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

Abstract

Background

The global increase in caesarean sections (CS), currently at 21.1% of all deliveries, has led to a rise in uterine scar defects, or ‘niches’, at the hysterotomy site. These niches, detectable in 13%–84% of cases via transvaginal ultrasound (TVS) and 42%–84% through sonohysterography (SHG), may contribute to gynaecological complications, including abnormal uterine bleeding, chronic pain and secondary infertility. Niche-associated risks for in vitro fertilisation (IVF) outcomes remain underexplored, and this study aims to evaluate their impact on clinical pregnancy rates.

Methods and analysis

This multicentre, prospective, non-interventional study will involve 250 women with a history of CS and secondary infertility undergoing IVF in 14 reproductive units of French Hospital. Participants will be assessed using SHG and TVS to determine niche presence (measurements of the length, depth and width of the niche, and residual myometrial thickness (RMT)). A niche is diagnosed by an indentation of at least 2 mm at the site of the caesarean scar, with a large niche defined as RMT <3 mm. The primary outcome is clinical pregnancy rate, with secondary outcomes including live birth rates, biochemical pregnancies and obstetric complications. Multivariate logistic regression will control for confounders. The duration of the inclusion period is estimated to be 42 months.

Ethics and dissemination

The study protocol was approved by the relevant French medical review board, ‘Comité de Protection des Personnes Sud Méditerranée IV’, on 10 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. Informed consent will be obtained from all participants. The findings will be published in peer-reviewed journals and presented at relevant meetings.

Trial registration number

ClinicalTrials.gov, ID: NCT04869007. Registered on 16 August 2020.

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• The multicentric and prospective design with the involvement of multiple hospitals across France.

• A standardised diagnostic method will be used with transvaginal ultrasound and sonohysterography with clear criteria for identifying niches, ensuring uniformity in data collection and diagnosis.

• Clear outcome measures are defined and specifically focused on clinical pregnancy rates and other relevant in vitro fertilisation outcomes.

• The study is large and powered to address the primary objective.

• The observational design can limit the strength of conclusions.

Background

The global prevalence of caesarean sections (CS) continues to rise, accounting for 21.1% of all deliveries worldwide.¹ Rates range from as low as 5% in sub-Saharan Africa to as high as 42.8% in Latin America. This trend is projected to increase further, with estimates suggesting that CS may account for nearly 28% of deliveries by 2030, according to the WHO.^{1 2}

A uterine scar defect, or uterine niche, was first defined by Morris in 1995 as a scar dehiscence or abnormality at the site of the hysterotomy following a CS.³ The prevalence of niches varies depending on the diagnostic modality used. Transvaginal ultrasound (TVS) detects niches in 13%–84% of cases, while sonohysterography (SHG) reports a prevalence of 42%–84%.⁴

Several diagnostic methods are available, including two-dimensional and three-dimensional TVS, SHG, hysteroscopy and MRI, with TVS and SHG being the most accessible and cost-effective options, requiring minimal specialised training.^{4 5} However, due to potential limitations—such as missing a niche if only the sagittal plane is examined or if intrauterine fluid is absent—the European Niche Taskforce recommended, in 2019, using a Delphi method,⁶ that niches should be assessed in both the sagittal and transverse planes and that saline or gel infusion could be used to enhance diagnostic accuracy. A niche was then defined as an indentation at the CS scar site with a depth of at least 2 mm. No consensus exists on the definition of a large niche, but a niche could be considered large when the residual myometrial thickness (RMT) is less than 2 mm or 3 mm.⁴

Uterine niches can lead to long-term complications, including gynaecological symptoms such as abnormal uterine bleeding and chronic pelvic pain, secondary infertility and an elevated risk of obstetric complications. These obstetric risks include ectopic pregnancy within the scar, placental disorders, such as placenta previa and placenta accreta, and uterine rupture.^{4 7}

Surgical management of uterine niches can be performed hysteroscopically, vaginally or via laparoscopy, depending on the RMT being <3 mm. These procedures are generally considered safe, are associated with few complications and offer a swift recovery. Symptom resolution is achieved in 85%–93% of cases.^{7 8} Additionally, surgical intervention may improve fertility outcomes, particularly in women with secondary infertility.⁵ A recent prospective cohort study of 133 women reported a pregnancy rate of 60%, 2 years following laparoscopic niche repair in women with secondary infertility.⁹ However, high-quality evidence supporting these findings remains scarce.

