PREPARE: protocol for a stepped wedge trial to evaluate whether a risk stratification model can reduce preterm deliveries among women with suspected or confirmed preterm pre-eclampsia.

BACKGROUND: Preeclampsia (PE) is a major cause of short and long-term morbidity for affected infants, including consequences of fetal growth restriction and iatrogenic prematurity. In Brazil, this is a special problem as PE accounts for 18% of preterm births (PTB). In the PREPARE (Prematurity REduction by Pre-eclampsia cARE) study, we will test a novel system of integrated care based on risk stratification and knowledge transfer, to safely reduce PTB. METHODS: This is a stepped wedge cluster randomised trial that will include women with suspected or confirmed PE between 20 + 0 and 36 + 6 gestational weeks. All pregnant women presenting with these findings at seven tertiary centres in geographically dispersed sites, throughout Brazil, will be considered eligible and evaluated in terms of risk stratification at admission. At randomly allocated time points, sites will transition to risk stratification performed according to sFlt-1/PlGF (Roche Diagnostics) measurement and fullPIERS score with both results will be revealed to care providers. The healthcare providers of women stratified as low risk for adverse outcomes (sFlt-1/PlGF ≤38 AND fullPIERS< 10% risk) will receive the recommendation to defer delivery. sFlt-1/PlGF will be repeated once and fullPIERS score twice a week. Rates of prematurity due to preeclampsia before and after the intervention will be compared. Additionally, providers will receive an active program of knowledge transfer about WHO recommendations for preeclampsia, including recommendations regarding antenatal corticosteroids for foetal benefits, antihypertensive therapy and magnesium sulphate for seizure prophylaxis. This study will have 90% power to detect a reduction in PTB associated with PE from a population estimate of 1.5 to 1.0%, representing a 33% risk reduction, and 80% power to detect a reduction from 2.0 to 1.5% (25% risk reduction). The necessary number of patients recruited to achieve these results is 750. Adverse events, serious adverse events, both anticipated and unanticipated will be recorded. DISCUSSION: The PREPARE intervention expects to reduce PTB and improve care of women with PE without significant adverse side effects. If successful, this novel pathway of care is designed for rapid translation to healthcare throughout Brazil and may be transferrable to other low and middle income countries. TRIAL REGISTRATION: ClinicalTrials.gov : NCT03073317.

Creating biobanks in low and middle-income countries to improve knowledge - The PREPARE initiative.

The Millennium Development Goal 5, a project signed in 2000, intended to improve maternal health and reduce maternal mortality by 75% by 2015. Despite all efforts, little progress has been achieved in low and middle-income countries (LMIC) and 99% of all maternal deaths related to pre-eclampsia (PE) still occur in these settings. It is important to determine whether women in LMIC, where PE carries a greater risk than in high-income countries (HIC), have unique risk factors. Some variances may alter the risk, severity and pertinent pathophysiology of PE. We posit based upon this, that women from LMIC may have biomarkers specific to this population. Discovering such specific biomarkers and testing the relevance of biomarkers developed in high-income populations could increase the clinical usefulness of these analyses without increasing cost-effective approaches for prediction of PE. Here we briefly describe our platform to develop the PREPARE - Biobank in tertiary hospitals or basic units for antenatal care from 6 different cities in Brazil. The PREPARE - Biobank has been developed with two arms. The first arm is a cross-sectional study that will collect clinical information and biosamples from more than 1000 women who developed preterm PE. The second arm is a cohort study of 7000 women. It will collect clinical information and longitudinal biosamples from women at three times during pregnancy, <16 weeks, between 28 and 32 weeks and at delivery or diagnosis of adverse outcomes. The biobank will be supported and complemented by a Brazilian database using the CoLab COLLECT Database.

Effect of preeclampsia on blood pressure in newborn very low birth weight infants.

