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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.

      Key words

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      Introduction

      Classical obstetrical teaching characterizes preeclampsia as a single pathophysiological entity with the defining features of hypertension in association with proteinuria,
      • Perry I.J.
      • Beevers D.G.
      The definition of pre-eclampsia.
      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).
      • Brown M.A.
      • Magee L.A.
      • Kenny L.C.
      • et al.
      Hypertensive disorders of pregnancy: ISSHP classification, diagnosis, and management recommendations for international practice.
      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,
      • Valensise H.
      • Vasapollo B.
      • Gagliardi G.
      • Novelli G.P.
      Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease.
      and women with this condition are at risk of cardiovascular dysfunction categorized as heart failure many months after delivery.
      • Melchiorre K.
      • Sutherland G.R.
      • Liberati M.
      • Thilaganathan B.
      Preeclampsia is associated with persistent postpartum cardiovascular impairment.
      These findings are in contrast with those of Easterling et al
      • Easterling T.R.
      • Benedetti T.J.
      • Schmucker B.C.
      • Millard S.P.
      Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study.
      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.
      • Tay J.
      • Foo L.
      • Masini G.
      • et al.
      Early and late preeclampsia are characterized by high cardiac output, but in the presence of fetal growth restriction, cardiac output is low: insights from a prospective study.
      FGR occurs more in conjunction with early-onset preeclampsia,
      • Lees C.
      • Marlow N.
      • Arabin B.
      • et al.
      TRUFFLE Group
      Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE).
      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.
      Figure thumbnail gr1
      Figure 1Schematic representation of changes in the cardiac parameters and arterial function in PE, FGR, or the combination of both complications
      • Easterling T.R.
      • Benedetti T.J.
      • Schmucker B.C.
      • Millard S.P.
      Maternal hemodynamics in normal and preeclamptic pregnancies: a longitudinal study.
      FGR, fetal growth restriction; PE, preeclampsia.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.

      Lessons From Adult Hypertension

      The fact that two phenotypes of preeclampsia exist with diametrically opposite cardiovascular characteristics may not be so surprising when set against evidence gleaned from hypertension outside of pregnancy. Adult hypertension was viewed as a single pathophysiological disorder caused by an elevated peripheral vascular resistance. However, it is now appreciated that the hemodynamics underlying essential hypertension are more complex, and that it can be divided broadly into 3 basic groups. Phenotypically, these groups differ in the age of onset and the pattern of blood pressure elevation––systolic, diastolic, or systolic and diastolic.
      • Franklin S.S.
      • Gustin 4th, W.
      • Wong N.D.
      • et al.
      Hemodynamic patterns of age-related changes in blood pressure. The Framingham Heart Study.
      The prevalence of hypertension is strongly age-related, varying from approximately 5% in patients under the age of 30 years to 90% in those aged more than 90 years. Elevation only in the systolic blood pressure (isolated systolic hypertension) is the most common presentation in young people and those aged more than 60 years, whereas elevated systolic and diastolic pressure (mixed hypertension) predominates in the patients aged between 30 and 60 years. Blood pressure is most commonly considered to be the product of the cardiac output and peripheral vascular resistance and is presented as follows:
      Mean arterial pressure=cardiac output×peripheral vascular resistance
      Detailed hemodynamic studies in the 1960s and 1970s
      • Frohlich E.D.
      • Ulrych M.
      • Tarazi R.C.
      • Dustan H.P.
      • Page I.H.
      A hemodynamic comparison of essential and renovascular hypertension. Cardiac output and total peripheral resistance: supine and tilted patients.
      clearly demonstrated that mixed hypertension in middle-aged individuals is predominantly associated with elevated peripheral vascular resistance. This is thought to be caused by resistance vessel remodeling,
      • Folkow B.
      Structure and function of the arteries in hypertension.
      and is effectively irreversible. Conversely, the cardiac output is normal or slightly low.
      Young individuals with isolated systolic hypertension mainly have an elevated cardiac output, with a low or normal peripheral vascular resistance.
      • McEniery C.M.
      • Yasmin W.S.
      • Wallace S.
      • et al.
      Increased stroke volume and aortic stiffness contribute to isolated systolic hypertension in young adults.
      Interestingly, Julius
      • Julius S.
      Transition from high cardiac output to elevated vascular resistance in hypertension.
      hypothesized that hypertension may actually start as a high-output cardiac state, and that the need to limit tissue perfusion may lead to changes in the resistance vessels and thus a transformation into a high-resistance, low-output cardiac state. Data from a study by Lund-Johansen
      • Lund-Johansen P.
      Hemodynamics in early essential hypertension.
      many years before, support this transitional hypothesis. It also raises the possibility that intervention during the high-output stages of hypertension may prevent resistance vessel remodeling, and thus the development of fixed hypertension, which requires life-long therapy.
      In contrast to the observations in younger hypertensives, the main hemodynamic abnormality in older individuals with isolated systolic hypertension is increased aortic stiffness
      • Yasmin
      • McEniery C.M.
      • Wallace S.
      • et al.
      Matrix metalloproteinase-9 (MMP-9), MMP-2, and serum elastase activity are associated with systolic hypertension and arterial stiffness.
      rather than an elevated resistance or cardiac output. The human aorta contains a large proportion of elastin, which allows it to buffer the cyclical changes in pressure caused by the intermittent left ventricular ejection of blood into the arterial tree. This phenomenon makes the cardiovascular system more efficient, minimizes peak (systolic) pressure, and maintains a diastolic pressure. Pulse pressure (the difference between the systolic and diastolic pressures) is related to the aortic stiffness and stroke volume as follows:
      Pulse pressure≅aortic stiffness×stroke volume
      The aorta progressively stiffens with age
      • Avolio A.P.
      • Deng F.Q.
      • Li W.Q.
      • et al.
      Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in China.
      owing to the mechanical degeneration of the elastin fibers and other processes such as calcium deposition. For reasons that are not fully understood, this seems to be exaggerated or accelerated in some individuals and gives rise to a widened pulse pressure and thus systolic hypertension.
      • McEniery C.M.
      • Wilkinson I.B.
      The pressures of aging.

