**9. How to manage local cervical inflammatory lesions in women with UI?**

If you see an inflammatory cervical polyp, it should be excised in the office utilizing a sterile ring forceps. It should be sent for histopathologic assessment. Any bleeding from its pedicle can be controlled by simple gauze compression or rarely cauterization. Other lesions like ectopy, ectropion or chronic non-specific cervicitis can be treated by an ablative therapy. In a prospective study [14], we tested the efficacy, tolerability and safety of 70% trichloroacetic acid (TCA) painting versus monopolar spray coagulation of the cervix for treating persistent benign cervical lesions that failed to respond to local medications. We included a total of 246 cases with objective evidence of benign cervical lesions that were divided into 2 groups according to the line of management. Group A comprised 126 cases subjected to spray monopolar coagulation while group B comprised 120 cases subjected to trichloroacetic acid application. Cervical smearing and colposcopy with or without cervical biopsy to exclude underling malignant lesions was done. TCA painting or spray monopolar coagulation of the benign cervical lesion(s). Follow-up was performed to assess relief of symptoms and cervical mor‐ phology for one month. Main outcome measures include success of management tool, relief of symptoms and normal cervical morphology after one month of therapy. We achieved a statistically significant cure rate of cervical lesions after treatment in both groups without significant difference between both groups. Failure rate was reported more in group B than group A mainly due to hypertrophied ectopy and cervical polyp. Patient in group A reported low satisfaction (26.9%) and poor tolerability rate (44.5%) as compared to patients in group B, who reported high satisfaction (77.5%), and good tolerability rate (77.5%), this difference was statistically significant. We concluded that both topical application of 70% TCA and monopolar spray coagulation offer considerable efficacy, acceptable success rates and minimal complica‐ tions. Spray coagulation is significantly superior in terms of less persistent or incompletely healed lesions. Nevertheless, topical application of 70% TCA has the advantages of simplicity, higher patient tolerability and safety that can be widely used by gynecologists who have limited experience with surgical procedures. It is highly recommended if the cervical lesion is ectopy or non-specific cervicitis but not hypertrophic lesion like hypertrophic ectopy or polyp.

#### **9.1. Hidden genital tract infections in UI**

Hidden uterine factors of infertility may include thin endometrium, poor endometrial receptivity, and immunological incompatibility which have received good interest in modern practice [15]. Literally, little attention has been directed towards asymptomatic hidden intrauterine infections like Mycoplasma, Ureaplasma, Klebsiella and Chlamydia trachomatis particularly among infertile women [16].

#### **9.2. Prevalence of hidden intrauterine infections (IUI) in UI**

general gynecologists and a well-trained nurse is an acceptable alternative for detection of cervical premalignant or malignant lesions especially in low resource settings. Optimally, a Pap smear should be taken routinely from every patient. Any suspicion of premalignant or

**9. How to manage local cervical inflammatory lesions in women with UI?**

If you see an inflammatory cervical polyp, it should be excised in the office utilizing a sterile ring forceps. It should be sent for histopathologic assessment. Any bleeding from its pedicle can be controlled by simple gauze compression or rarely cauterization. Other lesions like ectopy, ectropion or chronic non-specific cervicitis can be treated by an ablative therapy. In a prospective study [14], we tested the efficacy, tolerability and safety of 70% trichloroacetic acid (TCA) painting versus monopolar spray coagulation of the cervix for treating persistent benign cervical lesions that failed to respond to local medications. We included a total of 246 cases with objective evidence of benign cervical lesions that were divided into 2 groups according to the line of management. Group A comprised 126 cases subjected to spray monopolar coagulation while group B comprised 120 cases subjected to trichloroacetic acid application. Cervical smearing and colposcopy with or without cervical biopsy to exclude underling malignant lesions was done. TCA painting or spray monopolar coagulation of the benign cervical lesion(s). Follow-up was performed to assess relief of symptoms and cervical mor‐ phology for one month. Main outcome measures include success of management tool, relief of symptoms and normal cervical morphology after one month of therapy. We achieved a statistically significant cure rate of cervical lesions after treatment in both groups without significant difference between both groups. Failure rate was reported more in group B than group A mainly due to hypertrophied ectopy and cervical polyp. Patient in group A reported low satisfaction (26.9%) and poor tolerability rate (44.5%) as compared to patients in group B, who reported high satisfaction (77.5%), and good tolerability rate (77.5%), this difference was statistically significant. We concluded that both topical application of 70% TCA and monopolar spray coagulation offer considerable efficacy, acceptable success rates and minimal complica‐ tions. Spray coagulation is significantly superior in terms of less persistent or incompletely healed lesions. Nevertheless, topical application of 70% TCA has the advantages of simplicity, higher patient tolerability and safety that can be widely used by gynecologists who have limited experience with surgical procedures. It is highly recommended if the cervical lesion is ectopy or non-specific cervicitis but not hypertrophic lesion like hypertrophic ectopy or polyp.

