Terbutaline pump maintenance therapy after threatened preterm labour for reducing adverse neonatal outcomes

  • Protocol
  • Intervention

Authors

  • Saifon Chawanpaiboon,

    Corresponding author
    1. Faculty of Medicine, Siriraj Hospital, Mahidol University, Department of Obstetrics and Gynaecology, Bangkok, Thailand
    • Saifon Chawanpaiboon, Department of Obstetrics and Gynaecology, Faculty of Medicine, Siriraj Hospital, Mahidol University, 2 Prannok, Bangkoknoi, Bangkok, 10700, Thailand. siscw@mahidol.ac.th.

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  • Malinee Laopaiboon,

    1. Khon Kaen University, Department of Biostatistics and Demography, Faculty of Public Health, Khon Kaen, Thailand
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  • Pisake Lumbiganon,

    1. Khon Kaen University, Department of Obstetrics and Gynaecology, Faculty of Medicine, Khon Kaen, Thailand
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  • Ussanee S Sangkomkamhang,

    1. Khon Kaen Hospital, Department of Obstetrics and Gynaecology, Khon Kaen, Thailand
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  • Therese Dowswell

    1. The University of Liverpool, Cochrane Pregnancy and Childbirth Group, Department of Women's and Children's Health, Liverpool, UK
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Abstract

This is the protocol for a review and there is no abstract. The objectives are as follows:

To assess the effects of continuous low-dose subcutaneous terbutaline infusion maintenance therapy after threatened preterm labour for reducing adverse neonatal outcomes. Safety and adverse maternal and neonatal outcomes will also be determined.

Background

Description of the condition

Preterm birth refers to a birth that occurs before 37 completed weeks of gestation. About 40% of preterm births are due to complications mandating early delivery such as placenta previa, pre-eclampsia, fetal growth restriction and infection. Approximately 30% of preterm births occur following preterm pre-labour rupture of membranes (PPROM) and the remainder are due to spontaneous preterm labour (Beck 2010). Preterm birth is the single most important cause of infant mortality, and is associated with long-term serious disability in children, including cerebral palsy and sensory and cognitive impairments (Elliott 2013; Goldenberg 2008; Pennell 2007).

Even though the ability of obstetric care providers to identify women at risk of preterm birth has improved, the potential interventions for prevention of spontaneous preterm birth remain limited, and overall, the incidence of preterm deliveries has not decreased (Callaghan 2006). This is partly explained by the rise over the last decade in near-term births and those associated with medical complications, while early deliveries from spontaneous preterm labours have decreased (Ananth 2006; Goldenberg 2008). Recent evidence reports that about 30% to 50% of pregnant women with threatened preterm labour who had only bed rest developed recurrent preterm labour, and 30% of these women proceeded to deliver preterm (Chawanpaiboon 2009; Chawanpaiboon 2011; Vatish 2005).

Many interventions have been introduced in an attempt to improve neonatal outcomes after preterm birth, including antepartum corticosteroid administration, exogenous surfactant therapy and new methods of mechanical ventilation. With the introduction of such interventions following very preterm birth or extremely preterm birth, neonates have more chances of survival, but they are at risk of neurological damage, and may face extended hospital stays (incurring high healthcare costs). Therefore, the prevention of preterm labour is very important to minimise or delay preterm birth. However, there is little definite evidence that interventions can prevent preterm labour or minimise preterm birth, and the goal is to identify preterm labour at the earliest possible time so that pregnancy prolongation can be obtained through acute and maintenance tocolysis. Pregnant women with threatened preterm labour at 34 weeks of gestation or less are usually treated with tocolytic therapy to inhibit uterine contractions. Tocolytics are used for at least 48 hours to allow corticosteroid administration to accelerate fetal lung maturity.

Description of the intervention

Terbutaline is a beta-2 adrenergic receptor agonist, which has been used as a treatment for preterm labour. It is an off-label drug and is not approved by the Food and Drug Administration (FDA). It is a pregnancy category B medication prescribed to stop uterine contractions. In recent years, terbutaline has only rarely been used as an intravenous tocolytic to treat acute threatened preterm labour because of concerns about its safety (Elliott 2013). However, in some settings, subcutaneous terbutaline (0.25mg subcutaneous terbutaline) has been used as a single dose as a test for whether the patient will stop contractions (false labour); if true preterm labour (contractions less than five minutes with cervical dilatation) occurs, intravenous magnesium or atosiban, or oral nifedipine, or indomethacin (oral/rectal suppositories) have been used as treatment (Valenzuela 2000). The aim of treatment is to inhibit labour for at least 48 hours. This time can then be used to administer steroid injections to the mother, which help fetal lung maturity, or allow transfer to the appropriate level of care in an attempt to reduce complications of prematurity (Hofmeyr 2009).

