Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial

Asif Ahmed, David Williams, Versha Cheed, Lee J Middleton, Shakil Ahmad, Keqing Wang, Alex T Vince, Peter Hewett, Kevin Spencer, Khalid S Khan, Jane P Daniels, Katherine Barber, Mark Kilby, Ellen Knox, Tara Sellman, Paula Trinham, Derek Tuffnell, Vicky Jones, Jennifer Syson, Neil ShahLaurie Deeks, Wendy Carter, Ed Dorman, Susannah Thomas, Deborah Harrington, Nicola Higgins, Mirriam Wilmott‐powell, Nigel Simpson, Vivian Dolby, Leanne Bricker, Steve Walkinshaw, Gillian Houghton, Heather Longworth, Catherine Williamson, Mandish Dhanjal, Muna Noori, Mavis Machirori, Richard Howard, Rebecca Murray, Sarah Weist, Fiona Denison, Isobel Crawford, Stephen Robson, Carly Allan, Jenny Myers, Giovanna Bernatavicius, Lynsey Moorhead, Lucy Chappell, Catherine Nelson‐piercy, David Williams, Rebecca Daley, Miguel Rosas, Ian Greer, Libor Vitek, Andy Shennan, Neil Marlow, Ann Marie Barnard, Jim Thornton, Janet Rennie, Janet Peacock, Fang Gao Smith, Carolyn Hyde, Isobel Crawford, Melissa Cudmore, Alex Furmston, Leanne Fulcher, Leanne Homer, Andrew Howman, Nicholas Hilken, Stephen Brown

Research output: Contribution to journalArticle

Abstract

Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.

Original languageEnglish
JournalBJOG
DOIs
Publication statusPublished - 12 Nov 2019

Fingerprint

Pravastatin
Vascular Endothelial Growth Factor Receptor-1
Pre-Eclampsia
Placebos
Random Allocation
Mothers
Parturition
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Pregnancy
Pregnancy Outcome
Cultured Cells
Intercellular Signaling Peptides and Proteins

Bibliographical note

© 2019 Royal College of Obstetricians and Gynaecologists.

Keywords

  • Anti-angiogenic factor
  • double-blind
  • perinatal mortality
  • placebo-controlled
  • pravastatin
  • pre-eclampsia
  • randomised trial
  • statin

Cite this

Ahmed, Asif ; Williams, David ; Cheed, Versha ; Middleton, Lee J ; Ahmad, Shakil ; Wang, Keqing ; Vince, Alex T ; Hewett, Peter ; Spencer, Kevin ; Khan, Khalid S ; Daniels, Jane P ; Barber, Katherine ; Kilby, Mark ; Knox, Ellen ; Sellman, Tara ; Trinham, Paula ; Tuffnell, Derek ; Jones, Vicky ; Syson, Jennifer ; Shah, Neil ; Deeks, Laurie ; Carter, Wendy ; Dorman, Ed ; Thomas, Susannah ; Harrington, Deborah ; Higgins, Nicola ; Wilmott‐powell, Mirriam ; Simpson, Nigel ; Dolby, Vivian ; Bricker, Leanne ; Walkinshaw, Steve ; Houghton, Gillian ; Longworth, Heather ; Williamson, Catherine ; Dhanjal, Mandish ; Noori, Muna ; Machirori, Mavis ; Howard, Richard ; Murray, Rebecca ; Weist, Sarah ; Denison, Fiona ; Crawford, Isobel ; Robson, Stephen ; Allan, Carly ; Myers, Jenny ; Bernatavicius, Giovanna ; Moorhead, Lynsey ; Chappell, Lucy ; Nelson‐piercy, Catherine ; Williams, David ; Daley, Rebecca ; Rosas, Miguel ; Greer, Ian ; Vitek, Libor ; Shennan, Andy ; Marlow, Neil ; Marie Barnard, Ann ; Thornton, Jim ; Rennie, Janet ; Peacock, Janet ; Gao Smith, Fang ; Hyde, Carolyn ; Crawford, Isobel ; Cudmore, Melissa ; Furmston, Alex ; Fulcher, Leanne ; Homer, Leanne ; Howman, Andrew ; Hilken, Nicholas ; Brown, Stephen. / Pravastatin for early-onset pre-eclampsia : a randomised, blinded, placebo-controlled trial. In: BJOG. 2019.
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abstract = "Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95{\%} CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95{\%} CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95{\%} CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.",
keywords = "Anti-angiogenic factor, double-blind, perinatal mortality, placebo-controlled, pravastatin, pre-eclampsia, randomised trial, statin",
author = "Asif Ahmed and David Williams and Versha Cheed and Middleton, {Lee J} and Shakil Ahmad and Keqing Wang and Vince, {Alex T} and Peter Hewett and Kevin Spencer and Khan, {Khalid S} and Daniels, {Jane P} and Katherine Barber and Mark Kilby and Ellen Knox and Tara Sellman and Paula Trinham and Derek Tuffnell and Vicky Jones and Jennifer Syson and Neil Shah and Laurie Deeks and Wendy Carter and Ed Dorman and Susannah Thomas and Deborah Harrington and Nicola Higgins and Mirriam Wilmott‐powell and Nigel Simpson and Vivian Dolby and Leanne Bricker and Steve Walkinshaw and Gillian Houghton and Heather Longworth and Catherine Williamson and Mandish Dhanjal and Muna Noori and Mavis Machirori and Richard Howard and Rebecca Murray and Sarah Weist and Fiona Denison and Isobel Crawford and Stephen Robson and Carly Allan and Jenny Myers and Giovanna Bernatavicius and Lynsey Moorhead and Lucy Chappell and Catherine Nelson‐piercy and David Williams and Rebecca Daley and Miguel Rosas and Ian Greer and Libor Vitek and Andy Shennan and Neil Marlow and {Marie Barnard}, Ann and Jim Thornton and Janet Rennie and Janet Peacock and {Gao Smith}, Fang and Carolyn Hyde and Isobel Crawford and Melissa Cudmore and Alex Furmston and Leanne Fulcher and Leanne Homer and Andrew Howman and Nicholas Hilken and Stephen Brown",
note = "{\circledC} 2019 Royal College of Obstetricians and Gynaecologists.",
year = "2019",
month = "11",
day = "12",
doi = "10.1111/1471-0528.16013",
language = "English",
journal = "BJOG",
issn = "1470-0328",
publisher = "Wiley-Blackwell",

