Endogenous digitalis-like factor(s), originally proposed as a
vasoconstrictor natriuretic hormone, was discovered in fetal and neonatal blood accidentally because it cross-reacts with antidigoxin
antibodies (ADAs). Early studies using immunoassays with ADA identified the
digoxin-like immuno-reactive factor(s) (EDLF) in maternal blood as well, and suggested it originated in the feto-placental unit. Mammalian
digoxin-like factors have recently been identified as at least two classes of
steroid compounds, plant derived ouabain (O), and several toad derived bufodienolides, most prominent being
marinobufagenin (MBG). A synthetic pathway for MBG has been identified in mammalian placental tissue. Elevated maternal and fetal EDLF, O and MBG have been demonstrated in
preeclampsia (PE), and inhibition of red cell membrane
sodium, potassium ATPase (Na, K
ATPase (NKA)) by EDLF is reversed by ADA fragments (ADA-FAB). Accordingly, maternal administration of a commercial ADA-
antibody fragment (FAB) was tested in several anecdotal cases of PE, and two, small randomized, prospective, double-blind clinical trials. In the first randomized trial, ADA-FAB was administered post-partum, in the second antepartum. In the post-partum trial, ADA-FAB reduced use of
antihypertensive drugs. In the second trial, there was no effect of ADA-FAB on blood pressure, but the fall in maternal
creatinine clearance (CrCl) was prevented. In a secondary analysis using the pre-treatment maternal level of circulating Na, K
ATPase (NKA) inhibitory activity (NKAI), ADA-FAB reduced the incidence of
pulmonary edema and, unexpectedly, that of severe neonatal intraventricular
hemorrhage (IVH). The fall in CrCl in patients given placebo was proportional to the circulating level of NKAI. The implications of these findings on the pathophysiology of the clinical manifestations PE are discussed, and a new model of the respective roles of placenta derived anti-angiogenic (AAG) factors (AAGFs) and EDLF is proposed.