      A Possible Latent Phase in Preeclampsia

      Pregnancy is a condition of physiological expansion in the volume of noncirculating and circulating body fluid. This expansion in volume is a potential stressor for the maternal cardiovascular system, as illustrated by those women who show cardiac signs of volume overload during an uncomplicated third trimester.
      • Melchiorre K.
      • Sharma R.
      • Khalil A.
      • Thilaganathan B.
      Maternal cardiovascular function in normal pregnancy: evidence of maladaptation to chronic volume overload.
      This is associated with a rise in the cardiac output from the second trimester to a plateau at term and with a decrease in the peripheral vascular resistance to a nadir in the early third trimester.
      • Andreas M.
      • Kuessel L.
      • Kastl S.P.
      • et al.
      Bioimpedance cardiography in pregnancy: a longitudinal cohort study on hemodynamic pattern and outcome.
      The change in cardiac output during gestation has recently been shown to be a strong determinant of birthweight,
      • Mahendru A.A.
      • Foo F.L.
      • McEniery C.M.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      Change in maternal cardiac output from preconception to mid-pregnancy is associated with birth weight in healthy pregnancies.
      with a higher cardiac output being associated with larger babies, and the converse also being true. In the latent phase of preeclampsia, longitudinal observations from the first trimester to term have shown 3 different patterns of evolutions of the cardiac output and peripheral vascular resistance. Early-onset preeclampsia with FGR presents with high peripheral vascular resistance from the first trimester onward,
      • Rang S.
      • van Montfrans G.A.
      • Wolf H.
      Serial hemodynamic measurement in normal pregnancy, preeclampsia, and intrauterine growth restriction.
      which is associated with a failure to adequately increase the cardiac output from the first to the second trimester.
      • Rang S.
      • van Montfrans G.A.
      • Wolf H.
      Serial hemodynamic measurement in normal pregnancy, preeclampsia, and intrauterine growth restriction.
      ,
      • Gyselaers W.
      • Vonck S.
      • Staelens A.S.
      • et al.
      Gestational hypertensive disorders show unique patterns of circulatory deterioration with ongoing pregnancy.
      The latter is most likely caused by extravasation of the intravascular fluids into the interstitium, as is illustrated by the high volume of extracellular water that is already present in the first trimester of early-onset preeclampsia.
      • Gyselaers W.
      • Vonck S.
      • Staelens A.S.
      • et al.
      Body fluid volume homeostasis is abnormal in pregnancies complicated with hypertension and/or poor fetal growth.
      It is important to mention that women who develop this type of preeclampsia already show low cardiac output and high peripheral vascular resistance before conception.
      • Rang S.
      • van Montfrans G.A.
      • Wolf H.
      Serial hemodynamic measurement in normal pregnancy, preeclampsia, and intrauterine growth restriction.
      ,
      • Foo F.L.
      • Mahendru A.A.
      • Masini G.
      • et al.
      Association Between prepregnancy cardiovascular function and subsequent preeclampsia or fetal growth restriction.
      Some women who develop a low cardiac output with high vascular resistance phenotype of preeclampsia in the late third trimester initially showed a high cardiac output and low peripheral vascular resistance in the first trimester, which subsequently converted to the low output with high vascular resistance circulation state during the course of the pregnancy.
      • Bosio P.M.
      • McKenna P.J.
      • Conroy R.
      • O’Herlihy C.
      Maternal central hemodynamics in hypertensive disorders of pregnancy.
      During this crossover, a short temporary state of “apparently normal” cardiovascular function is present. One explanation for this evolution is an endothelial dysfunction triggered by an intravascular overload with a subsequent increase in the vascular tone (peripheral vascular resistance) and a decrease in the cardiac output, as observed in pregnant women with obesity during an uncomplicated third trimester pregnancy.
      • Vonck S.
      • Lanssens D.
      • Staelens A.S.
      • et al.
      Obesity in pregnancy causes a volume overload in third trimester.
      Endothelial dysfunction caused by intravascular volume overload has been documented in nonpregnant individuals during hemodialysis
      • Mitsides N.
      • Cornelis T.
      • Broers N.J.H.
      • et al.
      Extracellular overhydration linked with endothelial dysfunction in the context of inflammation in haemodialysis dependent chronic kidney disease.
      and acute heart failure.
      • Colombo P.C.
      • Onat D.
      • Sabbah H.N.
      Acute heart failure as ”acute endothelitis”—interaction of fluid overload and endothelial dysfunction.
      For late-onset preeclampsia, frequently seen in women with obesity, high-output circulation is seen throughout all the stages of pregnancy, including the clinical stage of late-onset preeclampsia, during delivery, and postpartum
      • Easterling T.R.
      • Benedetti T.J.
      Preeclampsia: a hyperdynamic disease model.
      (Figure 2). The dual etiology of preeclampsia suggested by these two different evolutions of cardiovascular function in the latent phases of the disease is supported by the observation of bimodal skewing in the distribution of birthweight, with a higher prevalence of neonates who are either small or large for gestational age
      • Verlohren S.
      • Melchiorre K.
      • Khalil A.
      • Thilaganathan B.
      Uterine artery Doppler, birth weight and timing of onset of pre-eclampsia: providing insights into the dual etiology of late-onset pre-eclampsia.
      in women with preeclampsia.
      Figure thumbnail gr2
      Figure 2The longitudinal changes in cardiac output and peripheral resistance
      Longitudinal changes in cardiac output and peripheral resistance expressed as a product of 12-week measurements, reported in normal pregnancies,
      • Andreas M.
      • Kuessel L.
      • Kastl S.P.
      • et al.
      Bioimpedance cardiography in pregnancy: a longitudinal cohort study on hemodynamic pattern and outcome.
      early-onset preeclampsia,
      • Gyselaers W.
      • Vonck S.
      • Staelens A.S.
      • et al.
      Gestational hypertensive disorders show unique patterns of circulatory deterioration with ongoing pregnancy.
      late-onset preeclampsia type I (crossover),
      • Bosio P.M.
      • McKenna P.J.
      • Conroy R.
      • O’Herlihy C.
      Maternal central hemodynamics in hypertensive disorders of pregnancy.
      and late-onset preeclampsia type II (high-output).
      • Easterling T.R.
      • Benedetti T.J.
      Preeclampsia: a hyperdynamic disease model.
      Adapted from Gyselaers.
      • Gyselaers W.
      Preeclampsia is a syndrome with a cascade of pathophysiologic events.
      PE, preeclampsia.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.