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Ahmed, A, Williams, D, Cheed, V, Middleton, LJ, Ahmad, S, Wang, K, Vince, AT, Hewett, P, Spencer, K, Khan, KS, Daniels, JP, Barber, K, Kilby, M, Knox, E, Sellman, T, Trinham, P, Tuffnell, D, Jones, V, Syson, J, Shah, N, Deeks, L, Carter, W, Dorman, E, Thomas, S, Harrington, D, Higgins, N, Wilmott‐powell, M, Simpson, N, Dolby, V, Bricker, L, Walkinshaw, S, Houghton, G, Longworth, H, Williamson, C, Dhanjal, M, Noori, M, Machirori, M, Howard, R, Murray, R, Weist, S, Denison, F, Crawford, I, Robson, S, Allan, C, Myers, J, Bernatavicius, G, Moorhead, L, Chappell, L, Nelson‐piercy, C, Williams, D, Daley, R, Rosas, M, Greer, I, Vitek, L, Shennan, A, Marlow, N, Marie Barnard, A, Thornton, J, Rennie, J, Peacock, J, Gao Smith, F, Hyde, C, Crawford, I, Cudmore, M, Furmston, A, Fulcher, L, Homer, L, Howman, A, Hilken, N & Brown, S 2019, 'Pravastatin for early-onset pre-eclampsia: a randomised, blinded, placebo-controlled trial', BJOG. https://doi.org/10.1111/1471-0528.16013

Pravastatin for early-onset pre-eclampsia : a randomised, blinded, placebo-controlled trial. / Ahmed, Asif; Williams, David; Cheed, Versha; Middleton, Lee J; Ahmad, Shakil; Wang, Keqing; Vince, Alex T; Hewett, Peter; Spencer, Kevin; Khan, Khalid S; Daniels, Jane P; Barber, Katherine; Kilby, Mark; Knox, Ellen; Sellman, Tara; Trinham, Paula; Tuffnell, Derek; Jones, Vicky; Syson, Jennifer; Shah, Neil; Deeks, Laurie; Carter, Wendy; Dorman, Ed; Thomas, Susannah; Harrington, Deborah; Higgins, Nicola; Wilmott‐powell, Mirriam; Simpson, Nigel; Dolby, Vivian; Bricker, Leanne; Walkinshaw, Steve; Houghton, Gillian; Longworth, Heather; Williamson, Catherine; Dhanjal, Mandish; Noori, Muna; Machirori, Mavis; Howard, Richard; Murray, Rebecca; Weist, Sarah; Denison, Fiona; Crawford, Isobel; Robson, Stephen; Allan, Carly; Myers, Jenny; Bernatavicius, Giovanna; Moorhead, Lynsey; Chappell, Lucy; Nelson‐piercy, Catherine; Williams, David; Daley, Rebecca; Rosas, Miguel; Greer, Ian; Vitek, Libor; Shennan, Andy; Marlow, Neil; Marie Barnard, Ann; Thornton, Jim; Rennie, Janet; Peacock, Janet; Gao Smith, Fang; Hyde, Carolyn; Crawford, Isobel; Cudmore, Melissa; Furmston, Alex; Fulcher, Leanne; Homer, Leanne; Howman, Andrew; Hilken, Nicholas; Brown, Stephen.