After successful tocolysis for threatened preterm labour, little evidence exists to show that oral terbutaline is effective for maintenance therapy (Goldenberg 2002), but subcutaneous terbutaline has been used as a maintenance tocolytic following initial treatment (Elliott 2013). A portable terbutaline pump is used to infuse terbutaline subcutaneously. It is similar to an insulin pump. The initial minimum rate is started, increasing as needed to stop uterine contraction. When continuous terbutaline is administered via a programmable pump, with assessment of uterine contractions to individualise bolus therapy, significant pregnancy prolongation has been noted. However, both the basal infusion and bolus rates (four to six/24 hours - 0.25 mg) need to be determined in consultation with the pharmacist, taking account of weight, height, volume of distribution and renal clearance (Elliott 2013).

Terbutaline is easily absorbed subcutaneously and is not expensive. Pump therapy has the advantages over oral therapy because of lower total daily dose, fewer side effects and less tachycardia, faster onset of action and good tolerability (Elliott 2004, Perry 1995). Continuous subcutaneous terbutaline infusion has been associated with an extremely low incidence of serious adverse events. (Elliott 2004; Perry 1995) On the other hand, high doses of terbutaline by the intravenous route have been associated with serious maternal side effects including pulmonary oedema, myocardial ischaemia, cardiac arrhythmias, hypotension and metabolic alterations and significantly associated with comorbid factors such as multi-fetal gestations, sepsis, pre-eclampsia, cardiac arrhythmias (Iams 2009).

How the intervention might work

The rationale for maintenance therapy after threatened preterm labour for preventing preterm birth is based on a number of factors including (1) persistence of the underlying condition stimulating uterine contraction as this may cause a recurrence; (2) an episode of recent uterine contraction may mean that the myometrium has a low threshold for recurrence; and (3) positive feedback from myometrial contractility can result in further contraction (Soloff 2000).

Therefore, maintenance tocolytic therapy with a terbutaline pump has been attempted to prolong pregnancy and decrease preterm birth. Home therapy is possible and stress from prolonged intravenous tocolysis decreased, although uterine contractions should continue to be assessed at home so that the bolus doses can be individualised and so that repeat episodes of preterm labour can be detected as early as possible (Elliott 2013).

Why it is important to do this review

Terbutaline has been used in clinical practice to inhibit uterine contractions, although in the United States, the FDA currently has not approved its use during pregnancy and there have been concerns about its use in pregnancy (FDA 2011). Previous evidence regarding the effectiveness of terbutaline pump for maintenance therapy after successful tocolysis has been mixed and inconclusive (Hayes 2008). Two randomised controlled trials (Guinn 1998; Wenstrom 1997), involving 94 participants, of whom 39 used the terbutaline pump, did not show positive results. However, observational studies examining the use of subcutaneous terbutaline infusion have shown improvements in pregnancy prolongation, neonatal outcome, and cost (Lam 1987; Lam 1988; Lam 1998; Perry 1995). Perry 1995 and Elliott 2004 studied almost 18,000 patients and found the incidence of adverse maternal effects to be similar in women whether or not they were exposed to subcutaneous terbutaline.

Objectives

To assess the effects of continuous low-dose subcutaneous terbutaline infusion maintenance therapy after threatened preterm labour for reducing adverse neonatal outcomes. Safety and adverse maternal and neonatal outcomes will also be determined.

Methods

Criteria for considering studies for this review

Types of studies

All published, unpublished and ongoing randomised controlled trials (including cluster-randomised trials) comparing outcomes between women given terbutaline pump maintenance therapy and controls given alternative therapy, placebo, or no therapy after successful arrest of threatened preterm labour. We will not include studies where allocation to groups is not truly random (e.g. allocation by day of the week).

We will include trials reported in abstracts if results are reported by randomisation group and provided sufficient information is reported (or can be obtained from the authors) to allow us to assess risk of bias.

Types of participants

Singleton or multifetal pregnant women with intact membranes who have had at least one episode of threatened preterm labour that was halted by tocolytic therapy.