      Cardiovascular Physiology in Pregnancy

      To understand the different patterns of pathologic modifications in the maternal cardiovascular function in complicated pregnancies, it is useful to summarize the expected changes in a healthy pregnancy. From the very early stages of gestation, the maternal cardiovascular system experiences major changes in the different parameters, and these modifications are the key for a successful and uncomplicated pregnancy. Different parameters can show an increase or decrease, which varies in magnitude depending on the parameter itself and the gestational age. The most important changes to consider involve blood volume expansion, central hemodynamics, modifications in the cardiac mass, and arterial vascular function.
      As has been mentioned, pregnancy, above all, is a condition of prolonged maternal blood volume overload, particularly in the third trimester. Compared with prepregnancy, the blood volume increases by 40% at term, mainly because of a 45% to 55% increase in the plasma volume and a 20% to 30% increase in the erythrocyte mass.
      • Longo L.D.
      Maternal blood volume and cardiac output during pregnancy: a hypothesis of endocrinologic control.
      Modification to the central hemodynamics and in the cardiac structure are strongly connected with these changes.
      Arguably the most informative hemodynamic parameter is cardiac output, which reflects the growing demand of the cardiovascular system during gestation, and, as such, it starts to increase soon after the beginning of pregnancy.
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      The magnitude and trend of this increase have been described recently in a meta-analysis by Meah et al
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      who showed that the cardiac output increases by 15% in the first trimester when compared with the prepregnancy value, then peaks in the early third trimester to 31% higher than the prepregnancy value (+1.5 L/min), and then decreases by 6% in the late third trimester. These results were obtained from the analysis of both cross-sectional and longitudinal studies, but most of them lacked prepregnancy measurements of the same subjects and not all of them were performed using the same technique. Studies in which women were recruited before pregnancy and subsequently followed throughout pregnancy generally included only a few subjects (8–69), and reported contrasting results about the magnitude of change (17%–49% above the prepregnancy value) and the gestational age at the peak of cardiac output (12–38 weeks of gestation).
      • Atkins A.F.J.
      • Watt J.M.
      • Milan P.
      • Davies P.
      • Crawford J.S.
      A longitudinal study of cardiovascular dynamic changes throughout pregnancy.
      • Capeless E.L.
      • Clapp J.F.
      Cardiovascular changes in early phase of pregnancy.
      • Robson S.C.
      • Hunter S.
      • Boys R.J.
      • Dunlop W.
      Serial study of factors influencing changes in cardiac output during human pregnancy.
      • Clapp 3rd, J.F.
      • Capeless E.
      Cardiovascular function before, during, and after the first and subsequent pregnancies.
      • Spaanderman M.E.A.
      • Meertens M.
      • van Bussel M.
      • Ekhart T.H.A.
      • Peeters L.L.H.
      Cardiac output increases independently of basal metabolic rate in early human pregnancy.
      • Lof M.
      • Olausson H.
      • Bostrom K.
      • Janerot-Sjöberg B.
      • Sohlstrom A.
      • Forsum E.
      Changes in basal metabolic rate during pregnancy in relation to changes in body weight and composition, cardiac output, insulin-like growth factor I, and thyroid hormones and in relation to fetal growth.
      • Ogueh O.
      • Brookes C.
      • Johnson M.R.
      A longitudinal study of the maternal cardiovascular adaptation to spontaneous and assisted conception pregnancies.
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      • Petersen J.W.
      • Liu J.
      • Chi Y.Y.
      • et al.
      Comparison of multiple non-invasive methods of measuring cardiac output during pregnancy reveals marked heterogeneity in the magnitude of cardiac output change between women.
      • Masini G.
      • Foo L.F.
      • Cornette J.
      • et al.
      Cardiac output changes from prior to pregnancy to post partum using two non-invasive techniques.
      Our group, using different methodologies, recently reported that a rise in the peak cardiac output occurred earlier and more modestly than previously thought (+1.05 L/min or 17.5% above the prepregnancy value at 15.2 weeks’ gestation as measured using the inert gas rebreathing technique; +0.47 L/min or 7.7% above the prepregnancy value at 10.4 weeks’ gestation as measured using the pulse wave velocity).
      • Masini G.
      • Foo L.F.
      • Cornette J.
      • et al.
      Cardiac output changes from prior to pregnancy to post partum using two non-invasive techniques.
      As the product of stroke volume and heart rate, the cardiac output increase is driven more by the progressive rise in the heart rate, which peaks in the third trimester (20%–24% higher than the prepregnancy value), than stroke volume (13% increase from the prepregnancy value in the second trimester).
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      ,
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      ,
      • Osman M.W.
      • Nath M.
      • Khalil A.
      • Webb D.R.
      • Robinson T.G.
      • Mousa H.A.
      Longitudinal study to assess changes in arterial stiffness and cardiac output parameters among low-risk pregnant women.
      The decrease in the peripheral vascular resistance with gestational age is associated with a reduction in the uterine artery and fetal umbilical Doppler impedance.
      • Tay J.
      • Masini G.
      • McEniery C.M.
      • et al.
      Uterine and fetal placental Doppler indices are associated with maternal cardiovascular function.
      ,
      • Masini G.
      • Tay J.
      • McEniery C.M.
      • et al.
      Maternal cardiovascular dysfunction is associated with hypoxic cerebral and umbilical Doppler changes.
      This is detectable from the early stages of pregnancy and is driven by vasodilatory mediators. The peripheral vascular resistance inversely reflects the changes in the cardiac output, progressively decreasing until the third trimester when the lowest value of 30% below the prepregnancy level is reached and then showing a slight increase until term.
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      ,