The association between uterine niche and secondary infertility is not fully understood. Gurol Guranci et al reported that CS reduced the probability of subsequent pregnancy by 10% (risk ratio (RR) 0.91; 95% CI 0.87 to 0.95), compared with previous vaginal delivery.¹⁰ However, this analysis did not differentiate between women with and without a niche. Naji et al demonstrated that the presence of a niche may interfere with embryo implantation and increase the risk of miscarriage.¹¹ A very recent meta-analysis of Vitagliano et al assessed the impact of niches on in vitro fertilisation (IVF) outcomes, showing that patients with uterine niches had lower live birth, clinical pregnancy and implantation rates, along with a higher risk of miscarriage.¹² Patients with a caesarean scar but no niche exhibited live birth rates comparable to those with a history of vaginal delivery, suggesting that the negative effect on IVF outcomes is attributed to the niche itself rather than the CS alone. However, the studies included in this meta-analysis were predominantly retrospective.

In light of these findings, our aim is to prospectively evaluate the impact of uterine niches on IVF success rates.

Methods and analysis

Study design/aim

The primary aim of this study is to evaluate the association between the presence of a uterine niche and the clinical pregnancy rate following IVF (first or second attempt) in patients with a caesarean-scarred uterus.

This is a multicentric, parallel-group, comparative, non-interventional, exploratory and prospective study. Recruitment will be conducted at 14 medical centres across France, including University Hospitals in Angers, Brest, Limoges, Nîmes, Rennes, Saint-Étienne, Tenon Teaching Hospital in Paris, La Sagesse Clinic in Rennes, Sud Francilien Hospital and Créteil Hospital.

Enrolment

Inclusion criteria

Women aged 18 and 43 years, with a history of at least one CS (single or multiple scars) and secondary infertility requiring assisted reproductive technology (ART) (IVF or IVF with intracytoplasmic sperm injection (ICSI)), will be invited to participate. All participants must undergo SHG and TVS as part of pre-ART assessments to determine the presence or absence of a uterine niche. Exclusion criteria include patients with uterine scars not involving the lower uterine segment or those unwilling to participate in the study. Patients will be excluded if SHG and TVS evaluations are not performed.

Sample size calculation

At the Angers University Hospital reproductive unit, the clinical pregnancy rate following IVF is approximately 26%. Among patients with a scarred uterus, data from 2017 and 2018 revealed that seven patients each year had a caesarean scar without a significant niche, while a significant niche was found in eight patients in 2017 and six patients in 2018.

Given a 50% relative reduction in clinical pregnancy rates for patients with a niche (similar to the impact of hydrosalpinx or submucosal fibroids on ART outcomes),^{13 14} a sample size of 226 patients is required to achieve 80% power with a 5% alpha risk (unilateral) using the Casagrande and Pike method.¹⁵ To account for an estimated 10% loss to follow-up, 250 patients with scarred uteri undergoing ART will be recruited.

Intervention

At the initial ART consultation, patients will receive oral and written information about the study (online supplemental material). If they consent, their eligibility will be confirmed during the consultation, and SHG and TVS will be used to assess the presence or absence of a niche. The patients will then be attributed either to the ‘niche+’ group or the ‘niche−’ group. Specific measurements will be taken to define the niche: the length and depth of the niche and RMT in the sagittal plane and the width of the niche in the transversal plane. The niche volume will be calculated. A niche is diagnosed by an indentation of at least 2 mm at the site of the caesarean scar, with a large niche defined as RMT <3 mm.

