Of mice and women: Statins as a potential treatment to prevent preeclampsia in antiphospholipid syndrome.

Pregnancy complications in antiphospholipid syndrome APS have been associated with placental insufficiency. While in vitro and ex vivo studies suggest that the placenta is the main target organ in obstetric APS, in vivo data was missing. Using 111In labelled antiphospholipid antibodies (aPL) and single photon emission computed tomography we identified the placenta as the main organ target in a new mouse model of obstetric APS that closely resembles the clinical scenario. The cause of placental insufficiency in APS was attributed to the procoagulant effects of aPL antibodies. However, we demonstrated that APS is a proinflammatory syndrome. Based on our previous findings on the crucial role of complement activation in placental mal perfusion in APS, we developed an MRI-based method in which anti-complement C3-targeted ultrasmall superparamagnetic iron oxide (USPIO) nanoparticles were used for the noninvasive detection of complement activation in placenta in utero. C3 deposition was detected in the placenta using this novel method, confirming the role of inflammation in obstetric APS. Management of obstetric APS is based on attenuating the procoagulant state. In many cases, however, there is no evidence of decidual thrombosis and instead inflammatory signs are present. Current treatment fails in a significant number of pregnancies- raising the need to explore other therapies to improve obstetrical outcome. Based on our preclinical studies in which pravastatin prevented adverse pregnancy outcomes in mouse models of preeclampsia and APS we performed translational studies in women. Our aim was to investigate the clinical use of pravastatin in APS women refractory to classical treatment LDA+LMWH that developed PE and/or severe IUGR. Eleven pregnant women with APS that developed PE or severe IUGR despite conventional antithrombotic therapy were treated with pravastatin (20mg/day) when signs of placental insufficiency (PE, IUGR) were observed. After pravastatin addition, placental blood flow and maternal symptoms of PE improved significantly leading to live birth in 100% of the patients. The beneficial effects of pravastatin were observed as early as 10 days, with a mean response time of 14.08 ± 3.25. Pregnancies survived 14 weeks [IQR 12–15] in patients cotreated with pravastatin. In this group. all babies were born close to term and alive and are now healthy while the neonates in the group that did not receive pravastatin experienced still births, preterm birth, were admitted at NICU and some of tem showed developmental abnormalities. Our study indicates that the addition of pravastatin at the time of onset of PE or severe IUGR to conventional treatment is worthy of further assessment in the management of women with APS and preeclampsia. RCT should be organized to confirm these observations.