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      ,
      • Petersen J.W.
      • Liu J.
      • Chi Y.Y.
      • et al.
      Comparison of multiple non-invasive methods of measuring cardiac output during pregnancy reveals marked heterogeneity in the magnitude of cardiac output change between women.
      Despite the increase in the cardiac output, the offset by the increased vascular compliance, and decrease in the peripheral vascular resistance, the mean arterial pressure shows a nadir in the second trimester (−9% from before the pregnancy) and a gradual return to prepregnancy levels near term
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      ,
      • Clapp 3rd, J.F.
      • Capeless E.
      Cardiovascular function before, during, and after the first and subsequent pregnancies.
      ,
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      ,
      • Poppas A.
      • Shroff S.G.
      • Korcarz C.E.
      • et al.
      Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load.
      ,
      • Valensise H.
      • Novelli G.P.
      • Vasapollo B.
      • et al.
      Maternal cardiac systolic and diastolic function: relationship with uteroplacental resistances. A Doppler and echocardiographic longitudinal study.
      (Figure 3).
      Figure thumbnail gr3
      Figure 3The cardiovascular changes from before conception to postpartum
      Graphical representation of the changes in the mean arterial pressure, heart rate, cardiac output, and peripheral vascular resistance from preconception to postpartum. Data are presented as mean values. Adapted from Mahendru et al.
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
      As a consequence of these considerable hemodynamic changes during the course of gestation, the maternal heart experiences profound remodeling. A progressive increase in the left ventricular mass has been reported widely, most markedly in the third trimester (34% above the prepregnancy values).
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      ,
      • Valensise H.
      • Novelli G.P.
      • Vasapollo B.
      • et al.
      Maternal cardiac systolic and diastolic function: relationship with uteroplacental resistances. A Doppler and echocardiographic longitudinal study.
      The left ventricular cavity dimension is increased proportionally to the left ventricular wall thickness, leading to eccentric myocardial hypertrophy, which reflects the increase in the preload (owing to the maternal relative blood volume overload).
      • Melchiorre K.
      • Sharma R.
      • Thilaganathan B.
      Cardiac structure and function in normal pregnancy.
      These changes are comparable with the physiological hypertrophy of an athlete who shares several common characteristics such as increased myocardial angiogenesis, the absence of fibrosis, and reversibility.
      • Chung E.
      • Leinwand L.A.
      Pregnancy as a cardiac stress model.
      Changes in the large artery function are predictors of cardiovascular risk in nonpregnant subjects.
      • Mancia G.
      • Fagard R.
      • Narkiewicz K.
      • et al.
      2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      The loss of the elastic properties of the aorta and the consequent rise in arterial stiffness cause an increase in blood pressure, as previously discussed.
      • Foo F.L.
      • McEniery C.M.
      • Lees C.
      • Khalil A.
      International Working Group on Maternal Hemodynamics
      Assessment of arterial function in pregnancy: recommendations of the International Working Group on Maternal Hemodynamics.
      In a normal pregnancy, the pulse wave velocity, which is a measurement of the blood flow velocity in the aorta, and augmentation index, a parameter that provides a measure of the pressure wave reflection through the muscular arterial tree, decrease from the first weeks of pregnancy and reach the lowest value in the second trimester, followed by a rise during the third trimester.
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      ,
      • Masini G.
      • Foo L.F.
      • Cornette J.
      • et al.
      Cardiac output changes from prior to pregnancy to post partum using two non-invasive techniques.
      ,
      • Poppas A.
      • Shroff S.G.
      • Korcarz C.E.
      • et al.
      Serial assessment of the cardiovascular system in normal pregnancy. Role of arterial compliance and pulsatile arterial load.
      ,
      • Iacobaeus C.
      • Andolf E.
      • Thorsell M.
      • et al.
      Longitudinal study of vascular structure and function during normal pregnancy.
      ,
      • Khalil A.
      • Jauniaux E.
      • Cooper D.
      • Harrington K.
      Pulse wave analysis in normal pregnancy: a prospective longitudinal study.
      A gradual return to the prepregnancy cardiovascular profile occurs postpartum, with different parameters restoring at different rates. The cardiac output remains significantly higher than the prepregnancy value for up to 1 year postpartum (+12% from the prepregnancy values) and a similar behavior is observed for the left ventricular mass, whereas the peripheral vascular resistance is reported to be lower than or similar to the prepregnancy value depending on the study.
      • Meah V.L.
      • Cockcroft J.R.
      • Backx K.
      • Shave R.
      • Stöhr E.J.
      Cardiac output and related haemodynamics during pregnancy: a series of meta-analyses.
      ,
      • Clapp 3rd, J.F.
      • Capeless E.
      Cardiovascular function before, during, and after the first and subsequent pregnancies.
      ,
      • Mahendru A.A.
      • Everett T.R.
      • Wilkinson I.B.
      • Lees C.C.
      • McEniery C.M.
      A longitudinal study of maternal cardiovascular function from preconception to the postpartum period.
      This observation could explain the more marked changes in the hemodynamic profile observed in parous women who have previously experienced a low-risk pregnancy. These women, in fact, show a more rapid rise in the cardiac output, an increase in the cardiac volume, and a fall in the peripheral vascular resistance during gestation, with all of these changes being of a greater magnitude when compared with the observations in nulliparous women.
      • Clapp 3rd, J.F.
      • Capeless E.
      Cardiovascular function before, during, and after the first and subsequent pregnancies.
      ,
      • Ling H.Z.
      • Guy G.P.
      • Bisquera A.
      • Poon L.C.
      • Nicolaides K.H.
      • Kametas N.A.
      The effect of parity on longitudinal maternal hemodynamics.

