Cesarean Scar Defect (Isthmocele) and Secondary Infertility: A Systematic Review of Reproductive Significance

Cesarean delivery is one of the most frequently performed surgical procedures worldwide, and its increasing use has heightened interest in potential long-term maternal consequences [ 1 , 2 ]. One such consequence is cesarean scar defect (CSD), also termed isthmocele or uterine niche, which is generally defined as an indentation or pouch-like defect in the myometrium at the site of a previous cesarean scar [ 3 ]. Secondary infertility refers to difficulty achieving a subsequent pregnancy after at least one previous pregnancy. CSD has received increasing attention because of its association with abnormal uterine bleeding, pelvic symptoms, and possible adverse reproductive outcomes. The reported prevalence of uterine niche varies considerably across studies, partly because of differences in diagnostic definitions, imaging modalities, timing of assessment, and study populations. Transvaginal ultrasonography and saline infusion sonography or sonohysterography are commonly used for diagnosis, with assessment typically including niche depth and width, residual myometrial thickness (RMT), and the presence of intrauterine or intracavitary fluid [ 3 , 4 ]. Although many niches may be incidental or asymptomatic, others are associated with postmenstrual spotting, abnormal uterine bleeding, pelvic pain, dysmenorrhea, dyspareunia, technical difficulty during embryo transfer, secondary infertility, and adverse reproductive outcomes [ 5 , 6 ]. Clinically, niche size, RMT, fluid accumulation, and associated symptoms may help distinguish an incidental anatomical finding from a defect that is potentially relevant to fertility. The relationship between CSD and impaired fertility is multifactorial. Proposed pathways include retention of blood or mucus within the defect, persistent intrauterine fluid, local inflammation or chronic endometritis, altered endometrial receptivity, abnormal uterine contractility, and anatomical or technical difficulties during assisted reproduction [ 5 - 7 ]. These anatomical and functional abnormalities also provide a rationale for surgical correction in selected women with significant symptoms, infertility, or unfavorable scar characteristics. Surgical approaches include hysteroscopic, laparoscopic, robotic-assisted laparoscopic, vaginal, abdominal, and combined techniques. However, patient-selection criteria, RMT thresholds, choice of surgical approach, and the magnitude of reproductive benefit remain insufficiently standardized [ 7 , 8 ]. Previous systematic reviews have examined CSD mainly in relation to diagnosis, fertility, and surgical management [ 4 , 6 , 8 , 9 ], including a recent systematic review and meta-analysis evaluating isthmocele, surgical repair, and fertility outcomes [ 8 ]. However, clinically relevant evidence remains fragmented across scar anatomy, intrauterine fluid and inflammation, assisted reproduction, uterine function, and reproductive outcomes after repair. Bringing these findings together may help identify scar characteristics that are more likely to be relevant to infertility and may support closer evaluation or individualized management in selected patients. The present review therefore focuses on the broader reproductive significance of CSD rather than considering the anatomical defect, fertility outcomes, or surgical treatment in isolation. The primary objective of this systematic review was to evaluate the evidence regarding the association between CSD/isthmocele and secondary infertility or adverse reproductive outcomes among women with previous cesarean delivery. Secondary objectives were to characterize fertility-relevant diagnostic and anatomical features, evaluate outcomes in assisted-reproduction settings and after surgical repair, and examine proposed mechanisms linking CSD with impaired implantation and fertility.

Methods Reporting Framework and Protocol Status This systematic review was conducted and reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 statement [ 10 ]. The review question, eligibility criteria, search strategy, study-selection process, data-extraction approach, risk-of-bias assessment methods, and synthesis plan were defined before final study selection and data extraction. This review was not prospectively registered in PROSPERO (International Prospective Register of Systematic Reviews), OSF (Open Science Framework), or another registry. No deviations occurred between the initial review design and the final study selection, data extraction, risk-of-bias assessment, outcome interpretation, or narrative synthesis. The final literature search was conducted on July 10, 2026. Review Question and Eligibility Framework The review question was: among women of reproductive age with a history of cesarean delivery, what evidence is available regarding the association between CSD, isthmocele, uterine niche, or cesarean scar diverticulum and secondary infertility or reproductive outcomes, and what diagnostic, anatomical, assisted reproductive technology, surgical, and pathophysiological findings may explain this association? The PICOS (Population, Intervention, Comparison, Outcomes, Study design) framework used to define eligibility is summarized in Table  1 . ART: assisted reproductive technology; CSD: cesarean scar defect; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; PICOS: population, intervention or exposure, comparator, outcomes, and study design. Eligibility Criteria Studies were eligible if they included women with a previous cesarean delivery and evaluated CSD, isthmocele, uterine niche, cesarean scar diverticulum, or cesarean scar syndrome in relation to fertility or reproductive outcomes. In this review, these terms were treated as equivalent