In: BJOG, 12.11.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Pravastatin for early-onset pre-eclampsia

T2 - a randomised, blinded, placebo-controlled trial

AU - Ahmed, Asif

AU - Williams, David

AU - Cheed, Versha

AU - Middleton, Lee J

AU - Ahmad, Shakil

AU - Wang, Keqing

AU - Vince, Alex T

AU - Hewett, Peter

AU - Spencer, Kevin

AU - Khan, Khalid S

AU - Daniels, Jane P

AU - Barber, Katherine

AU - Kilby, Mark

AU - Knox, Ellen

AU - Sellman, Tara

AU - Trinham, Paula

AU - Tuffnell, Derek

AU - Jones, Vicky

AU - Syson, Jennifer

AU - Shah, Neil

AU - Deeks, Laurie

AU - Carter, Wendy

AU - Dorman, Ed

AU - Thomas, Susannah

AU - Harrington, Deborah

AU - Higgins, Nicola

AU - Wilmott‐powell, Mirriam

AU - Simpson, Nigel

AU - Dolby, Vivian

AU - Bricker, Leanne

AU - Walkinshaw, Steve

AU - Houghton, Gillian

AU - Longworth, Heather

AU - Williamson, Catherine

AU - Dhanjal, Mandish

AU - Noori, Muna

AU - Machirori, Mavis

AU - Howard, Richard

AU - Murray, Rebecca

AU - Weist, Sarah

AU - Denison, Fiona

AU - Crawford, Isobel

AU - Robson, Stephen

AU - Allan, Carly

AU - Myers, Jenny

AU - Bernatavicius, Giovanna

AU - Moorhead, Lynsey

AU - Chappell, Lucy

AU - Nelson‐piercy, Catherine

AU - Williams, David

AU - Daley, Rebecca

AU - Rosas, Miguel

AU - Greer, Ian

AU - Vitek, Libor

AU - Shennan, Andy

AU - Marlow, Neil

AU - Marie Barnard, Ann

AU - Thornton, Jim

AU - Rennie, Janet

AU - Peacock, Janet

AU - Gao Smith, Fang

AU - Hyde, Carolyn

AU - Crawford, Isobel

AU - Cudmore, Melissa

AU - Furmston, Alex

AU - Fulcher, Leanne

AU - Homer, Leanne

AU - Howman, Andrew

AU - Hilken, Nicholas

AU - Brown, Stephen

N1 - © 2019 Royal College of Obstetricians and Gynaecologists.

PY - 2019/11/12

Y1 - 2019/11/12

N2 - Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.

AB - Objective: Women with pre-eclampsia have elevated circulating levels of soluble fms-like tyrosine kinase-1 (sFlt-1). Statins can reduce sFlt-1 from cultured cells and improve pregnancy outcome in animals with a pre-eclampsia-like syndrome. We investigated the effect of pravastatin on plasma sFlt-1 levels during pre-eclampsia. Design: Blinded (clinician and participant), proof of principle, placebo-controlled trial. Setting: Fifteen UK maternity units. Population: We used a minimisation algorithm to assign 62 women with early-onset pre-eclampsia (24 +0–31 +6 weeks of gestation) to receive pravastatin 40 mg daily (n = 30) or matched placebo (n = 32), from randomisation to childbirth. Primary outcome: Difference in mean plasma sFlt-1 levels over the first 3 days following randomisation. Results: The difference in the mean maternal plasma sFlt-1 levels over the first 3 days after randomisation between the pravastatin (n = 27) and placebo (n = 29) groups was 292 pg/ml (95% CI −1175 to 592; P = 0.5), and over days 1–14 was 48 pg/ml (95% CI −1009 to 913; P = 0.9). Women who received pravastatin had a similar length of pregnancy following randomisation compared with those who received placebo (hazard ratio 0.84; 95% CI 0.50–1.40; P = 0.6). The median time from randomisation to childbirth was 9 days [interquartile range (IQR) 5–14 days] for the pravastatin group and 7 days (IQR 4–11 days) for the placebo group. There were three perinatal deaths in the placebo-treated group and no deaths or serious adverse events attributable to pravastatin. Conclusions: We found no evidence that pravastatin lowered maternal plasma sFlt-1 levels once early-onset pre-eclampsia had developed. Pravastatin appears to have no adverse perinatal effects. Tweetable abstract: Pravastatin does not improve maternal plasma sFlt-1 or placental growth factor levels following a diagnosis of early preterm pre-eclampsia #clinicaltrial finds.

KW - Anti-angiogenic factor

KW - double-blind

KW - perinatal mortality

KW - placebo-controlled

KW - pravastatin

KW - pre-eclampsia

KW - randomised trial

KW - statin

UR - https://onlinelibrary.wiley.com/doi/abs/10.1111/1471-0528.16013

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DO - 10.1111/1471-0528.16013

M3 - Article

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JF - BJOG

SN - 1470-0328

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