Standard ART protocols will be followed, and blood human chorionic gonadotropin (hCG) levels will be measured 14 days after embryo transfer to confirm pregnancy. If positive, hCG testing will be repeated at 48 hours and weekly until 6–7 weeks after oocyte retrieval, when a TVS will be performed. Obstetric data will be collected if delivery occurs at the same facility; otherwise, patients will be contacted by phone 1 year after a positive pregnancy test.

Participant timeline

The patient timeline is shown in figure 1 following the Standard Protocol Items: Recommendations for Interventional Trials guidelines,¹⁶ with the study starting in September 2024 and follow-up expected to conclude in June 2026.

Figure 1. Schedule of the NICHE-assisted reproductive technology timeline, using the Standard Protocol Items: Recommendations for Interventional Trials figure. hCG, human chorionic gonadotropin.

Outcomes

Primary outcome

The primary outcome is the clinical pregnancy rate (visualisation of a gestational sac on TVS) following IVF or IVF-ICSI in patients with and without a niche.

Secondary outcomes

Other criteria evaluating the diagnosis of niche or results of IVF or IVF with ICSI will be assessed:

• Biochemical pregnancy rate: early pregnancy loss with positive urine or blood hCG but no ultrasound evidence of pregnancy.

• Evolving pregnancy rate: defined by the presence of an intrauterine gestational sac and embryonic cardiac activity on ultrasound between 11 and 13 weeks and 6 days of gestation.

• Live birth rate: defined as the birth of a living infant after 22 weeks of gestation or weighing ≥500 g.

• The rate of ectopic pregnancy at the caesarean scar site.

• Complications during embryo transfer: composite outcome, including false passages, rigid catheter uses or placement of Pozzi forceps.

• Obstetric complications at birth: composite outcome, including placental disorders, uterine rupture, postpartum haemorrhage, gestational age at delivery and mode of delivery.

• Immediate neonatal complications: including birth weight <10th percentile, Apgar score, umbilical cord pH, lactate levels and neonatal intensive care unit admissions.

Data collection

Demographic and clinical data, including infertility parameters (hormonal levels, ovarian reserve and semen analysis), and details regarding the CS (indication and postoperative complications) will be recorded during the initial consultation. Results of SHG, ovarian stimulation, embryo transfer and subsequent outcomes will be collected prospectively.

Data management

Data will be recorded in paper observation notebooks and entered into an EPIDATA database managed by the Clinical Research and Innovation Unit (DRCI) at Angers University Hospital. Patients will be identified by a unique ID number, ensuring anonymity. 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. Patients are identified via a centre number or a file number per centre. A correspondence list is kept in each centre.

Periodic audits will be performed to ensure data completeness and accuracy. Corrections will be made by data managers, following the predefined data validation plan, before the database is locked for final analysis. 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 French penal code).

Patient and public involvement statement

Patients and the public were not directly involved in the design of this study.

Statistical analysis

For qualitative variables, results will be reported as numbers and percentages, with comparisons made using Pearson’s χ² test (or Fisher’s exact test where applicable). For quantitative variables, the primary quartiles (median and 25th and 75th percentiles) will be reported and visualised using box-plot diagrams. In cases where normality is confirmed (using a Q–Q plot), the mean and SD, along with the 95% CI, will be provided. The Student’s t-test will be used for comparisons if normality is met; otherwise, the Mann-Whitney U test will be applied. A p value of less than 0.05 will indicate statistical significance.

Two analyses will be conducted: one with a niche defined as an indentation at the site of the CS scar with a depth of at least 2 mm and one focusing solely on ‘large niche’, defined as a RMT of less than 3 mm.

To achieve the primary objective, the association between the presence of a niche and clinical pregnancy rates after IVF (IVF or IVF with ICSI) in patients with a scarred uterus will be tested in univariate and multivariate logistic regressions to minimise the risk of confounding bias.

