Niche In CEsarean Scar Trial (NICEST)

Study Overview
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Brief Summary
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Rationale: Cesarean delivery (CD) rates are increasing rapidly worldwide. The consequences of cesarean section not only affect the next pregnancies such as uterine rupture or malplacentation but also cause many gynecological complications or infertility due to the formation of cesarean scar defect (CSD) or Niche. One of the major factors for Niche formation is the techniques of hysterotomy closure at the time of cesarean delivery. Most common hysterotomy closures include single and double layers closure. However, there is limited literature to prove which technique decreases niche creation and associated gynecological complications. Objective: To compare the effect of uterine closure techniques during CD on the formation of Niche evaluated on transvaginal ultrasound and gynecological complications. Study design: a double-blinded, single-center, randomized clinical trial. Setting: Hanoi Obstetrics & Gynecology Hospital (HOGH), Viet Nam. Study population: All women at gestational age ≥ 37 0/7 weeks who undergo a primary CD (planned or unplanned). Intervention: After informed consent, women will be randomized to either unlocked single layer closure or unlocked double-layer closures of cesarean uterine scar in a 1:1 ratio Primary outcome: The proportion of Niche over time (at 6, 12, 18, 24 months after CD) in the two groups. Power calculation: A sample size of 389 women is needed for each group. Nature and extent of the burden and risks associated with participation, benefit, and group relatedness: Both uterine closure methods followed by the Vietnam Ministry of Health (VN-MOH), transvaginal ultrasound is also not harmful. It is believed that there are no potential increased risks to patients taking part in this trial because of the standard care and management they receive.

Detailed Description
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Pregnancies at term, indicated for cesarean delivery for the first time, will be fully consulted information related to this study before surgery. Written consent will be obtained from each eligible pregnant woman before randomization into the study. After signing the informed consent form, eligible women will be randomly assigned in a 1:1 ratio to receive either single-layer closure or double-layer closure, using block randomization with a variable block size of 4, 6. The computer-generated random list will be prepared by an independent statistician who has no other involvement in the study. To ensure allocation concealment, opaque and sealed envelopes will be prepared and controlled by two administrative staff in the Clinical Trial Unit who have no involvement in clinical work. Whenever there is an eligible participant, these two staff will hand over the envelope in sequence to the clinician. As the result, surgeons will not be blinded, but participants and sonographers will be unaware of closure techniques. Apart from randomization, patients will be followed up and treated according to local protocol. The cesarean section with two uterine scar closure techniques will be performed by well-trained obstetricians. Participants and sonographers will be blinded for the closure technique. Intervention (double-layer closure) In both study groups, women will undergo a CD following a standard way with respect to the mode of hysterotomy, non-closure of the peritoneum. In the intervention group, double-layer closure of the uterus will be performed using unlocked multifilament continuous running sutures for both layers and the endometrial layer will be included in the first layer. The second layer is a continuous running suture that imbricates the first layer. Control group (single-layer closure) The control group will receive a single-layer closure using unlocked continuous running multifilament sutures and the endometrial layer will be included. Complication during surgery The cases that have complications during surgery will be excluded from the study. Complications encompass: Maternal mortality Maternal admitted ICU Hysterectomy Damage to internal organs (bowel, bladder or ureters). Complications during postoperative period requiring further surgery. Follow-up Participants will be contacted via telephone to notify about follow-up visits within 10 days of the first day of every menstrual cycle at 6 months, 12 months, 18 months, 24 months (give or take 2 weeks). Every regular follow-up visit, the participants will be examined and transvaginal ultrasound followed by saline infusion sonohysterography to evaluate Niche. The ultrasound evaluation is standardized as proposed by the latest standard of ISUOG(2019). Reproductive outcomes at two years follow-up: Percentage of women that conceived at any time during the follow-up duration, time of conception, and results of said pregnancies (ongoing pregnancy, terminated pregnancy due to medical/ social indication). Niche evaluation Every regular follow-up visit, the participants will be examined and transvaginal ultrasound followed by sonohysterography to evaluate Niche. The Niche evaluation is standardized as proposed by the latest standard of ISUOG(2019).

