Impact of cesarean scar defects on the success of assisted human reproduction: The NICHE- ART prospective cohort study protocol

Impact of cesarean scar defects on the success of assisted human reproduction: The NICHE- ART prospective cohort study protocol | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Study protocol Impact of cesarean scar defects on the success of assisted human reproduction: The NICHE- ART prospective cohort study protocol Audrey ASTRUC, Delphine DESEINE, Magalie BOUGUENET, Andrew SPIERS, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4029966/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: The prevalence of caesarean sections worldwide continues to rise, increasing the risk of obstetric complications. Isthmocele, defined as a dehiscence of the hysterotomy following a caesarean section, can lead to intermenstrual bleeding or pelvic pain. Studies have shown that surgical treatment of isthmoceles reduces the incidence of metrorrhagia. In these studies, the authors noted that patients with abnormal bleeding outside the cycle were also more frequently affected by secondary infertility. However, isthmocele surgery can result in intrauterine adhesions and synechiae, which are also recognized as potentially deleterious to fertility. The impact of the presence of an isthmocele on the results of ART must therefore be demonstrated before any attempt at treatment, and this will require larger-scale prospective studies, using a consensus definition of the isthmocele based on sonohysterography (currently considered the "gold standard" examination). Methods: We designed a multicentric prospective study that will be conducted in 10 French Reproductive Medicine centers. We will include women consulting for infertility with a history of scarred uterus. During sonohysterography and transvaginal ultrasound, a specific measurement is taken to define the presence or absence of an isthmocele, and to classify patients into one of two groups: "isthmocele +" or "isthmocele -". The main objective of the study is to investigate the association between the presence of an isthmocele and the clinical pregnancy rate obtained after in vitro fertilization in patients with a scarred uterus (single or multi-scarred). The primary outcome is clinical pregnancy rate, as defined by the visualization of gestational sac on the transvaginal ultrasound. We will need to include 250 women with a scarred uterus undergoing ART. The duration of the inclusion period is estimated to be 42 months. Discussion: If our study shows a reduction in the clinical pregnancy rate in the presence of an isthmocele, this could lead to a change in clinical practices for patients undergoing ART. Indeed, surgical management of the isthmocele could be discussed prior to ART by informing the patient of the benefit-risk balance of the operation. Trial registration: ClinicalTrials.gov, ID:. NCT04869007. Registered on August 16 th , 2020. caesarean scar defect Isthmocele Infertility in vitro fertilization Clinical pregnancy rate Figures Figure 1 Background The prevalence of caesarean sections (CS) continues to increase around the world. CS represent 21% of deliveries in France and in the world and is expected to keep increasing around 28% by 2030 according to the WHO (1,2). Uterine defect, or isthmocele, or uterine niche, was defined by Morris in 1995 as a scarring abnormality with a dehiscence of the hysterotomy following a caesarean section (3). Prevalence of isthmocele varies depending on the exam used for the diagnosis: between 13 and 84% with transvaginal ultrasound (TVS) and between 42 and 84% with sonohysterography (SHG) (4) . As to date, a standardized definition of isthmocele does not exist. Many exams can be performed for the diagnosis such as 2D and 3D transvaginal ultrasound, sonohysterography, hysteroscopy, MRI; although transvaginal ultrasound and sonohysterography are the most feasible, cost-effective methods requiring the least amount of training (4,5). As an isthmocele can be missed during transvaginal ultrasound if only searched in the sagittal plane or if there isn’t intra uterine fluid, the European Niche Taskforce recommended in 2019 using a modified Delphi method (6) that a niche should be searched both in the transvaginal and sagittal planes and that the use of saline or gel is preferred. They agreed on a definition of a niche as an indentation at the site of the CS scar with a depth of at least 2 mm. In recent studies, a large niche should be when considered when the residual myometrial thickness (RMT) is of less than 2 or 3mm (4). Isthmocele leads to long term complications such as gynecological symptoms (abnormal uterine bleeding, chronic pelvic pain), secondary infertility and to an increased risk of obstetrical complications such as ectopic pregnancy in cesarean scar defects, placental disorders (placenta previa or accreta) or uterine rupture (4,7). Surgical management of isthmocele can be performed either by hysteroscopy or vaginally / laparoscopy depending on whether the RMT is < 3mm. Either way, they are simple procedures with very few complications (7,8), a quick recovery and allow in 85% to 93% the resolution of symptoms (8). Surgical management of isthmocele may also have an impact on secondary infertility (5). A recent prospective cohort (133 women) found a pregnancy rate of 60% 2 years after laparoscopic management of isthmocele on women with secondary infertility (9). Also, there is still lacking high quality evidence on the matter. The association between isthmocele and secondary infertility is not well described. Gurol Guranci et al. reported that a caesarean section reduces the probability of subsequent pregnancy by 10% [relative risk (RR) 0.91; 95% 0.87–0.95] on average, compared with a previous vaginal delivery (10). However, no distinction was made if an isthmocele was present or not. Naji et al. found that isthmocele could impact on the embryo implantation site and lead to more miscarriages (11). A very recent meta-analysis of Vitagliano et al. evaluating the effect of isthmocele on IVF success showed that patients with isthmocele had lower live birth rate, clinical birth rate, implantation rate and a higher miscarriage rate (12). Interestingly, they found that patients with a history of a scarred uterus without isthmocele had a similar live birth rate to those with a history of vaginal delivery, which attributed the negative effect on IVF to the isthmocele and not the cesarian section. However, the studies included were only retrospective studies. In this context, we aim to evaluate prospectively the impact of isthmoceles on IVF success. Methods Study design/Aim Our aim is to investigate the association between the presence of an isthmocele and the clinical pregnancy rate obtained after IVF (first or second attempt) in patients with a scarred uterus. The study will have a multicentric, parallel group, comparative, non-interventional, exploratory, and prospective design. Recruitment will be done among patients consulting for care in the Reproductive Unit in each of the 10 public hospitals in, France. Enrollment Inclusion criteria Women between 18 and 43 years old, French speaking, with a history of at least one caesarean section (single or multi-scarred uterus) and a secondary infertility requiring ART techniques (IVF