when they referred to a defect or niche at the site of a previous cesarean incision. Eligible studies could also report assisted reproductive technology (ART) outcomes, diagnostic or anatomical findings, outcomes after surgical repair, or plausible fertility-related mechanisms. Studies involving broader populations were included only when relevant CSD or fertility subgroup data were reported separately. Studies were excluded if they involved an ineligible population, did not assess CSD or an equivalent scar-niche condition, lacked a relevant fertility, reproductive, ART, diagnostic, anatomical, surgical, or mechanistic outcome, or provided insufficient extractable information. Reviews and other non-original reports, protocols without completed results, conference abstracts without full-text reports, animal or laboratory-only studies, and single-case reports without extractable group-level data were excluded. Reports that focused exclusively on cesarean scar pregnancy were excluded unless they provided eligible information on isthmocele, infertility, or broader reproductive outcomes. For duplicate or overlapping reports, the most complete peer-reviewed report with the most relevant extractable data was retained. Reports that could not be assessed reliably in English were excluded. Reports for which the full text could not be retrieved were recorded separately as reports not retrieved and were not included in the full-text eligibility assessment. Studies were not excluded on the basis of methodological quality or risk-of-bias assessment. Risk-of-bias assessment was conducted after study inclusion and was used to inform interpretation of the evidence rather than to determine eligibility. Information Sources and Search Strategy A systematic literature search was conducted in PubMed/MEDLINE and Scopus from database inception to July 10, 2026, without a publication-date restriction. Embase and the Cochrane Central Register of Controlled Trials were not searched. The strategy was adapted to the indexing structure and field syntax of each database. Search concepts covered CSD-related terminology, fertility and pregnancy outcomes, ART and embryo transfer, intrauterine fluid and inflammatory features, uterine function, and surgical repair. Records retrieved from PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus were exported into a standardized spreadsheet and consolidated. Duplicate checking was based on title, authors, publication year, digital object identifier (DOI), journal, and publisher information. The combined database searches identified 506 records. After removal of 71 duplicate records, 435 unique database records remained. Supplementary literature discovery used Google Scholar, PubMed Central, publisher webpages, DOI records, backward and forward citation tracking, and manual screening of relevant reference lists. These sources were used to identify potentially eligible reports rather than as formal bibliographic databases. Supplementary records were verified against bibliographic or full-text sources before eligibility assessment. Supplementary searching identified 11 additional records, resulting in a total of 446 records available for title and abstract screening across database and supplementary sources. Only completed English-language full-text reports containing sufficient extractable information were eligible. Database-specific search strategies are summarized in Table  2 . DOI: digital object identifier; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; TITLE-ABS-KEY: title, abstract, and keywords. Study Selection All identified records were consolidated in a standardized spreadsheet, and duplicates were removed before screening. Potentially overlapping reports were checked at full text, with the most complete peer-reviewed report retained when necessary. Study selection was conducted in two stages. Two reviewers independently screened titles and abstracts against the eligibility criteria. Records considered potentially eligible by either reviewer proceeded to full-text assessment. The same reviewers then independently assessed the available full-text reports. Disagreements were resolved through discussion and consensus. A third reviewer adjudicated disagreements that remained unresolved. Reports that could not be obtained were recorded as not retrieved. A specific reason for exclusion was documented for every report assessed at the full-text stage, using categories corresponding to the prespecified eligibility criteria. A formal inter-reviewer agreement statistic was not calculated. Data Extraction Two reviewers independently extracted data from each included study using a standardized Excel extraction sheet (Microsoft Corporation, Redmond, Washington, United States). The extraction form was piloted on a small sample of included studies and refined before final extraction. Extracted variables were grouped into study characteristics (author, year, country, design, setting, sample size or analytical denominator, and population); diagnostic and anatomical features (diagnostic method, niche definition, RMT, niche dimensions, and intrauterine or intracavitary fluid); exposure or intervention, comparator, and follow-up; and fertility, pregnancy, ART, surgical, mechanistic, and adverse outcomes when reported. The completed extraction records were compared for completeness and consistency. Disagreements were resolved through discussion and consensus, with third-reviewer adjudication available when required. Study authors were not contacted to obtain additional or missing information. Outcomes The primary outcomes were secondary infertility; pregnancy-related outcomes, including spontaneous conception, pregnancy, clinical pregnancy, live birth, and miscarriage; and implantation or ART/in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) outcomes