Clinical trial NCT05312775: Niche In CEsarean Scar Trial (NICEST)
Official title: Single Versus Double-layer Closure of The Cesarean Scar In Niche Development: A Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: NA
Conditions: Niche
Keywords: single-layer uterine closure
double-layer uterine closure
niche
Lead sponsor: Hanoi Obstetrics and Gynecology Hospital
Sponsor class: OTHER
First posted: 2022-04-06
Enrollment: 938
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: 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: 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).

Eligibility criteria: 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.

Primary outcomes:
measure: The proportion of Niche at 6 months after cesarean delivery of Single-layer uterine closure group
timeFrame: from delivery to 6 months from delivery
measure: The proportion of Niche at 12 months after cesarean delivery of Single-layer uterine closure group
timeFrame: from delivery to 12 months from delivery
measure: The proportion of Niche at 18 months after cesarean delivery of Single-layer uterine closure group
timeFrame: from delivery to 18 months from delivery
measure: The proportion of Niche at 24 months after cesarean delivery of Single-layer uterine closure group
timeFrame: from delivery to 24 months from delivery
measure: The proportion of Niche at 6 months after cesarean delivery of Double-layer uterine closure group
timeFrame: from delivery to 6 months from delivery)
measure: The proportion of Niche at 12 months after cesarean delivery of Double-layer uterine closure group
timeFrame: from delivery to 12 months from delivery
measure: The proportion of Niche at 18 months after cesarean delivery of Double-layer uterine closure group
timeFrame: from delivery to 18 months from delivery
measure: The proportion of Niche at 24 months after cesarean delivery of Double-layer uterine closure group
timeFrame: from delivery to 24 months from delivery
Secondary outcomes:
measure: Number of participants with post-partum hemorrhage.
timeFrame: Within 24 hours from delivery
measure: Number of participants having uterine atony
timeFrame: During operation
measure: Number of participants with maternal infection
timeFrame: from delivery until maternal hospital discharge, assessed up to 28 days after delivery
measure: Number of participants having postmenstrual spotting in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Duration of postmenstrual spotting in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Number of participants suffering from dysmenorrhea in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Dysmenorrhea severity in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Number of participants suffering from suprapubic pain in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Suprapubic pain severity in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Number of participants suffering from dyspareunia in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Dyspareunia severity in women with Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Niche length
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Niche depth
timeFrame: : from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Number of branches of Niche
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Residual myometrial thickness (RMT)
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Ratio of residual myometrial thickness per adjacent myometrial thickness (RMT/AMT)
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Niche-vesicovaginal fold distance
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Niche-external os distance
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Evaluating the correlation between Niche characteristics and gynecological symptoms
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Evaluating factors contributing to Niche development
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
measure: Comparison between the rate of niche detection by regular TVUS and sonohysterography
timeFrame: from delivery to 6 months, 12 months, 18 months, 24 months after cesarean delivery, up to 24 months from delivery
Other outcomes:
measure: Reproductive outcome during 2 years of follow-up
timeFrame: 24 months from delivery
Locations:
city: Hà Nội
country: Vietnam
facility: Hanoi Obstetrics and Gynecology Hospital
state: Hanoi
Study officials:
affiliation: Hanoi Obstetric and Gynecology Hospital
name: Anh D Nguyen, PhD. MD
role: STUDY_DIRECTOR
affiliation: Hôpital Necker-Enfants Malades
name: Yves Ville, PhD. MD
role: STUDY_CHAIR
affiliation: Hanoi Obstetric and Gynecology Hospital
name: Ha TT Nguyen, PhD.MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Hanoi Obstetric and Gynecology Hospital
name: Giang TT Duong, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Delport S. Global epidemiology of use of and disparities in caesarean sections. Lancet. 2019 Jul 6;394(10192):23-24. doi: 10.1016/S0140-6736(19)30717-2. Epub 2019 Jul 4. No abstract available.
citation: Naji O, Wynants L, Smith A, Abdallah Y, Saso S, Stalder C, Van Huffel S, Ghaem-Maghami S, Van Calster B, Timmerman D, Bourne T. Does the presence of a Caesarean section scar affect implantation site and early pregnancy outcome in women attending an early pregnancy assessment unit? Hum Reprod. 2013 Jun;28(6):1489-96. doi: 10.1093/humrep/det110. Epub 2013 Apr 12.
citation: Naji O, Wynants L, Smith A, Abdallah Y, Stalder C, Sayasneh A, McIndoe A, Ghaem-Maghami S, Van Huffel S, Van Calster B, Timmerman D, Bourne T. Predicting successful vaginal birth after Cesarean section using a model based on Cesarean scar features examined by transvaginal sonography. Ultrasound Obstet Gynecol. 2013 Jun;41(6):672-8. doi: 10.1002/uog.12423.