or IVF with ICSI) will be invited to participate to the study. A sonohysterography and a transvaginal ultrasound examination as part of the pre-ART assessment to evaluate the presence or absence of an isthmocele will have to be performed prior to the inclusion. Patients with a uterine scar other than from a low segment or who refuse to participate to the study will not be included. Sample size calculation In the Angers University Hospital Reproductive unit, the overall pregnancy rate with IVF is approximately 26%. Regarding the population of patients with a scarred uterus, data collected in this unit in 2017 and 2018 shows that 7 patients each year had a scarred uterus without a significant isthmocele. A significant isthmocele was found in 8 patients in 2017 and 6 patients in 2018. When considering the impact of an isthmocele, a relative decrease in the clinical pregnancy rate, among patients undergoing ART, of 50% is considered to be clinically significant. This limit is similar among other pathologies affecting ART, such as hydrosalpinx or the presence of submucosal myomas (13,14). It is necessary to include a minimum of 226 patients (for an isthmocele prevalence estimated at 50% based on our 2017 data) with a power of 80% and an alpha risk set at 5% with a bilateral calculation (Casagrande and Pike method). (15) To anticipate loss of follow-up (estimated at approximately 10%), it is planned to include 250 patients with scarred uterus managed with ART in the cohort. Intervention During the initial ART consultation, the study is presented (oral information and distribution of a brochure) to patients consulting for infertility and with a history of caesarean section. ART treatment assessment (blood tests and imaging: TVS and SHG) is prescribed If they agree to take part in the study, the non-opposition of eligible patients is collected during this consultation (pre-inclusion). For patients agreeing to participate in the study, a specific measurement is made during the TVS and SHG examination in order to determine the presence or absence of an isthmocele. Inclusion in the study is validated after a successful examination that confirms the presence or absence of an isthmocele. The patients are then attributed either to the: "isthmocele +” group or "isthmocele -“group. An isthmocele will be diagnosed when indentation is found at the site of the CS scar with a depth of at least 2 mm. A large isthmocele will be considered when the RMT is <3mm on SHG. As part of the standard ART treatment, blood hCG tests are carried out 14 days after embryo transfer to detect a possible pregnancy. If the blood hCG levels are positive, the test is repeated 48 hours later and again a week later to survey the evolution of the blood hCG levels. At 6 to 7 weeks after oocyte puncture, an ultrasound scan is performed in the Reproductive department if the blood hCGs level is greater than 10 IU/L with a satisfactory evolution after 48 hours. In the case of pregnancy and delivery in the same hospital as the ART treatment, obstetrical data is collected by the investigators from the obstetrical file. In the case of delivery at another facility, patients were contacted by telephone one year after a positive pregnancy test (hCG). Participant timeline The patient timeline is shown in Figure 1 using the Spirit Guidelines (16). Outcome Primary Outcome Our primary outcome will be to compare the clinical pregnancy rate (as defined by the visualization of gestational sac on the transvaginal ultrasound) obtained after in vitro fertilization (or IVF with ICSI) in patients with and without isthmocele. Secondary outcomes Other criteria evaluating the diagnosis of isthmocele or results of IVF or IVF with ICSI will be assessed: The rate of biochemical pregnancies: early termination of pregnancy with positive urine or blood hCG that is then negative without ultrasound localization of the pregnancy. The rate of evolving pregnancies: a biochemical and evolving pregnancy is defined by the presence of an intrauterine gestational sac and an embryo with cardiac activity visible during an ultrasound examination between 11 weeks and 13 weeks and 6 days of amenorrhea. Live birth rate: live birth defined as the birth of a living child after 22 weeks’ gestational age, or weighing ≥ 500g. The rate of ectopic pregnancies on scar tissue from caesarean section. The rate of complications during embryo transfer (composite criteria associating false passages, the need to use a rigid catheter or the placement of a Pozzi forceps). The rate of obstetric complications in the event of birth (composite criteria associating placental disorders, uterine rupture, post-partum hemorrhage, term at delivery, type of birth). The rate of immediate neonatal complications (birth weight < 10th percentile, Apgar score, pH and lactate, rate of transfer to an intensive care unit). Data collection Among patients accepting to participate to the study, during the initial consultation socio-demographic data and the couple's medical history are collected. During the second ART consultation, the results of the treatment assessment are collected, the presence or absence of an isthmocele on the SHG examination. Subsequently, the data relative to ovarian stimulation, the methods of triggering and embryo transfer are collected prospectively by the investigator. Data management All data for this study are collected in a paper observation notebook from valid source documents (patient medical records). Patients are identified by a unique number. In order to avoid any misidentification of patients, the initials of the surname and first name, as well as the month and year of birth are also collected. The paper records are centralised at the Angers university hospital and entered into an EPIDATA database managed by the Angers University Hospitals Delegation of Clinical Research and Innovation (DRCI). The data collected does not mention the identity of the patients (surnames, first names, date of birth are not used). Patients are identified via a center number or a file number per center. A correspondence list is kept in each center. Checks are regularly carried out to verify the consistency and completeness of the data entered. The list of checkpoints is defined jointly by the coordinating investigator and DRCI's Data Management Unit, in the studies data validation plan. Correction requests are processed by the data manager. They are sent to the investigating center, which make the necessary corrections to resolve the correction requests. A list of typical corrections that can be made by the data managers is defined in the studies data validation plan. The database will be locked for the final analysis. The database is locked in accordance with the procedure established by DRCI. Persons with direct access to the data are to take all necessary precautions to ensure the confidentiality of information relating to the persons participating in the study and in particular regarding their identity and the results obtained. These persons are subject to professional secrecy (according to the conditions defined by articles 226-13 and 226-14 of the penal code). Statistical Analysis For qualitative variables, the results are reported as numbers and percentages and then compared using Pearson's Chi-square test (or Fisher's exact test). For