OBJECTIVE: To test the hypothesis that very low birth infants born to mothers with preeclampsia have higher blood pressure over the first week of life than infants whose mothers did not have preeclampsia. METHOD: Infants born at<1,350 g who survived at least one week were stratified by gestational age ( or= 29 completed weeks) and grouped by the presence or absence of preeclampsia. Highest and lowest systolic and mean and diastolic blood pressures were recorded for each of the first seven days of life. Serial blood pressures were analyzed by repeated measures ANOVA: The presence of hypertension (defined as >or= 3 days with the highest systolic blood pressure>90th percentile for gestational age stratum and day-specific range) was analyzed by binary logistic regression. RESULTS: Infants >or= 29 weeks gestational age born to mothers with preeclampsia had higher blood pressures than did controls. Infants or= 29 weeks gestation. The long-term significance of this finding is not known.

Low blood pressure among very-low-birth-weight infants with fetal vessel inflammation.

OBJECTIVE: To test the hypothesis that fetal vessel inflammation (FVI: funisitis and/or fetal vasculitis) is associated with lower blood pressure (BP) over the first week of life and an increased risk of periventricular leukomalacia (PVL) among premature infants. STUDY DESIGN: A total of 255 infants born at <1350 g to normotensive mothers were stratified by gestational age (GA) and grouped by presence/absence of FVI on placental pathology. Daily highest (Hi) and lowest (Lo) systolic BP (BP(sys)), mean BP (BP(mn)) and diastolic BP (BP(dia)) over first 7 days of life were analyzed by repeated measures ANOVA and regression analysis. Cranial ultrasounds were obtained at 2 weeks of life. RESULTS: Infants > or =30 weeks gestation with FVI had lower HiBP(sys), HiBP(mn), HiBP(dia), LoBP(sys), LoBP(mn) and LoBP(dia) (p<0.001) than did infants without FVI. Infants with PVL (all < or =27 weeks gestation) had lower LoBP(mn) and LoBP(dia) (p<0.01) than controls. FVI did not increase the risk of PVL in these infants. CONCLUSION: FVI and PVL are associated with reduced BP over the first week of life.

Hemodynamic disturbances in premature infants born after chorioamnionitis: association with cord blood cytokine concentrations.

Chorioamnionitis and elevated cord blood inflammatory cytokine concentrations are associated with detectable disturbances of systemic and cerebral hemodynamics in premature newborns. Fifty-five infants (25-31 wk gestation) were enrolled. Chorioamnionitis was defined by placental histology. IL-6, IL-1beta, and tumor necrosis factor-alpha were quantified by ELISA. Blood pressure, heart rate, cardiac output, stroke volume, fractional shortening, and middle cerebral artery blood flow velocities were measured at 3 +/- 1 h after birth. Chorioamnionitis was evident in 22 placentas and was associated with increased IL-6 (p < 0.001), IL-1beta (p = 0.035), and heart rate (p = 0.027); and with decreased mean and diastolic blood pressure (p = 0.026 and p = 0.019, respectively). IL-6 concentration correlated inversely with systolic, mean, and diastolic blood pressures. Right ventricular cardiac output was elevated (p = 0.028) in infants with fetal vessel inflammation. Maternal temperature >or=38.0 degrees C and newborn immature-to-total white blood cell ratio >or=0.4 were associated with significant decreases in left ventricular fractional shortening (p = 0.001 and p = 0.005, respectively). Neither chorioamnionitis nor elevated cytokine concentrations were associated with changes in middle cerebral artery Doppler blood flow velocities. Chorioamnionitis and elevated cord blood IL-6 concentrations are associated with decreased blood pressure in premature newborns. Inflammation of the fetal vessels and nonspecific indicators of infection are associated with disturbances in cardiac function. Infants with chorioamnionitis and elevated cytokine concentrations do not manifest changes in cerebral Doppler indices within the first few postnatal hours. We speculate that cytokine-associated systemic hemodynamic disturbances in premature infants born after chorioamnionitis predispose such infants to perinatal brain injury.