Repeat prenatal corticosteroid prior to preterm birth: a systematic review and individual participant data meta-analysis for the PRECISE study group (prenatal repeat corticosteroid international IPD study group: assessing the effects using the best level of evidence) - study protocol

Background The aim of this individual participant data (IPD) meta-analysis is to assess whether the effects of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies are modified in a clinically meaningful way by factors related to the women or the trial protocol. Methods/Design The Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) Group will conduct an IPD meta-analysis. The PRECISE International Collaborative Group was formed in 2010 and data collection commenced in 2011. Eleven trials with up to 5,000 women and 6,000 infants are eligible for the PRECISE IPD meta-analysis. The primary study outcomes for the infants will be serious neonatal outcome (defined by the PRECISE International IPD Study Group as one of death (foetal, neonatal or infant); severe respiratory disease; severe intraventricular haemorrhage (grade 3 and 4); chronic lung disease; necrotising enterocolitis; serious retinopathy of prematurity; and cystic periventricular leukomalacia); use of respiratory support (defined as mechanical ventilation or continuous positive airways pressure or other respiratory support); and birth weight (Z-scores). For the children, the primary study outcomes will be death or any neurological disability (however defined by trialists at childhood follow up and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (for example, corrected visual acuity worse than 6/60 in the better eye) or deafness (for example, hearing loss requiring amplification or worse)). For the women, the primary outcome will be maternal sepsis (defined as chorioamnionitis; pyrexia after trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal pyrexia). Discussion Data analyses are expected to commence in 2011 with results publicly available in 2012.

trial entry requiring the use of antibiotics; puerperal sepsis; intrapartum fever requiring the use of antibiotics; or postnatal pyrexia). Discussion: Data analyses are expected to commence in 2011 with results publicly available in 2012.

Background
Clinical significance of respiratory distress syndrome and other neonatal morbidities in preterm birth Respiratory distress syndrome, as a consequence of immature lung development, is a complication of preterm birth and the major cause of early neonatal mortality and morbidity [1,2]. Infants born very preterm (less than 32 weeks' gestation) often require respiratory support, with significant numbers requiring assisted ventilation, and 9.4% remain dependent on oxygen therapy 28 days after birth and are diagnosed with chronic lung disease [1]. Of infants born very preterm admitted for neonatal intensive care, a substantial proportion (21.6%) will have an intraventricular haemorrhage (IVH) with 5.8% being Grade 3 or 4 IVH; 1.7% will have cystic periventricular leukomalacia; and 4.1% of babies will have severe retinopathy of prematurity [1]. Children born preterm who survive have an increased risk of re-hospitalisation after discharge home and a recognised higher risk of subsequent long-term neurodevelopmental impairments, including cerebral palsy [3,4], than do children born at term. The personal and emotional costs for affected individuals and their families are high, as are the immediate and long-term monetary costs of these morbidities for parents and society [3][4][5][6].
Strategies to reduce the risk of neonatal respiratory disease for preterm birth continue to receive considerable attention [7][8][9]. A single course of prenatal corticosteroids compared with placebo has not been shown to be effective in babies who are born more than seven days after treatment [7]. Specifically, there is insufficient evidence of a reduction in the incidence of respiratory distress syndrome or neonatal mortality [7,10,11] and birth weight is significantly reduced [7]. This evidence led to the suggestion [12] and uptake into clinical practice within Australia [13] and other countries [14], with minimal formal assessment, of repeating the dose of prenatal corticosteroids in the 34% to 40% [7,10] of women who remained at risk of preterm birth seven or more days after the initial course.
Observational studies, with their inherent risk of bias, have given conflicting results, some suggesting adverse effects of repeat corticosteroids on measures of foetal growth [15] and on delayed development in early childhood [16], whilst others have indicated a possible reduction in cerebral palsy [17]. Given the need for better quality evidence about the benefits and harms of repeat prenatal corticosteroids, randomised clinical trials have now been reported [18][19][20][21][22][23][24][25][26][27].
A recent Cochrane systematic review of published aggregate data was unable to answer some important clinical questions which this individual participant data (IPD) meta-analysis will address [28].