Types of interventions

Terbutaline pump maintenance therapy compared with alternative drug therapy, placebo, or no therapy.

Types of outcome measures

Primary outcomes

Reduction in serious neonatal morbidity and mortality.

Secondary outcomes
Neonatal
  1. Preterm birth less than 37 completed weeks.

  2. Very preterm birth (less than 34 completed weeks).

  3. Extremely preterm birth (less than 28 completed weeks).

  4. Perinatal mortality.

  5. Birthweight.

  6. Respiratory distress syndrome.

  7. Periventricular haemorrhage.

  8. Need for mechanical ventilation.

  9. Neurological sequelae (general intelligence, hearing, vision, cerebral palsy and disability).

  10. Admission to neonatal intensive care unit.

Maternal
  1. Cardiovascular complications (death, cardiac arrest, myocardial infarction, arrhythmia, hypotension).

  2. Other serious complications (pulmonary oedema, hepatitis).

  3. Side effects (chest pain, palpitations, shortness of breath, hyperglycaemia, hypokalaemia).

  4. Maternal compliance with therapy.

  5. Maternal satisfaction of therapy.

  6. Breastfeeding at hospital discharge.

Healthcare system
  1. Rehospitalisation for threatened preterm labour.

  2. Cost effectiveness of treatment.

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:

  1. monthly searches of the Cochrane Central Register of Controlled Trials (CENTRAL);

  2. weekly searches of MEDLINE;

  3. weekly searches of Embase;

  4. handsearches of 30 journals and the proceedings of major conferences;

  5. weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.

Details of the search strategies for CENTRAL, MEDLINE and Embase, the list of handsearched journals and conference proceedings, and the list of journals reviewed via the current awareness service can be found in the ‘Specialized Register’ section within the editorial information about the Cochrane Pregnancy and Childbirth Group.

Trials identified through the search activities described above are each assigned to a review topic (or topics). The Trials Search Co-ordinator searches the register for each review using the topic list rather than keywords.

Searching other resources

We will review citations of reference lists of included papers identified through the above search strategy and assess their suitability for inclusion in the review.

We will not apply any language restrictions.

Data collection and analysis

Selection of studies

Two review authors (Saifon Chawanpaiboon (SC) and Usanee Sangkomkamhang (US)) will independently assess for inclusion all the potential studies we identify as a result of the search strategy. We will resolve any disagreement through discussion or, if required, we will consult the third author (Pisake Lumbiganon (PL)).

Data extraction and management

We will design a form to extract data. For eligible studies, two review authors (SC and US) will extract the data using the agreed form. We will resolve discrepancies through discussion with a third review author (Malinee Laopaiboon (ML)). We will enter data into Review Manager software (RevMan 2012) and check them for accuracy.

When information regarding any of the above is unclear, we will attempt to contact authors of the original reports to provide further details

Assessment of risk of bias in included studies

Three review authors (SC, ML and PL) will independently assess risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions (Higgins 2011). We will resolve any disagreement by discussion.

(1) Random sequence generation (checking for possible selection bias)

We will describe for each included study the method used to generate the allocation sequence in sufficient detail to allow an assessment of whether it should produce comparable groups.

We will assess the method as:

  • low risk of bias (any truly random process, e.g. random number table; computer random number generator);

  • high risk of bias (any non-random process, e.g. odd or even date of birth; hospital or clinic record number);

  • unclear risk of bias.

(2) Allocation concealment (checking for possible selection bias)

We will describe for each included study the method used to conceal allocation to interventions prior to assignment and will assess whether intervention allocation could have been foreseen in advance of, or during recruitment, or changed after assignment.

We will assess the methods as:

  • low risk of bias (e.g. telephone or central randomisation; consecutively numbered sealed opaque envelopes);

  • high risk of bias (open random allocation; unsealed or non-opaque envelopes, alternation; date of birth);

  • unclear risk of bias.

(3.1) Blinding of participants and personnel (checking for possible performance bias)

We will describe for each included study the methods used, if any, to blind study participants and personnel from knowledge of which intervention a participant received. We will consider that studies are at low risk of bias if they were blinded, or if we judge that the lack of blinding would be unlikely to affect results. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess the methods as:

  • low, high or unclear risk of bias for participants;

  • low, high or unclear risk of bias for personnel.