      Hemodynamic Measurements in Pregnancy

      Assessment of the cardiovascular function in pregnancy has become more relevant in the previous few decades because of the body of work reporting significant links between the maternal cardiovascular function and disorders such as preeclampsia, FGR, and gestational diabetes. Studies on cardiovascular function in association with preeclampsia have largely focused on the arterial function and circulatory hemodynamics. These are described below.

      Arterial function

      Arterial function differs significantly in cases of preeclampsia when compared with gestational age-matched normotensive controls.
      • Hausvater A.
      • Giannone T.
      • Sandoval Y.H.
      • et al.
      The association between preeclampsia and arterial stiffness.
      Arterial function is quantified by studying the stiffening of large vessels; vessel stiffness increases with age, genetic predisposition, or disease processes such as arteriosclerosis. Indices of arterial stiffness include the velocity of the blood flow (pulse wave velocity), the amplitude of the blood waveform (augmentation index), or endothelial function studies (flow-mediated dilatation or forearm blood flow). In the case of pulse wave velocity, the velocity of the pressure wave is inversely related to the vessel elasticity and compliance and is an independent predictor of cardiovascular mortality and morbidity. There are no reported normal limits for the pulse wave velocity in pregnancy, although a value of <10 m/s is within the range for healthy, nonpregnant women.
      • Baulmann J.
      • Schillings U.
      • Rickert S.
      • et al.
      A new oscillometric method for assessment of arterial stiffness: comparison with tonometric and piezo-electronic methods.
      The pulse wave velocity increases with maternal weight and age, but it is not influenced by parity. In women with a high risk for preeclampsia, an increased pulse wave velocity provided a detection rate of 82% with a 10% false-positive rate in predicting early-onset preeclampsia, but only a 20% detection rate in predicting late-onset preeclampsia.
      • Katsipi I.
      • Stylianou K.
      • Petrakis I.
      • et al.
      The use of pulse wave velocity in predicting pre-eclampsia in high-risk women.
      The aortic pulse wave velocity is considered the gold standard when determining arterial function, but the carotid-femoral arterial pulse wave velocity is commonly used as a pragmatic surrogate, because it covers the region that exhibits the greatest age-related stiffening (Figure 4). A variety of noninvasive devices utilizing computerized oscillometry, applanation tonometry, or Doppler have been utilized to study the pulse wave velocity in pregnancy, because most devices have been validated against invasive testing in nonpregnant cohorts.
      • Foo F.L.
      • McEniery C.M.
      • Lees C.
      • Khalil A.
      International Working Group on Maternal Hemodynamics
      Assessment of arterial function in pregnancy: recommendations of the International Working Group on Maternal Hemodynamics.
      Figure thumbnail gr4
      Figure 4Assessment of the carotid-femoral arterial pulse wave velocity
      Carotid-femoral arterial pulse wave velocity calculated as the time delay between the pressure waveforms (Δt) and divided by the distance (Δd) measured between the carotid and femoral arteries.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
      The augmentation index is a measure of the arterial pressure waveform and is quantified as the ratio of the pressure difference in relation to the pulse pressure and is expressed as a percentage (Figure 5). Significantly higher augmentation index levels have been observed in the subclinical stage of preeclampsia,
      • Savvidou M.D.
      • Kaihura C.
      • Anderson J.M.
      • Nicolaides K.H.
      Maternal arterial stiffness in women who subsequently develop pre-eclampsia.
      and the augmentation index is proposed to be a useful predictive marker for risk modeling when combined with other variables such as the central systolic blood pressure.
      • Khalil A.
      • Garcia-Mandujano R.
      • Maiz N.
      • Elkhouli M.
      • Nicolaides K.H.
      Longitudinal changes in maternal hemodynamics in a population at risk for pre-eclampsia.
      The augmentation index is commonly estimated from either the radial or the brachial artery waveform, using approaches such as tonometry or oscillometric devices to assess the upper limb waveform (Table 1). This is then transformed using an algorithm to derive the aortic augmentation index.
      Figure thumbnail gr5
      Figure 5Determinants of the arterial augmentation index (Aix)
      Aix (%) is calculated as (P2−P1/PP)×100, where P2 represents augmentation pressure and P1 represents forward wave.
      PP, pulse pressure.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
      Table 1Methodologies commonly used to assess arterial function
      TonometryOscillometric fluid distentionDoppler ultrasoundMechanotransducer
      Widely used in research studies; results can be affected by body habitusAffordable and noninvasive; not validated against invasive devicesCan be used with ultrasound machines that are already available; requires trainingWidely used in early studies; errors can be associated with distance estimation signals
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.

