Adverse pregnancy outcomes are major health risks to pregnant women and can increase maternal risk for cardiovascular disease. However, clinical risk factors are not always well-correlated with development of adverse pregnancy outcomes. The renin-angiotensin system (RAS) is a hormone system composed of two arms with opposing actions that plays a major role in cardiovascular function in pregnant and non-pregnant individuals. In the current study, we investigated whether the normal activity of the RAS during pregnancy was dysregulated in pregnancies complicated by adverse outcomes. In a retrospective study of 74 women followed prospectively for pregnancy-hypertension and related adverse outcomes, we used a novel mass spectrometry-based methodology to quantify serum concentrations of multiple angiotensin peptides and enzymatic activity of angiotensin-converting enzyme 2 (ACE2) and neprilysin in the first and third trimesters of pregnancy. There were n=46 women meeting the primary endpoint of a composite of adverse outcomes, and n=28 women without pregnancy complications. Serum concentrations of components of the classical RAS, those involved in the formation and action of the main bioactive peptide, angiotensin II, were increased during healthy pregnancy, but markedly suppressed in adverse outcome pregnancies. In contrast, components of the counter-regulatory, or alternative, RAS, such as ACE2, neprilysin, and angiotensin-1-5, were moderately increased in healthy pregnancy but more robustly increased in pregnancies with adverse outcomes. Our results indicate that a shift in the activation of the classical arm to the alternative arm of the RAS portends the development of adverse outcomes of pregnancy.

M. Poglitsch is an employee at Attoquant Diagnostics, a company developing angiotensin-based biomarkers for hypertension. The other authors report no conflicts.

The work was supported in part by a grant from the Kentucky BIRCWH Program, NIDA 5K12DA035150 (RS) and by the Kentucky Childrens Hospital Childrens Miracle Network Research Fund.

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