Hysteroscopy in the Treatment of Myometrial Scar Defect (Diverticulum) Following Cesarean Section Delivery: A Systematic Review and Meta-Analysis

Various management approaches have been developed to treat symptoms and prevent complications of the cesarean diverticulum. This systematic review aims to report the outcomes and fertility-related effects of hysteroscopy on women with myometrial scar defects after the cesarean section. Following the formulation of the patient/population, intervention, comparison, and outcomes (PICO) criteria, a systematic search was conducted on seven databases. Finally, a total of 18 studies were included for this systematic review and meta-analysis. All of the included patients suffered from post-cesarean section scars and presented with abnormal bleeding, pain, or secondary infertility. The overall pooled symptomatic improvement rate was 78.83% (95% CI: 72.46-85.76%); however, there was significant heterogeneity among the analyzed studies (I2=87%; p-value: <0.001) and a significant risk of bias (p-value: <0.001). The overall resolution/improvement rate after adjusting for possible bias was higher, 92.82% (95% CI: 85.17-100%). The overall pregnancy rate was 69.77% (95% CI: 59.03-82.48%), while in the individual studies the rates varied, ranging from 25% to 80%. Nevertheless, there was moderate heterogeneity among the included studies (I2=56%; p-value=0.011). In contrast, there was no significant risk of bias among the included studies (p-value=0.100). Furthermore, the meta-regression analyses did not show any significant effect of different follow-up durations on the overall effect size for both outcomes. In conclusion, there is still a need for high-quality, comparative studies with larger sample sizes and long-term follow-up periods to draw firm conclusions. Moreover, future studies should consider the minimum myometrial thickness that is sufficient to complete a healthy pregnancy.


Introduction And Background
Delivery through cesarean sections has been on the rise recently [1]. Despite being less painful than a natural delivery, it is associated with many complications. A cesarean scar may be complicated by rupture or dehiscence, uterine rupture, and abnormally adherent placenta, and hence may affect pregnancy [2]. During the ultrasonography examination, a triangular section is often noticed within the myometrium in the lower uterine segment where the cesarean section was performed [3,4]. It has been reported in a large portion of pregnant women after routine evaluations with transvaginal sonography and transvaginal sonohysterography [5][6][7]. It has been observed in women after cesarian operations as an anechoic "filling defect" area, most probably occurring after multiple cesarean deliveries. This defect is also known as the niche and was first reported in pregnant women in 2001 [3,5,6], and its definition is still controversial [8]. The two parts that form it are as follows: a hypoechoic part representing the defect, and a scar fibrotic tissue pouch within the myometrium.
The most common symptom of the niche is postmenstrual spotting or prolonged menstruation, which is usually associated with discomfort and is an alarm signal for gynecology examination [3,5]. This was first reported in 1975, which was followed by many studies later on [4,6,[9][10]. It occurs most probably due to the retention of blood in the niche as it can hinder the accumulated blood after pregnancy [4,11,12]. Another explanation is the formation of fragile blood vessels that can easily bleed and cause pain [13]. The prevalence rate of postmenstrual spotting is 30% in pregnant women with cesarean diverticula [7]. Other symptoms such as dysmenorrhea, hypogastric pain, micturition disorders, secondary infertility, and other chronic conditions have also been reported [7].
Various management approaches have been developed to treat symptoms and prevent complications of the cesarean diverticulum. Surgical removal of the uterus (hysterectomy) has been effectively used as a radical treatment method; however, it leads to infertility, and hence other approaches have been developed to help women maintain their fertility [4,14,15]. These include drainage of the accumulated blood in the uterine wall and coagulation of the fragile vessels to prevent further blood production (hysteroscopic resection) [16][17][18][19][20], hormonal intervention to decrease menstrual periods, and blood or abdominal or vaginal repairing of the niche by laparoscopy, or laparotomy [21][22][23][24]. The risks associated with invasive procedures include dehiscence and uterine bleeding or rupture [21]. Moreover, they have not been investigated by an adequate number of studies and, therefore, should be performed only when other non-invasive approaches

Quality assessment
Based on the heterogeneity of the included study designs, a decision to use the National Institutes of Health (NIH) quality assessment tool for rating the quality of evidence was proposed [27] (see Appendix for details). The quality of each study was determined by the authors and a librarian from the Ministry of Health (see Appendix for details).

Statistical analysis
All data were analyzed using the R software, version 4.0.1 [28]. Using the "meta" package, the prevalence rates of different outcomes were calculated [29]. The corresponding 95% CIs of the pooled effect size were calculated using the random effects model due to the presence of heterogeneity. Heterogeneity was assessed with Q statistics and I 2 test, and an I 2 value of >50% or a p-value of <0.05 was considered statistically significant [30].
The publication bias was assessed using Egger's regression test [31] and represented graphically by Begg's funnel plot [32] when there were 10 or more studies. A p-value of <0.10 in Egger's regression test was considered significant. Whenever publication bias was found, the trim-and-fill method of Duvall and Tweedie was applied to add studies that appeared to be missing [33] to enhance the symmetry. A leave-oneout sensitivity analysis was also performed by iteratively removing one study at a time to confirm that the study findings were not driven by any single study.

