Planned early delivery versus expectant management to reduce adverse pregnancy outcomes in pre-eclampsia in a low- and middle-income setting: study protocol for a randomised controlled trial (CRADLE-4 Trial)

Background: Pre-eclampsia is a pregnancy complication characterised by high blood pressure and multi-organ dysfunction in the mother. It is a leading contributor to maternal and perinatal mortality, with 99% of these deaths occurring in low- and middle-income countries (LMIC). Whilst clear guidelines exist for management of early-onset (< 34 weeks) and term (≥ 37 weeks) disease, the optimal timing of delivery in pre-eclampsia between 34+ 0 and 36+ 6 weeks is less clear. In a high-income setting, delivery may improve maternal outcomes without detriment to the baby, but this intervention is yet to be evaluated in LMIC. Methods: The CRADLE-4 Trial is a non-masked, randomised controlled trial comparing planned early delivery (initiation of delivery within 48 h of randomisation) with routine care (expectant management) in women with pre-eclampsia between 34+ 0 and 36+ 6 weeks’ gestation in India and Zambia. The primary objective is to establish whether a policy of planned early delivery can reduce adverse maternal outcomes, without increasing severe neonatal morbidity. Discussion: The World Health Organization recommends delivery for all women with pre-eclampsia from 37 weeks onwards, based on evidence showing clear maternal benefit without increased neonatal risk. Before 34 weeks, watchful waiting is preferred, with delivery recommended only when there is severe maternal or fetal compromise, due to the neonatal risks associated with early preterm delivery. Currently, there is a lack of guidance for clinicians managing women with pre-eclampsia between 34+ 0 and 36+ 6 weeks. Early delivery benefits the mother but may increase the need for neonatal unit admission in the infant (albeit without serious morbidity at this gestation). On the other hand, waiting to deliver may increase the risk of stillbirth, fetal growth restriction and hypoxic brain injury in the neonate as a result of severe maternal complications. This is especially true for LMIC where there is a higher prevalence of adverse events. The balance of risks and benefits therefore needs to be carefully assessed before making firm recommendations. This is the first trial evaluating the optimal timing of delivery in pre-eclampsia in LMIC, where resources and disease burden are considerably different. Trial registration: ISRCTN 10672137. Registered on 28 November 2019. The aim of this trial is to establish whether planned early delivery in pre-eclampsia between 34+ 0 and 36+ 6 weeks can reduce adverse pregnancy outcomes compared to expectant management in a low- and middle-income setting. The primary objectives of the study are: The secondary objectives of the study are: The trial will be conducted in five tertiary hospitals across India and Zambia, including their referring district healthcare facilities (sites listed on http://www.isrctn.com/ISRCTN10672137). An initial 6-month feasibility study was conducted across the proposed trial sites. This was a mixed-methods study consisting of semi-structured interviews with a cross-section of healthcare providers, focus group discussions with pregnant women and their relatives and a retrospective case notes audit evaluating gestation-specific maternal and neonatal outcomes in women with pre-eclampsia. The results of this feasibility study directly informed the development of the interventional phase protocol. Recruitment is anticipated to take 22 months based on an assumption that approximately 45 participants will be recruited per month (across all sites), with some allowance for unforeseen events and centres recruiting slower than expected. Daily visits by the research team to the relevant clinical areas at each healthcare facility will ensure that all potentially eligible participants are screened. In addition to this, key personnel at each of the referring healthcare facilities will be provided with a basic mobile phone and airtime in order to facilitate referrals of potentially eligible participants. The development of culturally appropriate trial materials for both participants and key members of their household will help to engage and inform potential participants. Dissemination of trial posters and flowcharts will ensure that clinical staff are well informed and aware of trial procedures. If necessary, additional strategies to boost trial recruitment (such as additional sites or small financial incentives for clinical staff will be considered). Women who meet the following criteria will be eligible for enrolment into the study: Women with any other co-morbidity (including pre-existing hypertension, diabetes, and HIV) or having had a previous caesarean section or with the fetus in any position will be eligible. Women with multi-fetal pregnancy will also be eligible. Women will be excluded from participation in the study if a decision has already been made to deliver within the next 48 h. Members of the research team will provide a full verbal explanation and written description (in the relevant local language) to women who meet the inclusion criteria (as above). Additionally, participant information videos in local languages have been developed to aid comprehension amongst both trial participants and their relatives. The woman will be given sufficient time to consider the information and to decide whether she will participate in the trial. Written informed consent will be sought from the woman and taken by an appropriately trained member of the research team. A woman’s participation in the study may be from 34 weeks’ gestation until primary discharge of the woman and her baby after birth (Fig. 1). Long-term follow-up will be considered by obtaining permission to contact participants later, but only after further ethical approval and governance has been ascertained. Both the maternal and neonatal short-term outcomes will be collected quickly as the time period from randomisation to outcome collection will not exceed 14 weeks (participants