Nordic Randomized Trial on Laparoscopic Versus Vaginal Cerclage

Study Overview
=================
Brief Summary
-----------------
Every year 15 million babies are born prematurely, which can lead to death or life-long disabilities. It is often caused by a dysfunction of the uterine cervix, which constitutes the narrow channel between the vagina and womb. During pregnancy, this channel must remain closed until the beginning of term labor. A weak cervix may not withstand the weight of the fetus, the amniotic fluid and the placenta and the cervical canal will open and cause late miscarriage or preterm delivery. To prevent this, a band (cerclage) can be applied around the cervix either vaginally or laparoscopically prior to a new pregnancy. To evaluate which treatment is best for most women, we will randomize (allocate by chance) women at risk for preterm birth, to either vaginal cerclage or laparoscopic cerclage in the Nordic countries and England

Detailed Description
-----------------
Both vaginal and abdominal cerclages are procedures that have been used to prevent preterm birth for more than 50 years. However, only one previous study (MAVRIC, Shennan et al. 2020) has compared the two methods in a randomised trial. Other than evidence from the MAVRIC trial there is uncertainty whether an abdominal cerclage should be preferred over vaginal cerclage, and which women would benefit from it the most. NORACT is an open, multicenter, superiority, randomized controlled trial with the overall objective to compare laparoscopic versus vaginal cerclage in woman in whom the clinician has equipoise as to whether an elective vaginal or abdominal cerclage will be the best intervention to prevent preterm birth. Participants will be recruited pre-pregnancy or in early pregnancy and randomised to vaginal or laparoscopic cerclage. If randomised to laparoscopic cerclage this will be inserted pre-pregnancy or before 10+0 weeks of gestation. The vaginal cerclage will be inserted during pregnancy, before 16+0 weeks of gestation. A total sample of 188 participants will be included to detect a target difference of 15% in the primary outcome between the two groups. The two primary outcomes are delivery before 32+0 weeks of gestation and baby death. The study extends from sites in Denmark, Sweden, Norway, Finland, Iceland, and the United Kingdom.

Official Title
-----------------
Nordic Randomized Trial on Laparoscopic Versus Vaginal Cerclage

Conditions
-----------------
Cervical Insufficiency, Preterm Birth

Intervention / Treatment
-----------------
* Procedure: Laparoscopic cerclage
* Procedure: Vaginal cerclage