Search results
A total of 800 records was found after searching within seven databases. The exclusion of 138 records was done after being determined as duplicates by the EndNote software (Clarivate, Philadelphia, PA). Furthermore, 609 records were excluded after the title and abstract screening. Further full-text screening resulted in the inclusion of 16 papers and another two papers were added after performing a manual search. In total, 18 studies were included for this systematic review and meta-analysis ( Figure 1).

Study characteristics and the quality of the included studies
A total of 18 studies were included with a total sample size of 1,165 individuals, and the individual sample sizes ranged from 18 to 273. The mean age of the included population ranged from 27.8 to 40 years ( Table 1). Regarding the risk of bias, four studies were graded as good quality, 12 were graded as fair quality, and two studies were of poor quality (Tables 2-5 in the Appendix section).

Symptomatic improvement
Symptomatic improvement was defined as the improvement or complete resolution of the symptoms, including AUB or pelvic pain, following hysteroscopic treatment. A total of 18 studies, with 698 patients, were included in the analysis of the last follow-up assessment of symptoms resolution/improvement following hysteroscopic treatment. The overall pooled improvement rate was 78.83% (95% CI: 72.46-85.76%); however, there was significant heterogeneity among the analyzed studies (I 2 =87%; p-value: <0.001) ( Figure 2). The contribution of each study to the overall heterogeneity is shown in Figure 3. The studies by Shi et al. [34] and Calzolari et al. [35] alone contributed >40% of the overall estimated heterogeneity. The leave-one-out sensitivity analysis showed the same high rates of improvement/resolution, indicating that the effects are not driven by one study (Figure 4).

FIGURE 4: A leave-one-out sensitivity analysis of the symptomatic improvement outcomes
There was a significant risk of bias (p-value: <0.001) when tested using Egger's regression test. The funnel plot with the trim-and-fill method added eight studies to adjust for funnel plot symmetry, as shown in Figure 5. The overall resolution/improvement rate after adjusting for possible bias was higher, 92.82% (95% CI: 85.17-100%). The meta-regression analysis did not show any significant effect of different follow-up durations on the overall effect size (estimate=0.002, standard error=0.004, p-value=0.588) ( Figure 6).

Pregnancy rate
The pregnancy rate was defined as the number of women who aimed to get pregnant and conceived successfully following the hysteroscopic treatment. The data of pregnancy rates following hysteroscopic treatment, at the last follow-up time point, were available for 11 studies, including 172 patients with secondary infertility. The overall pregnancy rate was 58.71% (95% CI: 59.03-82.48%), while in the individual studies the rates varied, ranging from 25% to 100%. Nevertheless, there was moderate heterogeneity among the included studies (I 2 =56%; p=0.012) (Figure 7).

