{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:44:47Z","timestamp":1791931487605,"version":"4.3.4"},"reference-count":17,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T00:00:00Z","timestamp":1718668800000},"content-version":"unspecified","delay-in-days":17,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004359","name":"Swedish Research Council","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"crossref"}]},{"name":"The National Health and Medical Research Council","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Mercy Health Foundation","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/501100007687","name":"Swedish Society of Medicine","doi-asserted-by":"crossref","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}],"id":[{"id":"10.13039\/501100007687","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Merck Healthcare KGaA Darmstadt","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"name":"Wallenberg Center for Molecular and Translational Medicine","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2024,5,21]]},"published-print":{"date-parts":[[2024,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Preterm pre-eclampsia is a leading cause of maternal morbidity and mortality. The Pre-eclampsia Intervention 2 (PI 2) trial suggested that metformin sustained release (XR) may prolong gestation by a week in pregnant women undergoing expectant management (7.6\u2009days, geometric mean ratio 1.39, 95% CI 0.99 to 1.95; p=0.057). These findings should be confirmed with a larger sample size, and we need to know if such a prolongation improves neonatal outcome. Here, we describe the protocol for such a follow-up trial.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The PI 3 trial is a phase III, intention-to-treat, double-blind, placebo-controlled randomised clinical trial to assess if metformin XR can prolong gestation and improve neonatal outcomes in women undergoing expectant management for preterm pre-eclampsia. We will recruit women who are between 26+0\u2009and 31+6 weeks pregnant. Women will be randomised to receive either 3 g metformin XR or an identical placebo in divided daily doses. The primary outcome is prolongation of pregnancy. Secondary outcomes are neonatal birth weight and length of neonatal care admission (an indicator of neonatal health at birth). All other outcomes will be exploratory. We will record tolerability and adverse events. We plan a sample size of 500 participants to be powered for the primary and secondary outcomes.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>PI 3 has ethical approval (Health Research Ethics Committee 2, Stellenbosch University, Protocol number M21\/03\/007, Project ID 21639, Federal Wide Assurance Number 00001372, Institutional Review Board Number IRB0005239), and is registered with the Pan African Clinical Trial Registry (PACTR202104532026017) and the South African Medicine Control Council (20211211). Data will be presented at international conferences and published in peer-reviewed journals.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>PACTR202104532026017)<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2023-082880","type":"journal-article","created":{"date-parts":[[2024,6,18]],"date-time":"2024-06-18T22:50:14Z","timestamp":1718751014000},"page":"e082880","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":8,"title":["Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial"],"prefix":"10.1136","volume":"14","clinical-trial-number":[{"clinical-trial-number":"nct06033131","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0406-8964","authenticated-orcid":false,"given":"Catherine Anne","family":"Cluver","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa"},{"name":"Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Melbourne University, Heidelberg, Victoria, Australia"},{"name":"Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5202-9428","authenticated-orcid":false,"given":"Lina","family":"Bergman","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa"},{"name":"Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrik","family":"Imberg","sequence":"additional","affiliation":[{"name":"Statistiska Konsultgruppen, Gothenburg, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8337-550X","authenticated-orcid":false,"given":"Ben W","family":"Mol","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Monash Medical School, Monash University, Melbourne, Victoria, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Hall","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrie","family":"Bekker","sequence":"additional","affiliation":[{"name":"Department of Paediatrics, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adrienne","family":"Gordon","sequence":"additional","affiliation":[{"name":"Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Brownfoot","sequence":"additional","affiliation":[{"name":"Translational 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