An interventional pilot study protocol on the effect of extra virgin olive oil on women with preeclampsia risk.

Background: Preeclampsia (PE), a multisystem and complex disorder diagnosed when maternal hypertension manifests after 20 weeks of gestation with proteinuria, is one of the direct causes of maternal morbidity and mortality, in addition to bleeding and infection. Despite its critical impact, effective preventive dietary interventions are scarce. Oxidative stress and microvascular damage are central to PE pathophysiology. Extra virgin olive oil (EVOO), particularly early harvested EVOO (EVOOEH), is rich in antioxidant compounds and may mitigate these issues. Methods: This randomized, single-masked (investigator and data analysis) interventional pilot study protocol will enroll 156 high-risk pregnant women (8 to 16 weeks of gestation) at Barzilai University Medical Center. Participants will be allocated to two parallel arms: the EVOOEH arm (n=78), receiving 42 mL/day (three tablespoons) of EVOOEH in addition to general Ministry of Health (MOH) dietary recommendations for 4 weeks; and the Control arm (n=78), receiving MOH dietary recommendations only. Low-dose aspirin prophylaxis will be co-administered, if indicated. Adherence will be monitored via phone calls and assessment of maternal whole blood and plasma hydroxytyrosol (HT) at recruitment and approximately four weeks post-intervention initiation. Primary outcomes are incidence of gestational diabetes mellitus (GDM), PE, Cesarean section, preterm birth, and small for gestational age (SGA) newborns. Secondary outcomes include post-intervention maternal 1-hour glucose challenge test (GCT) and serum ratio of soluble fms-like tyrosine kinase 1 to placental growth factor (sFlt-1/PlGF), as well as maternal blood pressure, gestational age at delivery, and newborn percentile. Blood samples will be analyzed for serum 25-hydroxyvitamin D [25(OH)D], sFlt-1/PlGF ratio and HT. Statistical analysis will include use of JMP Pro software, with compared by chi-squared or Fisher's exact tests for categorical variables and Student's t-tests or Wilcoxon rank-sum tests for continuous variables when appropriate. Multivariate analyses will be performed for significant variables. Discussion: This pilot study will provide crucial insights into the potential of EVOOEH as a dietary intervention for reducing PE risk in high-risk pregnancies, addressing a significant gap in current preventive strategies. This protocol study findings can inform larger-scale trials and contribute to evidence-based nutritional recommendations for PE prevention. Trial Registration: This study was registered on ClinicalTrials.gov (NCT06759545).