Summary of the Cochrane systematic review of the aggregate data in 2011
It remains unclear whether repeat dose(s) of prenatal corticosteroids are beneficial. The most recent Cochrane systematic review that assesses the use of repeat prenatal corticosteroids for women at risk of preterm birth to prevent neonatal respiratory disease included ten trials (over 4,730 women and 5,650 babies) with low to moderate bias [28].
There was diversity in the inclusion and exclusion criteria for the ten included trials, with wide variation in the reasons women were at risk of preterm birth (preterm labour, preterm prelabour rupture of the membranes, antepartum haemorrhage, pre-eclampsia, foetal growth restriction, cervical incompetence and multiple pregnancy); the gestational age women were eligible (from 24 to 34 weeks); and the time of treatment prior to expected preterm birth. All women received a single course of prenatal corticosteroids one week or more before trial entry. However, the type, amount and timing regimen for administration of the corticosteroid given before the trial varied between trials.
Treatment of women who remain at risk of preterm birth seven or more days after an initial course of prenatal corticosteroids with repeat dose(s), compared with no repeat corticosteroid treatment, reduced the risk of their infants being affected by the primary outcomes, respiratory distress syndrome (risk ratio (RR) 0.83, 95% confidence interval (CI) 0.75 to 0.91; eight trials; 3,206 infants; numbers needed to treat (NNT) 17, 95% CI 11 to 32) and serious infant outcome (RR 0.84, 95% CI 0.75 to 0.94; seven trials; 5,094 infants; NNT 30, 95% CI 19 to 79).
Treatment with repeat dose(s) of corticosteroid was associated with a reduction in mean birth weight (mean difference -75.8 g, 95% CI -117.6 g to -34 g; nine trials; 5,626 infants). However, outcomes that adjusted birth weight for gestational age (birth weight Z-scores, birth weight multiples of the median and small for gestational age) did not differ between treatment groups.
For maximising benefit and minimising harm, many questions remain. How can the potentially important benefits observed be applied to individual women who have different reasons for, and levels of risk, of preterm birth? If repeat prenatal corticosteroids are to be recommended, what are the optimal gestational ages for administration, the optimal number of repeat treatments that should be given, and at what dose and timing? Individual participant meta-analysis of the data from the 11 trials now available may help to answer these questions.
Overcoming limitations: conducting an individual participant data meta-analysis Analysis of thoroughly checked and updated data from individual participants in all the available randomised trials has been described as the gold standard in systematic reviews [29]. Estimates of treatment effects are often different from those obtained from aggregate published data due to inclusion of additional or updated data. The methods and advantages of IPD review have been well described [30,31].
An integral component of conducting an IPD metaanalysis is the formation of an international collaborative group of trialists where all researchers endorse the IPD protocol and provide data from their trials. This generates additional benefits that include more complete identification of trials and of trial details; compliance with standard definitions; provision of missing data on characteristics of trials, all women who were randomised and their babies, and outcomes; more balanced interpretation, endorsement and global dissemination of results; and better clarification and consensus on future research needed with the opportunity for on-going international collaborations [32].

Objectives
Our aim is to assess, using IPD meta-analyses, the effects on important clinical outcomes of repeat prenatal corticosteroid treatment given to women at risk of preterm birth to benefit their babies, both shortterm and long-term, and whether treatment effects differ in a clinically meaningful way between important pre-specified participant-level and trial-level characteristics.

Research Questions
For maximising benefit and minimising harm, the main research questions to be addressed in this review are: 1. Are repeat prenatal corticosteroids more effective in some women by reason of their risk of preterm birth? 2. If the use of repeat prenatal corticosteroids is recommended, what is the best gestational age to maximise benefit? 3. What dose, number of repeat doses and timing prior to birth is optimal? 4. What is the minimal effective and safe dose of repeat prenatal corticosteroids? 5. Is a single rescue steroid dose effective?

Methods/Design
Study design IPD meta-analysis.

Inclusion and exclusion criteria for the studies
Studies, published or unpublished, will be included if they were randomised trials with adequate allocation concealment and report data on one or more of the pre-stated outcomes. Quasi-random study designs will not be included. As of September 2011, 11 trials with up to 5,000 women and 6,000 infants are eligible for the Prenatal Repeat Corticosteroid International IPD Study Group: assessing the effects using the best level of Evidence (PRECISE) IPD meta-analysis [18][19][20][21][22][23][24][25][26][27]33] ( Table 1).
Eligibility of trials will be assessed independently and unblinded for author and journal by two members of the PRECISE IPD Project Team. Any differences in opinion regarding eligibility will be resolved by discussion. If IPD are unavailable for any eligible trial, the trial will still be included in the review and aggregate data will be used for sensitivity analyses wherever possible.

