Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

doi:10.1136/bmjopen-2023-082880

. 2024 Jun 18;14(6):e082880.

doi: 10.1136/bmjopen-2023-082880.

Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

Catherine Anne Cluver^{1

2

3}, Lina Bergman^{4

5}, Henrik Imberg⁶, Ben W Mol⁷, David Hall⁴, Adrie Bekker⁸, Adrienne Gordon⁹, Fiona Brownfoot^{2

3}, Tu'uhevaha J Kaitu'u-Lino^{2

3}, Susan P Walker^{2

3}, Stephen Tong^{2

3

10}

Affiliations

¹ Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa cathycluver@sun.ac.za.
² Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Melbourne University, Heidelberg, Victoria, Australia.
³ Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.
⁴ Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa.
⁵ Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁶ Statistiska Konsultgruppen, Gothenburg, Sweden.
⁷ Department of Obstetrics and Gynaecology, Monash Medical School, Monash University, Melbourne, Victoria, Australia.
⁸ Department of Paediatrics, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa.
⁹ Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁰ Translational Obstetrics Group and Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.

PMID: 38890136
PMCID: PMC11191812
DOI: 10.1136/bmjopen-2023-082880

Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

Catherine Anne Cluver et al. BMJ Open. 2024.

. 2024 Jun 18;14(6):e082880.

doi: 10.1136/bmjopen-2023-082880.

Authors

Affiliations

¹ Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa cathycluver@sun.ac.za.
² Translational Obstetrics Group, Department of Obstetrics and Gynaecology, Mercy Hospital for Women, Melbourne University, Heidelberg, Victoria, Australia.
³ Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, Victoria, Australia.
⁴ Department of Obstetrics and Gynaecology, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa.
⁵ Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
⁶ Statistiska Konsultgruppen, Gothenburg, Sweden.
⁷ Department of Obstetrics and Gynaecology, Monash Medical School, Monash University, Melbourne, Victoria, Australia.
⁸ Department of Paediatrics, Stellenbosch University, Faculty of Medicine and Health Sciences, Cape Town, South Africa.
⁹ Discipline of Obstetrics, Gynaecology and Neonatology, Faculty of Medicine and Health, University of Sydney, Sydney, New South Wales, Australia.
¹⁰ Translational Obstetrics Group and Department of Obstetrics and Gynaecology, University of Melbourne, Mercy Hospital for Women, Heidelberg, Melbourne, Victoria, Australia.

PMID: 38890136
PMCID: PMC11191812
DOI: 10.1136/bmjopen-2023-082880

Abstract

Introduction: 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 days, 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.

Methods: 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 and 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.

Ethics and dissemination: 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.

Trial registration number: PACTR202104532026017).

Keywords: Clinical Trial; Fetal medicine; Maternal medicine; Neonatology; Pregnancy; Randomized Controlled Trial.

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Conflict of interest statement

Competing interests: None declared.

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References

1. Chappell LC, Cluver CA, Kingdom J, et al. . Pre-Eclampsia. Lancet 2021;398:341–54. 10.1016/S0140-6736(20)32335-7 - DOI - PubMed
1. Abalos E, Cuesta C, Grosso AL, et al. . Global and regional estimates of Preeclampsia and Eclampsia: A systematic review. Eur J Obstet Gynecol Reprod Biol 2013;170:1–7. 10.1016/j.ejogrb.2013.05.005 - DOI - PubMed
1. Moodley J. Maternal deaths due to hypertensive disorders of pregnancy: data from the 2014-2016 saving mothers’ report. Obstet Gynaecol Forum 2018;28:28–32. Available: https://journals.co.za/doi/abs/10.10520/EJC-11ea64a35b
1. Suppo de Souza Rugolo L, Bentlin M, Petean Trindade CE. Preeclampsia: early and late neonatal outcomes. Neoreviews 2012;13:e532–41. 10.1542/neo.13-9-e532 - DOI
1. Fanaroff AA, Stoll BJ, Wright LL, et al. . Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147. 10.1016/j.ajog.2006.09.014 - DOI - PubMed

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[1] Chappell LC, Cluver CA, Kingdom J, et al. . Pre-Eclampsia. Lancet 2021;398:341–54. 10.1016/S0140-6736(20)32335-7 - DOI - PubMed

[2] Chappell LC, Cluver CA, Kingdom J, et al. . Pre-Eclampsia. Lancet 2021;398:341–54. 10.1016/S0140-6736(20)32335-7 - DOI - PubMed

[3] Abalos E, Cuesta C, Grosso AL, et al. . Global and regional estimates of Preeclampsia and Eclampsia: A systematic review. Eur J Obstet Gynecol Reprod Biol 2013;170:1–7. 10.1016/j.ejogrb.2013.05.005 - DOI - PubMed

[4] Abalos E, Cuesta C, Grosso AL, et al. . Global and regional estimates of Preeclampsia and Eclampsia: A systematic review. Eur J Obstet Gynecol Reprod Biol 2013;170:1–7. 10.1016/j.ejogrb.2013.05.005 - DOI - PubMed

[5] Moodley J. Maternal deaths due to hypertensive disorders of pregnancy: data from the 2014-2016 saving mothers’ report. Obstet Gynaecol Forum 2018;28:28–32. Available: https://journals.co.za/doi/abs/10.10520/EJC-11ea64a35b

[6] Moodley J. Maternal deaths due to hypertensive disorders of pregnancy: data from the 2014-2016 saving mothers’ report. Obstet Gynaecol Forum 2018;28:28–32. Available: https://journals.co.za/doi/abs/10.10520/EJC-11ea64a35b

[7] Suppo de Souza Rugolo L, Bentlin M, Petean Trindade CE. Preeclampsia: early and late neonatal outcomes. Neoreviews 2012;13:e532–41. 10.1542/neo.13-9-e532 - DOI

[8] Suppo de Souza Rugolo L, Bentlin M, Petean Trindade CE. Preeclampsia: early and late neonatal outcomes. Neoreviews 2012;13:e532–41. 10.1542/neo.13-9-e532 - DOI

[9] Fanaroff AA, Stoll BJ, Wright LL, et al. . Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147. 10.1016/j.ajog.2006.09.014 - DOI - PubMed

[10] Fanaroff AA, Stoll BJ, Wright LL, et al. . Trends in neonatal morbidity and mortality for very low birthweight infants. Am J Obstet Gynecol 2007;196:147. 10.1016/j.ajog.2006.09.014 - DOI - PubMed

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Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

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Does metformin prolong pregnancy in preterm pre-eclampsia? A study protocol for a South African, hospital-based double-blind, randomised, placebo-controlled trial

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