Progestational agents for treating threatened or established preterm labour
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The principal objective of this review is to determine if the use of progestational agents is effective as a form of treatment or co‐treatment for women with threatened or established preterm labour with intact membranes.
Background
Preterm labour is one of the commonest complications of pregnancy (Haram 2003), and it results in preterm birth which is defined by the World Health Organization as delivery before completion of 37 weeks of gestation (WHO 1977). Prematurity is a leading cause of perinatal morbidity and mortality in many countries and is associated with 60% to 80% of deaths of infants without congenital abnormalities (Guyer 1996). Neonates born prematurely, especially those delivered before 32 weeks of gestation, are at risk of developing various complications including respiratory distress syndrome, necrotising enterocolitis and intraventricular haemorrhage. These often lead to a prolonged stay in the neonatal intensive care unit and the need for different interventions. Having preterm delivery can therefore be devastating for the parents who inevitably experience significant emotional turmoil and distress.
Various drugs and strategies have been used for the treatment of preterm labour. The pharmacologic agents currently used include betamimetics, calcium channel blockers, nitric oxide donors, magnesium, cyclo‐oxygenase inhibitors and oxytocin receptor antagonists. Studies of these drugs have shown mixed results with little effect in improving pregnancy duration and insufficient data to confirm a definite beneficial effect on neonatal morbidity or mortality (Berkman 2003). Although betamimetics are effective in delaying birth for 48 hours, which allows the administration of corticosteroids and in‐utero transfer to tertiary centres, they are associated with significant side‐effects that may be harmful to mothers (Anotayanonth 2004; Berkman 2003). Calcium channel blockers are therefore suggested to be the preferred agents should tocolysis be indicated. However, the use of calcium channel agonists for treatment of preterm labour also does not lead to statistically significant improvements in important neonatal outcomes such as admission to neonatal intensive care unit, low Apgar score and perinatal mortality (King 2003). Oxytocin receptor antagonists seem particularly promising as an effective tocolytic agent with minimal adverse effects (Lamont 2003). However, a Cochrane review on the use of this tocolytic agent does not support the superiority of atosiban over betamimetics or placebo in terms of the tocolytic efficacy or neonatal outcome (Papatsonis 2005). In addition, its current cost is prohibitive. Insufficient data are available for the use of cyclo‐oxygenase inhibitors (King 2005) or nitric oxide donors (Duckitt 2002) for women in preterm labour. Magnesium sulphate is not recommended as a tocolytic agent as it is ineffective at delaying preterm birth and is associated with increased mortality for the child (Crowther 2002). There is thus a need for further therapeutic options that are effective, affordable, and safe.
Progesterone is known to have an inhibitory effect on uterine contractility (Lye 1978) and is thought to play a key role in the maintenance of pregnancy until term (Henderson 2001; Karalis 1996). In animal studies, progesterone decreases the concentration of oxytocin (Fuchs 1983) and alpha‐adrenergic receptors (Roberts 1977; Williams 1977) in the myometrium, as well as local synthesis of prostaglandin F2 (Thoburn 1979). Progesterone is also able to modify the ultrastructural organisation of the myometrium by inhibiting the appearance of gap junctions, and preventing co‐ordinated muscular contraction (Garfield 1982). Different routes of administration of progesterone have been described in the literature. These include weekly intramuscular injections from 16 to 20 weeks through to 36 weeks (Meis 2003) and daily vaginal progesterone suppositories from 24 weeks to 34 weeks of gestation (da Fonseca 2003).The safety of progesterone therapy in pregnancy is also well established (Check 1986). Several small studies (Hartikainen 1980; Hauth 1983; Johnson 1975; LeVine 1964; Papiernik 1970) have been conducted to test the effect of progestational agents for the prevention of preterm labour, but a systematic review at the end of the 1980s (Goldstein 1989) concluded that progestational agents were not effective for that purpose. However, another meta‐analysis (Keirse 1990) analysing only trials using 17 alpha‐hydroxyprogesterone caproate found a significant reduction in low birthweight babies in the treated group. Interest in progestational agents for the prevention of preterm birth in high‐risk women has also recently been revived with the publication of two randomised controlled trials (da Fonseca 2003; Meis 2003) showing a reduction in the rate of preterm delivery in treated women.
So far, the focus has been on the use of progestational agents to pre‐empt the onset of preterm labour in high‐risk women. The use of progestational agents for the treatment of threatened or established preterm labour has not been extensively studied. Two small randomised controlled trials have been performed with encouraging results (Erny 1986; Noblot 1991). Unfortunately, the work of these investigators has not been followed through. We expect that, with the revived interest in progestational agents in relation to preterm birth, research will resume in this area. We propose to continue surveying the literature for studies on this subject with a view to performing a meta‐analysis in order to assess the efficacy of progestational agents in the treatment of threatened or established preterm labour.
Objectives
The principal objective of this review is to determine if the use of progestational agents is effective as a form of treatment or co‐treatment for women with threatened or established preterm labour with intact membranes.
