Pessary Versus Progesterone in Singletons

The Effectiveness of Cervical Pessary Versus Vaginal Progesterone for the Prevention of Preterm Birth in Women With Singleton Pregnancies and Short Cervix: a Multicenter Randomized Controlled Trial

My Duc Phu Nhuan Hospital HCMC, Vietnam, Quang Ninh Obstetrics and Pediatrics Hospital, Quang Ninh, Vietnam

This study compares the effectiveness of cervical pessary to vaginal progesterone for prevention of preterm birth in women with singleton pregnancies and a cervix ≤25 mm. Participants will be randomly assigned in a 1:1 ratio to receive cervical pessary or vaginal progesterone.

This open label, multi-center, randomized controlled trial aims to compare the effectiveness of cervical pessary to vaginal progesterone for prevention of PTB in women with singleton pregnancies and a cervix ≤25 mm. All women at 16 0/7 to 22 0/7 weeks with singleton pregnancies will undergo cervical length (CL) measurement and digital examination at screening routinely. Women with a CL ≤25 mm will be eligible for the study. Subjects meeting the study criteria will be randomized into two groups: (1) treated with cervical pessary (Arabin) or (2) treated with 200 mg vaginal progesterone, once daily. After written informed consent, women will be randomly assigned in a 1:1 ratio to receive a cervical pessary or progesterone. Assignment to treatment allocation will be done via a web portal hosted by HOPE Research Center, Vietnam. The randomization schedule will be computer-generated at HOPE Research Center, with a permuted random block size of 2, 4 or 6. Blinding will not be possible due to the nature of interventions. For those who randomised to pessary group, a pessary certified by European Conformity (Arabin®, Dr Arabin GmbH & Co KG, Germany) will be inserted through the vagina, upward around the cervix by 2-4 senior clinicians, who had experienced with pessary used at each site, within one week of randomization. Women allocated to progesterone group will be receiving 200 mg vaginal progesterone, purchased from the manufacturer (Cyclogest® 200 mg, Actavis, United Kingdom), once daily at bedtime. They will be given a monitoring sheet and instructed to note everyday the date of using. In case of premature rupture of membranes, active vaginal bleeding, other signs of preterm labor or severe patient discomfort, the pessary may be removed. If participants develop (threatened) preterm labor, they will receive treatment per local protocol. Intervention will be stopped at 370/7 weeks of gestation or at delivery. Along side with this trial, another study will be conducted to determine how changes in peripheral blood and cervical inflammatory markers are impacted by progesterone versus pessary. Because of that, participants will be asked to take 5 ml blood sample and cervical-vaginal discharge sampling at the time of randomization, 4-8 weeks after randomization and before giving birth. A cost-effectiveness analysis will also be conducted alongside this RCT. Data will be reported in a separated paper.

Participants will be randomised to either pessary or progesterone in a 1:1 ratio with a variable block size of 2, 4 or 6.

Cervical pessary (Arabin) will be inserted to participants at 16-22 weeks and removed at 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort.

Vaginal progesterone (Cyclogest 200 mg) once a day will be used, from 16-22 to 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort.

Arabin (cervical pessary) will be inserted at 16-22 weeks and removed at 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort

Vaginal progesterone (Cyclogest 200 mg) once a day will be used, from 16-22 to 37 weeks of pregnancy or in case of premature rupture of membranes, signs of preterm labour or patient severe discomfort.

Birth spontaneously before 28 weeks' gestation, including preterm spontaneous rupture of membranes, preterm premature rupture of membranes (PPROM)

Birth spontaneously before 34 weeks' gestation, including preterm spontaneous rupture of membranes, preterm premature rupture of membranes (PPROM)

Birth spontaneously before 37 weeks' gestation, including preterm spontaneous rupture of membranes, preterm premature rupture of membranes (PPROM)

The birth of at least one newborn, regardless of gestational age, that exhibits any sign of life such as respiration, heartbeat, umbilical pulsation or movement of voluntary muscles

Apgar score at 5 minute after birth. 5-minute Apgar score of 7-10 as reassuring, a score of 4-6 as moderately abnormal, and a score of 0-3 as low in the term infant and late-preterm infant.

Foetal or neonatal death, intraventricular haemorrhage, respiratory distress syndrome, necrotizing enterocolitis or neonatal sepsis

presence of tachypnoea >60/minute, sternal recession and expiratory grunting, need for supplemental oxygen, and a radiological picture of diffuse reticulogranular shadowing with an air bronchogram

Repeated neonatal cranial ultrasound by the neonatologist according to the guidelines on neuro-imaging described by de Vries et al

Including vaginal discharge, vaginal bleeding, vaginal infection (confirmed by vaginal discharge culture)

Inclusion Criteria: Singleton pregnancies Cervical length ≤ 25 mm, measured by TVS at the second-trimester ultrasonography (16 0/7-22 0/7 weeks of gestation) Not participating in any other study which has intervention on maternity or fetus at the same time Provision of written informed consent to participate as shown by a signature on the patient consent form. Exclusion Criteria: Cervical dilation with visible amniotic membranes or amniotic membranes prolapsed into the vagina Major congenital abnormalities of the fetus Presence of severe vaginal discharge Presence of vaginitis or cervicitis Presence of vaginal bleeding Preterm premature rupture of membranes Premature labor without ruptured membrane at the time of screening Suspected chorioamnionitis Unable to have cervical pessary inserted Cerclage or pessary in place

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