PREPARE, Prematurity Reduction by Pre-eclampsia Care

Study Overview
=================
Brief Summary
-----------------
Investigators will test a novel system of integrated care, to promote the use of the WORLD HEALTH ORGANIZATION Guidelines for the management of pre-eclampsia and initiate the use of a structured risk assessment strategy to reduce the incidence of preterm delivery from pre-eclampsia by providing obstetricians with the confidence to safely defer delivery of women with pre-eclampsia, identified to be of low risk.

Detailed Description
-----------------
This proposal (PREPARE), led by Brazilian investigators in collaboration with the Global Pregnancy Collaboration (CoLab) is centred on 7 hospital centres and their 23 satellite community health centres (UBSs). There are two clinical initiatives: First, a programme of systematic knowledge transfer (KT) to encourage adoption of the WHO Guidelines to prevent pre-eclampsia as part of routine antenatal care (Objective 1); second an intervention to reduce unnecessary preterm deliveries for the management of pre-eclampsia. CoLab investigators have developed methods to identify those women with preterm pre-eclampsia whose pregnancies can be safely prolonged.4-6 In Objective 2.1, these methods will be applied to women presenting with definite or suspected pre-eclampsia at < 37 weeks' gestation. Investigators will determine the likelihood of an imminent adverse outcome in these women using Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio (sFlT-1/PlGF) measurement and fullPIERS clinical assessment. Prior studies with these approaches indicate more than 98% negative predictive value for adverse outcomes for both.4-6 Investigators will delay delivery in those whose risk is low, caring for patients in accordance with evidence-based WHO guidelines.Unlike medications, management cannot be tested in a blinded way. Management needs integrated skills and commitment from caregivers. Hence, a standard randomized controlled trial is inappropriate. Instead investigators propose a Stepped Wedge Design to study outcomes in the 7 geographically diverse study centres, throughout Brazil. At least 6 women with preterm pre-eclampsia will deliver at each centre every month. The primary outcome will be a lower rate of PRETERM BIRTH due to pre-eclampsia as a proportion of total deliveries in the centre(s) after implementation of the plan compared to prior to its introduction. The study will have 80% power to demonstrate a 25% reduction (2.0 - 1.5%). Investigators will assess maternal and foetal adverse events as secondary outcomes. Objective 2.2 will institute an intense program of knowledge transfer to implement the new management techniques. In Objectives 2.3 and 2.4 will determine patient and provider satisfaction and the economic impact of the care plan. In Objective 3 will establish a biobank and database to begin to assess demographic factors and biological analytes that may help identify unique predictive and diagnostic/pathophysiological features for pre-eclampsia in the Brazilian population (that may extend to other low and middle income countries (LMIC)). For two years at routine visits (≤16 weeks, 28-32 weeks) at each UBS, relevant data and plasma, serum, urine and DNA samples will be stored to the appropriate standards in the biorepository (at least 7000 cases). Investigators estimate that will acquire samples at delivery in at least 5000 of these women. For four years, biological samples from women with pre-eclampsia or other adverse outcomes and 2 matched controls will be collected at admission for labour (an additional 3,000 subjects). Objective 4 will initiate pilot studies to identify novel biomarkers, and compare these and other known pathophysiological factors with those from LMIC (Africa, India) and HIC using samples from CoLab. Additional funding will be sought for expansion and validation (e.g. Merck for Mothers). Investigators will also seek funding to address risk stratification in apparently low risk women, based on the samples collected at 28-32 weeks. Objective 5 will promote intellectual interactions and collaboration between the seven centres and CoLab. Ability to understand and cure complex adverse pregnancy outcomes leading to acute and long-range disability in children requires intensive collaboration across usual silos including hospitals and nations. The coordinators anticipate the interaction of investigators and care providers in the seven centres will foster intellectual collaboration and improved standardized care. Brazilian investigators will become members of CoLab, increasing its unique vision, expertise and resources (current data and biological materials from 28 centres). worldwide).

Official Title
-----------------
PREPARE, Prematurity Reduction by Pre-eclampsia Care

Conditions
-----------------
Pre-Eclampsia, Premature Birth

Intervention / Treatment
-----------------
* Diagnostic Test: FullPIERS and sFlit/PLGF (Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: pregnancy before 16 weeks delivery at designed maternity center Exclusion Criteria: not viable fetus

Ages Eligible for Study
-----------------
Minimum Age: 10 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: stepped-wedge cluster-randomised trial in seven clusters
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: INTERVENTION<br>Clinical protocol using FullPIERS and sFlit/PLGF ratio (Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio) | Diagnostic Test: FullPIERS and sFlit/PLGF (Soluble fms-Like Tyrosine Kinase-1-to-Placental Growth Factor Ratio)<br>* Once the centre is randomised to receive the intervention, all eligible women will have serum sFlt1/PlGF measurement performed and fullPIERS assessment and both results will be revealed to the care providers. This will include all women with pre-eclampsia or suspected pre-eclampsia cared for at the main hospital centres (and not be limited to women referred to the hospital from the community health centres). sFlt-1/PlGF will be tested by immunoassays (Roche Platform®). The result read out is provided by specific machines provided by Roche in less than one hour, which permits rapid clinical decision-making. Risk stratification using fullPIERS will be performed on tablet computers using a pre-defined risk scoring system integrated within the MedSciNet database.<br>|
| No Intervention: CONTROL<br>Usual clinic control | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| patients with preterm preeclampsia | proportion of women delivered in the centres with preterm pre-eclampsia (deliveries with preterm pre-eclampsia/ total deliveries), where preterm is <37 weeks' gestation | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| proportion of women delivered in the centers who delivered prematurely | proportion of women delivered with preterm pre-eclampsia/ total deliveries for pre-eclampsia, where preterm is <37 weeks' gestation | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| proportion of women delivered in the centres with preterm pre-eclampsia | proportion of women delivered in the centres with preterm pre-eclampsia (deliveries with preterm pre-eclampsia/ total deliveries), where preterm is <34 weeks' gestation | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| RATE PRETERM PRE-ECLAMPSIA DELIVERIES | proportion of women delivered with preterm pre-eclampsia/ total deliveries for pre-eclampsia, where preterm is <34 weeks' gestation | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| maternal morbidity and mortality defined as a composite of maternal mortality and features of 4a-4f | 4a. HELLP syndrome cases of HELLP syndrome in women with pre-eclampsia 4b. pulmonary oedema cases of pulmonary oedema in women with pre-eclampsia 4c. eclampsia proportion of women with eclampsia 4d. cerebrovascular accident (CVA) cases of maternal cerebrovascular accident (stroke or coma) in women with pre-eclampsia 4e. renal dysfunction cases of renal dysfunction in women with pre-eclampsia, where criteria is serum creatinine of >150 | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| frequency of severe hypertension | systolic BP ≥ 160 mmHg or diastolic BP ≥ 110 mm/Hg | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| placental abruption | cases of placental abruption | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| mode of delivery (total C-sections) | total number of reported C-sections | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| stillbirth | cases of stillbirth at >20 weeks | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| early neonatal mortality | cases of neonatal mortality at <7 days | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 
| admission to the neonatal care unit | cases of admission to the neonatal care unit due to prematurity related to pre-eclampsia | researchers will be assessing and reporting outcome through month 1 to month 34 of the study | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Preterm Infants, Premature Birth, Placenta growth factor, Prenatal Care, PERINATAL MORTALITY, Pre-Eclampsia