Official Title
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Single Versus Double-layer Closure of The Cesarean Scar In Niche Development: A Randomized Clinical Trial

Conditions
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Niche

Intervention / Treatment
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* Procedure: Double-layer uterine closure
* Procedure: Single-layer uterine closure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Pregnant women who undergo a primary CD (planned or unplanned) Age ≥ 18 years. Gestational age ≥ 37 0/7 weeks Exclusion Criteria: Previous major uterine surgery (e.g. laparoscopic or laparotomic fibroid resection, septum resection). Women with abnormal menstrual bleeding (e.g. cervical dysplasia, communicating hydrosalpinx, uterine anomaly or endocrine disorders disturbing ovulation, drugs, polyps, fibroids, etc.). Women with dysmenorrhea, dyspareunia, suprapubic pain. Abnormal placenta: Placenta privia, Placenta percreta… in the current pregnancy.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Single-layer uterine closure<br>Women will undergo a CD following a standard way with respect to the mode of hysterotomy, non-closure of the peritoneum. The control group will receive a single-layer closure using unlocked continuous running multifilament sutures and the endometrial layer will be included | Procedure: Single-layer uterine closure<br>* The control group will receive a single-layer closure using unlocked continuous running multifilament sutures and the endometrial layer will be included<br>|
| Active Comparator: Double-layer uterine closure<br>Women will undergo a CD following a standard way with respect to the mode of hysterotomy, non-closure of the peritoneum. In the intervention group, double-layer closure of the uterus will be performed using unlocked multifilament continuous running sutures for both layers and the endometrial layer will be included in the first layer. The second layer is a continuous running suture that imbricates the first layer | Procedure: Double-layer uterine closure<br>* In the intervention group, double-layer closure of the uterus will be performed using unlocked multifilament continuous running sutures for both layers and the endometrial layer will be included in the first layer. The second layer is a continuous running suture that imbricates the first layer<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The proportion of Niche at 6 months after cesarean delivery of Single-layer uterine closure group | The proportion of Niche at 6 months after cesarean delivery of Single-layer uterine closure group. | from delivery to 6 months from delivery | 
| The proportion of Niche at 12 months after cesarean delivery of Single-layer uterine closure group | The proportion of Niche at 12 months after cesarean delivery of Single-layer uterine closure group. | from delivery to 12 months from delivery | 
| The proportion of Niche at 18 months after cesarean delivery of Single-layer uterine closure group | The proportion of Niche at 18 months after cesarean delivery of Single-layer uterine closure group. | from delivery to 18 months from delivery | 
| The proportion of Niche at 24 months after cesarean delivery of Single-layer uterine closure group | The proportion of Niche at 24 months after cesarean delivery of Single-layer uterine closure group. | from delivery to 24 months from delivery | 
| The proportion of Niche at 6 months after cesarean delivery of Double-layer uterine closure group | The proportion of Niche at 6 months after cesarean delivery of Double-layer uterine closure group. | from delivery to 6 months from delivery) | 
| The proportion of Niche at 12 months after cesarean delivery of Double-layer uterine closure group | The proportion of Niche at 12 months after cesarean delivery of Double-layer uterine closure group. | from delivery to 12 months from delivery | 
| The proportion of Niche at 18 months after cesarean delivery of Double-layer uterine closure group | The proportion of Niche at 18 months after cesarean delivery of Double-layer uterine closure group. | from delivery to 18 months from delivery | 
| The proportion of Niche at 24 months after cesarean delivery of Double-layer uterine closure group | The proportion of Niche at 24 months after cesarean delivery of Double-layer uterine closure group. | from delivery to 24 months from delivery | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of participants with post-partum hemorrhage. | Defined as blood loss more than 1000ml with 24 hours after cesarean delivery | Within 24 hours from delivery | 
| Number of participants having uterine atony | Defined as use of two or more uterotonics other oxytocin; other surgical interventions such as compression by hand and/or sutures, uterine arteries ligation, embolization, hypogastric arteries ligation, or balloon tamponade | During operation | 
| Number of participants with maternal infection | Maternal infection as defined: Fever: defined as axillary temperature ≥ 37.5 degrees Celsius. Start of intravenous broad-spectrum antibiotics (with evidence of infection confirmed by clinical and subclinical presentation) Endometritis, myometritis or urinary tract infection (proven positive vaginal discharge/urine culture) | from delivery until maternal hospital discharge, assessed up to 28 days after delivery | 