(3.2) Blinding of outcome assessment (checking for possible detection bias)

We will describe for each included study the methods used, if any, to blind outcome assessors from knowledge of which intervention a participant received. We will assess blinding separately for different outcomes or classes of outcomes.

We will assess methods used to blind outcome assessment as:

  • low, high or unclear risk of bias.

(4) Incomplete outcome data (checking for possible attrition bias due to the amount, nature and handling of incomplete outcome data)

We will describe for each included study, and for each outcome or class of outcomes, the completeness of data including attrition and exclusions from the analysis. We will state whether attrition and exclusions were reported and the numbers included in the analysis at each stage (compared with the total randomised participants), reasons for attrition or exclusion where reported, and whether missing data were balanced across groups or were related to outcomes. Where sufficient information is reported, or can be supplied by the trial authors, we will re-include missing data in the analyses which we undertake.

We will assess methods as:

  • low risk of bias (e.g. no missing outcome data; missing outcome data balanced across groups);

  • high risk of bias (e.g. numbers or reasons for missing data imbalanced across groups; ‘as treated’ analysis done with substantial departure of intervention received from that assigned at randomisation);

  • unclear risk of bias.

(5) Selective reporting (checking for reporting bias)

We will describe for each included study how we investigated the possibility of selective outcome reporting bias and what we found.

We will assess the methods as:

  • low risk of bias (where it is clear that all of the study’s pre-specified outcomes and all expected outcomes of interest to the review have been reported);

  • high risk of bias (where not all the study’s pre-specified outcomes have been reported; one or more reported primary outcomes were not pre-specified; outcomes of interest are reported incompletely and so cannot be used; study fails to include results of a key outcome that would have been expected to have been reported);

  • unclear risk of bias.

(6) Other bias (checking for bias due to problems not covered by (1) to (5) above)

We will describe for each included study any important concerns we have about other possible sources of bias.

We will assess whether each study was free of other problems that could put it at risk of bias:

  • low risk of other bias;

  • high risk of other bias;

  • unclear whether there is risk of other bias.

(7) Overall risk of bias

We will make explicit judgements about whether studies are at high risk of bias, according to the criteria given in the Cochrane Handbook (Higgins 2011). With reference to (1) to (6) above, we will assess the likely magnitude and direction of the bias and whether we consider it is likely to impact on the findings. We will explore the impact of the level of bias through undertaking sensitivity analyses - see Sensitivity analysis.

Measures of treatment effect

Dichotomous data

For dichotomous data, we will present results as summary risk ratio with 95% confidence intervals.

Continuous data

For continuous data, we will use the mean difference if outcomes are measured in the same way between trials. We will use the standardised mean difference to combine trials that measure the same outcome, but use different methods.

Unit of analysis issues

We will included only parallel individual randomised controlled trials in this review. The unit of analysis will be women.

Cluster-randomised trials

We will include cluster-randomised trials in the analyses along with individually-randomised trials. We will adjust their sample sizes using the methods described in the Cochrane Handbook (Higgins 2011) using an estimate of the intracluster correlation co-efficient (ICC) derived from the trial (if possible), from a similar trial or from a study of a similar population. If we use ICCs from other sources, we will report this and conduct sensitivity analyses to investigate the effect of variation in the ICC. If we identify both cluster-randomised trials and individually-randomised trials, we plan to synthesise the relevant information. We will consider it reasonable to combine the results from both if there is little heterogeneity between the study designs and the interaction between the effect of intervention and the choice of randomisation unit is considered to be unlikely.

We will also acknowledge heterogeneity in the randomisation unit and perform subgroup analysis to investigate the effects of the randomisation unit.

Cross-over trials

Cross-over trials are not a suitable design for this type of intervention and will not be included.

Other unit of analysis issues

If we include any trials with more than two arms (multi-arm trials), we will include data for all arms relevant to the scope of the review. Where appropriate, we will combine arms (using methods described in the Cochrane Handbook (Higgins 2011)) to create a single pair-wise comparison. If it is not appropriate to combine arms, we will present results separately for each arm, sharing results for the control group between each to avoid double counting (for dichotomous outcomes we will divide the number of events and total sample by two, for continuous outcomes we will assume the same mean and standard deviation but halve the control sample size for each comparison).

We will include studies recruiting women with multiple pregnancies. We are aware that in multiple pregnancies outcomes for neonates are not independent; where sufficient information is available we will therefore adjust data for multiple pregnancies using the methods described in the Cochrane Handbook (Higgins 2011).