quantitative variables, the primary quartiles (median and 25° and 75° percentile) are reported in the form of a box-plot diagram. In case of normality of the variable (Q-Q plot) the mean and standard deviation as well as the 95% confidence interval are to be specified. If possible, the student’s t-test is used for comparison tests. If this is not possible, the Mann Whitney test is carried out. P-values of less than 5% indicate a significant difference. Two analysis will be run : one with isthmocele defined as an indentation at the site of the CS scar with a depth of at least 2 mm and one focusing only on large isthmocele defined as a RMT < 3mm. To achieve the primary objective of the study, which is to investigate the association between the presence of an isthmocele and the clinical pregnancy rate obtained after in vitro fertilization (IVF or IVF with ICSI) in patients with a scarred uterus (single or multi-scarred), standard tools of descriptive statistics are to be employed. Data will be compared using a Chi2 test (or an exact File test if necessary). To satisfy the secondary objectives of the study which is to explore the associations between the presence of an isthmocele and other criteria evaluating the results of IVF (or IVF with ICSI) in patients with a scarred uterus (single or multi-scarred), similar descriptive diagrams and comparative tests will be used. Due to the exploratory nature of the study, a multivariate analysis (binary logistic regression or multifactorial linear regression) that considers the binary variable "isthmocele" and the other risk factors associated with implantation failure will be conducted. The number of variables to be included in the model will depend on the pregnancy rate within the cohort (estimated at approximately 25% in the case of a scarred uterus based on the department’s figures). At least five variables in addition to the "isthmocele" variable could therefore be taken into account in our final analysis. A residue analysis will be conducted to validate the proposed model. The significance threshold is set at 0.05 and all tests will be bilateral. Analyses will be conducted using R and Excel software. Discussion In this study, we hypothesize that isthmocele will have a negative impact on IVF results. It is known that CS lower the pregnancy and birth rates of around 10% compared to vaginal delivery (10). However, few data exist on the implications of isthmocele in secondary infertility (17,18). On the current hypothesis, one is that isthmocele might provide a detrimental environment for sperm penetration and embryo implantation (19) by the accumulation of intra uterine fluid acting like in other gynecological conditions such as hydrosalpinx (13), the increased inflammation within the niche (11,20), the distorted myometrial contractility due to the uterine scar. In a prospective study on 364 women presenting secondary infertility (21), significantly more bacteria colonies including among other colonies more Gram neg rods (E.Coli, Pseudomonas Aeruginosa) were found in uterine niche than in patients without a uterine niche or without CS (respectively 89.6%, 69.6% and 49.7%). If we make the analogy with chronic endometriosis (22,23), we might hypothesize that it could influence IVF results. Another observation is that a large niche could affect the accessibility for an embryo transfer (19) with difficulty accessing the uterine cavity with the transfer catheter especially in retroflexed uterus using more manipulation affecting the quality of the embryo transfer (24). If clinical symptoms are associated with isthmocele on the other hand, whether the size or volume‘s niche is correlated to the symptoms’ apparition is not clear. A question Mohr-Sasson et al. tried to answer on their study of 282 women where although there were no differences in niches’ sizes between symptomatic and asymptomatic women, when taken separately, infertility was associated with a RMT of less than 2.5mm (25). If our hypothesis is confirmed, this trial will provide evidence that isthmocele can affect IVF and can change the way we handle secondary infertility after a history of caesarian. The surgical management improves the general symptoms of isthmoceles but evidence on an amelioration of a secondary infertility is unclear. In a prospective cohort of Vervoort et al. on 101 patients, laparoscopic resection of uterine niche allowed a decrease in the niche depth and a disappearance of intra uterine fluid which is promising for women suffering from secondary infertility (26). In the meta-analysis of Vitale et al. , it was found pregnancy rates of 88,75 % after hysteroscopic management, 45,1% after laparoscopic management but the studies didn’t specify the couple fertility history prior to the surgery (8). In the meta analysis of Verbeckt et al. , the benefit of niche surgery in women with infertility on reproductive outcome could not be answered as only one retrospective study on 61 patients addressed the question (relative risk, 2.41; 95% CI, 1.32–4.39 in favour of the surgery) (18). Thus, further studies will be needed to propose surgical management before starting the ART treatment . Abbreviations CS: Caesarean section TVS: Transvaginal Ultrasound SHG: Sonohysterography RMT: Residual Myometrial Thickness IVF: In Vitro Fertilization ART: Assisted Reproductive Techniques Declarations Ethics approval and consent to participate. The study protocol has been approved by relevant French authorities Comité de Protection des Personnes Sud Méditerranée IV on the 10th of November 2020 and recorded prospectively (before the inscription of the first participant) under the number ID-RCB: 2020-A02068-31. The study will be conducted according to the guidelines of the Declaration of Helsinki. Prior to the study, all participants will read the informed consent form. The consent obtained from study participants will be written. Consent for publication Not Applicable Availability of data and materials Not applicable Competing interests The authors declare that they have no competing interests. Funding No funding to report. Angers University Hospital is the trial sponsor. Authors' contributions G.L. is the primary investigator who assisted in the trial design and contributed to writing the report. G.L. and A.A. will be involved in trial supervision and trial design. G.L. is responsible for the trial concept. 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The alteration of intrauterine microbiota in chronic endometritis patients based on 16S rRNA sequencing analysis. Ann Clin Microbiol Antimicrob. 12 janv 2023;22(1):4. Moreno I, Simon C. Relevance of assessing the uterine microbiota in infertility. Fertil Steril. août 2018;110(3):337‑43. Phillips JAS, Martins WP, Nastri CO, Raine-Fenning NJ. Difficult embryo transfers or blood on catheter and assisted reproductive outcomes: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. juin 2013;168(2):121‑8. Mohr-Sasson A, Dadon T, Brandt A, Shats M, Axcelrod M, Meyer R, et al. The association between uterine scar defect (niche) and the presence of symptoms. Reprod Biomed Online. août 2023;47(2):103221. Vervoort A, Vissers J, Hehenkamp W, Brölmann H, Huirne J. The effect of laparoscopic resection of large niches in the uterine caesarean scar on symptoms, ultrasound findings and quality of life: a prospective cohort study. BJOG Int J Obstet Gynaecol. févr 2018;125(3):317‑25. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4029966","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Study protocol","associatedPublications":[],"authors":[{"id":278087491,"identity":"0061cf10-2193-4185-9e43-f903ebbc0488","order_by":0,"name":"Audrey ASTRUC","email":"data:image/png;base64,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","orcid":"","institution":"Angers University Hospital","correspondingAuthor":true,"prefix":"","firstName":"Audrey","middleName":"","lastName":"ASTRUC","suffix":""},{"id":278087492,"identity":"e587bbc2-0a5a-47f7-bf1c-45a4cae4a0bf","order_by":1,"name":"Delphine DESEINE","email":"","orcid":"","institution":"Angers University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Delphine","middleName":"","lastName":"DESEINE","suffix":""},{"id":278087493,"identity":"75933753-313b-4c23-bd9a-fd3cc2eda6f0","order_by":2,"name":"Magalie BOUGUENET","email":"","orcid":"","institution":"Angers University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Magalie","middleName":"","lastName":"BOUGUENET","suffix":""},{"id":278087494,"identity":"c4800850-0ad1-4610-a720-4386d450255d","order_by":3,"name":"Andrew SPIERS","email":"","orcid":"","institution":"Angers University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Andrew","middleName":"","lastName":"SPIERS","suffix":""},{"id":278087495,"identity":"7f58c5fa-5de2-47de-9f68-5af5da5885c5","order_by":4,"name":"Pascale MAY-PANLOUP","email":"","orcid":"","institution":"Angers University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pascale","middleName":"","lastName":"MAY-PANLOUP","suffix":""},{"id":278087496,"identity":"e0a68ec8-b3fe-409b-b297-fff551e79e57","order_by":5,"name":"Pierre Emmanuel BOUET","email":"","orcid":"","institution":"Angers University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Pierre","middleName":"Emmanuel","lastName":"BOUET","suffix":""},{"id":278087497,"identity":"fd67814b-5de3-4bd0-a819-9ee517162e69","order_by":6,"name":"Guillaume LEGENDRE","email":"","orcid":"","institution":"Angers University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Guillaume","middleName":"","lastName":"LEGENDRE","suffix":""}],"badges":[],"createdAt":"2024-03-07 17:46:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4029966/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4029966/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":52536628,"identity":"f1de2290-9904-4836-86bf-67b1e0f1d708","added_by":"auto","created_at":"2024-03-12 16:36:01","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23483,"visible":true,"origin":"","legend":"\u003cp\u003eSchedule of the NICHE-ART Timeline, using the SPIRIT figure\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4029966/v1/8fed612124f18c105d73ba3b.png"},{"id":58651566,"identity":"e7eb1c0d-9f29-4195-89bb-ff97fdd88f17","added_by":"auto","created_at":"2024-06-19 10:15:17","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":305876,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4029966/v1/81065289-b9a7-4a68-a89e-ee85d5fcabf9.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of cesarean scar defects on the success of assisted human reproduction: The NICHE- ART prospective cohort study protocol","fulltext":[{"header":"Background","content":"\u003cp\u003eThe prevalence of caesarean sections (CS) continues to increase around the world. CS represent 21% of deliveries in France and in the world and is expected to keep increasing around 28% by 2030 according to the WHO\u0026nbsp;(1,2).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eUterine defect, or isthmocele, or uterine niche, was defined by Morris in 1995 as a scarring abnormality with a dehiscence of the hysterotomy following a caesarean section\u0026nbsp;(3). Prevalence of isthmocele varies depending on the exam used for the diagnosis: between 13 and 84% with transvaginal ultrasound (TVS) and between 42 and 84% with sonohysterography (SHG)\u0026nbsp;(4)\u0026nbsp;.\u003c/p\u003e\n\u003cp\u003eAs to date, a standardized definition of isthmocele does not exist. Many exams can be performed for the diagnosis such as 2D and 3D transvaginal ultrasound, sonohysterography, hysteroscopy, MRI; although transvaginal ultrasound and sonohysterography are the most feasible, cost-effective methods requiring the least amount of training\u0026nbsp;(4,5). As an isthmocele can be missed during transvaginal ultrasound if only searched in the sagittal plane or if there isn\u0026rsquo;t intra uterine fluid, the European Niche Taskforce recommended in 2019 using a modified Delphi method\u0026nbsp;(6)\u0026nbsp;that a niche should be searched both in the transvaginal and sagittal planes and that the use of saline or gel is preferred. They agreed on a definition of a niche as an indentation at the site of the CS scar with a depth of at least 2 mm. In recent studies, a large niche should be when considered when the residual myometrial thickness (RMT) is of less than 2 or 3mm\u0026nbsp;(4).\u003c/p\u003e\n\u003cp\u003eIsthmocele leads to long term complications such as gynecological symptoms (abnormal uterine bleeding, chronic pelvic pain), secondary infertility and to an increased risk of obstetrical complications such as ectopic pregnancy in cesarean scar defects, placental disorders (placenta previa or accreta) or uterine rupture\u0026nbsp;(4,7).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSurgical management of isthmocele can be performed either by hysteroscopy or vaginally / laparoscopy depending on whether the RMT is \u0026lt; 3mm. Either way, they are simple procedures with very few complications\u0026nbsp;(7,8), a quick recovery and allow in 85% to 93% the resolution of symptoms\u0026nbsp;(8). Surgical management of isthmocele may also have an impact on secondary infertility\u0026nbsp;(5). A recent prospective cohort (133 women) found a pregnancy rate of 60% 2 years after laparoscopic management of isthmocele on women with secondary infertility\u0026nbsp;(9). Also, there is still lacking high quality evidence on the matter.\u003c/p\u003e\n\u003cp\u003eThe association between isthmocele and secondary infertility is not well described. Gurol Guranci \u003cem\u003eet al.\u003c/em\u003e reported that a caesarean section reduces the probability of subsequent pregnancy by 10% [relative risk (RR) 0.91; 95% 0.87\u0026ndash;0.95] on average, compared with a previous vaginal delivery\u0026nbsp;(10). However, no distinction was made if an isthmocele was present or not. Naji \u003cem\u003eet al.\u003c/em\u003e found that isthmocele could impact on the embryo implantation site and lead to more miscarriages\u0026nbsp;(11). \u0026nbsp;A very recent meta-analysis of Vitagliano \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003eevaluating the effect of isthmocele on IVF success showed that patients with isthmocele had lower live birth rate, clinical birth rate, implantation rate and a higher miscarriage rate\u0026nbsp;(12). Interestingly, they found that patients with a history of a scarred uterus without isthmocele had a similar live birth rate to those with a history of vaginal delivery, which attributed the negative effect on IVF to the isthmocele and not the cesarian section. However, the studies included were only retrospective studies.