Pessary or cerclage (PC study) to prevent recurrent preterm birth: a non-inferiority, randomised controlled trial

Annabelle L van Gils; Charlotte E van Dijk; Bouchra Koullali; Malou A Lugthart; Bo B Bet; Maud D van Zijl; Marijke C van der Weide; H Marieke Knol; Begoña Martinez de Tejada; Sanne J Gordijn; Eline S A van den Akker; Marieke Sueters; Marjon A de Boer; Brenda B J Hermsen; Yolanda M de Mooij; Sabina de Weerd; Wilhelmina M van Baal; Marion E van Hoorn; Martijn A Oudijk; Brenda M Kazemier; Ben Willem J Mol; Eva Pajkrt; PC Research Group

doi:10.1016/j.eclinm.2024.102945

Pessary or cerclage (PC study) to prevent recurrent preterm birth: a non-inferiority, randomised controlled trial

EClinicalMedicine. 2024 Nov 25:78:102945. doi: 10.1016/j.eclinm.2024.102945. eCollection 2024 Dec.

Authors

Annabelle L van Gils^{1

2}, Charlotte E van Dijk^{1

2}, Bouchra Koullali^{1

2}, Malou A Lugthart^{1

2}, Bo B Bet^{1

2}, Maud D van Zijl^{1

2}, Marijke C van der Weide¹, H Marieke Knol³, Begoña Martinez de Tejada⁴, Sanne J Gordijn⁵, Eline S A van den Akker⁶, Marieke Sueters⁷, Marjon A de Boer^{2

8}, Brenda B J Hermsen⁶, Yolanda M de Mooij⁹, Sabina de Weerd¹⁰, Wilhelmina M van Baal¹¹, Marion E van Hoorn¹², Martijn A Oudijk^{2

8}, Brenda M Kazemier^{1

2}, Ben Willem J Mol^{13

14}, Eva Pajkrt^{1

2}; PC Research Group

Collaborators

PC Research Group:
Eva Pajkrt, Ben Willem Mol, Brenda Miranda Kazemier, Maud Désirée Van Zijl, Bouchra Koullali, Malou Anne Lugthart, Bo Belle Bet, Charlotte Elisabeth Van Dijk, Annabelle Liselotte Van Gils

Affiliations

¹ Department of Obstetrics and Gynaecology, Amsterdam UMC Location University of Amsterdam, Meibergdreef 9, Amsterdam, the Netherlands.
² Amsterdam Reproduction and Development Research Institute, Amsterdam, the Netherlands.
³ Department of Obstetrics and Gynaecology, Isala Hospital, Zwolle, the Netherlands.
⁴ Department of Paediatrics, Gynaecology and Obstetrics, University Hospitals of Geneva and Faculty of Medicine, Geneva, Switzerland.
⁵ Department of Obstetrics, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.
⁶ Department of Obstetrics and Gynaecology, Onze Lieve Vrouwe Gasthuis, Amsterdam, the Netherlands.
⁷ Department of Obstetrics and Gynaecology, Leiden University Medical Center (LUMC), Leiden, the Netherlands.
⁸ Department of Obstetrics and Gynaecology, Amsterdam UMC, Location Vrije Universiteit Amsterdam, Boelelaan 1117, Amsterdam, the Netherlands.
⁹ Department of Obstetrics and Gynaecology, Zaans Medisch Centrum, Zaandam, the Netherlands.
¹⁰ Department of Obstetrics and Gynaecology, Albert Schweitzer Hospital, Dordrecht, the Netherlands.
¹¹ Department of Obstetrics and Gynaecology, Flevoziekenhuis, Almere, the Netherlands.
¹² Department of Obstetrics and Gynaecology, HAGA Hospital, The Hague, the Netherlands.
¹³ Department of Obstetrics and Gynaecology, Monash University, Clayton, Australia.
¹⁴ Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen, UK.

Abstract

Background: Previous spontaneous preterm birth (sPTB) is a strong risk indicator for recurrent preterm birth (PTB). Cervical cerclage is an accepted intervention to prevent recurrent PTB in high risk patients. Cervical pessary might be a less invasive alternative. The objective of this study is to determine whether a cervical pessary is non-inferior to cerclage in the prevention of recurrent PTB.

Methods: We performed an international, open-label, non-inferiority, randomised controlled trial in 21 hospitals between March 2014 and December 2022. We included singleton pregnancies with an indication for cerclage based on either multiple previous sPTBs <34 weeks or with a previous sPTB <34 weeks and an asymptomatic mid-trimester short cervix (≤25 mm). Randomisation was 1:1, stratified by centre and indication, to cervical pessary or vaginal cerclage. Primary outcome was PTB <32 weeks. Secondary outcomes included (s)PTB rates, obstetric, and maternal outcomes and a composite of adverse perinatal outcomes including perinatal mortality and severe neonatal morbidity. Analysis was by intention-to-treat. Treatment effect was expressed as relative risk (RR), absolute risk difference (aRD) and 95% confidence intervals (CI). Sample size was calculated at 400 participants with a non-inferiority margin for pessary of 10%, meaning that non-inferiority is proven if the upper limit of the CI of the risk difference is <10%. Trial registration at ICTRP: NL-OMON26958.

Findings: We randomised 261 participants to pessary (n = 133) or cerclage (n = 128). After the third interim analysis (n = 228 participants), recruitment was halted due to safety concerns and the apparent challenge in establishing non-inferiority of pessary treatment. PTB <32 weeks occurred in 44/130 cases after pessary vs 30/125 cases after cerclage (33.8% vs 24.0% aRR 1.4, 95% CI 0.95-2.1, p = 0.09, aRD 9.8% 95% CI -1.2 to 20.9). The composite of adverse perinatal outcomes occurred in 42 cases after pessary compared to 29 cases in cerclage (32.2% vs 23.2%; RR 1.4 95% CI 0.93-2.1 p = 0.1) and consisted mainly of perinatal death (22.3% vs 14.4% RR 1.5 95% CI 0.9-2.6 p = 0.1).

Interpretation: Non-inferiority of cervical pessary compared to cerclage in preventing recurrent PTB <32 weeks was not proven. Cerclage is the recommended treatment.

Funding: ZonMw (#837002406), a Dutch Organisation for Health Research and Development.

Keywords: Cerclage; Cervical insufficiency; Pessary; Preterm birth; Recurrence.