Laparoscopic and Hysteroscopic Findings in A Selected Group of Women with Unexplained Infertility: A Cross-Sectional Study

Infertility is one of the major issues in the personal and social lives of approximately 10-15% of couples, affecting them during their reproductive age. Infertility is defined as not becoming pregnant after one year of unprotected intercourse at reasonable intervals. Among the different categories of infertility, unexplained infertility (UI), is a type of infertility with a prevalence of 15-50%. A diagnosis of UI is confirmed when ovulation, tubal patency, and spermogram fail to show an underlying factor as a cause of normal conception ( 1 ). Management of UI is a debated issue. Various treatments have been suggested to cure this problem. For instance, Custers et al. ( 2 ) have recommended a six-month expectant management in women with UI. Some studies suggest performing diagnostic laparoscopy in patients with UI to determine the optimal management plan ( 3 - 7 ). Alternatively, other studies recommend laparoscopy only in women with UI and a history of chronic pelvic pain, previous surgery that causes significant pelvic adhesions, previous pelvic infection, or a history of ectopic pregnancy (EP) ( 3 , 4 ). Some investigators and clinicians explain that laparoscopy could be postponed until three courses of ovarian stimulation and intrauterine insemination (IUI) had been done and found to be ineffective in achieving a successful pregnancy ( 5 ). In contrast, others suggest that ovarian stimulation and IUI, as well as switching to in vitro fertilization (IVF) should rather be considered in the case of infertility. In their perspective, laparoscopy is not essential in determining the etiology of UI because an increased live birth rate is faster reachable by IVF than laparoscopy ( 6 ). Thus, a universal management protocol for UI has not yet been established. Pelvic pathologies such as minimal and mild endometriosis, pelvic and periadnexal adhesions, and false negative reports of hysterosalpingography (HSG) compatible with tubal patency may be missed, while each of these pathologies may be the cause of UI ( 7 ). They have different prevalences in various countries, ranging from 3% ( 8 ) to 80% ( 9 ). Fertility treatments may be enhanced by performing laparoscopy, diagnosis, and in some cases surgical correction of these pathologies ( 10 ). Currently, the epidemiology of such abnormalities in Iranian women with UI is yet to be evaluated; hence, we decided to assess the findings of laparoscopy and hysteroscopy in selected patients with UI to determine the incidence of various related pathological conditions, in order to apply the best management method for them.

In this study, 96 women with UI were included. Fiftynine (61.4%) women had primary infertility, while 37 (38.6%) suffered from secondary infertility. The mean age, body mass index (BMI), infertility duration, and other demographic characteristics are presented in Table 1 . As can be seen, there were no statistically significant differences between the two groups of primary and secondary infertility in terms of age (P=0.771), BMI (P=0.051), infertility duration (P=0.841), past medical history (P=0.202), and irregular menstrual cycles (P=0.392). However, the secondary infertility group had a significantly higher number of previous laparoscopy or laparotomy (P=0.007). Infertility duration for the participants ranged from 2 to 10 years. Although there were no differences between the two groups in duration of infertility, patients in the secondary infertility group were older than the primary group. Hypertension (HTN) and diabetes mellitus (DM) were the common issues in the patients (12.5 and 7.3%, respectively). Recurrent abortions and previous dilatation and curettage (D&C) were seen in 6.3 and 5.2% of the patients, respectively. Among the participants, 15.6% had previous cesarean section procedures, 16.7% had previous laparotomy for gynecological causes, and 15.7% had irregular cycles. In patients with primary infertility, 25 out of the 59 patients (42.3%), and in patients with secondary infertility 16 out of the 37 patients (43.2%) had laparoscopic abnormalities. Finally, in the primary and secondary groups, 20 of the 59 participants (33.8%) and 8 of the 37 participants (21.6%), respectively, had hysteroscopic abnormalities. Endometriosis (21.8%) followed by tubal pathology (13.5%) were the most common laparoscopy findings in both groups. Also, uterine septum (7.2%) followed by endometritis (6.2%) were the most common intrauterine pathologies observed in the participants (Tables 2 , 3 ). Baseline characteristics of participants with unexplained infertility Data are presented as mean ± SD or n (%). BMI; Body mass index, DM; Diabetes mellitus, HTN; Hypertension, D&C; Dilatation and curettage, *; Independent sample t test, **; Fisher’s exact test, and ***; Chi-Square. Findings at laparoscopy Data are presented as n (%). IM; Intramural, SS; Subserosal, **; Fisher’s exact test, and ***; Chi-Square. Findings at hysteroscopy Data are presented as n (%). **; Fisher’s exact test and ***; Chi-Square.