will be followed up until primary discharge of mother and baby post-delivery) and in many cases will be less. Outcome collection will end 42 days after the final participant has been recruited (or sooner if primary discharge of mother and baby occurs before this endpoint). Schedule of participant enrolment, interventions and assessment in the trial (SPIRIT figure) At all stages, it will be made clear to the woman that she is free to withdraw from the trial at any time without the need to provide any reason or explanation. Participants will be made aware that this decision will have no impact on any aspect of their continuing care. For a woman allocated to the expectant management group, if clinical needs dictate delivery prior to 37 weeks’ gestation based on local criteria, this will not constitute withdrawal from the trial allocation. For a woman allocated to the planned delivery group, if the woman should decide that she does not wish to proceed with the planned delivery and instead chooses to be monitored by her attending clinician, this will not constitute withdrawal from the study. Outcomes will be recorded on the web-based database after a review of case notes by trained members of the research team. This will be done contemporaneously and completed no later than 24 h after the mother and baby have been discharged. Confirmation of maternal and neonatal outcome data will be undertaken with an additional sign-off by the site’s principal investigator for each participant and constant communication with the relevant clinical teams. Primary short-term maternal outcome will include maternal mortality and morbidity based on the miniPIERS composite [11] (see Table 1 for full list) of adverse maternal outcomes (with the addition of severe hypertension) during pregnancy and delivery until primary hospital discharge. Full definitions of individual components of the primary short-term maternal outcome Primary short-term perinatal outcome will include composite of one or more of antenatal/intrapartum stillbirth or neonatal death (but not deaths due to congenital anomalies) or neonatal unit admissions > 48 h due to neonatal morbidity (necessitating admission to the neonatal unit according to local guidelines) until primary hospital discharge. Secondary maternal outcomes will include assessment of: Secondary perinatal outcomes will include assessment of: Written consent will be sought from the woman only after she has been given a full verbal explanation and written description of the trial (via the participant information leaflet, in her preferred language). The local research team at each site are fluent in English and the relevant local languages spoken by the majority of the population across the trial sites (Bemba and Nyanja at the Zambian sites, Kannada at the Indian sites). The participant information leaflet will be read aloud to women who are unable to read it themselves. Partners and relatives will be included in the discussion but may not consent on the woman’s behalf. Additionally, three short video clips addressing key topics (pre-eclampsia, trial participation and the neonatal unit) will be made available to all potentially eligible participants, particularly those with limited literacy. Written informed consent will be given using an informed consent form, completed, signed (thumbprints also accepted) and dated by the woman and signed by the member of the research team who obtained informed consent. After written informed consent has been obtained, a member of the research team will enter the baseline maternal details onto the online database and perform randomisation, communicating the results directly to the woman and her clinical team. Antenatal, intrapartum and postpartum care will be in accordance with local guidelines and capacity at each site. Delivery will typically be through induction according to local protocol (most commonly oral or vaginal administration of misoprostol). The schedule of care for each group will be as follows: The intervention is planned delivery, to be undertaken as soon as feasible (aimed to be commenced within 48 h) after randomisation. Use of antenatal corticosteroids for fetal lung maturity will be at the discretion of the clinician, in accordance with local guidelines (confirmed as readily available across all facilities). Postnatal care will be in accordance with local protocols and guidelines. Expectant management involves close monitoring of the maternal and fetal condition until the woman reaches 37 weeks, or a crisis develops necessitating delivery. Delivery is recommended if the woman develops severe pre-eclampsia. This is in accordance with the World Health Organization guidelines [4] which are followed at all of the proposed trial sites. Following randomisation to either the planned delivery group or expectant management group, the time of onset of planned delivery (first method for induction of labour or time of planned caesarean section along with the indication) or onset of spontaneous labour will be recorded for all women. This will enable the monitoring of adherence to protocol for both study groups to be reviewed and protocol deviations to be identified and investigated. The sample size for the CRADLE 4 study is calculated on the ability to detect a clinically important reduction in the primary maternal outcome: a short-term composite based on the presence of one or more of 22 maternal morbidities. Based on data acquired at the sites prior to start of the main trial, we anticipate an event rate of 80% for the primary maternal outcome in the expectant management arm. We have calculated that a sample size of 558 would provide 90% power to detect a 15% relative risk reduction. If the trial is recruiting well, we will continue to recruit 872 participants which would give 90% power to detect a 12.5% relative risk reduction and greater precision to detect secondary outcomes. The data monitoring committee (DMC) will review the primary event rate and usual safety data and make a recommendation to continue or stop. A one-sided non-inferiority analysis is planned for the primary neonatal composite. Our