Reply: Preeclampsia has 2 phenotypes that require different treatment strategies

Abstract

We thank Drs Jha and Jha for the points they raised in relation to our Expert Review. 1 Their fundamental point is that the underlying causes of the cardiovascular changes in preeclampsia are complex, and the sequence of the changes are incompletely understood; in this we concur. The authors take issue with our comment "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," arguing that "a combination of low cardiac output and increased vascular resistance may not necessarily be a volume-depleted state." The key distinction here is that both the intravascular and the extravascular fluids contribute to what Jha and Jha refer to as "volume." We agree that an increase in the extravascular fluid may occur together with increased peripheral resistance in a low cardiac output state, particularly in the latent phase of early-onset preeclampsia. Hence our statement on preeclampsia with fetal growth restriction (FGR) that, "Early-onset preeclampsia with FGR presents with high peripheral vascular resistance from the first trimester onward, which is associated with a failure to adequately increase the cardiac output from the first to the second trimester. The latter is most likely caused by the extravasation of the intravascular fluids into the inter-stitium, as is illustrated by the high volume of extracellular water that is already present in the first trimester of early-onset preeclampsia." Drs Jha and Jha state that "Notably, none of the studies has ever reported intravascular volume depletion in early-onset preeclampsia." Although these studies are difficult to undertake in pregnancy for the reasons that the authors state, an increase in the total body water in preeclampsia has been described to happen in association with a reduced cardiac output, implying that an increased extravascular compartment and a fluid-depleted intravascular compartment are associated with vasocontriction. 2,3 It is possible for intravascular fluid depletion to coexist with vasoconstriction in a relatively "over-filled" vascular compartment; hence the propensity of women with severe preeclampsia to develop pulmonary edema. Furthermore, Scholten and others have reported a low intra-vascular volume in formerly preeclamptic patients, most of whom had early-onset preeclampsia, and its association of this with later hypertension 4 ; they also reported that a low plasma volume after preeclampsia is associated with concentric remodeling of the heart and a higher pressure. 5 We agree that both volume depletion and/or a reduction in cardiac contractility could lead to a low cardiac output; in this Expert Review we describe the measures of cardiac output and not cardiac contractility. Nevertheless, we and others report consistent findings showing the differences in respect of cardiac output and vascular resistance in late and early preeclampsia (the latter perhaps defined more appropriately as "preeclampsia with fetal growth restriction") 6 , and these differences should not be ignored whatever the etiology. We note Drs Jha and Jha's comments in relation to the interrelationship between the vascular resistance, intra-vascular volume, cardiac output, and the systolic and dia-stolic blood pressure in the different phenotypes and their suggestion that vascular-endothelial dysfunction may be similar. Indeed, we and others have shown that a similar level of vascular-endothelial dysfunction exists in both the phenotypes of preeclampsia as measured by the arterial augmentation index and pulse wave velocity 6 and that the maternal cardiovascular function may itself modulate fetal Doppler changes. 7 Drs Jha and Jha assert that "Suggesting a management strategy without a detailed understanding of the sequence of cardiovascular events may be counterproductive." The following is the situation that currently exists in the clinical sphere: the choice of antihypertensive drugs and fluid management is reactive, being based almost exclusively on local customs or guidelines and focused on targeting blood pressure control rather than on an assessment of the parameters that determine blood pressure. What we do know in respect of the sequence is that, the cardiac output is lower and the vascular resistance is higher before conception in healthy women who later develop preeclampsia and/or FGR. 8 Hence, despite our understanding of the cardiovascular changes in preeclampsia and their sequence remaining imperfect, our suggestion that "Comprehensive hemodynamic assessment of women with preeclampsia in addition to ultrasound and Doppler investigations of the fetus can guide a rational choice of antihy-pertensive and fluid management strategies in preeclampsia" must represent an improvement on the blind use of therapies in women who may be very unwell with compromised cardio-vascular function.