Cervical Pessary vs. Vaginal Progesterone for Preventing Premature Birth in IVF Twin Pregnancies

Study Overview
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Brief Summary
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To compare the effectiveness of cervical pessary (Arabin) and vaginal progesterone for preventing premature birth in twin pregnancies after IVF

Detailed Description
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This will be a randomized controlled trial. Women with twin pregnancies, at 16-22 weeks of gestation, will be invited to participate into the study. Subjects meeting the study criteria will be randomized into two groups: (1) treated with cervical pessary (Arabin) or (2) treated with 400mg vaginal progesterone, once daily. Randomization will be done by third party via telephone, using a computer generated random list, with a variable block size of 2, 4 or 8. Apart from randomization, patients will be examined and treated according to local protocol. Patients in pessary group will have an Arabin pessary placed within a week after randomization. A pessary certified by European Conformity (CE0482, MED/CERT ISO 9003/ EN 46003; Dr. Arabin, Witten, Germany) will be inserted through the vagina of the woman in the recumbent position and will be placed upward around the cervix. The research-team members who inserted the Arabin pessary have experience with Arabin pessary for singleton pregnancy before. Patients in progesterone group will use vaginal progesterone (Cyclogest 400mg) once daily before bedtime, starting from the day of randomization onwards. They will be given a monitoring sheet and instructed to note everyday the date of using. If they forget one dose of any night, and remember it in the next morning or afternoon, they will use immediately the forgotten dose and continue with the dose of that day at night. If one dose is missed until the next evening, there will be no compensation use, they will only use the dose of the next day. Any change in using medication should be noted in the monitoring sheet. In both groups, intervention will be stopped at 36 weeks of gestation or at delivery. All the participants will have follow-up visits every 4 weeks. If patients develop (threatened) preterm labor, they will receive treatment as routine practice. Statistical analyses will be by intention to treat. For dichotomous endpoints, we will calculate rates. These will be compared by calculating a relative risk and a 95% confidence interval. Between-group differences in non-continuous variables will be assessed using the χ2-test. Results of continuous variables were given in mean ± SD or in percentage. Between-group differences of continuous variables were assessed with the Student's t-test. We will consider correlation between neonatal endpoints when we analyse at the level of the child. We assessed time to delivery by Cox proportional hazard analysis and Kaplan-Meier estimates, and compared results with a log-rank test. We plan an exploratory subgroup analysis in women with a cervical length of less than the 25th percentile (according to the distribution in all twins), as well as 25th - 50th percentile, 50th - 75th percentile and > 75th percentile. We also plan an exploratory subgroups analyses for chorionicity. A p-value < 0.05 will be considered to indicate a statistically significant difference. The analysis will be done with statistical Package for Social Sciences version 19 (SPSS, USA). Sample size has been set at 290. This was incorporated in an amendment of the protocol, and was approved by the IRB on 22 Sept 2016.

Official Title
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The Effectiveness of Cervical Pessary Versus Vaginal Progesterone for Preventing Premature Birth in IVF Twin Pregnancies: a Randomized Controlled Trial.

Conditions
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Pregnancy

Intervention / Treatment
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* Device: Cervical pessary
* Drug: Vaginal progesterone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: To be eligible for enrolment into this trial, each female subject must fulfil all of the following criteria at the start of enrolment, unless specified otherwise: Women with a twin pregnancy (mono- and di-chorionic) 16 0/7 to 22 0/7 weeks of gestation Maternal age ≥ 18 yrs Cervical length less than 38 mm Informed consent Not participating in another PTB study at the same time Exclusion Criteria: To be eligible for enrolment in this study each subject must not meet any of the following criteria: History of cervical surgery Cervical cerclage in place Twin-to-twin transfusion syndrome Stillbirth or major congenital abnormalities in any of the fetus Severe vaginal discharge, acute vaginitis Premature rupture of membranes Premature labor