      Endothelial function

      The endothelial function is most commonly assessed by studying upper-arm, flow-mediated dilatation or forearm blood flow. Normal arteries dilate by 10% to 15% in response to blood flow. By definition, vasodilation measurements of <5% from the resting tone measurement indicate overt endothelial dysfunction.
      • Celermajer D.S.
      • Sorensen K.E.
      • Gooch V.M.
      • et al.
      Non-invasive detection of endothelial dysfunction in children and adults at risk of atherosclerosis.
      A reduced flow-mediated dilatation has been found in the first half of pregnancy in high-risk women who subsequently develop preeclampsia when compared with controls,
      • Noori M.
      • Donald A.E.
      • Angelakopoulou A.
      • Hingorani A.D.
      • Williams D.J.
      Prospective study of placental angiogenic factors and maternal vascular function before and after preeclampsia and gestational hypertension.
      and an increase in the flow-mediated dilatation has been observed in the postpartum period of preeclampsia cases,
      • Kuscu N.K.
      • Kurhan Z.
      • Yildirim Y.
      • Tavli T.
      • Koyuncu F.
      Detection of endothelial dysfunction in preeclamptic patients by using color Doppler sonography.
      suggesting a reversal of the endothelial dysfunction once preeclampsia has resolved. The devices and techniques to measure the arterial function in pregnancy is summarized in a consensus statement from the International Working Group of Maternal Hemodynamics (Foo et al
      • Foo F.L.
      • McEniery C.M.
      • Lees C.
      • Khalil A.
      International Working Group on Maternal Hemodynamics
      Assessment of arterial function in pregnancy: recommendations of the International Working Group on Maternal Hemodynamics.
      ).

      Cardiac output

      Early pregnancy is associated with significant increases in the cardiac output, and a corresponding decrease in the peripheral vascular resistance (Figure 3). The magnitude of these changes during pregnancy varies enormously among different studies and is probably reflective of the different measurement techniques, cohort designs, and reference points for the baseline and pregnancy data that were used. The cardiac output can be assessed using invasive techniques (eg, pulmonary artery catheterization either with direct Ficks or thermodilution adjunct methods) but these are mostly utilized in an intensive care setting in critically unwell women. Most commonly, and universally undertaken in obstetrical research settings, minimally invasive (eg, pulse-contour or transesophageal Doppler) or noninvasive (eg, cardiac magnetic resonance imaging, transthoracic echocardiography, and inert gas nonrebreathing) techniques are utilized. The measurement methodology and devices are summarized in a consensus statement by Bijl et al.
      • Bijl R.C.
      • Valensise H.
      • Novelli G.P.
      • et al.
      International Working Group on Maternal Hemodynamics
      Methods and considerations concerning cardiac output measurement in pregnant women: recommendations of the International Working Group on Maternal Hemodynamics.
      Table 2 also summarizes some of these methods. Once the cardiac output and blood pressure are measured, the peripheral vascular resistance can be calculated by dividing the mean arterial blood pressure by the cardiac output.
      Table 2Some of the methodologies commonly utilized to assess the maternal cardiac output
      Inert gas rebreathingContinuous suprasternal DopplerImpedance cardiographyTransthoracic echocardiography
      Minimal intraobserver variability, but expensive and requires ongoing consumable costsNo ongoing cost and validated against echocardiogramCan be performed in the supine position and easy to operateMachines and operators widely available; findings operator dependent
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.