In the present study, we observed that abnormal laparoscopic findings were more common than hysteroscopic ones in UI patients. The abnormal laparoscopic results were about 26% in the primary infertility group and 17% in the secondary infertility group. Endometriosis (21.8%) and tubal pathology (13.5%) were the most prevalent laparoscopy findings in both primary and secondary infertility groups. Abnormal hysteroscopic findings were 20 and 8.3% in primary and secondary groups, respectively. Uterine septum (7.2%) and endometritis (6.2%) were the most prevalent intrauterine pathologies in both groups. Many studies have investigated similar issues in order to find optimal treatments for UI patients. For instance, Firmal et al. ( 11 ) showed pelvic abnormalities in 36.7% of women with UI. Their participants failed to conceive after three or more cycles of ovulation induction and IUI. They concluded that laparoscopy may be considered in the work-up of a woman with UI. Tsuji et al. ( 9 ) indicated that 80.7% of patients had abnormal pathology based on laparoscopy results. They explained that women with UI and normal HSG should undergo diagnostic laparoscopy before ART. Our study showed abnormal laparoscopic findings in about 43% of the UI cases. All of the participants in the present study failed to become pregnant after 2-3 cycles of ovulation induction and IUI. Therefore, they underwent laparoscopy as they had one or more of the following conditions: a history of pelvic infection, a history of pelvic surgery, or a history of EP. The overall rate of endometriosis is 6-10% in the general population ( 12 ). In the current study, endometriosis was observed in about 22% of the participants with UI. This high incidence reflects the high rate of endometriosis in women with UI. All women in this study had mild to moderate endometriosis (not severe) that could easily be missed in TVS ( 13 ), so laparoscopy helps to detect and concomitantly treat this pathology and may even promote conceiving spontaneously. Other studies reported endometriosis in laparoscopy in 2.7% ( 8 ) to 63% ( 9 ) of women with UI. These differences in the prevalence of endometriosis studies are due to multifactorial of the disease nature ( 12 ). Providing a database on the prevalence of endometriosis in each country may be helpful in providing treatment plans for patients with UI. HSG is a screening test for evaluating tubes; however, it is recommended only in low-risk patients with tubal diseases. Nonetheless, laparoscopy could be a better option for confirming tubal patency in high-risk women. In addition, laparoscopy may correct some pathologies and increase the rates of both spontaneous and ART-mediated pregnancies ( 7 ). Therefore, HSG does not determine all tubal pathologies, as confirmed by previous studies. Firmal et al. ( 11 ) observed a 3.3% bilateral tubal block in laparoscopy in UI. Tsuji et al. ( 9 ) reported peritubal adhesion in 8.8% and tubal occlusion in 5.3% of women with UI based on laparoscopy. Mahran et al. ( 4 ) have found a 30% tubal factor in laparoscopy in women with infertility. The current study showed tubal pathologies such as fimbrial agglutination and adhesion in 13.5% of the UI cases. Therefore, laparoscopy detected and also treated these pathologies missed by HSG. The hysteroscope is considered the stethoscope for the uterus. Intrauterine pathology can be identified with hysteroscopy and is likely to have an adverse effect on reproductive outcomes. These pathologies include endometrial polyps, endometritis, intrauterine synechia, and mullerian anomalies ( 14 ). Makled et al. ( 15 ) showed that 86% of the abnormal findings were in hysteroscopy in women with UI. Endometrial polyp (31%), endometrial hyperplasia (15%), endometritis (14%), and uterine septum (3%) were the most frequent pathologies. They concluded that hysteroscopy and endometrial biopsy are both recommended for all women with UI. On the other hand, the Cochrane Database in 2018 revealed no evidence in favor of hysteroscopy as a tool in the basic fertility workup for screening women with UI in order to improve their reproductive success rates ( 16 ). Our data on abnormal hysteroscopy were 28.3% in women with UI, namely uterine septum (7.2%) and endometritis (6.2%). Although they were the most prevalent pathologies in our study, they had a low prevalence rate. So, it seems that further investigation is required to recommend universal hysteroscopy to all women with UI unless there are issues in the patient history or on TVS and HSG images. Mollo et al. ( 17 ) claim that hysteroscopic metroplasty improves the fertility of women with septate uterus and UI. Bakas et al. ( 18 ) included 68 women with various degrees of septate uterus and UI in their study and showed that clinical pregnancy and live birth rates were 44 and 36.8%, respectively, during a 12-month follow-up. They suggest that hysteroscopic septum resection in women with septate uterus and UI can postoperatively improve clinical pregnancy and live birth rate in women with UI. Abnormal development of the septal endometrium can corroborate incomplete differentiation and maturation of the endometrium covering the septum. Interestingly, partial uterine septum might be ignored in HSG reports by radiologists, and it might be mis-reported and considered as an arcuate uterus. Therefore, it is recommended that gynecologists review the HSG photos In fact, seven cases with uterine septum in our study were not reported by radiologists. Other studies have reported a relationship between chronic endometritis (CE) and recurrent implantation failure (RIF), suggesting a robust correlation between CE and defects in implantation and embryo development ( 19 ). Recent studies have investigated the relationship between CE and UI. Cicinelli et al. ( 19 ) showed a CE prevalence of 56.8% in the hysteroscopy of women with UI, which was also confirmed by histology. The abovementioned diagnosis and treatment of CE improve spontaneous pregnancy and live birth rate in such patients. In the study of Ghahiri et al. ( 20 ), the prevalence of endometritis in the UI group was 34%, while it was 21% in the anovulatory group, emphasizing the importance of endometritis evaluation in women with UI. They obtained the endometrial tissue using a pipelle. Endometritis was detected in 6.2% of the women with UI in the present study, which was lower than other studies. Still, it was the second abnormal result after uterine septum and was treated by prescribing antibiotics. Nowadays, different studies suggest different therapies for women with UI, including early laparoscopy procedures when UI is first diagnosed or performing late laparoscopy only in cases with three failed experiences of IUI, a history of pelvic pain, a history of pelvic surgery, and a history of pelvic infection. Additionally, some studies even recommend disregarding laparoscopy and switching to ART after three failures in IUI and ovarian stimulation ( 21 ). It seems that several factors influence decision-making on this issue. Female demographics such as age, infertility duration, history of pelvic pain, surgery, infection, surgeon expertise for performing laparoscopy, the clinical protocols in the country where the patient lives, cultural factors, the regional prevalence of endometriosis and the history of tubal and peritubal diseases are factors to be considered when selecting the best management plan for women with UI ( 22 - 24 ). Superficial endometriosis is only detected by laparoscopy, and ablation or excision of these problematic sections may help women with UI to become pregnant spontaneously. Still, even these effects are small and insignificant ( 25 ). In the current study, the prevalence of superficial endometriosis was three times more than the general population, so eliminating laparoscopy from the scope of UI seems futile. Further investigation will need to be conducted on performing hysteroscopy for women with UI. According to our study, uterine septum and endometritis were the most prevalent pathologies; however, the prevalence rates of these pathologies were not high enough to recommend universal hysteroscopy along with laparoscopy. Therefore, decisions should be made on a case-by-case basis. Nevertheless, laparoscopy has some complications such as vessel, bladder, and bowel injuries ( 26 ). Also, hysteroscopy has side effects like uterine perforation, bowel injury, and fluid deficit ( 27 ). So, it is necessary to schedule the patients with definitive indications for these procedures. The strength of the current study is evaluating the incidence of laparoscopic and hysteroscopic findings in women with UI, revealing that endometriosis was the most prevalent pathology. The limitation of the current study is that we had no follow-up and outcomes of laparoscopy and hysteroscopy of the patients with UI.

