Aldosterone, maternal volume status and healthy pregnancies: a cycle of differing views

In this month’s issue, Escher et al. [1] suggest that high aldosterone availability during pregnancy, measured as urinary tetra-aldosterone excretion, is associated with lower maternal blood pressure and larger, healthier neonates. The findings are preliminary with more studies required to confirm these authors’ suggestions, but of interest is that these data extend recent observations by this same group that recall past passionate debates concerning the volume status of normal gravidas and those developing preeclampsia. Also, the roles of the renin–angiotensin–aldosterone system (RAS), previously given short-shrift in discussions concerning preeclampsia’s pathogenesis and pathophysiology, have been resurrected by Escher et al.’s current observations and their previous publications, as well [1–4]. All agree that normal pregnancy is characterized by an absolute increment in both extracellular and intravascular volume (by some 6–7 L, at that), but investigators disagree on the meaning of these changes. For some (‘under-fill’ theory) it is an incomplete response to both the systemic vasodilation and markedly increased arterial global compliance characteristic of normal pregnancy, and indeed, the lower blood pressure and markedly stimulated RAS and aldosterone levels that persist during normal pregnancy are consistent with this paradigm. For others, this is an absolute hypervolaemia perhaps due to the higher levels of salt-retaining steroids that accompany gestation (‘overfill’ theory), and to still others, there is a constant resetting of the ‘volumestat’ as pregnancy progresses (‘normal-fill’ theory), the gravida always acting as if her current volume status were ‘normal’. There are data to support each view, detailed elsewhere [5,6], but the formulation popular with the authors of this commentary is that the observed physiologic changes characteristic of normal pregnancy, e.g. vasodilation, low normal blood pressure, increased cardiac output and activated RAS that responds normally to new volume challenges (e.g. salt loading or restrictions), appears consistent with the following formulation. There is an initial primary ‘under-filling’ very early in gestation, with rapid refilling, after which the gravida ‘senses’ her volume status as euvolaemia or ‘normal-fill’ throughout the remainder of her pregnancy [5,6]. There is a need to prove which of these theories of how pregnant women ‘sense’ their volumes is correct, as this should have relevance to designing the appropriate therapeutic approaches. The article of Escher et al. [1] by linking aldosterone availability to larger neonates and better pregnancy outcomes also recalls an older literature whose authors stressed that the magnitude of the increased plasma volume in pregnancy correlated with better fetal outcomes (reviewed in [7,8]). The rest of this commentary focuses on the volume status of preeclamptics and the status of the RAS in this disease. One of the most striking features of normal pregnancy, apparent both by physical examination and by haemodynamic and hormonal measurement, is early and marked vasodilation. The physiologic consequences—greater blood flow to the uteroplacental unit, increased renal blood flow and glomerular filtration rate, lower maternal blood pressure and increased cardiac output—are important accommodations to the growing fetus. Lower serum creatinine concentrations and increased plasma renin and aldosterone levels are some of the laboratory measures generally expected to accompany such physiological adaptations. In preeclampsia, characterized by hypertension and proteinuria after midgestation, the RAS is actually suppressed compared to women with uneventful gestations [5–7], although in most women, plasma renin activity and aldosterone levels are still considerably higher than in those with the non-pregnant state. The RAS is also suppressed in women with chronic hypertension who develop superimposed preeclampsia compared to hypertensive women who do not [9]. This suppression of the RAS occurs despite the fact that plasma volume, increased by ∼1.2 L in normal pregnancy, is lower in preeclampsia, the lowest values observed in women progressing to the convulsive phase of the disease eclampsia [6,10]. Again, and akin to differing interpretations given of the volume changes in normal