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Women in whom the clinician has equipoise as to whether an elective vaginal or abdominal cerclage will be the best intervention to prevent preterm birth. Not yet pregnant or <10 weeks' pregnant. Exclusion Criteria: Any circumstance under which the clinician is not willing to randomize is an exclusion criterion. Any condition or circumstance under which laparoscopic or vaginal cerclage surgery is contraindicated (i.e. on-going pregnancy of more than 10+0 gestational weeks). Language difficulties.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention<br>Laparoscopic cerclage | Procedure: Laparoscopic cerclage<br>* Classic or robot-assisted laparoscopic cerclage in non-pregnant or early pregnant women.<br>* Other names: Abdominal cerclage;|
| Experimental: Control<br>Vaginal cerclage | Procedure: Vaginal cerclage<br>* Transvaginal cerclage in pregnant women.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Delivery <32+0 weeks of gestation. | In the first subsequent viable pregnancy beyond 14+0 weeks of gestation. First prioritized primary outcome. | At birth. | 
| Baby death. | Loss of a viable pregnancy beyond 14+0 weeks of gestation, miscarriage, stillbirth or death of a live born infant. Second prioritized primary outcome. | From birth - four weeks after due date. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maternal mortality - surgery related. | Death. | 30 days after insertion of laparoscopic or vaginal cerclage. | 
| Maternal mortality. | Death. | From time of randomisation - 42 days after delivery. | 
| Maternal morbidity - surgery related. | Admission to ICU or a unit that provides 24-h medical supervision and is able to provide mechanical ventilation or continuous vasoactive drug support. | 30 days after insertion of laparoscopic or vaginal cerclage. | 
| Maternal morbidity | Admission to ICU or a unit that provides 24-h medical supervision and is able to provide mechanical ventilation or continuous vasoactive drug support. | From time of randomisation - 42 days after delivery. | 
| Harm to participant - surgery related. | One or more of the following: Damage to internal organs, need for re-operation, thromboembolic events (defined as deep vein thrombosis, pulmonary embolism or stroke), maternal cardiopulmonary arrest. | 30 days after insertion of laparoscopic or vaginal cerclage. | 
| Harm to participant | One or more of the following: Damage to internal organs, thromboembolic events (defined as deep vein thrombosis, pulmonary embolism or stroke), maternal cardiopulmonary arrest. | From time of cerclage procedure - 42 days after delivery. | 
| Bleeding - surgery related. | Blood loss > 500 ml. | 30 days after insertion of laparoscopic or vaginal cerclage. | 
| Bleeding - pregnancy related. | Blood loss > 1000 ml. | From time of cerclage procedure - 42 days after delivery. | 
| Maternal infection - surgery related. | Leading to antibiotic treatment, but not ICU. | 30 days after insertion of laparoscopic or vaginal cerclage. | 
| Maternal infection - pregnancy related. | Leading to antibiotic treatment, but not ICU | From time of cerclage procedure - 42 days after delivery | 
| Maternal serious infection - pregnancy related. | Admission to ICU due to serious infection. | From time of cerclage procedure - 42 days after delivery. | 
| Maternal serious infection - surgery related. | Admission to ICU due to serious infection. | 30 days after insertion of laparoscopic or vaginal cerclage. | 
| PPROM. | Preterm prelabour rupture of membranes, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Threatened preterm labour. | Threatened preterm labour requiring admission and intervention, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Onset of labour. | Spontaneous labor contractions, PROM, induction of labor, c-section. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Mode of birth. | Unassisted vaginal, assisted vaginal (ventouse or forceps), caesarean section (planned, non-planned). In the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Modified neonatal mortality. | Death of a liveborn child > 22+0 weeks of gestation. | From birth - four weeks after due date. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | 
| Neonatal mortality. | Death in the 1st 28 days of life > 22+0 weeks of gestation. | From birth - 28 days post delivery. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | 
| Fetal loss. | Composite of late miscarriage and stillbirth, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At due date. | 
| Late miscarriage. | Loss of viable pregnancy between gestational age 14+0-21+6, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At due date. | 
| Gestational age at birth. | Gestational age at birth, weeks and days, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Delivery < 28 weeks. | Birth before gestational age 28+0, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Delivery < 34 weeks. | Birth before gestational age 34+0, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Delivery < 37 weeks. | Birth before gestational age 37+0, in the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Birthweight. | Grams. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | At birth. | 
| Neonatal admission. | Number of consecutive days in hospital within 28 days from time of delivery. In the first subsequent viable pregnancy beyond 14 weeks of gestation. Any admission counts (SCBU, maternity ward, NICU) | From birth - four weeks after due date. | 
| CNS morbidity. | Intraventricular Hemorrhage Grade III and IV and/or Periventricular leukomalacia. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | From birth - four weeks after due date. | 
| Ocular morbidity. | Retinopathy requiring treatment. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | From birth - four weeks after due date. | 
| Gastrointestinal morbidity. | Necrotizing Enterocolitis (NEC) and/or SIP (Spontaneous intestinal perforation), requiring surgery. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | From birth - four weeks after due date. | 
| Respiratory support. | Mechanical ventilation or non-invasive ventilation. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | From birth - four weeks after due date. | 
| Respiratory distress syndrome (RDS). | Need for surfactant treatment. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | First two days of life. | 
| Early onset neonatal infection. | >5 days of i.v. antibiotics, where the treatment commences within the first week of life. In the first subsequent viable pregnancy beyond 14 weeks of gestation. | From birth - four weeks after due date. | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
cerclage