Types of participants
Women considered at risk of preterm birth (< 37 weeks gestation) who have already received a single course of prenatal corticosteroid seven or more days previously.

Types of interventions
Corticosteroid administered to the women intravenously, intramuscularly or orally, compared with either placebo or no placebo. Trials in which the foetus received corticosteroids directly will not be included.

Search strategy to identify potential trials
We will use the search strategy developed by the Cochrane Pregnancy and Childbirth Review Group for the Cochrane review, which identifies trials from quarterly searches of the Cochrane Central Register of Controlled Trials (CENTRAL); weekly searches of MEDLINE; hand searches of 30 journals and the proceedings of major conferences; weekly current awareness alerts for a further 44 journals plus monthly BioMed Central email alerts.
We will also search CENTRAL, MEDLINE and EMBASE to identify trials published since the search cut-off date of 31 August 2008 for the Cochrane review; using the terms [repeat or multiple] and [antenatal or prenatal] and [corticosteroid* or steroid* or glucocorticoid* or betamethason* or dexamethason* or hydrocortison*].
In addition we will access Current Controlled Trials http://www.controlled-trials.com and the Australian and New Zealand Trials Register http://www.anzctr.org.au to identify recently completed or on-going trials.
Experts in the field and trialists will be asked if they know of any unpublished or other trials.

Data collection and management
Data collected will include all women randomised and coded for anonymity (date of birth, centre identification); baseline data for descriptive purposes and analyses (reason at risk of preterm birth, gestational age at trial entry, plurality of the pregnancy, expected date of birth); details of the intervention given (date of randomisation, allocated intervention, type and dose of corticosteroid given, interval between treatments, whether re-treatment given and amount); and outcomes, to allow planned analyses.
Trialists will provide de-identified IPD in any convenient format by encrypted, electronic transfer where possible or other means as needed. The individual trial data will be recoded as required and stored in a custom designed secure database which will only be accessible by authorised personnel of the PRECISE Data Management Group. Trialists will be asked to verify all recoded data prior to any analysis and the data will not be used for any other purpose without permission of all collaborators.
The data will be checked with respect to range, internal consistency, missing or extreme values, errors and consistency with published reports. Trial details, such as randomisation methods, and intervention details will be cross-checked against published reports, trial protocols and data collection sheets. Inconsistencies or missing data will be discussed with the individual trialists and attempts will be made to resolve any problems by consensus. Each trial will be checked individually and the trial data will be sent to the trialists for verification.

Planned analyses
A detailed statistical analysis plan will be prepared by the PRECISE Data Management Group and agreed upon by the PRECISE IPD Project Team and the PRE-CISE International IPD Study Group prior to the data analyses. Any analyses conducted will be based on the checked and updated individual participant data from all available trials. All randomised participants with outcome data available will be included in the analyses, which will be performed on an intention to treat basis, according to the treatment allocation at randomisation. For each of the outcomes, a one-stage approach to analysis will be taken so that the IPD from all eligible trials are included in a single model [34]. Fitting a single model for each outcome variable will enable the variation across trials to be accounted for within the model by including a fixed trial effect. A treatment by trial interaction term will be tested to assess heterogeneity of treatment effect across trials. If excessive statistical heterogeneity in treatment effect or inconsistency across trials is detected (that is, if the trial by treatment interaction term is significant), then the rationale for combining trials will be questioned and the source of heterogeneity explored.
Binary outcomes will be analysed using log binomial regression models and results will be presented as risk ratios with 95% CI and associated two-sided P values. Continuous outcomes will be analysed using linear regression models and results will be presented as differences in means with 95% CI and two-sided P values. Correlation between outcomes due to multiple births will be taken into account using generalised estimating equations as appropriate.
Any differences in treatment effect between pre-specified subgroups will be assessed by testing a treatment by subgroup interaction term within the model [35].

Outcomes
Outcomes have been chosen to be most representative of the clinically important measures of effectiveness and safety, including serious outcomes, for the women and their babies. The definitions given by the trialists are used unless otherwise stated.

