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Case study: OPPTIMUM Impact Case Study

The OPPTIMUM trial was a study on the NIHR Clinical Research Network portfolio, supported by the CRN Reproductive Health and Childbirth Specialty.

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OPPTIMUM: Does progesterone prophylaxis prevent preterm labour and improve outcomes?

Key features

• February 2009 - April 2013

• A randomised, double-blind, placebo-controlled study: 1,228 participants

• 65 UK sites

• Funded by the Efficacy and Mechanism Evaluation (EME) programme (NIHR/MRC partnership)

• Chief Investigator: Professor Jane Norman, Professor of Maternal and Fetal Health, MRC Centre for Reproductive Health; Director of the Tommy’s Centre for Maternal and Fetal Health; Vice Principal, People and Culture; University of Edinburgh

Background and Investigation

It has been shown that administering progesterone can reduce the risk of a preterm birth and neonatal morbidity in women at high risk of these outcomes. However debate remains as to the long-term effects on children. The OPPTIMUM study aimed to look at whether the use of progesterone affects neonatal and childhood outcomes. Conducted using a randomised, double-blind, placebo-controlled study, OPPTIMUM involved women with clinical risk factors for preterm birth.

This included women who had previously had a spontaneous preterm birth at less than or equal to 34 weeks of gestation, a short cervix, or a positive fetal fibronectin test combined with other clinical risk factors for preterm birth (including second trimester loss, preterm premature fetal membrane rupture, or a history of a cervical 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 nonexistent or weak in women currently identified as high risk using current screening criteria. The results of OPPTIMUM have prompted the Patient-Centred Outcomes Research Institute (PCORI) to undertake international individual patient-level data analysis as part of a major review into the use of progesterone for preterm birth treament.

Value to the NHS

OPPTIMUM was the largest study to compare obstetric, neonatal, and childhood outcomes in high-risk, single pregnancy women being treated with vaginal progesterone to prevent preterm birth. It was also one of the few studies to look at childhood effects. In addition to the review being undertaken by PCORI, there is now a renewed search to identify women who might specifically benefit from progesterone administration.

OPPTIMUM has also highlighted the need to find alternative strategies to prevent preterm birth in women at risk. As such, it is likely that is has slowed down or arrested the trend of widespread use of vaginal progesterone for preterm prevention in UK practice.

The OPPTIMUM study illustrated the need for a collaborative, networked approach to answer an important clinical question. In 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 and 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