Clinical Research Network

Reproductive health and childbirth

OPPTIMUM
Does progesterone prophylaxis to prevent
preterm labour improve outcome?
It has been shown that administering progesterone
can reduce the risk of a preterm birth and neonatal Key features
morbidity in women at high risk of these outcomes. • February 2009 - April 2013
However debate remains as to the long-term effects
• A randomised, double-blind,
on children. The OPPTIMUM study aimed to look at
whether the use of progesterone affects neonatal and
placebo-controlled study: 1,228 participants
childhood outcomes. • 65 UK sites
• Funded by the Efficacy and Mechanism
Conducted using a randomised, double-blind, Evaluation (EME) programme (NIHR/MRC
placebo-controlled study, OPPTIMUM involved women
partnership)
with clinical risk factors for preterm birth. This included
women who had previously had a spontaneous preterm
• Chief Investigator: Professor Jane Norman,
birth at less than or equal to 34 weeks of gestation, a Professor of Maternal and Fetal Health, MRC
short cervix, or a positive fetal fibronectin test combined Centre for Reproductive Health; Director of
with other clinical risk factors for preterm birth the Tommy’s Centre for Maternal and Fetal
(including second trimester loss, preterm premature Health; Vice Principal, People and Culture;
fetal membrane rupture, or a history of a cervical University of Edinburgh
procedure to treat abnormal smears). During pregnancy,
fibronectin binds the fetal membranes to the lining of
the womb. High quantities of the substance increase the likelihood that women will have a preterm birth.
Women were randomly assigned to be treated from 22-24 to 34 weeks of gestation with daily vaginal
progesterone 200mg pessary or placebo. Randomisation was carried out through a web portal with participants,
investigators and others involved in giving the intervention, assessing outcomes and/or analysing data masked to
treatment allocation until the end of the study.
The study was funded by the Efficacy and Mechanism Evaluation (EME) Programme; a NIHR and Medical Research
Council (MRC) partnership. The NIHR Clinical Research Network (CRN) supported all 65 sites across the UK. This
included consideration of more than 15,000 women’s records and screening more than 5,800 women using
fibronectin testing. With this support from the NIHR CRN, the study recruited 1,228 women to time and target.
Outcomes and findings
The OPPTIMUM study had three primary outcomes:
1. Fetal death or delivery occurring before 34 weeks of
gestation (obstetric outcome)
2. A composite of death, bronchopulmonary dysplasia,
and brain injury on cerebral ultrasound (neonatal
outcome)
3. A standardised cognitive score at 22–26 months of
chronological age (childhood outcome)
The study had at least 80% power to detect what was
considered the minimal important clinical difference
for each of the three primary outcomes at 5% level of
significance.
The results showed that progesterone had no
significant effect on the primary obstetric, neonatal and
childhood outcome.
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.
The findings strongly suggest that the efficacy of
progesterone in improving outcomes is either non-
existent or weak in women currently identified as high Value to the NHS
risk using current screening criteria. OPPTIMUM was the largest study to compare obstetric,
The results of OPPTIMUM have prompted the neonatal, and childhood outcomes in high-risk,
Patient-Centred Outcomes Research Institute (PCORI) single pregnancy women being treated with vaginal
to undertake international individual patient-level progesterone to prevent preterm birth. It was also one
data analysis as part of a major review into the use of of the few studies to look at childhood effects.
progesterone for preterm birth treament. In addition to the review being undertaken by PCORI,
there is now a renewed search to identify women
who might specifically benefit from progesterone
“The OPPTIMUM study administration. OPPTIMUM has also highlighted the
illustrated the need for a need to find alternative strategies to prevent preterm
collaborative, networked birth in women at risk. As such, it is likely that is has
approach to answer an slowed down or arrested the trend of widespread use
of vaginal progesterone for preterm prevention in UK
important clinical question. In
practice.
doing so, it has challenged the
presumption of progesterone’s
benefit which was previously prevalent and
prompted further scrutiny into the role for
progesterone prophylaxis in the prevention
of preterm birth.“
Nigel Simpson, Senior Lecturer in Obstetrics &
Gynaecology, University of Leeds

Key publications:
• Study site: www.opptimum.org.uk
• Vaginal progesterone prophylaxis for preterm birth (the OPPTIMUM study): a multicentre, randomised,
double-blind trial, J.Norman et al. The Lancet, 2016
• Trial protocol OPPTIMUM - does progesterone prophylaxis for the prevention of preterm labour improve
outcome? BMC Pregnancy & Childbirth, 2012
CRN100