Primary outcomes
For the infants 1. serious outcome, defined by the PRE-CISE International IPD Study Group as one of death (foetal, neonatal or infant), severe respiratory disease, severe IVH (grade 3 and 4), chronic lung disease (oxygen dependent at 36 weeks postnatal age), definite necrotising enterocolitis, severe retinopathy of prematurity (Stage 3 or worse in the better eye) or cystic periventricular leukomalacia 2. use of respiratory support, defined as mechanical ventilation or continuous positive airways pressure or other respiratory support 3. birth weight (Z-scores) [36]. For the children 1. death or any neurosensory disability at childhood follow up, and may include developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness (for example, corrected visual acuity worse than 6/60 in the better eye) or deafness (for example, hearing loss requiring amplification or worse). For the women 1. maternal sepsis, defined as chorioamnionitis during labour, pyrexia after trial entry requiring the use of antibiotics, puerperal sepsis, intrapartum fever requiring the use of antibiotics or postnatal pyrexia. 3. any neurosensory disability, defined as developmental delay or intellectual impairment (developmental quotient or intelligence quotient more than one standard deviation below the mean), cerebral palsy (abnormality of tone with motor dysfunction), blindness or deafness, at follow up later in childhood 4. major neurosensory disability, defined as any moderate or severe neurosensory impairment 5. survival free of major neurosensory disability (alive and without major disability) 6. growth assessments at childhood follow up (Zscores for weight, head circumference, height) [37] 7. child behaviour 8. child temperament 9. respiratory disease 10. blood pressure. For the women 1. chorioamnionitis during labour 2. pyrexia after trial entry requiring the use of antibiotics 3. puerperal sepsis 4. intrapartum fever requiring the use of antibiotics 5. postnatal pyrexia 6. death 7. preterm prelabour rupture of the membranes after trial entry 8. hypertension 9. mode of birth (normal vaginal birth, operative vaginal birth, Caesarean section) 10. postpartum haemorrhage 11. breastfeeding at hospital discharge 12. postnatal depression 13. adverse effects of corticosteroid therapy (including gastrointestinal upset, glucose intolerance, insomnia, pain at the injection site, bruising at the injection site, infection at injection site, weight gain, Cushing appearance). Use of health services 1. length of antenatal hospitalisation for the women 2. length of postnatal hospitalisation for the women 3. maternal admission to intensive care unit 4. admission to neonatal intensive care unit 5. length of stay in neonatal intensive care unit 6. length of neonatal hospitalisation.

Planned subgroup analyses
Where sufficient data exist, subgroup comparisons will be conducted using the five infant, child and maternal primary outcomes, as well as the individual components of each composite outcome. Any differences in treatment effect between subgroups will be assessed by testing a treatment by subgroup interaction term within the model. Some subgroups may be combined if data are insufficient.

Subgroups
Trial-level characteristics 1. Type of repeat prenatal corticosteroid treatment given (betamethasone or dexamethasone). 2. Number of repeat doses planned to be given. 3. Minimum planned interval between the initial corticosteroid and the first repeat dose.
4. Minimum planned interval between repeat steroid treatments.
5. Planned dose of corticosteroid per repeat treatment. 6. Planned dose of repeat steroid drug exposure per week.
7. Total dose of repeat steroid drug planned. Participant-level characteristics 1. Reason the woman was considered to be at risk of preterm birth (preterm labour, the presence or absence of ruptured membranes, antepartum haemorrhage, pre-eclampsia and/or eclampsia, foetal growth restriction, suspected foetal jeopardy, cervical incompetence, maternal disease and multiple pregnancy).
2. Purpose trial treatment given (prophylaxis against preterm birth; 'rescue therapy' when preterm birth is imminent; other).
6. Actual rescue treatment versus weekly treatment.
Additional exposure analyses 1. Number of repeat doses actually given. 2. Minimum actual interval between the initial corticosteroid and the first trial treatment.
3. Minimum actual interval between repeat trial treatments.
4. Actual dose of trial treatment given per repeat treatment.
5. Actual dose of repeat trial treatment exposure per week. 6. Total actual trial treatment exposure.

Planned sensitivity analyses
To assess whether the results are robust to trial design and quality, the following sensitivity analyses will be performed on the primary outcomes, as well as the individual components of each composite outcome (unless otherwise specified): exclusion of trials with small sample size (less than 100 study participants); exclusion of trials with high rate of missingness and/or exclusions where the losses are considered to have the potential to impact on the results; inclusion of aggregate data from trials where individual participant data are unavailable; exclusion of trials where not all variables used to define the outcome were collected (composite outcomes only); and random effects models with trial included as a random effect (all primary and secondary outcomes).