data acquired at the sites prior to starting the main trial showed an event rate of 24% for the primary neonatal outcome. Complete data on 480 women (240 per group) are required for 90% power to exclude a difference against planned delivery of 10% or more. To exclude a difference of 7.5%, 852 women (426 per group) are needed. The calculation uses a one-sided significance test and confidence interval and assumes that the true event rate is 24%. This is in line with the planned sample size as detailed above. Randomisation will be managed by a secure web-based randomisation facility hosted by MedSciNet. The allocation ratio of intervention (planned early delivery) to control (expectant management) will be 1:1. Participants will be stratified by centre and minimised by parity (0 or ≥ 1), single/multi-fetal pregnancy (singleton or multi-fetal) and gestational age (34+ 0–34+ 6, 35+ 0–35+ 6, 36+ 0–36+ 6) at randomisation. MedSciNet will write the randomisation programme and hold the allocation code. Following randomisation, a clinician will then arrange for delivery or ongoing expectant management as the randomisation indicates. Due to the nature of this study, masking of clinicians, nursing staff and participants is not possible. In view of arrangements for the conduct of the trial at these sites, it is not feasible to arrange for a separate team of outcome assessors masked to intervention allocation. Data analysis will be conducted masked to group allocation. Much of the outcome data for this trial are routinely recorded clinical items that can be obtained from the clinical notes. No additional blood or tissue samples are required for this study. Outcomes will be recorded prospectively using case report forms (CRFs). When possible, online versions will be used (eCRFs) and outcomes therefore recorded directly on the trial database. If, due to power shortages or lack of internet connectivity, this is not feasible, paper case report forms will be used, and data then directly transcribed into the database. The DMC will ensure the wellbeing of study participants and will periodically review study progress and outcomes as well as reports of unexpected serious adverse events (SAEs). The DMC will, if appropriate, make recommendations regarding continuance of the study or modification of the study protocol. An adverse event is any untoward medical occurrence in a participant, which does not necessarily have to have a causal relationship with this intervention. Due to the high incidence of adverse events routinely expected in this patient population, only those adverse events identified as serious will be recorded for the trial. A serious adverse event is any untoward medical occurrence that: Expected SAEs are those events which are expected in the patient population or as a result of the routine care/treatment of a patient. The following events are expected in women with pre-eclampsia and their infants and will be recorded as part of outcome collection (during a woman’s participation in the trial—from randomisation until primary hospital discharge of either mother or baby) but do not require reporting as SAEs. An unexpected SAE is any event that meets the definition of a SAE and is not detailed in the list above as expected. The following events, whilst not entirely unexpected in this population, are nevertheless serious enough that they should be reported. However, we anticipate that these will be more related to the disease process in this setting and not directly related to the intervention. With this in mind, they will be aggregated and reviewed on a 3-monthly basis by the DMC. All SAEs (described above) will be recorded from randomisation to postnatal discharge from hospital of mother and baby. Unexpected SAEs for both the mother and infant will be recorded and reported to the DMC as described above. Details of the SAE should be recorded on an SAE form (either electronically via the study database or in paper format). Paper forms will be emailed to the trial coordinating team. An SAE occurring to a participant will be reported to the research ethics committee that gave a favourable opinion of the study where in the opinion of the principal investigator the event was ‘related’ (resulted from administration of any of the research procedures) and ‘unexpected’ in relation to those procedures. Reports of related and unexpected SAEs will be submitted within 15 working days of the principal investigator becoming aware of the event, using the health research authority (HRA) report of serious adverse event form. All reported SAEs will be reviewed by the DMC at regular intervals throughout the study. The principal investigator will inform all investigators concerned of relevant information that could adversely affect the safety of participants. The site research team will be responsible for the day-to-day smooth running of the trial at a recruiting site. The central trial research team will monitor recruitment against targets, provide staff education and training and monitor the completeness and quality of collected data. The study monitor will perform regular visits to all recruiting centres and will verify the source data for selected participants during these visits. The primary analysis for all maternal outcomes will be by the intention to treat principle with participants analysed in the groups to which they are assigned regardless of deviation from the protocol or intervention received. We will analyse the difference between arms in the randomisation to delivery interval (3 monthly) to ensure intervention compliance. Women in the expectant management arm will frequently be delivered prior to 37 weeks of gestation due to clinical need and this will not be considered a protocol deviation. The primary analysis for all perinatal and infant outcomes will be both an intention to treat and a per-protocol analysis, since the hypothesis under examination for these outcomes is a non-inferiority hypothesis. The per-protocol analysis will exclude babies of women who do not receive the allocated intervention as per protocol and will be further defined in the statistical