FIGURE 7: Forest plot for pregnancy rates following hysteroscopic treatment of myometrial scar defect (diverticulum)
The contribution of each study to the overall heterogeneity is shown in Figure 8. In contrast, there was no significant risk of bias among the included studies (p-value=0.100). Moreover, the meta-regression analysis did not show any significant effect of different follow-up durations on the overall effect size (estimate=0.008, standard error=0.009, p-value=0.360) (Figure 9).  throughout pregnancy. Since they affect a sensitive part of women's bodies and their management is essential pertaining to the prognosis of their sexual lives, niches ought to be treated carefully. Management approaches include non-invasive therapies, which consist of hormonal treatments to decrease the time or blood flow of the menstrual cycles, and surgical therapies, which aim to mechanically stop the bleeding from the target area. One of the most minimally invasive and effective procedures is hysteroscopy. It is widely used to inspect the uterus and help in the diagnosis of abnormal vaginal bleeding. Moreover, it is associated with fewer morbidities and allows patients to continue with their pregnancies safely in a short time. As it is a minimally invasive procedure for managing AUB, it has been associated with shorter times of bleeding and high levels of patient satisfaction after the procedure.
All of the included patients suffered from post-cesarean section scars and presented with abnormal bleeding, pain, or secondary infertility. This is an updated meta-analysis on the effect of hysteroscopy in the management of AUB due to post-cesarean scars. This study analysis showed that among 698 patients with post-cesarean complications including bleeding, pain, and secondary infertility and who underwent hysteroscopy, the non-adjusted overall improvement was 78.83%. Although the improvement rate was high, the calculated heterogeneity between the included studies was recorded to be significant (p-value: <0.001). However, the heterogeneity in Shi et al. [34] and Calzolari et al. [35] alone contributed to 50% of the overall estimated heterogeneity. This is because of the short period of follow-up, the nature of data selection, and the small sample size of included patients in those studies. Moreover, although Vegas et al. [36] had a 97.37% improvement rate, the rate was not solely influenced by these high results, as the leave-one-out sensitivity analysis showed (Figure 4). A statistical significance was also found in the risk of bias (p-value=0.001).
Consequently, there was an adjustment of the asymmetry in the funnel plot representing all studies, and the overall improvement rate was found to be 92.82%. On the other hand, Feng et al. [37] reported a rate of 87% decrease in AUB after management with hysteroscopy, but a higher rate of 100% with laparoscopy, and 93% with the vaginal repair. Moreover, the same author reported the rate of pain relief to be 97% with hysteroscopy and 100% with laparoscopy while secondary infertility decreased in more patients after hysteroscopy [37].
The overall pregnancy rate was found to be 69.77% with a significant heterogeneity (p-value=0.012) among the 11 studies that reported it at the end of the overall follow-up period [35,36,[38][39][40][41][42]. Along with the highest improvement rates, Tanimura et al. [43] and Lei et al. [44] also reported the highest pregnancy rates (100%) in women who underwent hysteroscopy as a surgical intervention for niches, while Xie et al. [41] reported the lowest rates (25%). Other endoscopic procedures have also been reported. Many studies reported a significant improvement in the pregnancy rate after performing laparoscopy in patients presenting with secondary infertility [45][46][47]. Tanimura et al. [43] compared the pregnancy rates between women with niches who underwent hysteroscopy and others who underwent laparoscopy and found that the pregnancy rate was higher in the hysteroscopy group (100%) than the laparoscopy one (55.56%). Combined hysteroscopy-guided laparoscopic arthroplasty was also reported to reflect a high pregnancy rate (80%) [45].
The heterogeneity between the improvement and post-treatment pregnancy rates could be attributed to the difference in methodology and management criteria due to the lack of globally specific definitions. A commonly reported factor for an increased incidence of pregnancy is myometrial thickening. Sufficient thickness will prevent uterine rupture during normal contractions. However, the reported minimal thickness of the myometrium sufficient for safe vaginal births has varied. Lastly, Bujold et al. [49] reported a 2.8-mm minimal thickness in women with a history of post-cesarean diverticula, while Sen et al. reported a lower value of 2.5 [50]. Therefore, vaginal birth should not be performed in patients with myometrial thickness beneath these values, according to these authors [49,50].
To date, this is the largest and most recent systematic review and meta-analysis conducted on this topic. It provides high-quality evidence with a comprehensive assessment of risk-of-bias heterogeneity, heterogeneity, and possible confounding effects of different follow-up durations. Limitations to this study include the considerable heterogeneity in symptomatic improvement outcomes and the lack of defined criteria for hysteroscopic procedures, which indicates that interpretation of the results should be done with caution. However, as mentioned above, no clear criteria have been approved universally. Moreover, the small sample size and the nature of data collection of some of the included studies may have played a role in the risk of bias. Finally, long follow-up periods should be applied to study the long-term outcomes of pregnancy. In this study, however, no significant effect was found regarding the different reported follow-up periods on this study rates (p-value=0.374).

Conclusions
There is still a need for high-quality, comparative studies with larger sample sizes and long-term follow-up periods to arrive at firm conclusions regarding this topic. Moreover, future studies should consider the minimum myometrial thickness that is sufficient to complete a healthy pregnancy.   2. Was the method of randomization adequate (i.e., use of randomly generated assignment)?

Appendices
3. Was the treatment allocation concealed (so that assignments could not be predicted)?
4. Were study participants and providers blinded to the treatment-group assignment?
5. Were the people assessing the outcomes blinded to the participants' group assignments?
6. Were the groups similar at baseline on important characteristics that could affect outcomes (e.g., demographics, risk factors, comorbid conditions)?
7. Was the overall drop-out rate from the study at endpoint 20% or lower of the number allocated to treatment?
8. Was the differential drop-out rate (between treatment groups) at endpoint 15 percentage points or lower?
9. Was there high adherence to the intervention protocols for each treatment group?
10. Were other interventions avoided or similar in the groups (e.g., similar background treatments)?
11. Were outcomes assessed using valid and reliable measures and implemented consistently across all study participants?
12. Did the authors report that the sample size was sufficiently large to be able to detect a difference in the main outcome between groups with at least 80% power?
13. Were the outcomes reported or subgroups analyzed prespecified (i.e., identified before analyses were conducted)?
14. Were all randomized participants analyzed in the group to which they were originally assigned, i.e., did they use an intention-to-treat analysis?    1. Was the research question or objective in this paper clearly stated and appropriate?

Reference
2. Was the study population clearly specified and defined?
3. Did the authors include a sample-size justification?
4. Were controls selected or recruited from the same or similar population that gave rise to the cases (including the same timeframe)?
5. Were the definitions, inclusion and exclusion criteria, algorithms or processes used to identify or select cases and controls valid, reliable, and implemented consistently across all study participants?
6. Were the cases clearly defined and differentiated from controls?
7. If less than 100 percent of eligible cases and/or controls were selected for the study, were the cases and/or controls randomly selected from those eligible?
8. Was there use of concurrent controls? 9. Were the investigators able to confirm that the exposure/risk occurred prior to the development of the condition or event that defined a participant as a case?
10. Were the measures of exposure/risk clearly defined, valid, reliable, and implemented consistently (including the same time period) across all study participants?
11. Were the assessors of exposure/risk blinded to the case or control status of participants? 12.
Were key potential confounding variables measured and adjusted statistically in the analyses? If matching was used, did the investigators account for matching during study analysis?

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.