Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study)

a multicentre, randomised, double-blind trial

Jane Elizabeth Norman, Neil Marlow, Claudia-Martina Messow, Andrew Shennan, Phillip R. Bennett, Steven Thornton, Stephen C. Robson, Alex McConnachie, Stavros Petrou, Neil J. Sebire, Tina Lavender, Sonia Whyte, John Norrie, OPPTIMUM study group

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Abstract

BACKGROUND: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.

METHODS: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.

FINDINGS: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27).

INTERPRETATION: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.

FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

Original languageEnglish
Pages (from-to)2106-2116
Number of pages11
JournalThe Lancet
Volume387
Issue number10033
Early online date24 Feb 2016
DOIs
Publication statusPublished - May 2016

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Premature Birth
Multicenter Studies
Progesterone
Placebos
Obstetrics
Pregnancy
National Institutes of Health (U.S.)
Program Evaluation
Biomedical Research
Premature Rupture Fetal Membranes
Research
Parturition
Bronchopulmonary Dysplasia
Intention to Treat Analysis
Fetal Death
Wales
Scotland
Second Pregnancy Trimester
Pregnancy Outcome
Random Allocation

Cite this

Norman, J. E., Marlow, N., Messow, C-M., Shennan, A., Bennett, P. R., Thornton, S., ... OPPTIMUM study group (2016). Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial. The Lancet, 387(10033), 2106-2116. https://doi.org/10.1016/S0140-6736(16)00350-0

Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study) : a multicentre, randomised, double-blind trial. / Norman, Jane Elizabeth; Marlow, Neil; Messow, Claudia-Martina; Shennan, Andrew; Bennett, Phillip R.; Thornton, Steven; Robson, Stephen C.; McConnachie, Alex; Petrou, Stavros; Sebire, Neil J.; Lavender, Tina; Whyte, Sonia; Norrie, John; OPPTIMUM study group.

In: The Lancet, Vol. 387, No. 10033, 05.2016, p. 2106-2116.

Research output: Contribution to journalArticle

Norman, JE, Marlow, N, Messow, C-M, Shennan, A, Bennett, PR, Thornton, S, Robson, SC, McConnachie, A, Petrou, S, Sebire, NJ, Lavender, T, Whyte, S, Norrie, J & OPPTIMUM study group 2016, 'Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial', The Lancet, vol. 387, no. 10033, pp. 2106-2116. https://doi.org/10.1016/S0140-6736(16)00350-0
Norman, Jane Elizabeth ; Marlow, Neil ; Messow, Claudia-Martina ; Shennan, Andrew ; Bennett, Phillip R. ; Thornton, Steven ; Robson, Stephen C. ; McConnachie, Alex ; Petrou, Stavros ; Sebire, Neil J. ; Lavender, Tina ; Whyte, Sonia ; Norrie, John ; OPPTIMUM study group. / Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study) : a multicentre, randomised, double-blind trial. In: The Lancet. 2016 ; Vol. 387, No. 10033. pp. 2106-2116.
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title = "Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised, double-blind trial",
abstract = "BACKGROUND: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.METHODS: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.FINDINGS: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95{\%} CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95{\%} CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11{\%}) of 610 patients in the placebo group and 59 (10{\%}) of 616 patients in the progesterone group (p=0·27).INTERPRETATION: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.",
author = "Norman, {Jane Elizabeth} and Neil Marlow and Claudia-Martina Messow and Andrew Shennan and Bennett, {Phillip R.} and Steven Thornton and Robson, {Stephen C.} and Alex McConnachie and Stavros Petrou and Sebire, {Neil J.} and Tina Lavender and Sonia Whyte and John Norrie and {OPPTIMUM study group}",
note = "Acknowledgments We thank the members of the Trial Steering and Data Monitoring Committee and all the people who helped in the conduct of the study (including the OPPTIMUM collaborative group and other clinicians listed in the appendix). We are grateful to Paul Piette (Besins Healthcare Corporate, Brussels, Belgium) and Besins Healthcare for their kind donation of active and placebo drug for use in the study, and to staff of the pharmacy and research and development departments of the participating hospitals. We are also grateful to the many people who helped in this study but who we have been unable to name, and in particular all the women (and their babies) who participated in OPPTIMUM. OPPTIMUM was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute of Health Research (NIHR) partnership, award number G0700452, revised to 09/800/27. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales. The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, National Health Service, NIHR, or the Department of Health. The funder had no involvement in data collection, analysis or interpretation, and no role in the writing of this manuscript or the decision to submit for publication.",
year = "2016",
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TY - JOUR

T1 - Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study)

T2 - a multicentre, randomised, double-blind trial

AU - Norman, Jane Elizabeth

AU - Marlow, Neil

AU - Messow, Claudia-Martina

AU - Shennan, Andrew

AU - Bennett, Phillip R.