analysis plan. All outcomes will be analysed adjusting for minimisation factors at randomisation where possible [14]. Where possible, continuous outcomes will be adjusted for baseline measurements of the same variable [15]. Binary outcomes will be analysed using log binomial regression models. Results will be presented as adjusted risk ratios with associated confidence intervals (CI). If the model does not converge, logistic regression with robust variance estimation will be used [16]. Continuous outcomes will be analysed using linear regression models. Results will be presented as differences in means with associated CIs. 95% CIs will be presented for all primary outcomes and 99% CIs for secondary outcomes. For the analysis of perinatal outcomes, we will treat all infants (singletons or multiples) separately, adjusting standard errors for clustering by mother. Pre-specified subgroup analyses will be undertaken for gestation at randomisation (test for trend) and for single vs. multi-fetal pregnancy, country and region (with a region being tertiary centre and referring healthcare facilities). The consistency of the effect of planned delivery vs. expectant management across subgroups will be assessed using a likelihood ratio test for interaction. Loss to follow-up is expected to be about 5% for the short-term outcomes. A secondary per-protocol analysis will look at the primary outcomes according to the treatment actually received and time of randomisation. The primary maternal outcome is maternal mortality and morbidity based on miniPIERS [11] plus severe hypertension (Table 1) during pregnancy or before hospital discharge. The maternal mortality and morbidity component of the primary outcome will be reported separately, as will the severe hypertension component. Additionally, a maternal mortality and morbidity composite of components detected by a clinical diagnosis only will be reported separately (outlined in further detail in the statistical analysis plan). Health care resource use will include information collected on the management of pre-eclampsia, maternal hospital length of stay related to pre-eclampsia and delivery, maternal intensive care unit admissions and perinatal neonatal unit admissions and hospital length of stay. Health care resource use will be costed using published sources and will be reported in United States Dollars (USD); costs will be reported in local currencies where possible. Mode of onset and mode of delivery will also be included in the costing. Means and standard deviations will be reported for health care resource items and costs. Linear regression and bootstrapping will be used to calculate the difference between treatment groups and 95% confidence intervals, adjusting for minimisation factors at randomisation. The end of the intervention phase will be when the last participating mother and infant have been discharged from hospital, or 42 days after the final participant has been recruited (whichever occurs sooner). For regulatory purposes, the end of the trial is defined as the date when the study database is locked. An end of study declaration will be made to the approving research ethics committees within 3 months of this date. In the light of interim data and other evidence from relevant studies, the DMC will inform the trial steering committee (TSC) if, in its view, there is proof beyond reasonable doubt that the data indicate that the trial should be terminated. A decision to inform the TSC of such a finding will in part be based on statistical considerations. A purposeful sample of participants will be approached for consent to a qualitative interview exploring their experience of the trial intervention (or usual care arm). The impact of external factors (specifically resource availability and health system factors) on the effectiveness of the implementation of the intervention will be assessed by conducting an audit of key resources available at each participating healthcare facility at regular (6 monthly) intervals during the trial, which will be reported using descriptive statistics. A subgroup analysis of the main trial results by site will identify any meaningful variations by site, which may be influenced by local resource availability. Anonymised data be will collected by the local research team under the supervision of the trial coordinator. When possible, all anonymised data will be directly entered onto a secure, online database (MedSciNet). If the low-resource nature of the environments where we will be collecting the data means this is not possible, the local research team will be trained to accurately transfer any paper-based data onto MedSciNet, whilst maintaining confidentiality always. Consent forms and source data where paper based will be kept in files in secure areas at each central site. Only healthcare providers involved in trial participants’ care, research assistants, the local trial coordinator and the UK-based trial manager will have access to these. All paper documents will be stored securely and kept in confidence in compliance with the UK Data Protection Act 1998. All data entered on the MedSciNet database in each facility will be automatically stored and backed up. Collection and storage of clinical data in the database will be governed by the UK Data Protection Act 1998. All participants will be given a unique trial identifier and no personal information will be entered into the clinical trial database or sample database. Personal contact information will be held on a local database kept in a locked environment, after gaining written informed consent from trial participants. All MedSciNet data is stored on high-capacity servers that are operated by an external company. Servers are stored in locked rooms, with system monitoring 24 × 7, physical surveillance and surveillance cameras. A tape backup system is used for backing up the database. The MedSciNet database will remain live for 1 year following completion of the main trial. A copy of this will then be kept on the KCL server for 20 years following the trial completion date, in accordance with the KCL Data retention schedule.