associated with CSD or isthmocele. Secondary outcomes included diagnostic and anatomical characteristics, such as RMT, niche depth, width or volume, intrauterine or intracavitary fluid, and hysteroscopic, sonographic, or hysterosalpingographic findings. Additional secondary outcomes included symptom and anatomical improvement after surgical repair and mechanistic findings involving chronic inflammation, chronic endometritis, altered uterine contractility, microbiome or mycobiome changes, pelvic adhesions, tubal factors, endometriosis, and other plausible implantation-related pathways. Differences in outcome definitions, measurement methods, assessment timing, analytical denominators, and follow-up duration were considered during synthesis. Risk-of-Bias Assessment Two reviewers independently assessed risk of bias using appraisal tools selected according to study design. Observational cohort and case-control studies primarily examining exposure-outcome associations were evaluated using the Newcastle-Ottawa Scale (NOS) [ 11 ]. Analytical cross-sectional studies were assessed using the JBI Critical Appraisal Checklist for Analytical Cross-Sectional Studies, while case series were assessed using the JBI Critical Appraisal Checklist for Case Series [ 12 ]. Non-randomized comparative studies of surgical or other interventional approaches were assessed using ROBINS-I (Risk Of Bias In Non-randomized Studies - of Interventions) [ 13 ]. For studies that could reasonably be classified as either observational cohorts or non-randomized intervention studies, the tool was selected according to the primary objective: ROBINS-I for intervention comparisons and NOS for exposure-outcome associations. Particular attention was given to confounding by indication in surgical comparisons because the selected repair approach could be influenced by RMT, niche morphology, symptoms, fertility goals, and clinician preference. No randomized controlled trials were included; therefore, the Cochrane RoB 2 tool was not applied. Each study was assessed according to the domains and appraisal criteria specified by the relevant tool, including selection and comparability for NOS-assessed studies; eligibility, exposure assessment, confounding, and outcome assessment for JBI analytical cross-sectional studies; case definition, case inclusion, clinical reporting, follow-up, and outcome reporting for JBI case series; and confounding, participant selection, intervention classification, deviations from intended interventions, missing data, outcome measurement, and selective reporting for ROBINS-I-assessed studies. For presentation across appraisal tools, review-level summary judgments were expressed as low, moderate, or high concern, with "not applicable" used where relevant. JBI overall judgments reflected reviewer consensus on the number, severity, and likely impact of concerns; no numerical cutoff was applied. These summary labels were used to facilitate narrative comparison and did not replace the original tool-specific appraisal criteria. Disagreements in risk-of-bias judgments were resolved through discussion and consensus, with third-reviewer adjudication when required. Detailed domain-level assessments and overall judgments were presented separately for each appraisal tool. Risk-of-bias findings were used to guide interpretation of the evidence and were not used as post hoc exclusion criteria. Data Synthesis A structured narrative synthesis was performed because the included studies varied substantially in population, diagnostic criteria, intervention or exposure, comparator structure, outcome definition, analytical denominator, follow-up duration, and reporting format. A meta-analysis was not performed because sufficiently comparable effect estimates and consistently defined quantitative outcomes were unavailable across the included studies. Findings were organized into diagnostic and anatomical findings, fertility and reproductive outcomes, ART/IVF/ICSI outcomes, outcomes after surgical repair, and mechanistic or pathophysiological findings. Study designs were not treated as equivalent sources of evidence. Comparative observational studies were given greater interpretive weight than uncontrolled case series, while mechanistic and descriptive studies were used primarily to contextualize potential biological or clinical pathways. Causal conclusions were interpreted cautiously because the evidence base consisted entirely of non-randomized studies. A formal GRADE (Grading of Recommendations Assessment, Development, and Evaluation) assessment was not undertaken. Given the broad review question, heterogeneous observational designs, variable outcome definitions and measurement approaches, and the absence of sufficiently comparable effect estimates for pooled analysis, certainty was considered narratively according to study design, sample size, risk of bias, consistency, directness, and outcome-measurement heterogeneity. A meta-analysis was not performed because the included studies differed substantially in their populations, diagnostic criteria, interventions, comparator structures, reproductive denominators, follow-up durations, and outcome definitions. Accordingly, the findings were synthesized narratively. Results Study Selection The combined PubMed/MEDLINE and Scopus searches identified 506 records. After removal of 71 duplicates, 435 unique database records remained, and supplementary searching added 11 records. In total, 446 records underwent title and abstract screening, of which 361 were excluded. A total of 85 reports were sought for retrieval, and 35 reports could not be retrieved. This represented 41.2% of the reports sought for retrieval. The 35 unavailable reports were identified in closed-access sources, and their full texts