Hidden uterine factors of infertility may include thin endometrium, poor endometrial receptivity, and immunological incompatibility which have received good interest in modern practice [15]. Literally, little attention has been directed towards asymptomatic hidden intrauterine infections like Mycoplasma, Ureaplasma, Klebsiella and Chlamydia trachomatis

malignant lesions deserves a colposcopically-guided biopsy.

26 Genital Infections and Infertility

**9.1. Hidden genital tract infections in UI**

particularly among infertile women [16].

In an unpublished study, we tried to find out if women with UI have high prevalence of hidden intrauterine infections (IUI). We included 100 women allocated into two groups. A study group included 50 women with UI and control group included 50 fertile women who came for contraceptive advice. Sample size calculation was carried out using Epi Info software version 7 (CDC, 2012). A calculated sample of 82 (41 cases and 41 controls) was needed to detect an effect size of 0.1 between the two groups unexplained infertility and control group, with a p value < 0.05 and 80% power. Inclusion criteria for UI were criteria according to The Practice Committee of the American Society for Reproductive Medicine (ASRM) [17] which includes normal semen analysis at least twice, patent fallopian tubes as seen by hystrosalpingography (HSG) and positive ovulation utilizing ultrasound or serum progesterone in the second half of the cycle.

Exclusion criteria included current or recent use of systemic or local antibiotics, vaginal douches or creams in the preceding month. Inclusion criteria of the control group included new clients attending the family planning outpatient clinic asking for a contraceptive method and not complaining of recent or recurrent abnormal vaginal discharge. In both groups, patients were subjected to a detailed history taking stressing on possible use of vaginal creams or vaginal douches in the preceding month followed by thorough and meticulous vaginal and general examinations. Patients with evidence of overt upper or lower genital tract infection on routine clinical examination were also excluded from this study. In both groups, in lithotomy position, an un-lubricated bivalve vaginal speculum was inserted intravaginally then an endouterine swab was taken utilizing a soft 3 mm pipette. After injection of few milliliters of 0.9% saline, the aspirate was immediately sent to bacteriology department for assessment. The endouterine swab was incubated on Amies transport medium (Himedia), pleuropneumonialike organism broth (PPLO) (Himedia – Cat. No. M266), and brain heart infusion (BHI) (Himedia – Cat. No. M210), to isolate Mycoplasma hominis. The plates were kept under microaerophilic conditions at 37 ˚C. Liquid media were examined daily for 10 days for the color change indicating growth. Other media like columbia Agar base (Himedia – Cat. No. M144) and MacConkey Agar (Himedia – Cat. No. MM081), were used to identify other organisms by conventional methods. Vaginalis Agar (Himedia – Cat. No. M1057) medium was used to detect Gardnerella vaginalis. Part of the fluid was fixed on slides, frozen in acetone, and subjected to a direct immunofluorescence assay (IFA) with fluorescence isothiocyanate conjugated anti-chlamydia trachomatis monoclonal antibodies (Imagen TM Chlamydia, Dako Cytomation, UK). Detection of group B streptococci (GBS) was done by specific antiserum on the isolated colonies (HiStrep – Latex test kit – Himedia LK06-50NO). The isolated organisms were confirmed biochemically using API system (20A Biomerrieux RES 20300). All women with unexplained infertility (group A) were subjected to diagnostic laparoscopy using standard double puncture technique. Laparoscopic findings were correlated with bacteriologic findings.

There was a statistically insignificant difference between both groups regarding the age and residence (p value >0.05) and it was highly significant regarding parity (p value <0.001). Hidden IUI were diagnosed by culture and biochemical confirmation in 42 cases (84%) and 10 cases (20%) in both groups respectively with a high statistically significant difference (P=0.001). The most common organisms detected in the study group were Mycoplasma (24%), klebsiella (20%), Chlamydia (18%) and Proteus (10%). In group A, positive laparoscopic findings were reported in 33 patients (66 %). There was a significant correlation between the positive cases of hidden IUI and the pathological lesions diagnosed by laparoscopy (P Value= 0.0001). The most common laparoscopic abnormalities were hyperemic uterus, peritubal adhesions and chronic salpingitis which were reported in 10 (20%), 6 (12%) and 4 (8%) cases respectively, which demonstrate a highly significant correlation between confirmed hidden IUI and abnormal laparoscopic findings in UI. Laparoscopy revealed upper genital tract pathology in 30 cases (71.4%) of positive cases of hidden infections (42 cases) and it was negative in 3 cases (37.5%) of negative cases of hidden intrauterine infections (P Value= 0.0001). Cases with abnormal laparoscopic findings (33 cases) could be explained by positive culture of hidden intrauterine infection in UI group except 7 cases of endometriosis and 3 cases were culturefree. Abnormal laparoscopic findings were found more in positive cases with Mycoplasma (10 cases), Chlamydia (8 cases), Klebsiella (3 cases) and Proteus (2 cases) respectively.

