Statin Intervention for Severe Early-Onset Placental Insufficiency. (STATIN-PRE Trial)

Preeclampsia (PE) and intrauterine growth restriction (IUGR) arise as clinical manifestations of placental insufficiency. While significant strides have been made in the prevention of PE over the past decade, resulting in a noteworthy decline in its prevalence, both PE and IUGR persist as prominent contributors to peripartum morbidity, major causes of prematurity, and sources of neonatal complications and mortality. In severe instances of PE, the potential for serious complications extends throughout pregnancy and the postpartum period, and both entities have implications on long-term maternal and children cardiovascular risks in later life.

Despite the efforts to generate successful therapeutic strategies aimed to prolong pregnancy and attenuate prematurity-related morbidity, presently, the only effective cure is timely delivery, and pharmacological therapy aims to mitigate tertiary complications such as eclampsia or severe hypertension. PE and IUGR are considered orphan diseases by the European Medicines Agency. Therefore, there is an urgent need to investigate novel drugs aimed to improve maternal and neonatal outcomes and mitigate long term sequels. Between 24 and 28 weeks of pregnancy, every day of prolongation of the pregnancy is followed by a 1-2% reduction of neonatal mortality or severe morbidity.

HMG-CoA reductase inhibitors (HMG-CoA-RI), beyond their lipid-lowering effects, have been shown to improve endothelial function, placental perfusion, have anti-inflammatory and anti-oxidant effects, and up-regulation of angiogenesis with their "pleiotropic effects". These HMG-CoA-RI related beneficial properties suggest their potential protective potential during the acute phase of placental insufficiency and subsequent protection on cardiovascular maternal and fetal programming.

It is our WORKING HYPOTHESIS that 40 mgr of oral administration of pravastatin daily will prolong duration of pregnancy and will provide cardioprotection and additional benefits to both mother and neonates to that afforded by conventional management of PE and IUGR.

FIRST AIM: To assess that daily 40 mgr of oral administration of pravastatin in pregnant individuals with PE and/or IUGR between 24.0 and 29.6 weeks of gestation will prolong duration of pregnancy compared to conventional management.

SECOND AIM: Determine whether pravastatin improve cardiac function, placental perfusion, angiogenesis, total antioxidant status (TAS) and lipid profile during pregnancy and after pregnancy in both mothers and neonates in the intervention group compared to controls.

THIRD AIM: To evaluate changes in genetic expression profile in human tissues after treatment with novel statins' therapy.

FOURTH AIM: To include women's needs and expectations about PE, IUGR and preterm birth and future heath in order to improve the success of the translation into real changes in women and infant health.

Inclusion criteria

• Singleton fetus.
• Between 24+0 to 29+6 weeks of gestation at the inclusion.
• Early-onset severe PE: women with a diagnosis of severe-preterm PE who are candidates for expectant management and have no clinical indication for immediate delivery, based on the clinical assessments of the attending doctors.

And/or

• IUGR: Diagnosis of early onset IUGR according to the SMFM classification with umbilical artery Doppler with absent/reversed diastolic flow; or estimated fetal weight <10th percentile plus pulsatility index (PI) of umbilical artery Doppler >95th percentil.
• Able to give informed consent.

Exclusion criteria

• Established maternal or fetal compromise that necessitated immediate delivery
• Abnormal karyotype, structural abnormalities, or congenital infections.
• Treatment with pravastatin or other statins prior to inclusion.
• Lactose intolerance