CRADLE-4: Can Reduction of Adverse pregnancy outcomes occur with planned DeLivery vs.Expectant management in pre-eclampsia?

Pre-eclampsia affects approximately one in twenty-five pregnancies and is diagnosed by doctors when the mother develops high blood pressure and protein in her urine. The complications of this disorder are potentially very serious. Pre-eclampsia, particularly when it occurs early on in pregnancy, can result in severe problems for the mother such as fits, bleeding, and may even result in her death. The baby can be affected by a poorly functioning placenta, which leads to reduced blood flow, inadequate nutrition and poor oxygen supply which can result in reduced growth so that the infant may be born with a low birthweight and may even die. Death of the baby is common when the disease is not recognized in a timely fashion, common in a LMIC setting. Timely delivery of the baby will prevent many of these complications, but can also increase the risk of problems for the baby related to premature birth and immaturity.

In women who develop raised blood pressure or mild pre-eclampsia at the end of pregnancy, bringing on labour has been shown to reduce the risk of problems to the mother and also lower the caesarean section rate, without any increased risk to the baby. When pre-eclampsia occurs in early pregnancy, before the 34th week of pregnancy, the risk to the baby of being born early is high. In this case it is better not to deliver unless the mother or baby deteriorate. The risk/benefit of routinely delivering the baby between the 34th and 37th week of pregnancy is less clear. Approximately a third of women with pre-eclampsia present in this window, and the disease in more severe than at term. Delivery may prevent complications in the mother but might increase risks to the baby compared with delivery at term. This decision is even more complicated when women live in countries with less resources where there are fewer doctors, midwives, nurses, medical supplies and hospital beds and different cultural values.

In this trial we would aim to determine whether recognition and accurate diagnosis with delivery (bringing on labour within 48 hours or caesarean) or 'watch and wait' management is better for women with pre-eclampsia living in India and Zambia between the 34th and 37th week of pregnancy and their babies. 'Watch and wait', which medical professionals call 'expectant management', means that pregnant women will be closely observed and only be delivered if any complications arise in either the mother or the baby, or if the 37th week of pregnancy is reached.
To test this, pregnant women that have been diagnosed with pre-eclampsia using our CRADLE VSA device, who come into hospital or clinic between the 34th and 37th week of pregnancy but do not require immediate delivery, will be allocated by a computer (i.e. by chance, like tossing a coin) to delivery or expectant management. If they are allocated to delivery they may have to travel to a local hospital where they have the facilities for this. If they are allocated to expectant management they will continue to have the same care they would usually have had. This may include staying in hospital for observation or coming to clinic for regular check ups.
We will find out if there are fewer complications in the mother if we adopt the policy of immediate delivery. The study will also find out if this strategy leads to fewer babies being admitted to hospital, less frequent admission to a baby intensive care unit and if there are fewer deaths in this group when compared to those babies born to women in the 'wait and watch' group.
We have chosen to run this trial in India and Zambia as they have different health care systems and challenges. We will ensure we find out about how the strategy is affected in each country and about the experiences of women and their families so our results will be relevant to many other countries.

Pregnancy hypertension contributes 14% of deaths in pregnancy worldwide. This represents an estimated 60,000 deaths annualy worldwide. The WHO recommends that all women with pre-eclampsia at 37 weeks' gestation onwards are delivered. Experience from our work in eight LMIC countries has identified barriers in meeting this standard relating to detection and action. Prior to 34 weeks, expectant management is preferable as it reduces neonatal risk without increasing harm to the mother, although data for this comes mostly from a High Income setting. Guidance on the optimal timing of delivery for women between 34 and 37 weeks' is less clear. Early delivery would be beneficial to the mother and may also benefit the baby who is at risk of placental insufficiency resulting in unpredictable, rapid deterioration, e.g. placental abruption. However, the increased risk of neonatal morbidity associated with premature delivery needs to be defined and compared to the benefit of delivery. Especially in the context of LMIC settings with varying cultural and educational barriers to early delivery, compounded by challenges of resource availability.

The trial is a multicenter, individual randomized controlled trial across India and Zambia. The aim is to determine whether accurate identification of pre-eclampsia with planned early delivery after 34 weeks' of gestation will reduce maternal morbidity without increasing neonatal morbidity compared to routine care. The impact of cultural, political and socio-economical context will be evaluated in each setting with a scoping review, questionnaires, interviews and focus groups with women, their families, stakeholders and health care providers. A cost effectiveness analysis will be also undertaken. Results will therefore be generalizable across many low and middle income settings and have the capacity to directly impact local, national and international guidance on the management of this common pregnancy condition.

Pre-eclampsia effects approximately 10% of all pregnant women which means nearly 3,000,000 are affected in India and Zambia each year. It contributes an estimated 6,496 maternal deaths annually in these countries which are largely avoidable, in addition to causing severe morbidity for mother and baby resulting in lengthy costly hospital stays. By determining the optimal gestation to deliver the baby this trial has the potential to directly impact on the care pathway of women. This intervention requires no additional cost or equipment but has the potential to significantly reduce maternal and neonatal morbidity and mortality. In this context where women are often the main care-providers and in rural areas where they also generate the household income this will also benefit existing children, family and community as a whole.

Women will be screened for eligibility for inclusion in the trial at every level of healthcare facility. This means that all health care providers (HCP) working in these facilities will be trained in diagnosis of pre-eclampsia and provided with accurate tools to do so. This will benefit women from better detection of pre-eclampsia and subsequent management as well as improving the skills of the workforce. The CRADLE Vital Sign Alert device was developed specifically for use in low resource settings. It can accurately measure blood pressure and heart rate in pregnancy and displays results on an early warning system. It has been found to reduce the workload of HCPs, improve decision making and confidence in care. All facilities that screen women for eligibility in the trial will be able to benefit from improved access to equipment. The trial will require the presence of trained research staff that will span the health system, thus improving the visibility of research in areas that may not previously have benefited. It will also improve research capacity of all HCP who will gain knowledge and experience in trial conduct, eligibility criteria and documentation.

Our robust development phase with formal stakeholder analysis will ensure that barriers to delivery of the trial and future implementation are addressed from the trial start. A scoping review will explore the cultural, economical and political context relating to premature delivery in both India and Zambia. We will also undertake interviews to explore the experiences of women and their families of the intervention or routine care. This will improve the likelihood of success in this trial and ensure that results can easily be applied to other LMIC contexts. This is a complex area of clinical management where there is clear equipoise. A randomized-controlled trial to answer this important research question is underway across the UK but the results cannot be presumed to directly translate to LMIC. Rigorous description of context and the choice of two trial sites with different health systems and cultural values means that this learning will be directly generalizable to multiple low and middle income countries. This will be the first randomized controlled trial relating to timing of delivery in LMIC, and will include robust diagnosis and will be methodological sound to produce a definitive answer. It is anticipated that the results of the trial will directly impact on local, national and international guidelines to affect the management of women with pre-eclampsia worldwide.