#### **9.3. Discussion on prevalence of hidden IUI**

Hidden IUI may be a possible cause of UI [18]. This can be achieved by alterations in the intraperitoneal environment that may lead to an inflammatory process in the absence of visible abnormalities [19]. In our work, high prevalence of hidden IUI (84%) proved by culture of endouterine discharge in women with UI raise the recommendation that before starting a lengthy and costly list of sophisticated level II investigations of both partners, attention to hidden IUI is a mandatory basic step in UI. It has been found that women with tubal factor were two to three times more likely to have genital tract infections than women with other types of infertility [20]. We think that culture would be accepted as a basic screening tool for hidden IUI due to availability and feasibility in many hospitals. Screening test should not be expensive, time consuming or complicated before being extended to all hospitals particularly in low resource countries with limited resources.

Our work demonstrated a high prevalence of Mycoplasma (24%), klebsiella (20%), Chlamydia (18%) and Proteus (10%) among women with UI. These results of high prevalence compared to fertile women would call for more attention to screening protocols in all infertility units dealing with UI ideally prior to laparoscopic intervention. Due to high prevalence of Chla‐ mydia in infertile women in a previous study, screening for Chlamydia was recommended for cases with all cases with UI [18]. We reported Mycoplasma in about one quarter of positive cases. Likewise, mycoplasma was reported in 32% of infertile cases with a statistically significant difference from fertile group [12]. In this study, proteus infection was reported in 10% of infected cases. This particular organism is commonly noticed in the urinary system infections. Reporting it in the genital tract would requires more studies to define its role in infertility. Unlike others, we reported low prevalence of Ureaplasma in only 4% of cases despite its previous reports of up to 32% infertile cases [18]. This big difference may clarify the variability of frequency of hidden intrauterine infections in different populations and high‐ lights importance of studies on prevalence in each community.

Laparoscopic evaluation of infertility is the cornerstone test for tubal and peritoneal factors of infertility [21]. In this study we documented 33 cases (66%) with abnormal laparoscopic findings among the infertile group. Abnormal laparoscopic findings were reported in about 53 % of infertile women in a previous stud [22]. The most frequent abnormal laparoscopic finding in their study was pelvic adhesions. More frequent abnormal laparoscopic findings in UI up to 87.2% were reported by others [23] who described endometriosis lesions, peritubal adhesions and tubal obstruction. In a previous study, 114 women with UI were examined laparoscopically. Laparoscopy revealed pelvic pathology in 95 patients. Endometriosis, pelvic adhesions and tubal disease were observed and treated in 72, 46 and 24 patients, respectively. They could treat 72 patients of them, and 35 of them conceived using their own tubes. However they concluded that diagnostic laparoscopy should be strongly considered in UI work-up, and tubal efficacy should not be underestimated [24]. In our work, there was a significant correla‐ tion between the positive cases of BV and the pathological lesions diagnosed by laparoscopy especially hyperemic uterus, chronic salpingitis and peritubal adhesions (P Value= 0.0001). Subsequently, we recommend meticulous screening of women with these abnormal laparo‐ scopic findings for possibility of hidden intrauterine infections.

Performing laparoscopy for UI is not universally agreed and questionable since it is an invasive procedure with serious morbidities and mortalities. However, in an detailed book chapter, many benefits of performing endoscopic evaluation of cases of UI were well demonstrated [3].

Limitations of this study included small sample size of individual types of hidden intrauterine infections and lake of precise description of a particular abnormal laparoscopic finding for each organism are clear limitations of this study. Due to ethical considerations, both groups were not homogeneous in that the case group had undergone investigations such as ultrasound and HSG, while the controls had not. We could reasonably argue that instrumentation for HSG might cause retrograde infections that were later on detected at laparoscopy. Some of the "positive" laparoscopic findings are questionable and probably too subjective. This study would be a more meaningful study if included the impact of proper treatment on fertility of women with UI.

We concluded that despite being an underestimated cause of female infertility, hidden IUI are frequent and implicated in UI. Laparoscopy is very beneficial in explaining the effect of hidden intrauterine infections on the upper genital tract but it is not a screening tool for IUI. We recommend postoperative screening for hidden IUI in UI cases with abnormal laparoscopic findings. Further studies are required to test the impact of proper treating these infections on subsequent fertility in cases of UI.