      Cardiovascular Function Before Conception

      There is growing evidence that the prepregnancy blood pressure values and early gestational changes relate to the risk of developing new-onset gestational hypertension disorders
      • Wen S.W.
      • Tan H.
      • Retnakaran R.
      • et al.
      Pre-gravid predictors of new onset hypertension in pregnancy—results from a pre-conception cohort study in China.
      ,
      • Nobles C.J.
      • Mendola P.
      • Mumford S.L.
      • et al.
      Preconception blood pressure and its change Into early pregnancy: early risk factors for preeclampsia and gestational hypertension.
      and other complications such as fetal loss
      • Nobles C.J.
      • Mendola P.
      • Mumford S.L.
      • et al.
      Preconception blood pressure levels and reproductive outcomes in a prospective cohort of women attempting pregnancy.
      or placental malperfusion.
      • Atlass J.
      • Menke M.
      • Parks W.T.
      • Catov J.M.
      Pre-conception blood pressure and evidence of placental malperfusion.
      This is true not only for women diagnosed with chronic hypertension, but also for those with so-called prehypertension, defied either as systolic values between 130 and 140 mm Hg or diastolic values between 80 and 90 mm Hg.
      • Li N.
      • An H.
      • Li Z.
      • et al.
      Preconception blood pressure and risk of gestational hypertension and preeclampsia: a large cohort study in China.
      In the latter group, low cardiac output and high vascular resistance reflect temporary poor hemodynamic function already before conception.
      • Foo F.L.
      • Mahendru A.A.
      • Masini G.
      • et al.
      Association Between prepregnancy cardiovascular function and subsequent preeclampsia or fetal growth restriction.
      Importantly, the relationship between prehypertension and gestational hypertension exists with or without the use of aspirin
      • Nobles C.J.
      • Mendola P.
      • Mumford S.L.
      • et al.
      Preconception blood pressure and its change Into early pregnancy: early risk factors for preeclampsia and gestational hypertension.
      and accounts for all subtypes of gestational hypertension disorders.
      • Egeland G.M.
      • Klungsøyr K.
      • Øyen N.
      • Tell G.S.
      • Næss Ø.
      • Skjærven R.
      Preconception cardiovascular risk factor differences between gestational hypertension and preeclampsia: Cohort Norway Study.
      Physical exercise restores the plasma volume and venous compliance to near normal in formerly preeclamptic women,
      • Scholten R.R.
      • Hopman M.T.
      • Lotgering F.K.
      • Spaanderman M.E.
      Aerobic exercise training in formerly preeclamptic women: effects on venous reserve.
      improves arterial function, and reduces elevated blood pressure before conception.
      • Scholten R.R.
      • Thijssen D.J.
      • Lotgering F.K.
      • Hopman M.T.
      • Spaanderman M.E.
      Cardiovascular effects of aerobic exercise training in formerly preeclamptic women and healthy parous control subjects.
      ,
      • Hürter H.
      • Vontelin van Breda S.
      • Vokalova L.
      • et al.
      Prevention of pre-eclampsia after infertility treatment: preconceptional minimalisation of risk factors.
      These effects are associated with improvements in the cardiac output and peripheral vascular resistance and are observed in healthy or diseased individuals at all ages.
      • Chan E.
      • Giallauria F.
      • Vigorito C.
      • Smart N.A.
      Exercise training in heart failure patients with preserved ejection fraction: a systematic review and meta-analysis.
      • Larsen M.N.
      • Madsen M.
      • Nielsen C.M.
      • et al.
      Cardiovascular adaptations after 10 months of daily 12-min bouts of intense school-based physical training for 8–10-year-old children.
      • Buttery A.K.
      Cardiac rehabilitation for frail older people.
      These effects are most efficient when physical exercise is embedded in a program of patient education, stress management, and lifestyle interventions.
      • Rasouli M.
      • Pourheidari M.
      • Hamzeh Gardesh Z.
      Effect of self-care Before and During pregnancy to prevention and control preeclampsia in high-risk women.
      Despite good evidence from mechanistic studies, none were sufficiently powered to show a reduction in preeclampsia or the severity of preeclampsia in a subsequent pregnancy. It remains unclear whether pharmacologic interventions that tightly control blood pressure before conception or during pregnancy improves the gestational outcome.
      • Lu Y.
      • Chen R.
      • Cai J.
      • Huang Z.
      • Yuan H.
      The management of hypertension in women planning for pregnancy.
      ,
      • Reddy S.
      • Jim B.
      Hypertension and pregnancy: management and future risks.

      Therapeutic Implications of Different Preeclampsia Phenotypes

      The concept of different phenotypes of preeclampsia, detectable by noninvasive technologies in the latent subclinical stage of the disease,
      • Valensise H.
      • Vasapollo B.
      • Gagliardi G.
      • Novelli G.P.
      Early and late preeclampsia: two different maternal hemodynamic states in the latent phase of the disease.
      ,
      • Gyselaers W.
      • Vonck S.
      • Staelens A.S.
      • et al.
      Gestational hypertensive disorders show unique patterns of circulatory deterioration with ongoing pregnancy.
      opens perspectives about targeted management and prolonged gestation in preeclampsia. This does, of course, require knowledge of not only the blood pressure but the cardiac output and vascular resistance as well. These parameters can be obtained in real time using a variety of relatively inexpensive Doppler tools or whole-body impedance devices as we have described earlier. These devices are commonly used in operating theaters, critical care units, and emergency departments.
      In cases with a low blood volume, low cardiac output, and high resistance circulation characteristically associated with FGR, the use of nitric oxide (NO) donors, which is associated with plasma volume expansion, has shown improvements in the end diastolic blood flow velocity in the umbilical artery in parallel with a reduction in the maternal peripheral arterial resistance
      • Valensise H.
      • Vasapollo B.
      • Novelli G.P.
      • et al.
      Maternal and fetal hemodynamic effects induced by nitric oxide donors and plasma volume expansion in pregnancies with gestational hypertension complicated by intrauterine growth restriction with absent end-diastolic flow in the umbilical artery.
      and a beneficial effect on the maternal and neonatal outcomes.
      • Vasapollo B.
      • Novelli G.P.
      • Gagliardi G.
      • et al.
      Medical treatment of early-onset mild gestational hypertension reduces total peripheral vascular resistance and influences maternal and fetal complications.
      In the cases with a high blood volume, high cardiac output, and low vascular resistance that are characteristic of preeclampsia without FGR, reduction of the cardiac output and the systolic and diastolic blood pressures have been reported after the administration of the loop diuretic, furosemide.
      • Tamás P.
      • Hantosi E.
      • Farkas B.
      • Ifi Z.
      • Betlehem J.
      • Bódis J.
      Preliminary study of the effects of furosemide on blood pressure during late-onset pre-eclampsia in patients with high cardiac output.
      Diuretics are rarely used in the management of preeclampsia; their use in a woman with depleted intravascular volume could be dangerous. In contrast, the use of furosemide and hydrochlorothiazide in pregnancies complicated by heart failure has shown no teratogenic effects and only minor adverse effects such as neonatal jaundice, thrombocytopenia, imbalanced electrolytes, or clotting factors.
      • Halpern D.G.
      • Weinberg C.R.
      • Pinnelas R.
      • Mehta-Lee S.
      • Economy K.E.
      • Valente A.M.
      Use of medication for cardiovascular disease during pregnancy: JACC state-of-the-art review.
      This has stimulated international societies such as the European Society of Hypertension/European Cardiology Society and the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy to openly question the general recommendation of discouraging diuretic use during pregnancy.
      • Mancia G.
      • Fagard R.
      • Narkiewicz K.
      • et al.
      2013 ESH/ESC Guidelines for the management of arterial hypertension: the Task Force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC).
      ,
      Report of the National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy.
      The reduced cardiac output and increased vascular resistance linked to the heart rate changes now consistently found in clinical series studies on early preeclampsia, allow for pharmacologic intervention to be directed toward restoring the maternal cardiovascular status to optimal and to perfuse the peripheral tissues and placenta. The possibility of identifying a personalized targeted therapy on the basis of the hemodynamic profile of a patient to improve placental perfusion and fetal growth has been investigated in early stage studies. Reducing the vascular resistance and increasing the plasma volume so as to try and restore the maternal cardiovascular status by increasing the cardiac output is the main goal of the treatment. It is important to differentiate this intervention from the intervention required to treat late preeclampsia or, more correctly, preeclampsia that is not associated with FGR, which usually present with elevated cardiac output and low vascular resistances, mandating a different pharmacologic approach.
      • Vasapollo B.
      • Novelli G.P.
      • Gagliardi G.
      • et al.
      Medical treatment of early-onset mild gestational hypertension reduces total peripheral vascular resistance and influences maternal and fetal complications.