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Cervical pessary<br>Cervical pessary (Arabin) will be inserted to participants at 16-22 weeks and removed at 36 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort. | Device: Cervical pessary<br>* Arabin (cervical pessary) will be inserted at 16-22 weeks and removed at 36 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort<br>* Other names: Arabin;|
| Active Comparator: Vaginal Progesterone<br>Vaginal progesterone (Cyclogest 400 mg) once a day will be used, from 16-22 to 36 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort. | Drug: Vaginal progesterone<br>* Vaginal progesterone (Cyclogest 400 mg) once a day will be used, from 16-22 to 36 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort<br>* Other names: Cyclogest 400mg;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Preterm birth before 34 weeks of gestation | Birth before 34 weeks | At birth | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Intrauterine death before 24 weeks of gestation | Death of any fetus intrauterine before 24 weeks | From randomisation to 24 weeks | 
| Stillbirth | Baby born with no signs of life at or after 28 weeks | At birth | 
| Delivery before 24 weeks of gestation | Birth before 24 weeks | At birth | 
| Delivery before 28 weeks of gestation | Birth before 28 weeks | At birth | 
| Delivery before 32 weeks of gestation | Birth before 32 weeks | At birth | 
| Delivery before 37 weeks of gestation | Birth before 37 weeks | At birth | 
| Labour induction | Labor initiated with a method such as oxytocin, Foley bulb, or artificial rupture of membranes. | At birth | 
| Prelabour rupture of membrane | Prelabour rupture of membranes and gestational age less than 37 weeks | From randomization to less than 37 weeks | 
| Mode of delivery | Spontaneous, forceps/ventouse, emergency C-section, planned C-section | At birth | 
| Livebirth at any gestational age | Birth of at least one newborn that exhibits any sign of life, such as respiration, heartbeat, umbilical pulsation or movement of voluntary muscles | At birth | 
| Use of tocolytics drug | Use of tocolytics drug to prevent premature labor | From 24 weeks to 34 weeks | 
| Use of corticosteroids | Use of corticosteroids to prevent respiratory distressed syndrome | From 24 weeks to 34 weeks | 
| Admission days for preterm labor | Days admission to hospital due to preterm labor | From 24 weeks to 37 week | 
| Choriamnionitis | Intraamniotic infection | From randomization to birth | 
| Maternal morbidity | Thromboembolic complications, urinary tract infection treated with antibiotics, pneumonia, endometritis, hypertension disorder, eclampsia or HELLP syndrome, or death | From randomization to birth | 
| Birthweight | Weight of babies | At birth | 
| Birthweight < 1500g | Weight of babies < 1500g | At birth | 
| Birthweight < 2500g | Weight of babies < 2500g | At birth | 
| Congenital anomalies | Congenital malformation of newborn | At birth | 
| 5-minute Apgar score | Apgar score at 5 minute after birth | At birth | 
| 5-minute Apgar score < 7 | Apgar score < 7 at 5 minute after birth | At birth | 
| Admission to NICU | The admittance of newborn to NICU | Within 7 days after delivery | 
| Length of NICU admission | Number of days admittance of newborn to NICU | Up to 28 days after birth | 
| Severe respiratory distress syndrome | Grade 2 or worse, as diagnosed by Giedion et al | Within 24 hours after delivery | 
| Bronchopulmonary dysplasia | Diagnosed according to the international consensus guideline as described by Jobe and Bancalari | At time of discharge home or at 36 weeks of gestational age | 
| Intraventricular haemorrhage | Grade II B or worse, as diagnosed by repeated neonatal cranial ultrasound by the neonatologist according to the guidelines on neuro-imaging described by de Vries et al. and Ment et al | Up to 28 days after birth | 
| Necrotising enterocolitis | > stage 1, will be diagnosed according to Bell | Up to 28 days after birth | 
| Proven sepsis | The combination of clinical signs and positive blood cultures. | Up to 28 days after birth | 
| Death before discharge | Death of newborn before discharge from nursery | Up to 28 days after birth | 
| Maternal side effects | Vaginal discharge, fever, other signs of infections, pain, pessary repositioning and necrosis or rupture of the cervix | From randomisation to birth | 
| Withdrawal from treatment | Patient's discontinuation of arabin or vaginal progesterone use | From randomization to 36 weeks of gestation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Cervical pessary, Vaginal progesterone, Twins, Premature birth