Pravastatin and-L-arginine combination improves umbilical artery blood flow and neonatal outcomes in dichorionic twin pregnancies through an nitric oxide-dependent vasorelaxant effect

Abstract

The increase in fetal and neonatal morbidity and mortality associated with twin pregnancies correlates with an increased risk of preterm delivery, low birth weight, and intrauterine growth restriction (IUGR). Although the pathogenesis of IUGR is unclear and thus management remains a major challenge, feto-placental blood vessels are compromised, and altered umbilical blood flow is observed. In this pilot observational study we investigated the effects of pravastatin plus l-arginine on umbilical artery (umb art) blood flow. Between 2013 and 2016, five women received daily doses l-arginine and pravastatin when an umb art pulsatility index above limits for gestational age was observed and concerns about selective growth restrictions arose. All patients showed selective absent or reversed end-diastolic umbilical artery Doppler flow (AREDV) associated with increased perinatal mortality. Pravastatin (PRAV) plus l-arginine (l-Arg) treatment diminished umb art resistance significantly and allowed pregnancy to continue. No signs of acidosis or hypoxia, normal cardiotocography tracing, normal fetal movement and fetal weight gain were observed in the twins that showed abnormal umb art Dopplers. All neonates were born around 33 weeks (median 33 weeks, IQR [31.4-33.0]), thus diminishing substantially the chances for any prematurity-associated adverse neonatal outcomes. The infants now show normal growth and development. In in vitro studies, pravastatin induced relaxation of aortic rings. Murine studies identified were performed to investigate the mechanism behind PRAV+L-Arg beneficial effects. A nitric oxide (NO)-dependent synergistic vasorelaxant effect of PRAV+L-Arg was demonstrated using aortic rings. Increased levels of placental NO and increased synthesis of eNOS in placental endothelial cells were observed in mice treated with PRAV+L-Arg compared to untreated mice and mice treated with PRAV- or L-Arg alone. This study suggests that PRAV plus L-Arg might be a good therapeutic option to improve blood flow in umbilical arteries prolonging pregnancy and improving pregnancy outcomes in twins. A RCT should be organized to confirm these results.

Evaluating the Effect of Pravastatin in Early-Onset Fetal Growth Restriction: A Nonrandomized and Historically Controlled Pilot Study

“…6,21,26 The severity of Doppler findings and its progression over time is also related to poorer pregnancy prognosis. 21,27 In previous studies, pravastatin proved to induce better feto-placental circulation assessed by Doppler 16,28 ; however, in the present study, no significant improvement in Doppler parameters could be observed.…”

Placental nitric oxide formation and endothelium‐dependent vasodilation underlie pravastatin effects against angiogenic imbalance, hypertension in pregnancy and intrauterine growth restriction

“…Consequently, increases in placental NO caused by pravastatin resulted in adequate blood supply into foeto‐maternal interface; thus, NO allowed foeto‐placental development because it protected against unappropriated remodelling of the maternal uteroplacental vasculature induced by hypertensive pregnancy and that caused foeto‐placental growth restriction . Therefore, we believe that the effects of NO signalling may be due to their general effects on angiogenesis, endothelial cell growth, endothelium‐dependent vasodilation, vasculogenesis and placental development …”

“…Pravastatin has shown protective effects during foetal development in gestational hypertension in animals . In addition, in humans, pravastatin effects involved augmented levels of vasodilator NO that prevented the onset of pre‐eclampsia and attenuated the intrauterine growth restriction . However, these cholesterol‐independent mechanisms due to pravastatin have not yet been fully clarified in hypertensive disorders of pregnancy correlated with foetal growth restriction.…”

Pravastatin Improves Angiogenic Factors and Feto- Placental Doppler in Pregnancy with Early Severe Fetal Growth Restriction: A Case Report

“…Some studies suggest that statins could be a promising therapeutic or preventive strategy for placental insufficiency [8,9]. Significant clinical benefits and improvement in the angiogenic profile have been reported in patients with early-onset preeclampsia [10] and umbilical artery flow in twin pregnancies with discordant fetal growth seems to improve after pravastatin is started [11]; however, no previous studies reported the effect of pravastatin on the uterine artery Doppler and angiogenic factors of FGR single pregnancies in humans.…”