Preeclampsia affects 5-8% of all pregnant women and accounts for almost 15% of maternal mortality. Roughly 0.5% of preeclampsia is early onset and occurs at < 34 weeks gestation, thus annually affecting up to 20,000 U.S. women and infants. There is no treatment other than delivery. Expectant management of early onset preeclampsia (EOP) to gain in-utero time for the fetus has been reported; however half of the cases of preterm birth in women with EOP occur due to maternal complications such as development of severe hypertension or other end organ damage. It is believed that preeclampsia originates with shallow trophoblast invasion. This results in activation of the vascular endothelium with subsequent upregulation of soluble fms-tyrosine kinase (sFlt-1); stimulation of endothelin (ET)-1; and activation of ADPR-cyclase leading to potent vasocontriction. Nicotinamide is a water-soluble vitamin that inhibits ADPR-cyclase and thus acts to reduce the downstream effects of sFlt-1 upregulation. Using mouse models of preeclampsia characterized by ET-1 upregulation or abnormal placentation we show that nicotinamide reduces hypertension and proteinuria and increases maternal and fetal survival. Our phase I study of low-dose oral nicotinamide in 10 women with EOP demonstrates safety and tolerability. Building on our preclinical and phase I study findings, the objectives of this proposal are to test the effect of higher dose nicotinamide supplementation in women with EOP on maternal mean arterial pressure (MAP) and further evaluate its safety. Demonstration of beneficial effects of nicotinamide dietary supplementation on maternal BP will be the first evidence to date to support medical treatment of EOP to attempt to delay delivery. Successful completion of this proposal will guide the development of a future clinical study of this low cost, nontoxic dietary supplement for prolonging gestation in EOP. !
Nicotinamide (vitamin B3-amide) is a nontoxic water-soluble amide of vitamin B3 that lowers blood pressure and mortality in a mouse model of preeclampsia, probably via its inhibitory action on ADPR-cyclase. We will test the ability of nicotinamide to lower maternal blood pressure and reduce risk of development of severe hypertension in women with early-onset preeclampsia. Such effects would demonstrate feasibility of studying nicotinamide as a therapeutic in EOP to prolong gestation and reduce medically indicated preterm birth.