Carry Verberkt

The global rate of caesarean sections (CS) has significantly increased in recent years, currently averaging 21%, with an expected rise to approximately 30% by 2030. A complication of a CS is the development of a niche, defined as an indentation at the site of a CS scar, with a depth of at least 2 mm. Niche formation can lead to gynaecological symptoms such as abnormal bleeding, abdominal pain, and fertility problems.

The aim of this thesis was to investigate the development and prevention of a niche after a CS, along with long-term complications related to fertility and subsequent pregnancies. Additionally, the third part aimed to standardize the sonographic assessment of both a niche and a caesarean scar pregnancy (CSP).

Part I: Development and Prevention of a Niche
Chapter 2 presents a systematic review of 58 studies, we included 8 studies on aetiology, 16 on risk factors and 34 on preventive strategies. Histopathological findings linked to niche development were necrosis, inflammation and insufficient approximation of the uterine wound layers at CS. The notion that fibrosis and necrosis may result from ischemia or as a response to suture material and techniques gains credibility when considering the observed increase in niche incidence with each subsequent CS (from 62% after one CS to 77.8% after three CS). Adenomyosis was reported in four studies, with a prevalence of 5-25%. It is not clear whether the presence of adenomyosis is a co-finding as a result of the CS or that it plays a role in the aetiology of niche development. Numerous risk factors associated with niche development have been identified. Most prominent patient-related factors include multiple CS, body mass index (BMI) and smoking, reflecting the intricate interplay between lifestyle and surgical outcomes. Labour-related factors encompass pre-labour CS, extended cervical dilatation, premature rupture of membranes (PROM), infection and presenting part of the foetus at CS below the pelvic inlet. Surgery-related factors involve closure technique, suture material and level of the incision in the uterus.

In Chapter 3, we compared single-layer and double-layer uterine incision closure using non-locking sutures in women undergoing their first CS. This large multicentre randomized controlled trial (n=2292) showed no superiority of double-layer closure compared to single-layer closure in terms of postmenstrual spotting (1.26 days ±2.77 and 1.33 days ±3.00, respectively) at the 9-month follow-up. However, niche presence was slightly lower after single-layer closure three months after CS compared to the double-layer closure (69% and 74%, respectively, p=0.033). We also observed shorter operative time in the single-layer group. Also, double-layer closure was not considered cost-effective compared with single-layer closure from a societal and healthcare perspective. The 9-month follow-up could be too early to adequately evaluate gynaecological complaints, as 14.5% of women were still experiencing amenorrhea. Moreover, assessing the impact on reproductive outcomes at this stage may be premature. At 3-year follow-up we received questionnaires from 1648 (73.3%) of 2248 women, 830 (73.7%) in the single-layer group and 818 (72.9%) in the double-layer group. No differences were observed in live birth rates, our main outcome. Additionally, no differences in pregnancy rate, need for fertility treatments, mode of delivery or uterine ruptures in subsequent pregnancies. High rates of gynaecological symptoms including spotting (30-32%), dysmenorrhea (47-49%) and sexual dysfunction (FSFI score 23) are reported in both groups.

Subsequently, there are in addendum 3a and 3b two letters to the editor discussing the optimal closure technique, adding depth to our exploration.

We conducted a multicentre, randomized controlled trial in which we evaluated the effectiveness of application of an adhesion barrier on the uterine wound at CS in order to prevent niche-related gynaecological symptoms nine months after a first CS. The study protocol is described in Chapter 4. The primary outcome was dysmenorrhea at 9-months follow-up. Niche prevalence and presence of adhesions were assessed by ultrasound at three months as a secondary outcome. Sample size calculation showed that 114 women had to be included to find a difference in dysmenorrhea score.