could not be accessed through the available institutional or library routes. They were documented separately in the screening records and were not included in the full-text eligibility assessment. Consequently, 50 full-text reports were assessed for eligibility. Fourteen full-text reports were excluded for the following reasons: no extractable fertility or reproductive outcomes or insufficient relevant data (n = 5); wrong population or exposure, or an exclusive focus on cesarean scar pregnancy without eligible fertility data (n = 3); review, protocol, non-original report, or another ineligible study design (n = 3); duplicate or overlapping data (n = 2); and a non-English full text that could not be reliably assessed (n = 1). Overall, 36 studies were included in the final narrative synthesis [ 14 - 49 ]. The study-selection process is summarized in Figure  1 . PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses Study Characteristics The 36 included studies were published between 2019 and 2026 and represented 15 countries [ 14 - 49 ]. However, the geographical distribution was uneven, with a substantial concentration of evidence from China and comparatively limited representation from Western countries, low-resource settings, and other regions. Additional contributions came from Europe, other parts of Asia, the Middle East, and the United States. Complete country-level details are provided in Table 3 . ART: assisted reproductive technology; CE: chronic endometritis; CS: cesarean section; CSD: cesarean scar defect; CSS: cesarean scar syndrome; FET: frozen embryo transfer; HSG: hysterosalpingography; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; RMT: residual myometrial thickness; SI: secondary infertility; TVUS: transvaginal ultrasound The evidence base was entirely observational, and no randomized controlled trials were identified. The included designs comprised 15 cohort or comparative cohort studies [ 16 , 20 , 21 , 27 , 30 , 33 , 40 - 46 , 48 , 49 ], eight non-randomized surgical or clinical observational studies [ 17 , 18 , 22 , 29 , 32 , 34 , 38 , 39 ], eight case series [ 14 , 19 , 23 - 26 , 31 , 47 ], three case-control studies [ 15 , 35 , 36 ], and two cross-sectional studies [ 28 , 37 ]. Because the unit of analysis varied across studies and included individual participants, treatment cycles, and clinical records, a single combined sample size was not calculated. Of the 35 studies with a clearly reported denominator, 30 included fewer than 200 participants, cycles, or records [ 14 , 15 , 17 - 32 , 35 - 43 , 45 , 47 , 48 ]. One mechanistic study reported different denominators for separate analyses [ 16 ]. The included studies were grouped into five evidence domains. Surgical repair represented the largest domain (n = 20) and included hysteroscopic, laparoscopic, robotic-assisted laparoscopic, abdominal, transvaginal, and vaginal repair approaches [ 14 , 17 - 23 , 25 - 27 , 29 - 31 , 39 , 43 , 45 , 47 - 49 ]. Four studies directly evaluated assisted reproductive technology settings, including embryo-transfer timing, frozen embryo transfer after previous cesarean delivery, intracavitary fluid during ovarian stimulation, and uterine niche status during IVF or ICSI cycles [ 15 , 33 , 38 , 46 ]. Four studies focused primarily on diagnostic or anatomical assessment, including hysterosalpingography, two-dimensional (2D) and three-dimensional (3D) sonohysterography, niche depth, RMT, and intrauterine fluid [ 24 , 28 , 37 , 41 ]. One large observational study evaluated the prevalence and clinical profile of cesarean scar defects among women with previous cesarean delivery [ 34 ]. Seven studies examined mechanistic or pathophysiological pathways, which could be grouped broadly into inflammatory, anatomical or pelvic, microbial, and functional mechanisms [ 16 , 32 , 35 , 36 , 40 , 42 , 44 ]. Diagnostic methods varied according to the study objective and included transvaginal ultrasonography, saline infusion sonography or sonohysterography, hysteroscopy, hysterosalpingography, magnetic resonance imaging, and ultrasound speckle-tracking analysis. Definitions of cesarean scar defect were not uniform across studies. Several studies defined a niche using a depth threshold of at least 2 mm, whereas others focused on large defects characterized by RMT below 3 mm or less than 50% of the adjacent myometrial thickness [ 22 , 24 , 37 , 40 , 41 ]. The main characteristics of the included studies are summarized in Table  3 . Diagnostic and Anatomical Findings Diagnostic and anatomical studies focused mainly on niche depth, RMT, niche size, and intrauterine or intracavitary fluid, while postoperative studies also assessed restoration of the lower uterine segment. Across studies using laparoscopic, transvaginal, robotic-assisted, and vaginal repair, RMT generally increased after treatment [ 14 , 19 , 22 , 23 , 31 , 43 , 49 ]. Representative examples included an increase from 2.0 mm to 8.7 mm after laparoscopic repair [ 14 ], from 1.6 mm to 6.4 mm after transvaginal repair [ 19 ], and from 2.62 ± 1.14 mm to 7.18 ± 2.34 mm after vaginal repair [ 49 ]. Diagnostic studies provided complementary evidence for identifying fertility-relevant scar features. Alalfy et al. evaluated 110 women with secondary infertility planned for ICSI and supported 3D sonohysterography as a more detailed approach for scar measurement than two-dimensional assessment [ 28 ]. Pabuccu described the hysterosalpingography pocket sign in seven women with secondary infertility, suggesting that hysterosalpingography (HSG) may identify patients who require confirmatory scar assessment [ 24 ]. Sultan et al. reported a mean niche depth of 3.4 ± 1.1 mm and intrauterine fluid in 29 of 39 infertile women [ 37 ], whereas Klein Meuleman et al. found intrauterine fluid in 38 of 