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this context, we aim to evaluate prospectively the impact of isthmoceles on IVF success.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy design/Aim\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOur aim is to investigate the association between the presence of an isthmocele and the clinical pregnancy rate obtained after IVF (first or second attempt) in patients with a scarred uterus.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe study will have a multicentric, parallel group, comparative, non-interventional, exploratory, and prospective design. Recruitment will be done among patients consulting for care in the Reproductive Unit in each of the 10 public hospitals in, France.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEnrollment\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eWomen between 18 and 43 years old, French speaking, with a history of at least one caesarean section (single or multi-scarred uterus) and a secondary infertility requiring ART techniques (IVF or IVF with ICSI) will be invited to participate to the study. A sonohysterography and a transvaginal ultrasound examination as part of the pre-ART assessment to evaluate the presence or absence of an isthmocele will have to be performed prior to the inclusion. Patients with a uterine scar other than from a low segment or who refuse to participate to the study will not be included.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSample size calculation\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eIn the Angers University Hospital Reproductive unit, the overall pregnancy rate with IVF is approximately 26%. Regarding the population of patients with a scarred uterus, data collected in this unit in 2017 and 2018 shows that 7 patients each year had a scarred uterus without a significant isthmocele. A significant isthmocele was found in 8 patients in 2017 and 6 patients in 2018.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen considering the impact of an isthmocele, a relative decrease in the clinical pregnancy rate, among patients undergoing ART, of 50% is considered to be clinically significant. This limit is similar among other pathologies affecting ART, such as hydrosalpinx or the presence of submucosal myomas\u0026nbsp;(13,14).\u003c/p\u003e\n\u003cp\u003eIt is necessary to include a minimum of 226 patients (for an isthmocele prevalence estimated at 50% based on our 2017 data) with a power of 80% and an alpha risk set at 5% with a bilateral calculation (Casagrande and Pike method).\u0026nbsp;(15)\u003c/p\u003e\n\u003cp\u003eTo anticipate loss of follow-up (estimated at approximately 10%), it is planned to include 250 patients with scarred uterus managed with ART in the cohort.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eIntervention\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the initial ART consultation, the study is presented (oral information and distribution of a brochure) to patients consulting for infertility and with a history of caesarean section.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;ART treatment assessment (blood tests and imaging: TVS and SHG) is prescribed If they agree to take part in the study, the non-opposition of eligible patients is collected during this consultation (pre-inclusion).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor patients agreeing to participate in the study, a specific measurement is made during the TVS and SHG examination in order to determine the presence or absence of an isthmocele. Inclusion in the study is validated after a successful examination that confirms the presence or absence of an isthmocele. The patients are then attributed either to the: \u0026quot;isthmocele +\u0026rdquo; group or \u0026quot;isthmocele -\u0026ldquo;group. An isthmocele will be diagnosed when\u0026nbsp;indentation is found at the site of the CS scar with a depth of at least 2 mm. A large isthmocele will be considered when the RMT is \u0026lt;3mm on SHG.\u003c/p\u003e\n\u003cp\u003eAs part of the standard ART treatment, blood hCG tests are carried out 14 days after embryo transfer to detect a possible pregnancy. If the blood hCG levels are positive, the test is repeated 48 hours later and again a week later to survey the evolution of the blood hCG levels. At 6 to 7 weeks after oocyte puncture, an ultrasound scan is performed in the Reproductive department if the blood hCGs level is greater than 10 IU/L with a satisfactory evolution after 48 hours. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn the case of pregnancy and delivery in the same hospital as the ART treatment, obstetrical data is collected by the investigators from the obstetrical file. In the case of delivery at another facility, patients were contacted by telephone one year after a positive pregnancy test (hCG).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eParticipant timeline\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe patient timeline is shown in Figure 1 using the Spirit Guidelines (16).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eOutcome\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003ePrimary Outcome\u0026nbsp;\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOur primary outcome will be to compare the clinical pregnancy rate (as defined by the visualization of gestational sac on the transvaginal ultrasound) obtained after in vitro fertilization (or IVF with ICSI) in patients with and without isthmocele.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eSecondary outcomes\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eOther criteria evaluating the diagnosis of isthmocele or results of IVF or IVF with ICSI will be assessed:\u0026nbsp;\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eThe rate of biochemical pregnancies: early termination of pregnancy with positive urine or blood hCG that is then negative without ultrasound localization of the pregnancy.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eThe rate of evolving pregnancies: a biochemical and evolving pregnancy is defined by the presence of an intrauterine gestational sac and an embryo with cardiac activity visible during an ultrasound examination between 11 weeks and 13 weeks and 6 days of amenorrhea.\u003c/li\u003e\n \u003cli\u003eLive birth rate: live birth defined as the birth of a living child after 22 weeks\u0026rsquo; gestational age, or weighing\u0026nbsp;\u0026ge;\u0026nbsp;500g.\u003c/li\u003e\n \u003cli\u003eThe rate of ectopic pregnancies on scar tissue from caesarean section.\u003c/li\u003e\n \u003cli\u003eThe rate of complications during embryo transfer (composite criteria associating false passages, the need to use a rigid catheter or the placement of a Pozzi forceps).\u003c/li\u003e\n \u003cli\u003eThe rate of obstetric complications in the event of birth (composite criteria associating placental disorders, uterine rupture, post-partum hemorrhage, term at delivery, type of birth).\u003c/li\u003e\n \u003cli\u003eThe rate of immediate neonatal complications (birth weight \u0026lt; 10th percentile, Apgar score, pH and lactate, rate of transfer to an intensive care unit).\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eData collection\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong patients accepting to participate to the study, during the initial consultation socio-demographic data and the couple\u0026apos;s medical history are collected.