Dealing with missing data

For included studies, we will note levels of attrition. We will explore the impact of including studies with high levels of missing data in the overall assessment of treatment effect by using sensitivity analysis.

For all outcomes, we will carry out analyses, as far as possible, on an intention-to-treat basis, i.e. we will attempt to include all participants randomised to each group in the analyses, and all participants will be analysed in the group to which they were allocated, regardless of whether or not they received the allocated intervention. The denominator for each outcome in each trial will be the number randomised minus any participants whose outcomes are known to be missing.

Assessment of heterogeneity

We will assess statistical heterogeneity in each meta-analysis using the T², I² and Chi² statistics. We will regard heterogeneity as substantial if an I² is greater than 30% and either the T² is greater than zero, or there is a low P value (less than 0.10) in the Chi² test for heterogeneity. If we identify substantial heterogeneity, we will explore it by pre-specified subgroup analysis (see below).

Assessment of reporting biases

If there are 10 or more studies in the meta-analysis we will investigate reporting biases (such as publication bias) using funnel plots. We will assess funnel plot asymmetry visually. If asymmetry is suggested by a visual assessment, we will perform exploratory analyses to investigate it.

Data synthesis

We will carry out statistical analysis using the Review Manager software (RevMan 2012). We will use fixed-effect meta-analysis for combining data where it is reasonable to assume that studies are estimating the same underlying treatment effect: i.e. where trials are examining the same intervention, and the trials’ populations and methods are judged sufficiently similar. If there is clinical heterogeneity sufficient to expect that the underlying treatment effects differ between trials, or if substantial statistical heterogeneity is detected, we will use random-effects meta-analysis to produce an overall summary, if an average treatment effect across trials is considered clinically meaningful. The random-effects summary will be treated as the average range of possible treatment effects and we will discuss the clinical implications of treatment effects differing between trials.

If we use random-effects analyses, the results will be presented as the average treatment effect with 95% confidence intervals, and the estimates of T2 and I2.

Subgroup analysis and investigation of heterogeneity

If we identify substantial heterogeneity, we will investigate it using subgroup analyses. We will consider whether an overall summary is meaningful, and if it is, use random-effects analysis to produce it.

We plan to carry out the following subgroup analyses.

  • Single versus multiple pregnancy

Subgroup analysis will be restricted to the review's primary outcomes.

We will assess subgroup differences by interaction tests available within RevMan (RevMan 2012). We will report the results of subgroup analyses quoting the χ2 statistic and P value, and the interaction test I² value.

Sensitivity analysis

To test the robustness of results, we plan to use sensitivity analyses to examine the effect of including studies at high risk of bias (such as from lack of allocation concealment) on the overall estimates of effect for primary outcomes.

We will use the GRADE system to define the quality of evidence in a 'Summary of findings' table, following guidance in the Cochrane Handbook (Higgins 2011).

Acknowledgements

We would liked to thank Kavita Nanda, Lynley A Cook, Maria F Gallo and David A Grimes for kindly preparing the previous version of this review (Nanda 2002).

As part of the pre-publication editorial process, the protocol has been commented on by two peers (an editor and referee who is external to the editorial team), a member of the Pregnancy and Childbirth Group's international panel of consumers and the Group's Statistical Adviser.

Therese Dowswell's work was financially supported by the UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization. The named authors alone are responsible for the views expressed in this publication.

The National Institute for Health Research (NIHR) is the largest single funder of the Cochrane Pregnancy and Childbirth Group. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR, NHS or the Department of Health.

Contributions of authors

Saifon Chawanpaiboon, Malinee Laopaiboon, Pisake Lumbiganon and Ussanee Sangkomkamhang drafted the protocol. All review authors revised and approved the final version of the protocol. Therese Dowswell finalised the draft for editorial approval.

Declarations of interest

None known.

Sources of support

Internal sources

  • Faculty of Medicine, Siriraj Hospital, Mahidol University, Thailand.

  • Faculty of Medicine, Khon Kaen University, Thailand.

  • Faculty of Public Health, Khon Kaen University, Thailand.

  • Khon Kaen Hospital, Ministry of Public Health, Thailand.

  • University of Liverpool, UK.

External sources

  • Thai Cochrane Network, Australasian Cochrane Centre, Thailand.

  • UNDP-UNFPA-UNICEF-WHO-World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP), Department of Reproductive Health and Research (RHR), World Health Organization, Switzerland.

Ancillary