For the secondary objectives, which aim to explore the associations between a niche presence and other IVF outcomes in patients with a scarred uterus, descriptive statistics and comparative tests will initially be used. However, like the primary outcome, multivariate logistic regression (or multifactorial linear regression for continuous outcomes) will be employed to control for confounders and provide adjusted estimates. Given the exploratory nature of the study, every variable that is significant in the univariate analysis will be included in the multivariate models. Residual analysis will be conducted to validate the final model.

The significance threshold will be set at 0.05, and all tests will be two-sided. Analyses will be conducted using R and Excel software.

Ethics and dissemination

The study protocol has been approved by the relevant French medical review board, the French Committee for Protection of Persons Sud Méditerranée IV (ID-RCB: 2020-A02068-31; on 10 November 2020), and the trial is registered at ClinicalTrials.gov (NCT04869007). All procedures will adhere to the Declaration of Helsinki. Informed written consent will be obtained from all participants.

Study results will be disseminated in peer-reviewed journals as soon as possible and presented at relevant conferences.

Discussion

In this study, we hypothesise that the presence of a niche will have a negative impact on IVF outcomes. It is well established that CS reduces pregnancy and live birth rates by approximately 10% compared with vaginal delivery.¹⁰ However, data specifically addressing the role of the uterine niche in secondary infertility remains scarce.^{17 18} One hypothesis is that the niche may create a suboptimal environment for sperm penetration and embryo implantation,¹⁹ potentially due to the accumulation of intrauterine fluid, which acts similarly to hydrosalpinx in other gynaecological conditions.¹³ Additional factors may include increased inflammation within the niche^{11 20} and altered myometrial contractility secondary to the uterine scar, both of which may impair implantation. In a prospective study involving 364 women with secondary infertility,²¹ identified a significantly higher prevalence of bacterial colonisation in uterine niches compared with patients without a niche or without a history of CS (89.6%, 69.6% and 49.7%, respectively). The predominant bacteria identified were Gram-negative rods, such as Escherichia coli and Pseudomonas aeruginosa. Drawing parallels with chronic endometriosis,^{22 23} we can hypothesise that microbial colonisation within the niche may adversely affect IVF outcomes.

Another observation is that a large niche could complicate embryo transfer. Specifically, it may pose challenges in catheter navigation through the uterine cavity, particularly in cases of uterine retroflexion, requiring increased manipulation and potentially compromising embryo transfer quality.^{19 24}

The correlation between niche size and clinical symptoms remains uncertain. While some studies have found associations between niche characteristics and symptoms, the evidence is mixed. Kellner et al.²⁵ reported a significant association between dysmenorrhoea and RMT value (OR 0.82, 95% CI 0.71 to 0.95). In contrast, Mohr-Sasson et al found no significant differences in niche size between symptomatic and asymptomatic women. However, they noted that infertility was more frequently associated with an RMT of less than 2.5 mm.²⁶

If our hypothesis is confirmed, this study will provide valuable evidence supporting the notion that uterine niches negatively impact IVF success, potentially altering the management of secondary infertility in women with a history of CS. While surgical management has been shown to alleviate symptoms associated with uterine niches, its effect on improving secondary infertility remains unclear. A prospective cohort study by Vervoort et al, involving 101 patients, demonstrated that laparoscopic resection of uterine niches resulted in a reduction in niche depth and the resolution of intrauterine fluid, offering a promising therapeutic option for women with secondary infertility.²⁷ In a meta-analysis by Vitale et al, pregnancy rates of 88.75% were reported following hysteroscopic management and 45.1% following laparoscopic intervention. However, these studies did not specify the couples’ fertility history prior to surgery.⁸ Similarly, Verbeckt et al.’s meta-analysis noted that the benefits of niche surgery for infertility could not be conclusively determined, as only one retrospective study (61 patients) addressed the issue. This study reported a relative risk of 2.41 (95% CI 1.32 to 4.39) in favour of surgery improving reproductive outcomes.¹⁸ Therefore, further research is required to determine whether surgical intervention for uterine niches should be recommended before initiating ART treatments.