\u003c/p\u003e\n\u003cp\u003eDuring the second ART consultation, the results of the treatment assessment are collected, the presence or absence of an isthmocele on the SHG examination.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubsequently, the data relative to ovarian stimulation, the methods of triggering and embryo transfer are collected prospectively by the investigator.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eData management\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eAll data for this study are collected in a paper observation notebook from valid source documents (patient medical records).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePatients are identified by a unique number. In order to avoid any misidentification of patients, the initials of the surname and first name, as well as the month and year of birth are also collected.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe paper records are centralised at the Angers university hospital and entered into an EPIDATA database managed by the Angers University Hospitals Delegation of Clinical Research and Innovation (DRCI).\u0026nbsp;The data collected does not mention the identity of the patients (surnames, first names, date of birth are not used). Patients are identified via a center number or a file number per center. A correspondence list is kept in each center.\u003c/p\u003e\n\u003cp\u003eChecks are regularly carried out to verify the consistency and completeness of the data entered. The list of checkpoints is defined jointly by the coordinating investigator and DRCI\u0026apos;s Data Management Unit, in the studies data validation plan.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCorrection requests are processed by the data manager. They are sent to the investigating center, which make the necessary corrections to resolve the correction requests.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA list of typical corrections that can be made by the data managers is defined in the studies data validation plan.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe database will be locked for the final analysis. The database is locked in accordance with the procedure established by DRCI.\u003c/p\u003e\n\u003cp\u003ePersons with direct access to the data are to take all necessary precautions to ensure the confidentiality of information relating to the persons participating in the study and in particular regarding their identity and the results obtained. These persons are subject to professional secrecy (according to the conditions defined by articles 226-13 and 226-14 of the penal code).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical Analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor qualitative variables, the results are reported as numbers and percentages and then compared using Pearson\u0026apos;s Chi-square test (or Fisher\u0026apos;s exact test).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor quantitative variables, the primary quartiles (median and 25\u0026deg; and 75\u0026deg; percentile) are reported in the form of a box-plot diagram. In case of normality of the variable (Q-Q plot) the mean and standard deviation as well as the 95% confidence interval are to be specified. If possible, the student\u0026rsquo;s t-test is used for comparison tests. If this is not possible, the Mann Whitney test is carried out. P-values of less than 5% indicate a significant difference.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTwo analysis will be run : one with isthmocele defined as an indentation at the site of the CS scar with a depth of at least 2 mm and one focusing only on large isthmocele defined as a RMT \u0026lt; 3mm.\u003c/p\u003e\n\u003cp\u003eTo achieve the primary objective of the study, which is to investigate the association between the presence of an isthmocele and the clinical pregnancy rate obtained after in vitro fertilization (IVF or IVF with ICSI) in patients with a scarred uterus (single or multi-scarred), standard tools of descriptive statistics are to be employed. Data will be compared using a Chi2 test (or an exact File test if necessary).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTo satisfy the secondary objectives of the study which is to explore the associations between the presence of an isthmocele and other criteria evaluating the results of IVF (or IVF with ICSI) in patients with a scarred uterus (single or multi-scarred), similar descriptive diagrams and comparative tests will be used.\u003c/p\u003e\n\u003cp\u003eDue to the exploratory nature of the study, a multivariate analysis (binary logistic regression or multifactorial linear regression) that considers the binary variable \u0026quot;isthmocele\u0026quot; and the other risk factors associated with implantation failure will be conducted. The number of variables to be included in the model will depend on the pregnancy rate within the cohort (estimated at approximately 25% in the case of a scarred uterus based on the department\u0026rsquo;s figures).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAt least five variables in addition to the \u0026quot;isthmocele\u0026quot; variable could therefore be taken into account in our final analysis. A residue analysis will be conducted to validate the proposed model.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe significance threshold is set at 0.05 and all tests will be bilateral. Analyses will be conducted using R and Excel software.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this study, we hypothesize that isthmocele will have a negative impact on IVF results. It is known that CS lower the pregnancy and birth rates of around 10% compared to vaginal delivery\u0026nbsp;(10). However, few data exist on the implications of isthmocele in secondary infertility\u0026nbsp;(17,18). \u0026nbsp;On the current hypothesis, one is that isthmocele might provide a detrimental environment for sperm penetration and embryo implantation\u0026nbsp;(19)\u0026nbsp;by the accumulation of intra uterine fluid acting like in other gynecological conditions such as hydrosalpinx\u0026nbsp;(13), the increased inflammation within the niche\u0026nbsp;(11,20), the distorted myometrial contractility due to the uterine scar. In a prospective study on 364 women presenting secondary infertility\u0026nbsp;(21), significantly more bacteria colonies including among other colonies more Gram neg rods (E.Coli, Pseudomonas Aeruginosa) were found in uterine niche than in patients without a uterine niche or without CS (respectively 89.6%, 69.6% and 49.7%). If we make the analogy with chronic endometriosis\u0026nbsp;(22,23), we might hypothesize that it could influence IVF results.\u003c/p\u003e\n\u003cp\u003eAnother observation is that a large niche could affect the accessibility for an embryo transfer\u0026nbsp;(19)\u0026nbsp;with difficulty accessing the uterine cavity with the transfer catheter especially in retroflexed uterus using more manipulation affecting the quality of the embryo transfer\u0026nbsp;(24).