141 women with a large niche and unexplained infertility, although endometrial thickness did not differ significantly according to fluid status [ 41 ]. Overall, diagnostic assessment appeared most informative when scar morphology, RMT, fluid status, and reproductive context were considered together. The key diagnostic and anatomical findings are summarized in Table 4 . AUB: abnormal uterine bleeding; CSD: cesarean scar defect; HSG: hysterosalpingography; ICSI: intracytoplasmic sperm injection; MRI: magnetic resonance imaging; RMT: residual myometrial thickness; SHG: sonohysterography; SIS: saline infusion sonography; TVUS: transvaginal ultrasound Fertility, Reproductive, Surgical, and ART Outcomes Reproductive outcomes were reported most often after surgical repair, although denominators varied across studies. Overall, hysteroscopic and hysteroscopy-based studies showed pregnancies after treatment in selected women with infertility or fertility desire. Study-specific findings included pregnancy in nine of 16 infertile women after hysteroscopic isthmoplasty in Calzolari et al.'s study [ 25 ], three of seven women attempting conception after hysteroscopic correction in the study by Vegas Carrillo de Albornoz et al. [ 26 ], and 27 of 38 women after hysteroscopic surgery for cesarean scar syndrome in the study by Tsuji et al. [ 27 ]. Comparative studies reported pregnancy in 27 of 39 women after hysteroscopic resection versus 14 of 24 after vaginal repair in Yang et al.'s study [ 18 ], and in 13 of 25 after operative hysteroscopy versus five of 19 after diagnostic hysteroscopy in the study by Szafarowska et al. [ 29 ]. These findings suggest a reproductive signal after hysteroscopic management in selected patients, but non-randomized designs, anatomy-based procedure selection, and confounding by indication limit direct comparisons between approaches. Patients with thinner residual myometrium or more severe defect morphology may preferentially undergo reconstructive procedures, whereas patients with less severe defects may undergo hysteroscopic treatment; observed differences in pregnancy rates may therefore reflect baseline case selection rather than differences in treatment efficacy. Laparoscopic, robotic-assisted, abdominal, transvaginal, and vaginal reconstructive studies likewise linked anatomical restoration with subsequent fertility follow-up. Pregnancy was reported in 10 of 12 women in the infertility subgroup of the study by Karampelas et al. [ 31 ], 26 of 36 women with fertility follow-up after robotic-assisted laparoscopic repair in Almasarweh et al.'s study [ 22 ], 12 of 16 women desiring fertility after laparoscopic folding suture in Huang et al.'s study [ 23 ], eight of 20 women after abdominal repair in Ishikawa et al.'s study [ 39 ], and 218 of 495 women attempting pregnancy after vaginal repair in Yin et al.'s study [ 49 ]. Live-birth reporting was less consistent, but live births were documented after several reconstructive approaches, including hysteroscopic, laparoscopic, robotic-assisted, and vaginal repair [ 22 , 27 , 30 , 43 , 49 ]. ART-focused evidence suggested that CSD may influence reproductive outcomes through embryo-transfer, fluid-related, and implantation-related pathways. Regarding embryo-transfer timing, Baldini et al. reported cesarean scar pregnancy in two of 22 day-3 embryo transfers and in none of 76 day-5 transfers among women with isthmocele [ 15 ]. In relation to intracavitary fluid, Lawrenz et al. found that fluid developed in approximately 40% of women with isthmocele during ovarian stimulation, while frozen embryo-transfer outcomes were similar to controls when fluid was absent before transfer [ 38 ]. For broader reproductive outcomes, Zhang et al. reported lower clinical pregnancy and live-birth outcomes after frozen-thawed embryo transfer among women with CSD [ 33 ], and Yao W et al. reported lower implantation, clinical pregnancy, and live-birth outcomes together with higher early miscarriage among women with uterine niche [ 46 ]. The main reproductive, surgical, and ART outcomes are summarized in Table 5 . ART: assisted reproductive technology; CSD: cesarean scar defect; CSS: cesarean scar syndrome; FET: frozen embryo transfer; ICSI: intracytoplasmic sperm injection; IVF: in vitro fertilization; RMT: residual myometrial thickness Mechanistic and Pathophysiological Findings Inflammatory findings provided the clearest initial mechanistic signal linking CSD with impaired fertility. Nobuta et al. reported chronic endometritis in 65.8% of infertile women with cesarean scar syndrome compared with 46.0% of infertile comparators, together with higher tumor necrosis factor-alpha and interleukin-1 beta levels [ 16 ]. Wei et al. similarly reported a higher prevalence of chronic endometritis among women with CSD [ 44 ]. These findings support chronic endometrial inflammation as one plausible pathway through which the defect may affect reproductive function. Other studies extended the mechanistic model beyond inflammation. Chen et al. found marked bacterial and fungal differences between infertile women with CSD and infertile controls, supporting a possible microbiome-related pathway [ 35 ]. Born et al. identified histologically confirmed endometriosis in nearly half of women undergoing laparoscopic CSD repair, indicating that coexisting endometriosis may contribute to symptoms or fertility impairment in some patients [ 36 ]. Contractility studies also suggested a functional mechanism: Jordans et al. reported higher subendometrial contraction amplitude in women with a niche than in controls [ 40 ], while Klein Meuleman et al. (2025) found that laparoscopic repair increased RMT, reduced niche volume, resolved intrauterine fluid, and shifted contractility toward a more normal pattern [ 42 ]. Overall, mechanistic