Antenatal administration of progesterone for preventing spontaneous preterm birth
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
Primary
1. To assess the effects on maternal, fetal and neonatal outcomes of antenatal progesterone administered to women with a singleton pregnancy and an increased risk of spontaneous preterm birth when compared with either placebo or no intervention and also comparing different modes of administration.
2. To assess the effects on maternal, fetal and neonatal outcomes of antenatal progesterone administered to women with a multiple pregnancy and an increased risk of spontaneous preterm birth when compared with either placebo or no intervention and also comparing different modes of administration.
Secondary
A secondary objective of the review is to determine whether the effects are influenced by the following:
(1) treatment commencing before 24 weeks' gestation;
(2) factors responsible for increased risk of preterm labour:
(a) previous preterm birth;
(b) cervical incompetence.
Background
Preterm delivery is the major complication of pregnancy associated with perinatal mortality and morbidity and occurs in up to 6% to 10% of all births (Lumley 2003). Nearly half of all preterm births are due to preterm labour. Preterm birth is responsible for the majority of neonatal deaths not due to congenital anomalies and is the major cause of disability (e.g. blindness, deafness and cerebral palsy) in childhood (Hack 1999). Most mortality and morbidity occur with extreme prematurity prior to 32 weeks and especially before 28 weeks. However, whilst the incidence of death and long‐term handicap is relatively low in those born after 32 weeks, they make up over 80% of all preterm deliveries and therefore this group of infants has a significant impact upon the burden that preterm birth makes on public health (Kramer 2000).
Despite intensive research over the past few decades, no decrease in the incidence of preterm labour has occurred although there have been improved survival and outcomes for premature infants. Although many forms of medication used to stop uterine contractions (tocolytics) delay delivery for the period of a few days, they have not been shown to prevent preterm delivery or improve survival. Screening and treatment of vaginosis have not been shown to reduce preterm delivery (McDonald 2004) and dietary magnesium supplementation has not been shown to be beneficial (Makrides 2004).
Administration of progesterone for the prevention of miscarriage and preterm labour has been advocated in the past; however, there has always been uncertainty as to its efficacy (MacDonald 1989). Progesterone is an essential hormone for the continuation of pregnancy. Progesterone acts by suppressing myometrial contractility. In many animals, labour is induced by a fall in progesterone levels at term. However, this fall in serum progesterone has not been identified in humans. Local changes in progesterone effect have been postulated as a potential cause for the onset of labour. However, there is little evidence for this at present (Keelan 1997). The corpus luteum produces progesterone to maintain the early pregnancy until the placental production becomes sufficient. Removal of the ovaries in the first eight weeks of pregnancy or blockade of its action with the antiprogestin mifepristone (RU486) results in miscarriage. However, in later pregnancy, use of mifepristone results in increased uterine activity, increased cervical ripening and has been used to induce labour (Neilson 2003).
Preterm labour is multifactorial in origin. While the suppression or prevention of preterm labour should lead to improved survival through a lower incidence of premature delivery, there are theoretical reasons why a fetus may not survive without disability. It is possible that an intrauterine mechanism that would trigger preterm labour could also cause neurological injury to the fetus and that progesterone may prevent labour but not fetal injury.
Amongst the risk factors for preterm labour, previous preterm delivery is a strong predictor and the earlier the birth the more likely it is to be repeated at the same gestation (Hoffman 1984). Also multiple pregnancy is a strong risk factor for preterm delivery though the mechanisms may be different.
Progesterone may be administered in various forms and by various routes. These different formulations and modes of administration will have different absorption patterns and potentially have differing bio effects. Whilst no teratogenic effects have been described with most progesterones, there is little in the way of long‐term safety data.
The purpose of this review is to determine if there are any data to suggest that administration of progesterone antenatally would have a beneficial effect in preventing preterm delivery and whether this would have any beneficial effect upon the fetus and mother.
Objectives
Primary
1. To assess the effects on maternal, fetal and neonatal outcomes of antenatal progesterone administered to women with a singleton pregnancy and an increased risk of spontaneous preterm birth when compared with either placebo or no intervention and also comparing different modes of administration.
2. To assess the effects on maternal, fetal and neonatal outcomes of antenatal progesterone administered to women with a multiple pregnancy and an increased risk of spontaneous preterm birth when compared with either placebo or no intervention and also comparing different modes of administration.
Secondary
A secondary objective of the review is to determine whether the effects are influenced by the following:
(1) treatment commencing before 24 weeks' gestation;
(2) factors responsible for increased risk of preterm labour:
(a) previous preterm birth;
(b) cervical incompetence.
Methods
Criteria for considering studies for this review
Types of studies
All published and unpublished randomised controlled trials, in which progesterone was given for preventing preterm labour.
