Evaluation of the Arabin cervical pessary for prevention of preterm birth in women with a twin pregnancy and short cervix (STOPPIT-2): An open-label randomised trial and updated meta-analysis

Abstract

Background: Preterm-labour-associated preterm birth is a common cause of perinatal mortality and morbidity in twin pregnancy. We aimed to test the hypothesis that the Arabin pessary would reduce preterm-labour-associated preterm birth by 40% or greater in women with a twin pregnancy and a short cervix.

Methods and findings: We conducted an open-label randomised controlled trial in 57 hospital antenatal clinics in the UK and Europe. From 1 April 2015 to 14 February 2019, 2,228 women with a twin pregnancy underwent cervical length screening between 18 weeks 0 days and 20 weeks 6 days of gestation. In total, 503 women with cervical length ≤ 35 mm were randomly assigned to pessary in addition to standard care (n = 250, mean age 32.4 years, mean cervical length 29 mm, with pessary inserted in 230 women [92.0%]) or standard care alone (n = 253, mean age 32.7 years, mean cervical length 30 mm). The pessary was inserted before 21 completed weeks of gestation and removed at between 35 and 36 weeks or before birth if earlier. The primary obstetric outcome, spontaneous onset of labour and birth before 34 weeks 0 days of gestation, was present in 46/250 (18.4%) in the pessary group compared to 52/253 (20.6%) following standard care alone (adjusted odds ratio [aOR] 0.87 [95% CI 0.55-1.38], p = 0.54). The primary neonatal outcome-a composite of any of stillbirth, neonatal death, periventricular leukomalacia, early respiratory morbidity, intraventricular haemorrhage, necrotising enterocolitis, or proven sepsis, from birth to 28 days after the expected date of delivery-was present in 67/500 infants (13.4%) in the pessary group compared to 76/506 (15.0%) following standard care alone (aOR 0.86 [95% CI 0.54-1.36], p = 0.50). The positive and negative likelihood ratios of a short cervix (≤35 mm) to predict preterm birth before 34 weeks were 2.14 and 0.83, respectively. A meta-analysis of data from existing publications (4 studies, 313 women) and from STOPPIT-2 indicated that a cervical pessary does not reduce preterm birth before 34 weeks in women with a short cervix (risk ratio 0.74 [95% CI 0.50-1.11], p = 0.15). No women died in either arm of the study; 4.4% of babies in the Arabin pessary group and 5.5% of babies in the standard treatment group died in utero or in the neonatal period (p = 0.53). Study limitations include lack of power to exclude a smaller than 40% reduction in preterm labour associated preterm birth, and to be conclusive about subgroup analyses.

Conclusions: These results led us to reject our hypothesis that the Arabin pessary would reduce the risk of the primary outcome by 40%. Smaller treatment effects cannot be ruled out.

Trial registration: ISRCTN Registry ISRCTN 02235181. ClinicalTrials.gov NCT02235181.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests. JEN has received grants from government and charitable bodies for research into understanding the mechanism of term and preterm labour and understanding treatments. Within the last 3 years she has acted on a Data Safety and Monitoring Board for a study involving a preterm birth therapeutic agent for Glaxo Smith Kline, and has provided consultancy for Dilafor on drugs to alter labour progress. PRB reports personal fees from ObsEva Geneva, other from ObsEva Geneva, outside the submitted work; In addition, PRB has a patent PCT/GB1997/000529 WO1997031631 A1 Cox-2 selective inhibitors for managing labour and uterine contractions issued, a patent PCT/GB2004/001380 WO2005053705 A1 Use of a cyclopentenone prostaglandin for delaying the onset and/or preventing the continuation of labour (Priority Date Dec 2, 2003). issued, a patent PCT/GB2016/050618 Circulating miRNAs predictive of cervical shortening and preterm birth (Pending UK filing 6th March 2015 /Full international filing completed 7th March 2016). issued, a patent PCT/GB2016/050621 Rapid evaporative ionisation mass spectroscopy (REIMS) and Desorbtion Electrospray Ionisation Mass Spectroscopy (DESI-MS) analysis of swabs and biopsy samples. (Pending UK filing 6th March 2015 /Full international filing completed 7th March 2016 pending, a patent PCT/GB2019 Desorbtion Electrospray Ionisation Mass Spectroscopy (DESI-MS) analysis of swabs to predict vaginal microbiota. (Pending UK filing March 2019) pending, and a patent PCT/GB2019/Circulating miRNAs predictive of IUGR (Pending UK filing March 2019) pending. SCB reports grants from other from NIHR, NETSCC, HTA during the conduct of the study and personal fees and other from University of Copenhagen, Wellcome Trust, NIHR Global Health Research and French Cancer Institute outside the submitted work. SJS reports grants from NIHR HTA during the conduct of the study; being a member of the NIHR HTA General committee and receiving received other research funding from the NIHR (14/32/01 QUIDS), Wellcome Trust (209560/Z/17/Z) and CSO During the course of the study. SJS is a member of PLOS Medicine’s Editorial Board. NM reports personal fees from Shire-Takeda, personal fees from Novartis, personal fees from Glaxo-Smith-Klein, outside the submitted work. JN reports grants from University of Aberdeen and University of Edinburgh during the conduct of the study; and Membership of the following NIHR boards: CPR decision making committee; HTA Commissioning Board; HTA Commissioning Sub-Board (EOI); HTA Funding Boards Policy Group; HTA General Board; HTA Post-Board funding teleconference; NIHR CTU Standing Advisory Committee; NIHR HTA & EME Editorial Board; Pre-exposure Prophylaxis Impact Review Panel. ST has received grant funding from NIHR, other government and charity organisations. He provides commercial consultancy advice which has received financial compensation.

Figures

Fig 1. Participant flowchart.

* Bulging fetal membranes noted de novo since qualifying cervical length scan.

Fig 2. Meta-analysis of STOPPIT-2 and published data on the effectiveness of a cervical pessary in twin pregnancies in women with a short cervix in the prevention of preterm birth before 34 weeks gestation.