AU - Thornton, Steven

AU - Robson, Stephen C.

AU - McConnachie, Alex

AU - Petrou, Stavros

AU - Sebire, Neil J.

AU - Lavender, Tina

AU - Whyte, Sonia

AU - Norrie, John

AU - OPPTIMUM study group

N1 - Acknowledgments We thank the members of the Trial Steering and Data Monitoring Committee and all the people who helped in the conduct of the study (including the OPPTIMUM collaborative group and other clinicians listed in the appendix). We are grateful to Paul Piette (Besins Healthcare Corporate, Brussels, Belgium) and Besins Healthcare for their kind donation of active and placebo drug for use in the study, and to staff of the pharmacy and research and development departments of the participating hospitals. We are also grateful to the many people who helped in this study but who we have been unable to name, and in particular all the women (and their babies) who participated in OPPTIMUM. OPPTIMUM was funded by the Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute of Health Research (NIHR) partnership, award number G0700452, revised to 09/800/27. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales. The views expressed in this publication are those of the author(s) and not necessarily those of the MRC, National Health Service, NIHR, or the Department of Health. The funder had no involvement in data collection, analysis or interpretation, and no role in the writing of this manuscript or the decision to submit for publication.

PY - 2016/5

Y1 - 2016/5

N2 - BACKGROUND: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.METHODS: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.FINDINGS: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27).INTERPRETATION: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

AB - BACKGROUND: Progesterone administration has been shown to reduce the risk of preterm birth and neonatal morbidity in women at high risk, but there is uncertainty about longer term effects on the child.METHODS: We did a double-blind, randomised, placebo-controlled trial of vaginal progesterone, 200 mg daily taken from 22-24 to 34 weeks of gestation, on pregnancy and infant outcomes in women at risk of preterm birth (because of previous spontaneous birth at ≤34 weeks and 0 days of gestation, or a cervical length ≤25 mm, or because of a positive fetal fibronectin test combined with other clinical risk factors for preterm birth [any one of a history in a previous pregnancy of preterm birth, second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical procedure to treat abnormal smears]). The objective of the study was to determine whether vaginal progesterone prophylaxis given to reduce the risk of preterm birth affects neonatal and childhood outcomes. We defined three primary outcomes: fetal death or birth before 34 weeks and 0 days gestation (obstetric), a composite of death, brain injury, or bronchopulmonary dysplasia (neonatal), and a standardised cognitive score at 2 years of age (childhood), imputing values for deaths. Randomisation was done through a web portal, with participants, investigators, and others involved in giving the intervention, assessing outcomes, or analysing data masked to treatment allocation until the end of the study. Analysis was by intention to treat. This trial is registered at ISRCTN.com, number ISRCTN14568373.FINDINGS: Between Feb 2, 2009, and April 12, 2013, we randomly assigned 1228 women to the placebo group (n=610) and the progesterone group (n=618). In the placebo group, data from 597, 587, and 439 women or babies were available for analysis of obstetric, neonatal, and childhood outcomes, respectively; in the progesterone group the corresponding numbers were 600, 589, and 430. After correction for multiple outcomes, progesterone had no significant effect on the primary obstetric outcome (odds ratio adjusted for multiple comparisons [OR] 0·86, 95% CI 0·61-1·22) or neonatal outcome (OR 0·62, 0·38-1·03), nor on the childhood outcome (cognitive score, progesterone group vs placebo group, 97·3 [SD 17·9] vs 97·7 [17·5]; difference in means -0·48, 95% CI -2·77 to 1·81). Maternal or child serious adverse events were reported in 70 (11%) of 610 patients in the placebo group and 59 (10%) of 616 patients in the progesterone group (p=0·27).INTERPRETATION: Vaginal progesterone was not associated with reduced risk of preterm birth or composite neonatal adverse outcomes, and had no long-term benefit or harm on outcomes in children at 2 years of age.FUNDING: Efficacy and Mechanism Evaluation (EME) Programme, a Medical Research Council (MRC) and National Institute for Health Research (NIHR) partnership. The EME Programme is funded by the MRC and NIHR, with contributions from the Chief Scientist Office in Scotland and National Institute for Social Care and Research in Wales.

U2 - 10.1016/S0140-6736(16)00350-0

DO - 10.1016/S0140-6736(16)00350-0

M3 - Article

VL - 387

SP - 2106

EP - 2116

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10033

ER -