Methods
Criteria for considering studies for this review
Types of studies
All published, unpublished and ongoing randomised and quasi‐randomised trials.
Types of participants
Pregnant women diagnosed with established or threatened preterm labour. Established labour is defined as the presence of regular uterine contractions and cervical dilatation of at least 3 cm. For threatened labour, uterine contractions are present but cervical dilatation is either absent or is less than 3 cm.
Women of all risk groups, including multiple gestations, will be included and may be studied as subgroups if appropriate. However, women with diagnosed cervical incompetence will be excluded. Women with rupture of membranes will also be excluded.
Types of interventions
Progestational agents given either alone or in combination with other tocolytics, for the treatment of preterm labour, administered by any route and in any dose compared to a control group receiving another tocolytic, placebo or no treatment.
Types of outcome measures
Primary outcomes
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Very preterm birth (before 34 completed weeks of gestation).
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Low birthweight (less than 2500 g and less than 1500 g).
Secondary outcomes
Relate to outcomes for the neonate, measures of effectiveness, women's views, women's measures of satisfaction and costs.
Fetal and neonatal outcomes
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Admission to the neonatal intensive care unit.
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Apgar score less than seven at five minutes.
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Fetal, perinatal death, and neonatal death.
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Respiratory/gastrointestinal/neurological/other complications.
Measures of effectiveness
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Preterm birth within 24, 48 and 72 hours, and one week of commencing therapy.
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Delivery before 37, 32, and 28 completed weeks of gestation.
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Additional tocolytic therapy.
Adverse effects for women
Women's views and measures of satisfaction.
Costs.
Outcomes will be included in the analysis if data are available according to original allocation and reasonable measures are taken to minimise observer bias. Only outcomes with available data will appear in the analysis tables. Data that are not prestated will be extracted and reported as subsidiary outcomes. These will be clearly labelled as not prespecified. The possibility has to be borne in mind that such outcomes are only reported because the difference between the groups, as a result of chance, has reached conventional levels of statistical significance. In order to minimise the risk of bias, the conclusions will be based solely only on the prestated outcomes.
Search methods for identification of studies
Electronic searches
We will contact the Trials Search Co‐ordinator to search the Cochrane Pregnancy and Childbirth Group's Trials Register.
The Cochrane Pregnancy and Childbirth Group's Trials Register is maintained by the Trials Search Co‐ordinator and contains trials identified from:
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quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);
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monthly searches of MEDLINE;
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handsearches of 30 journals and the proceedings of major conferences;
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weekly current awareness search of a further 36 journals plus monthly BioMed Central email alerts.
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.
In addition, we will search the Central Register of Controlled Trials (The Cochrane Library) using the search strategy in Appendix 1.
We will search MEDLINE (January 1966 to current) using the search strategy Appendix 2.
We will search EMBASE (January 1985 to current) using the following strategy:
1 Premature‐labour (subject heading)
2 Progesterone (subject heading)
3 1 and 2
We will attempt to contact relevant organisations, individual researchers working in the field, and companies for unpublished data, confidential reports, and raw data from published trials. We will also check reference lists of all studies included to look for any additional studies.
We will not apply any language restrictions.
Data collection and analysis
(1) Selection of trials
Two review authors (LL Su and M Samuel) will independently examine the abstracts of studies identified by the search strategy. We will then retrieve the full publications of the qualifying abstracts. We will resolve discrepancies by discussion and by seeking the opinion of the third author (YS Chong).
(2) Assessment of methodological quality
Two review authors will independently assess trial quality according to the methods set out in section six of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005a).
The following features will be considered:
(a) method of randomisation;
(b) method of allocation concealment;
(c) blinding of participants, surgeons and outcome assessors;
(d) completeness of follow up.
We will score the allocation concealment of each study as A (adequate), B (unclear), C (inadequate) or D (not used) according to the rating system outlined in section 6.3 of the Cochrane Handbook for Systematic Reviews of Interventions section (Higgins 2005a).
(3) Data collection
Two review authors (LL Su and M Samuel) will independently extract data using the methods set out in section seven of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2005b). We will resolve discrepancies by discussion. Data will be extracted on the basis of an intention‐to‐treat analysis.
(4) Data synthesis
We will use relative risks for binary data and weighted mean difference for continuous data. When study designs are judged to be homogenous, we will combine the results from the various trials by calculating the pooled relative risks/weighted mean difference and their 95% confidence interval. If we identify high levels of heterogeneity (I2 greater than 50%) between studies, we will use a random‐effects model. In cases where study combination is not possible or appropriate, we will provide a narrative synthesis.
We will examine sources of potential heterogeneity by subgroup analyses. Subgroup analyses will be performed for women with threatened preterm labour and women with established preterm labour. If possible, subgroup analyses will be performed using interaction tests as described in Higgins 2005c and Deeks 2001. A sensitivity analysis will be done if the characteristics of the studies (e.g., blinding, concealment of allocation) or baseline characteristics of the patients (e.g., age, co‐morbidities) in the studies differ.
