Preeclampsia has two phenotypes which require different treatment strategies

The opinion on the mechanisms underlying the pathogenesis of preeclampsia still divides scientists and clinicians. This common complication of pregnancy has long been viewed as a disorder linked primarily to placental dysfunction, which is caused by abnormal trophoblast invasion, however, evidence from the previous two decades has triggered and supported a major shift in viewing preeclampsia as a condition that is caused by inherent maternal cardiovascular dysfunction, perhaps entirely independent of the placenta. In fact, abnormalities in the arterial and cardiac functions are evident from the early subclinical stages of preeclampsia and even before conception. Moving away from simply observing the peripheral blood pressure changes, studies on the central hemodynamics reveal two different mechanisms of cardiovascular dysfunction thought to be reflective of the early-onset and late-onset phenotypes of preeclampsia. More recent evidence identified that the underlying cardiovascular dysfunction in these phenotypes can be categorized according to the presence of coexisting fetal growth restriction instead of according to the gestational period at onset, the former being far more common at early gestational ages. The purpose of this review is to summarize the hemodynamic research observations for the two phenotypes of preeclampsia. We delineate the physiological hemodynamic changes that occur in normal pregnancy and those that are observed with the pathologic processes associated with preeclampsia. From this, we propose how the two phenotypes of preeclampsia could be managed to mitigate or redress the hemodynamic dysfunction, and we consider the implications for future research based on the current evidence. Maternal hemodynamic modifications throughout pregnancy can be recorded with simple-to-use, noninvasive devices in obstetrical settings, which require only basic training. This review includes a brief overview of the methodologies and techniques used to study hemodynamics and arterial function, specifically the noninvasive techniques that have been utilized in preeclampsia research.

Introduction

Classical obstetrical teaching characterizes preeclampsia as a single pathophysiological entity with the defining features of hypertension in association with proteinuria,¹ however, more recent definitions also include presentation with acute maternal kidney damage, abnormal liver function, neurologic impairment, pulmonary edema, hemolysis, thrombocytopenia, or fetal growth restriction (FGR).² The goal of therapy is to reduce the blood pressure with vasodilator drugs and in severe preeclampsia, in which there is a risk of pulmonary edema because of endothelial dysfunction, to prevent intravascular fluid overload by limiting fluid intake. This approach presupposes that preeclampsia is associated with both vasoconstriction and increased intravascular volume. From a mechanistic or physiological point of view, these two abnormalities are unlikely to coexist in the same person: it is more likely that a vasoconstricted state would exist with a depleted intravascular volume, and that increased intravascular fluid would exist with a relative state of vasodilatation. In fact, emerging evidence since the early 2000s suggests that preeclampsia may be caused by two opposing mechanisms that are represented by these two extremes.

Early-onset preeclampsia is associated with a low cardiac output and high vascular resistance,³ and women with this condition are at risk of cardiovascular dysfunction categorized as heart failure many months after delivery.⁴ These findings are in contrast with those of Easterling et al⁵ who found that women with preeclampsia had a higher cardiac output than healthy women in a longitudinal study. These apparently contradictory findings have been explained by the gestational age at the onset of preeclampsia, with the early-onset (before 34 weeks of gestation) condition being attributed to a low cardiac output, high vascular resistance, and a depleted intravascular fluid state and late-onset preeclampsia being associated with a high cardiac output, normal or low vascular resistance, and an intravascular fluid overload. More recently, work conducted by our group in women who were studied between 24 and 40 weeks of gestation, in which all of the cardiovascular measurements were adjusted for the gestational age at onset of the condition, suggested that the real distinction is between preeclampsia with FGR and preeclampsia with a normal sized fetus.⁶ FGR occurs more in conjunction with early-onset preeclampsia,⁷ less with late-onset preeclampsia. With a diagnosis of FGR, the maternal effects are similar to those observed in cases in which preeclampsia coexists with FGR (Figure 1) at any gestational age. Therefore, we suggest that the real distinction between the two forms of preeclampsia is less whether the condition has an early or a late onset and more whether the condition is associated with FGR or not. These findings have major implications for our understanding of the condition and better explain the clinical observation that therapies that work for one woman do not work for another. For example, fluid restriction and administration of the negative chronotrope labetalol (which may depress cardiac output) is unlikely to improve the clinical condition of a woman with intravascular volume depletion and a low cardiac output, nor will it improve the uteroplacental circulation and the fetal condition, however, this management is hardwired into most protocols for the management of preeclampsia across the world.