Part II: Long-term Complications of a Niche
We conducted a systematic review and meta-analysis, presented in Chapter 5, to investigate the impact of surgical interventions in women with a niche diagnosed with and without infertility on their fertility and pregnancy outcomes. A total of 21 studies were included (one RCT, one case series, five prospective and fourteen retrospective cohort studies), reporting on 889 women. The surgical techniques examined were hysteroscopic niche resection (HNR) in fourteen studies, vaginal niche resection (VNR) in seven studies, laparoscopic niche resection (LSNR) in seven studies, and laparotomic niche resection (LTNR) in two studies. Sixteen studies included women diagnosed with infertility, five included women without infertility, and nineteen reported on pregnancy outcomes. Women with a wish to conceive and who were diagnosed with a uterine niche were the subject of this study. We divided the participants into 2 groups: women with infertility, defined as the failure to conceive despite ≥12 months of regular unprotected sexual intercourse, in line with the definition of the World Health Organization, and women with a wish to conceive but without infertility. This division was made because we hypothesized that women with infertility may benefit more from niche surgery than women without infertility because in the first group, the presence of the niche may contribute to the failure to conceive. Our findings revealed no significant differences in live birth, pregnancy, and miscarriage rates among the different treatment options. Notably, the live birth rate was higher in the group with secondary infertility compared to women without infertility, regardless of the type of intervention. However, it is essential to approach the existing evidence with caution due to the lack of high-quality controlled trials, a high risk of bias, unclear inclusion and exclusion criteria, inadequate reporting on fertility history, and the use of various reproductive techniques.

In Chapter 6, we assessed four management strategies performed in our clinic for CSP: 1) expectant management, 2) local and systemic methotrexate (MTX), 3) curettage and 4) laparoscopic niche resection (LNR). Both surgical interventions (LNR and curettage) proved successful without the need for re-interventions in all treated women treated in our hospital, while MTX treatment succeeded in only 12.5% of the women. The subsequent ongoing pregnancy rate after CSP treatment was 81.1% with a live birth rate of 78.4%. We retrospectively categorized the CSPs in three types of CSP conform the guideline proposed by Jordans et al. We observed in our study that different management approaches are indicated for different types of CSPs. We generally offered expectant management or curettage for CSPs that did not cross the serosal line of the uterus and LNR for those that did.

Part III: Standardization of Evaluation
Uniform and accurate description and measurement of a niche are important for clinical assessment of symptoms, planning of surgical interventions and for research purposes. Recognizing this, a practical guideline for detailed uterine niche evaluation in non-pregnant women was developed by international gynecological experts through a Delphi procedure. To facilitate implementation of these uniform measurements described in this guideline, we created a step-by-step tutorial on how to perform a standardized sonographic evaluation of the uterine niche in non-pregnant women, Chapter 7. In Chapter 8, we present recommendations for the sonographic assessment and reporting of a CSP during the first trimester of pregnancy. A modified Delphi procedure was conducted, in which sixteen international experts in obstetric and gynecological sonography participated. A comprehensive literature search identified 58 relevant items for the definition, detection and evaluation of CSP. Through four Delphi rounds, a consensus was achieved for all items. The formulated definition and classification of CSP emphasize that it can only occur in the presence of a niche, and not in relation to a healed CS scar. A CSP can be classified depending on the location of the largest part of the GS in relation to the uterine cavity line, and on the existence of protrusion of the GS beyond the serosal line. It should be kept in mind that the type of CSP can change over time with advancing gestation.

The following types of CSP are defined:

- Type 1: the largest part of the GS crossing the uterine cavity line
- Type 2: the largest part of the GS is embedded in the myometrium and not crossing the uterine cavity line
- Type 3: the GS crossing the serosal line protruding outside the contour of the uterus.

Chapter 9 offers a practical guide for detecting and evaluating CSP, including characteristics distinguishing them from other types of pregnancies.

Two e-learning modules have been developed after our Delphi studies, which are freely available for all interested, see www.gynaecologyonline.com

Finally in Chapter 10, a summary of the main findings, clinical implications and suggestions for future research is provided. We explain the importance of uniform definitions and core outcome sets for niche and CSP evaluation. Although the type of uterine closure technique (single- or double-layer) does not appear to affect niche presence, surgical experience and adhesion prevention may play a role and requires further evaluation.