Does progesterone prophylaxis to prevent preterm labour improve outcome? (OPPTIMUM)
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Reproductive Biology
Abstract
Preterm delivery is the biggest single cause of death and disability amongst babies born in the UK. At present, no drug treatment has been demonstrated to improve the outcome for babies by preventing the onset of preterm labour. It has recently been shown that a natural hormone called progesterone may reduce the risk of preterm delivery by around 50%. In the proposed study, we will confirm or refute this effect on preterm delivery and more importantly determine whether it improves the outcome for the baby and child. Pregnant women at high risk of preterm delivery who agree to take part will be given either a progesterone or a placebo (dummy) pessary daily from 22-24 until 34 weeks of pregnancy. We will record when the woman gives birth, whether the baby survives, and if so its immediate health (including any brain damage or lung disease) and health at two years of age using a developmental assessment scale. We will also calculate the costs of NHS treatment. We hope to show that progesterone treatment reduces the risk of preterm birth, that it improves baby’s immediate health, it is associated with improved thinking ability of the child at two years, and it reduces NHS costs overall.
Technical Summary
Background:
Preterm delivery is the single biggest cause of perinatal mortality and morbidity, accounting for 75% of neonatal deaths. Two recent studies (da Fonseca et al. 2003; Meis, et al. 2003) and four meta-analyses (Sanchez-Ramos et al. 2005; Dodd, et al. 2005; Mackenzie et al 2006, Coomaraswamy et al 2006) have suggested that progesterone prevents preterm delivery in high risk women with singleton pregnancy. However, none of the meta-analyses demonstrated a convincing effect on perinatal mortality or morbidity and no studies have examined the important longer-term neurodevelopmental outcomes. We therefore concur with the conclusions of most of the meta-analyses and editorials that the routine use of progestational agents cannot be justified without evidence of improved outcomes for babies.
Rationale for trial:
The proposed trial will quantify the magnitude of the obstetric, neonatal and child health benefits of vaginal progesterone treatment and evaluate the cost effectiveness of treatment.
Design of trial in high-risk women:
Women will be recruited if there is an appropriate history or a short (less than 25 mm) cervix on ultrasound scan and a positive fetal fibronectin (fFN). Women will be randomised to receive either vaginal progesterone 200mg, or placebo, from 22 weeks gestation daily until 34 weeks gestation. The primary obstetric outcome is delivery before 34 weeks of gestation. The primary neonatal outcome is a composite of death and major morbidity. The primary childhood outcome is neurodevelopmental performance at 2 years of age (Bayley 2006). A formal economic evaluation is a key part of this study.
Implications for practice:
The results will be used to inform policy and practice by determining the clinical and cost effectiveness of progesterone for obstetric, neonatal and childhood outcomes in women at high risk of preterm birth. We will use an inexpensive generic formulation of natural progesterone so the results can be immediately translated into improved patient care if progesterone administration is indicated.
Expertise and personnel:
The applicants include obstetricians and neonatologists (with expertise in both preterm labour and in conducting clinical trials), statisticians, clinical triallists, a health economist, an expert on ascertaining consumer views. We have benefited from advice from lay collaborators. Thirty centres in the UK, with a combined annual delivery rate of 140,000 births have agreed to participate in this trial.
Preterm delivery is the single biggest cause of perinatal mortality and morbidity, accounting for 75% of neonatal deaths. Two recent studies (da Fonseca et al. 2003; Meis, et al. 2003) and four meta-analyses (Sanchez-Ramos et al. 2005; Dodd, et al. 2005; Mackenzie et al 2006, Coomaraswamy et al 2006) have suggested that progesterone prevents preterm delivery in high risk women with singleton pregnancy. However, none of the meta-analyses demonstrated a convincing effect on perinatal mortality or morbidity and no studies have examined the important longer-term neurodevelopmental outcomes. We therefore concur with the conclusions of most of the meta-analyses and editorials that the routine use of progestational agents cannot be justified without evidence of improved outcomes for babies.
Rationale for trial:
The proposed trial will quantify the magnitude of the obstetric, neonatal and child health benefits of vaginal progesterone treatment and evaluate the cost effectiveness of treatment.
Design of trial in high-risk women:
Women will be recruited if there is an appropriate history or a short (less than 25 mm) cervix on ultrasound scan and a positive fetal fibronectin (fFN). Women will be randomised to receive either vaginal progesterone 200mg, or placebo, from 22 weeks gestation daily until 34 weeks gestation. The primary obstetric outcome is delivery before 34 weeks of gestation. The primary neonatal outcome is a composite of death and major morbidity. The primary childhood outcome is neurodevelopmental performance at 2 years of age (Bayley 2006). A formal economic evaluation is a key part of this study.
Implications for practice:
The results will be used to inform policy and practice by determining the clinical and cost effectiveness of progesterone for obstetric, neonatal and childhood outcomes in women at high risk of preterm birth. We will use an inexpensive generic formulation of natural progesterone so the results can be immediately translated into improved patient care if progesterone administration is indicated.
Expertise and personnel:
The applicants include obstetricians and neonatologists (with expertise in both preterm labour and in conducting clinical trials), statisticians, clinical triallists, a health economist, an expert on ascertaining consumer views. We have benefited from advice from lay collaborators. Thirty centres in the UK, with a combined annual delivery rate of 140,000 births have agreed to participate in this trial.