Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study)
Introduction Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more spontaneous pregnancy losses from the time of conception until 24 weeks of gestation. Currently, an underlying cause can be identified in only a minority of the losses. Potentially, an impaired maternal immune re...
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2025-06-01
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| author | Saskia le Cessie Nan van Geloven Marie-Louise van der Hoorn Michael Eikmans Annemarie Mulders Eileen Lashley Jantien Visser Moniek van der Zanden Mariette Goddijn Tess Meuleman Salwan Al-Nasiry Harold Verhoeve Gijs Teklenburg Jan-Peter de Bruin Yentl Béquet Renate Van der Molen Elske van den Akker-van Marle Marloes Vermeulen Merel van den Berg Astrid Cantineau Dana Huppelschoten |
| author_facet | Saskia le Cessie Nan van Geloven Marie-Louise van der Hoorn Michael Eikmans Annemarie Mulders Eileen Lashley Jantien Visser Moniek van der Zanden Mariette Goddijn Tess Meuleman Salwan Al-Nasiry Harold Verhoeve Gijs Teklenburg Jan-Peter de Bruin Yentl Béquet Renate Van der Molen Elske van den Akker-van Marle Marloes Vermeulen Merel van den Berg Astrid Cantineau Dana Huppelschoten |
| author_sort | Saskia le Cessie |
| collection | DOAJ |
| description | Introduction Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more spontaneous pregnancy losses from the time of conception until 24 weeks of gestation. Currently, an underlying cause can be identified in only a minority of the losses. Potentially, an impaired maternal immune response targeting the semiallograft pregnancy may lead to miscarriage. While prior studies have explored the use of immune-suppressing corticosteroids to modulate the maternal immune system and hopefully improve pregnancy outcome, the absence of sufficiently powered randomised controlled trials (RCT) underscores the need for further research. The primary aim of this study is to evaluate if prednisolone administration in early pregnancy (20 mg daily for 6 weeks, then tapering doses for 2 weeks) in women with unexplained RPL leads to a higher live birth rate (LBR) in comparison to placebo. Additionally, the study assesses the tolerability, safety and the cost-effectiveness of this intervention. Finally, we will explore the effect of prednisolone in various subgroups (based on maternal age, number of previous pregnancy losses, presence of specific antibodies and pre-pregnancy endometrial immune cell level).Methods and analysis This ongoing multicentre, double-blind RCT will randomise 490 women with unexplained RPL and pregnancy <7 weeks to receive either prednisolone or placebo. Each participant will be followed up for 1 year, with digital questionnaires to assess depression, anxiety, medical expenses and productivity loss. We will also collect data on maternal and paternal demographics and neonatal outcomes. The sample size of 490 participants was calculated according to a minimally important increase in LBR of 12% (expecting a LBR of 63% in the general RPL population), including loss to follow-up (estimated at 5%). The analysis will follow the intention-to-treat principle.Ethics and dissemination This study was submitted under the Clinical Trial Regulation (CTR) in Clinical Trials Information System (CTIS) for assessment by the Central Committee on Research Involving Human Subjects (CCMO) under Clinical Trial number: 2023-503220-76-01. It received full approval on 29/01/2024. Study findings will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results by publishing them on the publicly available website of the study.Trial registration number This trial is registered in ClinicalTrials.gov (ID NCT05725512) and in CTIS (2023-503220-76-01). |
| format | Article |
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| language | English |
| publishDate | 2025-06-01 |
| publisher | BMJ Publishing Group |
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| series | BMJ Open |
| spelling | doaj-art-f98cd7121c2c44a6bbabbaa17a9dce5d2025-06-26T01:50:13ZengBMJ Publishing GroupBMJ Open2044-60552025-06-0115610.1136/bmjopen-2024-096545Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study)Saskia le Cessie0Nan van Geloven1Marie-Louise van der Hoorn2Michael Eikmans3Annemarie Mulders4Eileen Lashley5Jantien Visser6Moniek van der Zanden7Mariette Goddijn8Tess Meuleman9Salwan Al-Nasiry10Harold Verhoeve11Gijs Teklenburg12Jan-Peter de Bruin13Yentl Béquet14Renate Van der Molen15Elske van den Akker-van Marle16Marloes Vermeulen17Merel van den Berg18Astrid Cantineau19Dana Huppelschoten20Department of Clinical Epidemiology, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsDepartment of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The NetherlandsDepartment of Gynecology and Obstetrics, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsLaboratory of Reproductive Immunology, Department of Immunohematology and Blood transfusion, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsDepartment of Gynecology and Obstetrics, Erasmus Medical Center, Rotterdam, Zuid-Holland, The NetherlandsDepartment of Gynecology and Obstetrics, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsDepartment of Gynecology and Obstetrics, Amphia Hospital, Breda, The NetherlandsDepartment of Gynecology and Obstetrics, Medisch Centrum Haaglanden, Den Haag, Zuid-Holland, The