citation: Roberge S, Demers S, Berghella V, Chaillet N, Moore L, Bujold E. Impact of single- vs double-layer closure on adverse outcomes and uterine scar defect: a systematic review and metaanalysis. Am J Obstet Gynecol. 2014 Nov;211(5):453-60. doi: 10.1016/j.ajog.2014.06.014. Epub 2014 Jun 6.
citation: Hesselman S, Hogberg U, Ekholm-Selling K, Rassjo EB, Jonsson M. The risk of uterine rupture is not increased with single- compared with double-layer closure: a Swedish cohort study. BJOG. 2015 Oct;122(11):1535-41. doi: 10.1111/1471-0528.13015. Epub 2014 Aug 4.
citation: Clark EA, Silver RM. Long-term maternal morbidity associated with repeat cesarean delivery. Am J Obstet Gynecol. 2011 Dec;205(6 Suppl):S2-10. doi: 10.1016/j.ajog.2011.09.028. Epub 2011 Oct 6.
citation: Jordans IPM, de Leeuw RA, Stegwee SI, Amso NN, Barri-Soldevila PN, van den Bosch T, Bourne T, Brolmann HAM, Donnez O, Dueholm M, Hehenkamp WJK, Jastrow N, Jurkovic D, Mashiach R, Naji O, Streuli I, Timmerman D, van der Voet LF, Huirne JAF. Sonographic examination of uterine niche in non-pregnant women: a modified Delphi procedure. Ultrasound Obstet Gynecol. 2019 Jan;53(1):107-115. doi: 10.1002/uog.19049.
citation: Bij de Vaate AJ, van der Voet LF, Naji O, Witmer M, Veersema S, Brolmann HA, Bourne T, Huirne JA. Prevalence, potential risk factors for development and symptoms related to the presence of uterine niches following Cesarean section: systematic review. Ultrasound Obstet Gynecol. 2014 Apr;43(4):372-82. doi: 10.1002/uog.13199.
citation: Dodd JM, Anderson ER, Gates S, Grivell RM. Surgical techniques for uterine incision and uterine closure at the time of caesarean section. Cochrane Database Syst Rev. 2014 Jul 22;2014(7):CD004732. doi: 10.1002/14651858.CD004732.pub3.
citation: Di Spiezio Sardo A, Saccone G, McCurdy R, Bujold E, Bifulco G, Berghella V. Risk of Cesarean scar defect following single- vs double-layer uterine closure: systematic review and meta-analysis of randomized controlled trials. Ultrasound Obstet Gynecol. 2017 Nov;50(5):578-583. doi: 10.1002/uog.17401. Epub 2017 Oct 9.
citation: Hanacek J, Vojtech J, Urbankova I, Krcmar M, Krepelka P, Feyereisl J, Krofta L. Ultrasound cesarean scar assessment one year postpartum in relation to one- or two-layer uterine suture closure. Acta Obstet Gynecol Scand. 2020 Jan;99(1):69-78. doi: 10.1111/aogs.13714. Epub 2019 Sep 26.
citation: Stegwee SI, Jordans IPM, van der Voet LF, Bongers MY, de Groot CJM, Lambalk CB, de Leeuw RA, Hehenkamp WJK, van de Ven PM, Bosmans JE, Pajkrt E, Bakkum EA, Radder CM, Hemelaar M, van Baal WM, Visser H, van Laar JOEH, van Vliet HAAM, Rijnders RJP, Sueters M, Janssen CAH, Hermes W, Feitsma AH, Kapiteijn K, Scheepers HCJ, Langenveld J, de Boer K, Coppus SFPJ, Schippers DH, Oei ALM, Kaplan M, Papatsonis DNM, de Vleeschouwer LHM, van Beek E, Bekker MN, Huisjes AJM, Meijer WJ, Deurloo KL, Boormans EMA, van Eijndhoven HWF, Huirne JAF. Single- versus double-layer closure of the caesarean (uterine) scar in the prevention of gynaecological symptoms in relation to niche development - the 2Close study: a multicentre randomised controlled trial. BMC Pregnancy Childbirth. 2019 Mar 4;19(1):85. doi: 10.1186/s12884-019-2221-y.
citation: Dahlke JD, Mendez-Figueroa H, Maggio L, Sperling JD, Chauhan SP, Rouse DJ. The Case for Standardizing Cesarean Delivery Technique: Seeing the Forest for the Trees. Obstet Gynecol. 2020 Nov;136(5):972-980. doi: 10.1097/AOG.0000000000004120.