studies implicated multiple potential pathways, including scar anatomy, retained fluid, chronic inflammation, dysbiosis, endometriosis, pelvic adhesions, tubal factors, and altered uterine peristalsis. Mechanistic findings are summarized in Table 6 . CE: chronic endometritis; CI: confidence interval; CSD: cesarean scar defect; CSS: cesarean scar syndrome; HMB: heavy menstrual bleeding; IUF: intrauterine fluid; OR: odds ratio; RMT: residual myometrial thickness; TNF: tumor necrosis factor Risk of Bias Risk of bias was assessed according to study design and was used to guide interpretation rather than to determine eligibility. Overall, the most frequent limitations were retrospective design, small fertility subgroups, non-randomized procedure selection, confounding by indication, incomplete reproductive denominators, variable follow-up duration, and inconsistent reporting of pregnancy-attempt status. Cross-sectional and diagnostic studies generally had clearer eligibility and measurement procedures, whereas comparative surgical and ART studies were more vulnerable to selection bias and confounding because the treatment route, embryo-transfer strategy, or repair technique was often determined by niche anatomy, RMT, symptoms, fertility desire, or clinician preference. For clarity, risk-of-bias findings are presented by assessment tool and study design. Risk-of-bias judgments are presented as low risk, moderate risk, high risk, and not applicable. The NOS was used for observational cohort, case-control, and non-interventional comparative studies (Table  7 ). Most NOS-assessed studies had moderate overall concern. Yao et al.'s study [ 46 ] had lower concern across selection, comparability, and outcome domains. High overall concern was mainly driven by limited comparability, incomplete adjustment for confounding, and small or selected comparator groups, particularly in studies where fertility outcomes may have been influenced by baseline reproductive status, embryo-transfer strategy, symptoms, or underlying pelvic factors. L: low risk; M: moderate risk; H: high risk The JBI Analytical Cross-Sectional Checklist was used for cross-sectional diagnostic or prevalence studies. The JBI analytical cross-sectional risk-of-bias summary is presented in Table  8 . Cross-sectional evidence was useful for diagnostic and prevalence description but remained limited for causal inference. Alalfy et al.'s study [ 28 ] was judged to have low concern because the eligible population was clearly defined, imaging assessment was standardized, and the relevant diagnostic measurements were reported adequately. The study by Sultan et al. [ 37 ] had moderate concern because the population and diagnostic assessment were reasonably described, but control of confounding and statistical adjustment were limited. Alami et al.'s study [ 34 ] had high concern because the sampling approach, comparability, and control of potential confounding were less robust, making prevalence and symptom associations more vulnerable to selection and measurement bias. L: low risk; M: moderate risk; H: high risk; N/A: not applicable; JBI: Joanna Briggs Institute (formerly) The JBI Case-Series Checklist was used for single-arm case series and surgical follow-up cohorts (Table 9 ). Among the 15 studies assessed using the JBI Case Series Checklist, 10 had moderate overall risk of bias, two had low risk, and three had high risk. The main concerns were incomplete or unclear consecutive case inclusion, selection of analysis sets based on follow-up or image quality, variable completeness or duration of follow-up, and limited analytical methods in small uncontrolled studies. The studies by Coppenrath et al. [ 19 ] and Calzolari et al. [ 25 ] had the lowest overall concern. Higher overall concern was assigned to the stuy by Piriyev et al. [ 14 ], Klein Meuleman et al. [ 42 ], and Yin et al. [ 49 ], mainly because of follow-up-dependent inclusion, exclusion of a large proportion of potentially eligible participants, or substantial loss to follow-up and restriction of the final analysis population. L: low risk; M: moderate risk; H: high risk; JBI: Joanna Briggs Institute (formerly) ROBINS-I was used for non-randomized comparative intervention studies. The ROBINS-I risk-of-bias summary is presented in Table  10 . ROBINS-I assessments showed the highest concern among comparative surgical studies. The major limitation was confounding by indication: patients were not randomized to hysteroscopic, laparoscopic, vaginal, abdominal, or combined repair, and treatment selection was often influenced by RMT, niche size, symptoms, fertility desire, surgeon preference, or clinical severity. As a result, differences in pregnancy or live-birth outcomes between surgical approaches should not be interpreted as direct evidence that one technique is superior. These studies are best interpreted as supportive evidence for anatomy-guided management rather than definitive comparative effectiveness evidence. Accordingly, pregnancy and live-birth rates should be interpreted as study-specific outcomes in selected populations rather than as comparative estimates applicable across all surgical techniques. L: low risk; M: moderate risk; H: high risk; ROBINS-I: Risk Of Bias In Non-randomized Studies of Interventions Overall, the risk-of-bias assessment supports cautious interpretation. The evidence base provides clinically important signals linking CSD/isthmocele with infertility, ART outcomes, chronic inflammation, intrauterine fluid, altered contractility, and reproductive outcomes after repair. However, most evidence remains observational, and many fertility outcomes are vulnerable to selection bias, confounding, small sample size, and inconsistent denominator reporting. Therefore, risk of bias was incorporated into the