NetherlandsCentre for Reproductive Medicine, Department of Gynecology and Obstetrics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC Location AMC Department of Obstetrics Gynecology, Amsterdam, Noord-Holland, The NetherlandsDepartment of Gynecology and Obstetrics, Radboud University Medical Centre, Nijmegen, The NetherlandsDepartment of Gynecology and Obstetrics, Maastricht UMC+, Maastricht, The NetherlandsDepartment of Gynecology and Obstetrics, OLVG, Amsterdam, Noord-Holland, The NetherlandsDepartment of Gynecology and Obstetrics, Isala Hospital, Zwolle, Overijssel, The NetherlandsDepartment of Gynecology and Obstetrics, Jeroen Bosch Hospital, ’s-Hertogenbosch, Noord-Brabant, The NetherlandsDepartment of Gynecology and Obstetrics, Leiden University Medical Center, Leiden, Zuid-Holland, The NetherlandsDepartment of Laboratory Medicine, Laboratory for Medical Immunology, Radboud University Medical Center, Nijmegen, Gelderland, The NetherlandsDepartment of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The NetherlandsPatient association Freya”, Asperen, The NetherlandsCentre for Reproductive Medicine, Department of Gynecology and Obstetrics, Amsterdam Reproduction and Development Research Institute, Amsterdam UMC Location AMC Department of Obstetrics Gynecology, Amsterdam, Noord-Holland, The NetherlandsDepartment of Gynecology and Obstetrics, University Medical Center Groningen, Groningen, The NetherlandsDepartment of Gynecology and Obstetrics, Catharina Hospital, Eindhoven, Noord-Brabant, The NetherlandsIntroduction Recurrent pregnancy loss (RPL) is defined as the occurrence of two or more spontaneous pregnancy losses from the time of conception until 24 weeks of gestation. Currently, an underlying cause can be identified in only a minority of the losses. Potentially, an impaired maternal immune response targeting the semiallograft pregnancy may lead to miscarriage. While prior studies have explored the use of immune-suppressing corticosteroids to modulate the maternal immune system and hopefully improve pregnancy outcome, the absence of sufficiently powered randomised controlled trials (RCT) underscores the need for further research. The primary aim of this study is to evaluate if prednisolone administration in early pregnancy (20 mg daily for 6 weeks, then tapering doses for 2 weeks) in women with unexplained RPL leads to a higher live birth rate (LBR) in comparison to placebo. Additionally, the study assesses the tolerability, safety and the cost-effectiveness of this intervention. Finally, we will explore the effect of prednisolone in various subgroups (based on maternal age, number of previous pregnancy losses, presence of specific antibodies and pre-pregnancy endometrial immune cell level).Methods and analysis This ongoing multicentre, double-blind RCT will randomise 490 women with unexplained RPL and pregnancy <7 weeks to receive either prednisolone or placebo. Each participant will be followed up for 1 year, with digital questionnaires to assess depression, anxiety, medical expenses and productivity loss. We will also collect data on maternal and paternal demographics and neonatal outcomes. The sample size of 490 participants was calculated according to a minimally important increase in LBR of 12% (expecting a LBR of 63% in the general RPL population), including loss to follow-up (estimated at 5%). The analysis will follow the intention-to-treat principle.Ethics and dissemination This study was submitted under the Clinical Trial Regulation (CTR) in Clinical Trials Information System (CTIS) for assessment by the Central Committee on Research Involving Human Subjects (CCMO) under Clinical Trial number: 2023-503220-76-01. It received full approval on 29/01/2024. Study findings will be presented at conferences and published in a peer-reviewed journal. Participants will be informed about the results by publishing them on the publicly available website of the study.Trial registration number This trial is registered in ClinicalTrials.gov (ID NCT05725512) and in CTIS (2023-503220-76-01).https://bmjopen.bmj.com/content/15/6/e096545.full |
| spellingShingle | Saskia le Cessie Nan van Geloven Marie-Louise van der Hoorn Michael Eikmans Annemarie Mulders Eileen Lashley Jantien Visser Moniek van der Zanden Mariette Goddijn Tess Meuleman Salwan Al-Nasiry Harold Verhoeve Gijs Teklenburg Jan-Peter de Bruin Yentl Béquet Renate Van der Molen Elske van den Akker-van Marle Marloes Vermeulen Merel van den Berg Astrid Cantineau Dana Huppelschoten Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study) BMJ Open |
| title | Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study) |
| title_full | Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study) |
| title_fullStr | Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study) |
| title_full_unstemmed | Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study) |
| title_short | Effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss: a study protocol for a double-blind, placebo-controlled, multicentre, randomised controlled trial (PREMI-study) |
| title_sort | effect of prednisolone on live birth rate in women with unexplained recurrent pregnancy loss a study protocol for a double blind placebo controlled multicentre randomised controlled trial premi study |
| url | https://bmjopen.bmj.com/content/15/6/e096545.full |
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