Trials will be excluded if:
-
progesterone was administered for the treatment of preterm labour; or
-
progesterone was administered in the first trimester only for preventing miscarriage.
Types of participants
Women assessed as being at increased risk of spontaneous preterm birth (i.e. between 20 and 36 completed weeks of gestation).
Types of interventions
Administration of progesterone by any route for the prevention of preterm labour.
Types of outcome measures
Primary outcomes
Perinatal mortality
Preterm birth (less than 32 weeks' gestation)
Major neurodevelopmental handicap at two years of age
Secondary outcomes
Maternal
Threatened preterm labour
Prelabour spontaneous rupture of membranes
Adverse drug reaction
Pregnancy prolongation (interval between randomisation and delivery)
Mode of delivery
Number of antenatal hospital admissions
Satisfaction with the therapy
Use of tocolysis
Infant
Birth before 28 completed weeks
Birth before 34 completed weeks
Birth before 37 completed weeks
Gestation at birth
Birthweight less than the third centile for gestational age
Birthweight less than 2500 grams
Apgar score of less than seven at five minutes
Respiratory distress syndrome
Use of mechanical ventilation
Duration of mechanical ventilation
Intraventricular haemorrhage ‐ Grades III or IV
Periventricular leucomalacia
Retinopathy of prematurity
Retinopathy of prematurity ‐ Grades III or IV
Chronic lung disease
Necrotising enterocolitis
Neonatal sepsis
Fetal death
Neonatal death
Admission to neonatal intensive care unit
Neonatal length of hospital stay
Teratogenic effects (including virilisation in female infants)
Search methods for identification of studies
We will search the Cochrane Pregnancy and Childbirth Group trials register.
The Cochrane Pregnancy and Childbirth Group's trials register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
1. quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
2. monthly searches of MEDLINE;
3. handsearches of 30 journals and the proceedings of major conferences;
4. weekly current awareness search of a further 37 journals.
Details of the search strategies for CENTRAL and MEDLINE, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the 'Search strategies for identification of studies' section within the editorial information about the Cochrane Pregnancy and Childbirth Group.
Trials identified through the searching activities described above are given a code (or codes) depending on the topic. The codes are linked to review topics. The Trials Search Co‐ordinator searches the register for each review using these codes rather than keywords.
Data collection and analysis
We will use the standard methods of the Cochrane Collaboration (Clarke 2003). The four reviewers will work independently to select trials for inclusion and assess methodological quality. We will resolve differences in interpretation by discussion.
Quality assessment
We will consider four major sources of potential bias and methods of avoidance of these biases when assessing trial quality: (1) selection bias ‐ blinding of randomisation, (2) performance bias ‐ blinding of intervention, (3) attrition bias ‐ completeness of follow up, (4) detection bias ‐ blinding of outcome assessment. We will assign a quality rating for blinding of randomisation to each trial, using the criteria outlined in the Cochrane Reviewers' Handbook (Clarke 2003a): (A) adequate, (B) unclear, (C) inadequate, or (D) not used. We will assign a quality rating of (A) yes, (B) cannot tell, or (C) no, to the other quality components (blinding of intervention, completeness of follow up and blinding of outcome assessment). We will define high‐quality trials as those receiving an A rating for the criterion of blinding of randomisation (central‐computerised randomisation service or sealed, opaque envelopes) blinding of the intervention (use of a placebo) and less than 20% loss to follow up for major outcomes.
Data management and analysis
We will conduct data management and analysis using RevMan software (RevMan 2003). Four reviewers will independently extract data (Rob Cincotta, Greg Duncombe, Glenn Gardener, Vicki Flenady). We will seek missing data from investigators of individual trials as necessary in order to perform analyses on an intention‐to‐treat basis. We will undertake double data entry.
For individual trials, where possible, we will report mean differences (and 95% confidence intervals) for continuous variables. For categorical outcomes, we will report the relative risk and risk difference (and 95% confidence intervals). For the meta‐analysis, where possible, we will report weighted mean differences (and 95% confidence intervals) for continuous variables, and the relative risk and risk difference (and 95% confidence intervals) for categorical outcomes. We will calculate number needed to treat, where appropriate.
We will conduct meta‐analysis using the fixed effect model. We will assess heterogeneity by visual inspection of the outcomes tables and by using two statistics (H and I squared test) of heterogeneity (Higgins 2002). Where statistical heterogeneity is found, we will look for an explanation. If studies with heterogeneous results are found to be comparable, we will undertake the statistical synthesis of the results using a random effects model.
We will perform subgroup analyses as data permit as follows:
(1) treatment commencing before 24 weeks' gestation;
(2) different modes of administration: intramuscular versus oral, intramuscular versus vaginal, intramuscular versus intravenous;
(3) factors responsible for increased risk of spontaneous preterm birth:
(a) previous preterm birth;
(b) cervical incompetence.