Based on the findings of the present study, laparoscopic surgery is recommended in UI cases after three failed IUI and ovarian stimulation, a history of pelvic pain, pelvic surgery, and pelvic infection. however, it seems that further investigation is required to recommend universal hysteroscopy to all women with UI.

The current cross-sectional study was conducted on 96 women who had attended the infertility clinic at the educational hospitals of Isfahan University of Medical Sciences from March 2018 to February 2020, after approval of the committee of research ethics (IR.MUI. MED.REC.1398.486). A written consent was taken from every participant. Inclusion criteria were: woman aged 20-40 years, infertility duration >6-12 months depending on female age, spontaneous ovulatory cycles [confirmation by methods such as serial transvaginal ultrasonography (TVS), serum luteinizing hormone (LH) surge or mid-luteal progesterone], normal hormonal assay on day three of the cycle [follicle-stimulating hormone (FSH), estradiol], and normal TVS. All participants had unilateral or bilateral tubal patency on HSG. Spermograms were normal according to the World Health Organization (WHO) criteria. Participants included in the study had one or more of the following items: failed to become pregnant after 2-3 cycles of ovulation induction with clomiphene citrate and IUI, history of pelvic infection, history of pelvic surgery (high probability of pelvic adhesion), or history of EP. Laparoscopic surgery was performed under general anesthesia. A 10-mm port in an umbilical area and 2 or 3 additional 5-mm accessory ports were used. Exact pelvic and abdominal exploration was carried out, and tubal patency was checked with chromopertubation. Laparoscopic findings were recorded. Endometriotic implants were ablated or excised, and blunt and sharp adhesiolysis were performed. Tubal surgery, including adhesiolysis and fimbrioplasty, was done if necessary. Adequate irrigation was carried out at the end of the surgery. Hysteroscopy was performed in a low lithotomy position in the early follicular phase in all the patients, and hysteroscopic findings were again recorded. If any pathology was revealed in hysteroscopy, it was corrected. An endometrial biopsy was performed by fine curette to rule out endometritis upon finding no pathology. After data collection, each of the quantitative and qualitative data related to patients was entered separately in an Excel worksheet in the table of variables, and the necessary categories were created. The data were then analyzed by SPSS 23 (IBM Corp., Armonk, New York, USA) using the absolute number, relative frequency, mean, standard deviation, t test, Fisher’s Exact test and Chi-Squared test. A significance level of 95% was considered.