\u003c/p\u003e\n\u003cp\u003eIf clinical symptoms are associated with isthmocele on the other hand, whether the size or volume\u0026lsquo;s niche is correlated to the symptoms\u0026rsquo; apparition is not clear. A question Mohr-Sasson \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003etried to answer on their study of 282 women where although there were no differences in niches\u0026rsquo; sizes between symptomatic and asymptomatic women, when taken separately, infertility was associated with a RMT of less than 2.5mm\u0026nbsp;(25).\u003c/p\u003e\n\u003cp\u003eIf our hypothesis is confirmed, this trial will provide evidence that isthmocele can affect IVF and can change the way we handle secondary infertility after a history of caesarian. The surgical management improves the general symptoms of isthmoceles but evidence on an amelioration of a secondary infertility is unclear. In a prospective cohort of Vervoort \u003cem\u003eet al.\u0026nbsp;\u003c/em\u003eon 101 patients, laparoscopic resection of uterine niche allowed a decrease in the niche depth and a disappearance of intra uterine fluid which is promising for women suffering from secondary infertility\u0026nbsp;(26). \u0026nbsp;In the meta-analysis of Vitale \u003cem\u003eet al.\u003c/em\u003e, it was found pregnancy rates of 88,75 % after hysteroscopic management, 45,1% after laparoscopic management but the studies didn\u0026rsquo;t specify the couple fertility history prior to the surgery\u0026nbsp;(8). \u0026nbsp;In the meta analysis of Verbeckt \u003cem\u003eet al.\u003c/em\u003e, the benefit of niche surgery in women with infertility on reproductive outcome could not be answered as only one retrospective study on 61 patients addressed the question (relative risk, 2.41; 95% CI, 1.32\u0026ndash;4.39 in favour of the surgery)\u0026nbsp;(18). Thus, further studies will be needed to propose surgical management before starting the ART treatment\u003cstrong\u003e.\u003c/strong\u003e\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eCS: Caesarean section\u003c/p\u003e\n\u003cp\u003eTVS: Transvaginal Ultrasound\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSHG: Sonohysterography\u003c/p\u003e\n\u003cp\u003eRMT: Residual Myometrial Thickness\u003c/p\u003e\n\u003cp\u003eIVF: In Vitro Fertilization\u003c/p\u003e\n\u003cp\u003eART: Assisted Reproductive Techniques\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cem\u003eEthics approval and consent to participate.\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol has been approved by relevant French authorities Comit\u0026eacute; de Protection des Personnes Sud M\u0026eacute;diterran\u0026eacute;e IV on the 10th of November 2020 and recorded prospectively (before the inscription of the first participant) under the number ID-RCB: 2020-A02068-31. The study will be conducted according to the guidelines of the Declaration of Helsinki. Prior to the study, all participants will read the informed consent form. The consent obtained from study participants will be written.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eConsent for publication\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAvailability of data and materials\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eCompeting interests\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eFunding\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eNo funding to report. Angers University Hospital is the trial sponsor.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eAuthors\u0026apos; contributions\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eG.L. is the primary investigator who assisted in the trial design and contributed to writing the report. G.L. and A.A. will be involved in trial supervision and trial design. G.L. is responsible for the trial concept. PE.B., D.D., A.S., M.B. and A.A. assisted in site co-ordination. A.A., D.D. and G.L. wrote the manuscript. All authors have read and approved of the final manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eEnqu\u0026ecirc;te nationale p\u0026eacute;rinatale : r\u0026eacute;sultats de l\u0026rsquo;\u0026eacute;dition 2021. (s. d.). https://www.santepubliquefrance.fr/presse/2022/enquete-nationale-perinatale-resultats-de-l-edition-2021.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBetran AP, Ye J, Moller AB, Souza JP, Zhang J. Trends and projections of caesarean section rates: global and regional estimates. BMJ Glob Health. 1 juin 2021;6(6):e005671.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMorris H. Surgical Pathology of the Lower Uterine Segment Caesarean Section Scar: Is the Scar a Source of Clinical Symptoms? Int J Gynecol Pathol. janv 1995;14(1):16‑20.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKlein Meuleman SJM, Min N, Hehenkamp WJK, Post Uiterweer ED, Huirne JAF, De Leeuw RA. The definition, diagnosis, and symptoms of the uterine niche \u0026ndash; A systematic review.\u0026nbsp;Best Pract Res Clin Obstet Gynaecol. ao\u0026ucirc;t 2023;90:102390.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDominguez JA, Pacheco LA, Moratalla E, Carugno JA, Carrera M, Perez‐Milan F, et al.\u0026nbsp;Diagnosis and management of isthmocele (Cesarean scar defect): a SWOT analysis.\u0026nbsp;Ultrasound Obstet Gynecol. sept 2023;62(3):336‑44.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eJordans IPM, de Leeuw RA, Stegwee SI, Amso NN, Barri-Soldevila PN, van den Bosch T, et al.\u0026nbsp;Sonographic examination of uterine niche in non-pregnant women: a modified Delphi procedure. Ultrasound Obstet Gynecol. 2019;53(1):107‑15.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDonnez O. Cesarean scar defects: management of an iatrogenic pathology whose prevalence has dramatically increased. Fertil Steril. avr 2020;113(4):704‑16.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVitale SG, Ludwin A, Vilos GA, T\u0026ouml;r\u0026ouml;k P, Tesarik J, Vitagliano A, et al. From hysteroscopy to laparoendoscopic surgery: what is the best surgical approach for symptomatic isthmocele? A systematic review and meta-analysis. Arch Gynecol Obstet. janv 2020;301(1):33‑52.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVissers J, Hehenkamp WJK, Br\u0026ouml;lmann HAM, Lambalk CB, Huirne JAF. Reproductive outcomes after laparoscopic resection of symptomatic niches in uterine cesarean scars: Long‐term follow‐up on the prospective LAPNICHE study. Acta Obstet Gynecol Scand. d\u0026eacute;c 2023;102(12):1643‑52.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eGurol-Urganci I, Bou-Antoun S, Lim CP, Cromwell DA, Mahmood TA, Templeton A, et al. Impact of Caesarean section on subsequent fertility: a systematic review and meta-analysis. Hum Reprod. juill 2013;28(7):1943‑52.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eNaji O, Wynants L, Smith A, Abdallah Y, Saso S, Stalder C, et al. Does the presence of a Caesarean section scar affect implantation site and early pregnancy outcome in women attending an early pregnancy assessment unit?\u0026nbsp;Hum Reprod. 1 juin 2013;28(6):1489‑96.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVitagliano A, Cicinelli E, Vigan\u0026ograve; P, Sorgente G, Nicol\u0026igrave; P, Busnelli A, et al.\u0026nbsp;Isthmocele, not cesarean section per se, reduces in vitro fertilization success: a systematic review and meta-analysis of over 10,000 embryo transfer cycles. Fertil Steril. 10 nov 2023;S0015-0282(23)01996-9.