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

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

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

Study Overview

• Status: Completed
• Conditions: Pregnancy
• Intervention / Treatment: Device: Cervical pessary; Drug: Vaginal progesterone

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 300
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Vietnam
  • Tan Binh District
    • Ho Chi Minh City, Tan Binh District, Vietnam, 70000
      • My Duc Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Cervical pessary; 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; 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; Other Names: Arabin
ACTIVE_COMPARATOR: Vaginal Progesterone; 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; 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; Other Names: Cyclogest 400mg

What is the study measuring?

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
Death before discharge	Death of newborn before discharge from nursery	Up to 28 days after birth
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
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

Collaborators and Investigators

• Sponsor: Vietnam National University
• Collaborators: Mỹ Đức Hospital

Publications and helpful links

General Publications

• Dang VQ, Nguyen LK, Pham TD, He YTN, Vu KN, Phan MTN, Le TQ, Le CH, Vuong LN, Mol BW. Pessary Compared With Vaginal Progesterone for the Prevention of Preterm Birth in Women With Twin Pregnancies and Cervical Length Less Than 38 mm: A Randomized Controlled Trial. Obstet Gynecol. 2019 Mar;133(3):459-467. doi: 10.1097/AOG.0000000000003136.

Study record dates

Study Major Dates

• Study Start (ACTUAL): March 4, 2016
• Primary Completion (ACTUAL): November 2, 2017
• Study Completion (ACTUAL): November 2, 2017

Study Registration Dates

• First Submitted: November 30, 2015
• First Submitted That Met QC Criteria: December 3, 2015
• First Posted (ESTIMATE): December 8, 2015

Study Record Updates

• Last Update Posted (ACTUAL): December 22, 2017
• Last Update Submitted That Met QC Criteria: December 21, 2017
• Last Verified: December 1, 2017

More Information

Terms related to this study

• Keywords: Premature birth; Twins; Vaginal progesterone; Cervical pessary
• Additional Relevant MeSH Terms: Pregnancy Complications; Obstetric Labor Complications; Obstetric Labor, Premature; Premature Birth; Physiological Effects of Drugs; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Progestins; Progesterone
• Other Study ID Numbers: NCKH/CGRH_10_2015