| Number of participants having postmenstrual spotting in women with Niche | Postmenstrual spotting is brownish discharge for more than two days at the end of menstruation with a total duration (menstruation and spotting) of more than seven days, or intermenstrual bleeding that starts after the end of menstruation, assessed at 6 months, 12 months, 18 months and 24 months after delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Duration of postmenstrual spotting in women with Niche | Duration of postmenstrual spotting in women with Niche defined as the average number of days of postmenstrual spotting in 6 months, in which duration of postmenstrual spotting in each month will be counted as follows: days with brownish discharge (more than two days) when the total duration of menstruation and spotting exceeds seven days plus days with intermenstrual bleeding, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Number of participants suffering from dysmenorrhea in women with Niche | Number of participants suffering from dysmenorrhea in women with Niche, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Dysmenorrhea severity in women with Niche | Participants with dysmenorrhea self-assessed pain levels and scored 1 to 10 rely on the Numeric Rating Scale (NRS). The average score in span of 6 months will be calculated and the highest score will be noticed to reveal dysmenorrhea severity at 6 months, 12 months, 18 months, 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Number of participants suffering from suprapubic pain in women with Niche | Number of participants suffering from suprapubic pain in women with Niche, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Suprapubic pain severity in women with Niche | Participants with suprapubic pain self-assessed pain levels and scored 1 to 10 rely on the Numeric Rating Scale (NRS). The average score in span of 6 months will be calculated and the highest score will be noticed to reveal suprapubic pain severity at 6 months, 12 months, 18 months, 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Number of participants suffering from dyspareunia in women with Niche | Number of participants suffering from dyspareunia in women with Niche, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Dyspareunia severity in women with Niche | Participants with dyspareunia self-assessed pain levels and scored 1 to 10 rely on the Numeric Rating Scale (NRS). The average score in span of 6 months will be calculated and the highest score will be noticed to reveal dyspareunia severity at 6 months, 12 months, 18 months, 24 months after delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Niche length | The length at Niche base will be measured in the sagittal plane on transvaginal ultrasound, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Niche depth | The largest depth of Niche will be measured in the sagittal plane on ultrasound, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | : from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Number of branches of Niche | Number of branches of Niche will be measured in the transverse plane on transvaginal ultrasound, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Residual myometrial thickness (RMT) | Thinnest point of residual myometrial thickness will be measured in the sagittal plane on transvaginal ultrasound, regardless of direction (measured perpendicular to serosa but not necessarily to uterine cavity), from the main Niche or branch with the thinnest RMT. Fibroid is not included in RMT measurement, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Ratio of residual myometrial thickness per adjacent myometrial thickness (RMT/AMT) | Adjacent myometrial thickness will be measured close to Niche in the sagittal plane on transvaginal ultrasound, where myometrium is thickness. Ratio of RMT/AMT will be assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Niche-vesicovaginal fold distance | Distance between Niche and vesicovaginal fold will be measured in the sagittal plane on transvaginal ultrasound, from level of top main Niche (where residual myometrial thickness is smallest (dotted line)) to vesicovaginal fold, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Niche-external os distance | Distance between niche and external os will be measured parallel to cervical canal, from most distal point of niche to external os in the sagittal plane on transvaginal ultrasound, assessed at 6 months, 12 months, 18 months and 24 months after cesarean delivery. | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Evaluating the correlation between Niche characteristics and gynecological symptoms | Correlation between characteristics of Niche (include length, depth, branches, RMT, RMT/AMT, Niche-vesicovaginal fold distance and Niche-external os distance) and gynecological symptoms (involve postmenstrual spotting, dysmenorrhea, suprapubic pain and dyspareunia) will be analyzed at 6 months, 12 months, 18 months and 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Evaluating factors contributing to Niche development | Correlation between Niche formation and risk factors include labor (cervical dilation, duration of labor), planned or unplanned cesarean section, maternal factors, short-term outcomes such as uterine atony, post-partum hemorrhage, post-partum blood transfusion, maternal infection will be analyzed at 6 months, 12 months, 18 months and 24 months after cesarean delivery | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 
| Comparison between the rate of niche detection by regular TVUS and sonohysterography | Comparison between rate of niche detection (percentage) in all follow-up events by regular TVUS and sonohysterography | from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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single-layer uterine closure, double-layer uterine closure, niche