Multiple comparisons
A large number of outcomes are being investigated in this study, which increases the chance of observing 'false positive' results. However, all outcomes are important in giving a full clinical picture that considers the benefits and risks to both mothers and infants. We do not plan formal statistical adjustment of P values to account for multiple comparisons due to the non-independence of outcomes in this study. Results will be interpreted with caution.

Ethics and management issues
Ethical considerations Participants in the individual trials have previously given informed consent to participate in their respective trial. The data for this project are to be used for the purpose for which they were originally collected and are available through an agreement between all trialists of the collaborative group. These trialists remain the custodian of their original individual trial data at all times.

Project Management
For the purpose of this project, an international Collaborative Group, The PRECISE Group, will manage the project and consists of groups with specific responsibilities and tasks: The PRECISE IPD Project Team The PRECISE IPD Project Team is the Steering Group which is responsible for the project's management decisions and the daily management of the Collaboration. The Project Team's tasks are to design the project's protocol and analysis plan, organise The PRECISE Group Meetings and act as a liaison between all the members of The PRECISE Group. The PRECISE IPD Project Team will meet regularly every two to four months, usually by teleconference. The PRECISE Trialist Group Members of The PRE-CISE Trialist Group will be representatives of the eligible trials. For each trial, the first author will be invited to become a member of the Collaboration. If considered necessary or if there is no response from the first author, other investigators from the trials may be contacted (for example, the data manager or statistician). In order to keep The PRECISE Trialist Group updated, authors of new trials or previously unidentified trials will be contacted and invited to join the Collaboration in the course of the project. The Data Management Group and PRECISE IPD Statistical Team The data management group will be convened by the Chair of The PRECISE IPD Project Team and comprises statisticians from the data management centre and participating trials who will conduct the analyses. The data management group will be responsible for the storage and analyses of the IPD project data.

The PRECISE Group Meetings
Collaborative group face-to-face meetings will be organised at least twice during the study. Representatives of all eligible trials will be invited to attend those meetings. The meetings will be scheduled, if possible, in conjunction with international conferences. During those meetings, various aspects of the project will be discussed with all the collaborators, such as the project's design and conduct, the analysis plan and the interpretation and reporting of the results. The final collaborators' meeting is scheduled for 2012.

Publication of results
The final results of the study will be presented to the collaborators for discussion. The main manuscript will be prepared by The PRECISE IPD Project Team and Data Management Group and circulated to The PRE-CISE Group for comment and revision. The revised draft paper will be circulated for final comment and agreement prior to publication. PRECISE publications arising from these data will be authored with members of The PRECISE Group named where possible and on behalf of The PRECISE Collaboration as a whole. The names of all other collaborators participating will be acknowledged within the manuscript.

Discussion
The recently updated meta-analysis [28] showed that the short term benefits seen for babies support the use of repeat dose(s) of prenatal corticosteroids for women who have received an initial course of prenatal corticosteroids seven of more days previously and who remain at risk of preterm birth.
For maximising benefit and minimising harm, many questions remain. Are repeat prenatal corticosteroids more effective in some women by reason of their risk of preterm birth? If the use of repeat prenatal corticosteroids is recommended, what is the best gestational age to use for benefit? What dose, number of repeat doses and timing prior to birth is optimal?
The best way to answer these remaining questions is to utilise existing IPD from all women and babies enrolled in previous trials of repeat prenatal corticosteroids. This approach has been described as the 'gold standard' of systematic review methodology as it allows for more powerful and flexible analysis of both subgroups and outcomes. The PRECISE Group has been formed to undertake a meta-analysis based on IPD, to answer these important clinical questions. Provision of data by the participating collaborators commenced in 2010 and results will be ready for presentation in 2012. The National Health and Medical Research Council (NHMRC) is funding the PRECISE IPD Study through a project grant. This funding will support the collection of the individual participant data by the original investigators, data management and analyses and to organise the collaborators' meetings. The NHMRC is not involved in any other aspect of the project, such as the design of the project's protocol and analysis plan, the collection and the analyses of the project's data, or the interpretation and the publication of the study results.