed anomalies were confirmed in hysteroscopy, while 6% of patients were false-negative results.In the literature, some authors concluded that HSG is not an optimal method for diagnosing uterine anomalies (because of the impossibility of visualizing the outer contour of the uterus), while the threedimensional ultrasound technique may be an alternative method for MR (21).In literature data, magnetic resonance in the diagnosis of congenital uterine anomalies is successful in 29-60% (16,20).Complications in hysteroscopy in our subjects were recorded in 2%, mainly with complete septum uterus.Repeated hysteroscopy were needed in 5% of subjects, in the resection of a complete septum.In the available data, the percentage of re-intervention is 2% (4,22).Research data are also available for 64 patients with hysteroscopy septum resection, which had complications in the perforation of the uterine wall in 3% (13).In other studies, the overall percentage of intraoperative and postoperative complications was 1.7%, and the percentage of reintervention was 6% (13).In 20% of the subjects in our study, the presence of associated pathological changes was observed, of which polyps were in 17% of subjects, myomas in 2%, septum of vagina in 1% of subjects.In given literature data, in 8% of infertile patients with recurrent abortion, in hysteroscopy were diagnosed with myoma (23).In our study, 39 examinees (22%) experienced pregnancy after hysteroscopy in the observed period of 12 months.In a study similar to ours, out of 88 respondents in the observed period of 12 months after hysteroscopy resection, 41% of respondents had pregnancy (6).In similar studies, the monitoring period was on average 12 up to 68 months, with the overall percentage of pregnancies being 60%, and the percentage of live births was 45% (13).In our data, pregnancy was made spontaneously in 64% of pregnancies and 36% from the medically assisted fertilization process.33 women (85%) had pregnancy with child born in a term, out of which 28 women had spontaneous delivery and 5 women had surgical deliveries.6 pregnancies ended with miscarriage (15%).In the literature data, 61% of the patients are pregnant after hysteroscopy resection, with 25 pregnancies -13 from the IVF process, i.e. more than half (24).Also, the data of other authors indicate that the percentages of successful pregnancies after hysteroscopy increase in IVF processes (25).Therefore, some authors advise the routine use of office hysteroscopy as the basic method preceding the IVF / ICSI attempt, even in subjects with correct results in trans-vaginal ultrasound examination (26).In the literature, 63% of the respondents experienced pregnancy after hysteroscopy septum resection, while 56% of the subjects reported pregnancy in arquatus (8).Data from other studies indicate an improvement in fertility following hysteroscopy resections in other anomalies, except in the uterus bicornis (27).Data in some studies indicate that there is no statistically significant difference in pregnancy outcomes after hysteroscopy resection in uterus septum and uterus arquatus (28).Also, the incidence of complete and incomplete uterine septum among patients is dominated by the available data (24).Using the Hi square test, statistical significance (p <0.05) was obtained between the observed groups in the representation of the type of infertility, as well as in the number of previous abortions in the subjects of both groups.In the group of respondents who had a pregnancy after hysteroscopy, 56% of subjects were with secondary infertility, and they had a higher percentage of previous miscarriages.Similar data on the association of previous miscarriages with successful pregnancy after hysteroscopy septa resection can be found in several clinical studies (29,30).Data on various techniques of resection and outcome of surgery for later pregnancies and delivery of children at birth are available (31, 33).In the same research, comparisons were made of groups of patients with hysteroscopy and groups of patients without hysteroscopy with uterine abnormalities, in which according to the data there was an increase in the percentage of pregnancies, in attempts by IVF / ICSI (32).Women with congenital uterine abnormalities have poorer reproductive outcomes (a greater percentage of miscarriages in the first trimester, higher preterm birth rates, less pregnancy), regardless of whether they are spontaneous or induced attempts in the process of medically assisted fertilization, compared to women with normal uterus (33).Some studies also deal with the problem of additional therapy after hysteroscopy (34).According to research authors available in the literature, the worst prognosis for pregnancy is given to uterus unicornis, while the uterine septums (complete or incomplete) have the highest miscarriage rate in the first trimester (33,35).

Conclussion
• The most common congenital uterine anomalies in our study were incomplete and complete uterine septum (sub-septum 76% and septum 16%).
• A small number of patients with congenital anomalies have previous successful pregnancies completed by childbirth in a term (only 3%).
• More than one-third of the respondents had data of previous miscarriage in the first trimester (38%).
• Hysteroscopy is a safe endoscopic method, which allows the resection of longitudinal septum and sub-septum.The complications were present in 2% of hysteroscopy, and re-interventions were made in 5% of subjects, in the case of a complete septum of the uterus.
• In our research, more than 20% of respondents had a pregnancy after hysteroscopy in the observed period of 12 months, while in most of them pregnancy was completed by childbirth in term (85%).• Pregnant women were mostly diagnosed with septum and sub-septum of the uterus and hysteroscopy resection of changes was made.
•The percentage of miscarriages in women in study decreased from 38% before hysteroscopy to 15% after hysteroscopy.• This study shows percentage of uterine anomalies (uterus septum/sub-septum) at infertility patients and better obstetrical outcome, after the hysteroscopy resection of the uterine septum.