narrative synthesis and phrased cautiously rather than as definitive causal claims. Discussion The findings of this systematic review suggest that CSD/isthmocele may be associated with secondary infertility and adverse reproductive outcomes in selected women after cesarean delivery. Across the evidence base, the clinically important issue was not simply whether a niche was present, but whether it formed part of a fertility-relevant phenotype characterized by thin residual myometrium, intrauterine or intracavitary fluid, inflammatory changes, altered uterine contractility, or unfavorable conditions during assisted reproduction. This distinction is important in practice because many niches may be incidental, whereas others have anatomical or functional features that warrant closer fertility-focused assessment. Diagnostic and Anatomical Interpretation The diagnostic evidence indicates that CSD should not be interpreted as a simple present-or-absent finding. Fertility-relevant assessment appears to depend on the combination of RMT, niche size, fluid retention, associated symptoms, and, where relevant, functional imaging findings. Studies using sonohysterography, hysterosalpingography, transvaginal ultrasound, hysteroscopy, and speckle-tracking ultrasound showed substantial variation in scar morphology and function [ 24 , 28 , 37 , 40 - 42 ]. For clinicians, a large or thin-walled niche accompanied by intracavitary fluid, bleeding symptoms, or abnormal uterine dynamics is therefore more informative than an incidental small defect seen on imaging alone. Reproductive and Surgical Interpretation The reproductive evidence supports an association between CSD/isthmocele and impaired fertility, but it does not establish causation. Pregnancy and live-birth outcomes have been reported after hysteroscopic and reconstructive repair in selected women [ 14 , 17 - 23 , 25 - 27 , 29 - 31 , 39 , 43 , 45 , 47 - 49 ], but these studies used different patient-selection criteria, anatomical thresholds, surgical techniques, follow-up periods, and reproductive endpoints. Importantly, surgical treatment was not randomly assigned. Patients with very thin RMT, deeper defects, or unfavourable niche morphology may be preferentially directed toward laparoscopic, abdominal, robotic, transvaginal, or vaginal reconstruction, whereas patients with thicker residual myometrium may be more likely to undergo hysteroscopic treatment. This confounding by indication makes direct comparison of postoperative pregnancy rates unreliable. Therefore, a higher or lower pregnancy rate reported for one approach cannot be interpreted as proof of clinical superiority. The available evidence supports individualized, anatomy-guided treatment selection rather than a universal procedural hierarchy. Hysteroscopic treatment may be considered in selected less severe defects with adequate myometrial thickness, whereas reconstructive approaches may be considered when residual myometrium is thin or restoration of myometrial integrity is a major objective. Assisted Reproduction and Implantation-Related Findings ART-focused studies suggest that CSD may influence implantation through a combination of scar anatomy and the uterine environment [ 15 , 33 , 38 , 46 ]. Intracavitary fluid deserves particular attention because its presence or persistence before embryo transfer may be more clinically relevant than niche detection alone. In the available cohorts, fluid status around transfer, embryo-transfer strategy, comparator selection, and adjustment for confounders all influenced reported outcomes. Thus, intracavitary fluid may be a useful feature to consider when interpreting ART outcomes in women with CSD, but the current evidence is not sufficiently uniform to define a standard transfer or treatment strategy. Mechanistic Interpretation The mechanistic findings support a multifactorial model, but they should not be generalized to every woman with CSD. Evidence for chronic endometritis, inflammatory cytokine changes, or other inflammatory abnormalities came from selected studies and patient subsets rather than from biopsy or inflammatory-marker assessment across the entire evidence base [ 16 , 32 , 44 ]. Other studies suggested possible contributions from dysbiosis, coexisting endometriosis, pelvic or tubal factors, and altered subendometrial contractility [ 35 , 36 , 40 , 42 ]. These findings make biological sense when considered alongside retained fluid and scar anatomy, but they remain plausible mechanisms rather than universal features or proven causal pathways. Strength of the Evidence A strength of the evidence is that several study types point toward a similar clinical concept: some cesarean scar niches appear to have anatomical, functional, or reproductive relevance [ 14 - 49 ]. However, the strength of that convergence should not be overstated. The evidence is almost entirely observational and is affected by small or single-center cohorts, inconsistent definitions, heterogeneous comparators, variable follow-up, non-uniform study eligibility criteria, and different fertility outcomes. These differences reduce the precision of the overall inference and explain why narrative synthesis was more appropriate than quantitative pooling. Clinical and Research Implications The geographical concentration of the evidence may limit the generalizability of the findings. A substantial proportion of the included studies originated from China, where cesarean-delivery patterns, referral pathways, diagnostic practices, reproductive-health services, and access to specialized scar-repair surgery may differ from those in Western countries and low-resource settings. National guidelines and local diagnostic thresholds may influence which niches are considered clinically significant and which patients are referred for