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eZeyneloglu HB, Arici A, Olive DL. Adverse effects of hydrosalpinx on pregnancy rates after in vitro fertilization\u0026ndash;embryo transfer. Fertil Steril. sept 1998;70(3):492‑9.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDi Spiezio Sardo A, Di Carlo C, Minozzi S, Spinelli M, Pistotti V, Alviggi C, et al. Efficacy of hysteroscopy in improving reproductive outcomes of infertile couples: a systematic review and meta-analysis. Hum Reprod Update. juin 2016;22(4):479‑96.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eCasagrande JT, Pike MC. An improved approximate formula for calculating sample sizes for comparing two binomial distributions. Biometrics. sept 1978;34(3):483‑6.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChan AW, Tetzlaff JM, Altman DG, Laupacis A, G\u0026oslash;tzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 Statement: Defining Standard Protocol Items for Clinical Trials. Ann Intern Med. 5 f\u0026eacute;vr 2013;158(3):200.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eDiao J, Gao G, Zhang Y, Wang X, Zhang Y, Han Y, et al.\u0026nbsp;Caesarean section defects may affect pregnancy outcomes after in vitro fertilization-embryo transfer: a retrospective study. BMC Pregnancy Childbirth. d\u0026eacute;c 2021;21(1):487.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVerberkt C, Klein Meuleman SJM, Ket JCF, Van Wely M, Bouwsma E, Huirne JAF. Fertility and pregnancy outcomes after a uterine niche resection in women with and without infertility: a systematic review and meta-analysis. FS Rev. juill 2022;3(3):174‑89.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVissers J, Hehenkamp W, Lambalk CB, Huirne JA. Post-Caesarean section niche-related impaired fertility: hypothetical mechanisms. Hum Reprod. 1 juill 2020;35(7):1484‑94.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eBi B, Gao S, Ruan F, Shi Y, Jiang Y, Liu S, et al. Analysis on clinical association of uterine scar diverticulum with subsequent infertility in patients underwent cesarean section. Medicine (Baltimore). 15 oct 2021;100(41):e27531.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eHsu I, Hsu L, Dorjee S, Hsu CC. Bacterial colonization at caesarean section defects in women of secondary infertility: an observational study. BMC Pregnancy Childbirth. 18 f\u0026eacute;vr 2022;22(1):135.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eChen Q, Zhang X, Hu Q, Zhang W, Xie Y, Wei W. The alteration of intrauterine microbiota in chronic endometritis patients based on 16S rRNA sequencing analysis. Ann Clin Microbiol Antimicrob. 12 janv 2023;22(1):4.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMoreno I, Simon C. Relevance of assessing the uterine microbiota in infertility. Fertil Steril. ao\u0026ucirc;t 2018;110(3):337‑43.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003ePhillips JAS, Martins WP, Nastri CO, Raine-Fenning NJ. Difficult embryo transfers or blood on catheter and assisted reproductive outcomes: a systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol. juin 2013;168(2):121‑8.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eMohr-Sasson A, Dadon T, Brandt A, Shats M, Axcelrod M, Meyer R, et al. The association between uterine scar defect (niche) and the presence of symptoms. Reprod Biomed Online. ao\u0026ucirc;t 2023;47(2):103221.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eVervoort A, Vissers J, Hehenkamp W, Br\u0026ouml;lmann H, Huirne J. The effect of laparoscopic resection of large niches in the uterine caesarean scar on symptoms, ultrasound findings and quality of life: a prospective cohort study. BJOG Int J Obstet Gynaecol. f\u0026eacute;vr 2018;125(3):317‑25. \u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"caesarean scar defect, Isthmocele, Infertility, in vitro fertilization, Clinical pregnancy rate ","lastPublishedDoi":"10.21203/rs.3.rs-4029966/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4029966/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground: \u003c/em\u003eThe prevalence of caesarean sections worldwide continues to rise, increasing the risk of obstetric complications. Isthmocele, defined as a dehiscence of the hysterotomy following a caesarean section, can lead to intermenstrual bleeding or pelvic pain. Studies have shown that surgical treatment of isthmoceles reduces the incidence of metrorrhagia. In these studies, the authors noted that patients with abnormal bleeding outside the cycle were also more frequently affected by secondary infertility. However, isthmocele surgery can result in intrauterine adhesions and synechiae, which are also recognized as potentially deleterious to fertility. The impact of the presence of an isthmocele on the results of ART must therefore be demonstrated before any attempt at treatment, and this will require larger-scale prospective studies, using a consensus definition of the isthmocele based on sonohysterography (currently considered the \"gold standard\" examination).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eMethods: \u003c/em\u003eWe designed a multicentric prospective study that will be conducted in 10 French Reproductive Medicine centers. We will include women consulting for infertility with a history of scarred uterus. During sonohysterography and transvaginal ultrasound, a specific measurement is taken to define the presence or absence of an isthmocele, and to classify patients into one of two groups: \"isthmocele +\" or \"isthmocele -\". \u0026nbsp;The main objective of the study is to investigate the association between the presence of an isthmocele and the clinical pregnancy rate obtained after in vitro fertilization in patients with a scarred uterus (single or multi-scarred). The primary outcome is clinical pregnancy rate, as defined by the visualization of gestational sac on the transvaginal ultrasound. We will need to include 250 women with a scarred uterus undergoing ART. The duration of the inclusion period is estimated to be 42 months.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eDiscussion:\u003c/em\u003e If our study shows a reduction in the clinical pregnancy rate in the presence of an isthmocele, this could lead to a change in clinical practices for patients undergoing ART.\u003cem\u003e \u003c/em\u003eIndeed, surgical management of the isthmocele could be discussed prior to ART by informing the patient of the benefit-risk balance of the operation.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTrial registration: \u003c/em\u003eClinicalTrials.gov, ID:. NCT04869007. Registered on August 16\u003csup\u003eth\u003c/sup\u003e, 2020.\u003c/p\u003e","manuscriptTitle":"Impact of cesarean scar defects on the success of assisted human reproduction: The NICHE- ART prospective cohort study protocol","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-12 16:35:57","doi":"10.21203/rs.3.rs-4029966/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"cba1947b-fc29-422f-ae57-3bd337a40784","owner":[],"postedDate":"March 12th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-19T10:07:11+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-12 16:35:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4029966","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4029966","identity":"rs-4029966","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}