surgical treatment. Differences in healthcare access, IVF funding structures, insurance coverage, and availability of reproductive surgery may also affect patient selection and the likelihood of receiving assisted reproductive treatment. In addition, embryo-transfer practices and clinical decision-making may vary between healthcare systems, potentially influencing implantation, pregnancy, and live-birth outcomes. The Afghan cohort provides some representation from a lower-resource setting [ 34 ]; however, a single study cannot capture the diversity of reproductive-care pathways in low- and middle-income countries. Therefore, the findings should be applied cautiously outside the settings in which the primary evidence was generated. Clinically, the findings support individualized assessment of women with secondary infertility after cesarean delivery rather than routine intervention for every detected niche. A higher-risk fertility-related phenotype may be suggested by combinations of postmenstrual spotting or pelvic symptoms, thin residual myometrium, intracavitary fluid, recurrent implantation problems, or other adverse anatomical or functional features. In contrast, an asymptomatic small niche without these features may have less immediate reproductive significance. The current evidence does not support routine repair of all CSDs; management should be guided by symptoms, reproductive goals, scar anatomy, fluid status, and the broader infertility assessment. Future research should use standardized CSD definitions and patient-selection criteria, clearly separate confirmed secondary infertility from general fertility desire, and report RMT, niche dimensions, fluid status, and spontaneous versus ART-mediated conception consistently. Larger prospective comparative studies, and controlled trials where feasible, are needed to clarify which patients benefit from intervention and whether particular treatment approaches improve reproductive outcomes beyond the effects of baseline anatomy and other causes of infertility. Limitations This review has several limitations. The protocol was not prospectively registered in PROSPERO, OSF, or another systematic-review registry, which limits independent external verification of prespecified methods and outcomes. However, no deviations occurred between the initial review design and the final study selection, data extraction, risk-of-bias assessment, outcome interpretation, or narrative synthesis. The formal bibliographic search was limited to PubMed/MEDLINE and Scopus and did not include Embase or the Cochrane Central Register of Controlled Trials. This limitation may have reduced the comprehensiveness of the evidence base. However, the search was supplemented by Google Scholar, PubMed Central, publisher webpages, DOI records, citation tracking, and manual reference-list screening, and only those studies that were indexed only in Embase, Cochrane Central Register of Controlled Trials (CENTRAL), or other databases may have been missed, including some European publications, conference records, and clinical-trial-related evidence. Only completed English-language full-text reports with sufficient extractable data were included. Of the 85 reports sought for retrieval, 35 could not be obtained, corresponding to 41.2%. Although the reports were recorded as not retrieved and retrieval procedures were undertaken, their absence may have introduced availability or retrieval bias. Inaccessible reports may have differed from the included studies in publication year, setting, study quality, sample size, or direction of findings. These restrictions mean that relevant evidence may have been omitted and reduce confidence that the review captured the full range of published findings. The main limitation was substantial clinical and methodological heterogeneity. Included studies differed in their populations, inclusion and exclusion criteria, CSD definitions, anatomical thresholds, surgical or ART protocols, comparators, outcome definitions, analytical denominators, and follow-up periods. This variability precluded meaningful quantitative pooling and prevents the current evidence from defining a single standardized diagnostic or treatment pathway. Many studies were retrospective, non-randomized, single-center, or small, leaving the evidence vulnerable to selection bias, confounding by indication, and imprecision. Fertility and reproductive outcomes were also reported inconsistently, and publication bias or selective outcome reporting cannot be excluded. Taken together with the unretrieved reports and heterogeneity described above, these limitations mean that the overall findings should be interpreted as clinically suggestive rather than definitive comparative or causal evidence.

CSD/isthmocele may be associated with secondary infertility and adverse reproductive outcomes, particularly when accompanied by thin residual myometrium, intracavitary fluid, inflammatory changes, altered uterine contractility, or other unfavorable implantation-related features. Its reproductive significance should be assessed using scar morphology, residual myometrial thickness, fluid status, symptoms, and the broader infertility context rather than niche presence alone. Although surgical repair has been associated with anatomical improvement and subsequent pregnancies or live births in selected patients, the evidence remains observational and heterogeneous, with no single treatment approach shown to be universally superior. Therefore, not every detected isthmocele should be considered a cause of infertility or an automatic indication for surgery. Prospective comparative studies using standardized diagnostic criteria and clearly defined fertility and reproductive outcomes are needed to identify patients most likely to benefit from intervention.