      Treatment of hypertension

      There is no consensus on the relative efficacy and safety of the medications used to treat severe hypertension in pregnancy, and the most recent Cochrane review found insufficient data to recommend a specific drug.
      • Duley L.
      • Meher S.
      • Jones L.
      Drugs for treatment of very high blood pressure during pregnancy.
      The current drug choice in the obstetrical practice is empirical and simplistic and often linked to the experience and familiarity of the clinician with the drug, and it is therefore not based on the cardiovascular profile of the patient. Pharmacologic agents have different mechanisms of action, but they are often used interchangeably. The major categories are alpha- and beta-blockers (labetalol), which have a negative effect on the cardiac output, calcium channel blockers, which have a predominantly vasodilator mode of action, and centrally acting antihypertensive agents such as alpha-methyldopa. The gold standard aim of the medical treatment is to achieve blood pressure control, but this is usually administered “blindly” without considering the maternal hemodynamic profile.
      Therefore, a possible “intelligent” therapeutic approach to treat hypertensive disorders in pregnancy based on the maternal cardiovascular hemodynamic parameters is presented in Table 3.
      • Vasapollo B.
      • Novelli G.P.
      • Valensise H.
      Hemodynamic guided treatment of hypertensive disorders in pregnancy: is it time to change our mind?.
      To optimize rational antihypertensive therapy without jeopardizing the uteroplacental circulation for cases in which hemodynamic assessments can be undertaken, the following steps could be followed: (1) evaluate the blood pressure values to classify patients according to the following hemodynamic parameters: maternal heart rate, cardiac output, and peripheral vascular resistance; (2) choose the appropriate treatment on the basis of the hemodynamic profile (Table 4), considering the pharmacologic effects of the antihypertensive drug; and (3) verify the response to the drug treatment after a time interval of 4 to 7 days by performing a hemodynamic evaluation.
      Table 3Examples of pharmacologic treatment choices based on the maternal hemodynamic findings
      Cardiovascular parameterLow cardiac output and high vascular resistance phenotypeHigh cardiac output and low vascular resistance phenotype
      Maternal heart rate<70 bpm>90 bpm
      Calcium channel blockers (eg, nifedipine),Alpha- and beta-blockers
      NO donors, and fluids(eg, alpha methyldopa, labetalol) preferred
      Cardiac output<5 L/min>8 L/min
      Calcium channel blockers (eg, nifedipine), NO donors, and fluidsAlpha- and beta-blockers (eg, alpha methyldopa, labetalol)
      (early-onset preeclampsia)(late-onset preeclampsia)
      Peripheral vascular resistance>1400 dynes.s.cm−5<900 dynes.s.cm−5
      Calcium channel blockers (eg, nifedipine), NO donors, and fluidsAlpha- and beta-blockers (eg, alpha methyldopa, labetalol)
      (early-onset preeclampsia)(late-onset preeclampsia)
      Late preeclampsia, or that without FGR, is usually characterized by high cardiac output and low vascular resistances, whereas early preeclampsia, or preeclampsia associated with FGR, frequently shows low cardiac output and elevated peripheral vascular resistances.
      bpm, beats per minute; FGR, fetal growth restriction; NO, nitric oxide.
      Adapted from Vasapollo et al.
      • Vasapollo B.
      • Novelli G.P.
      • Valensise H.
      Hemodynamic guided treatment of hypertensive disorders in pregnancy: is it time to change our mind?.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
      Table 4Summary of the principal hemodynamic findings of the maternal cardiovascular adaptation in a normal pregnancy and in FGR
      ParameterNormal fetal growthFGR
      Heart rate
      Cardiac output↑↑↓↓
      Vascular resistance↓↓↑↑
      Ventricular mass↑↑↓↓
      FGR, fetal growth restriction; ↑, increased; ↓, decreased.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.

      Treatment of fetal growth restriction

      The findings that the maternal cardiac adaptation in cases of isolated FGR is linked with reduced ventricular mass, a reduction in the increase in the maternal heart rate, a reduced cardiac output, and an increased vascular resistance have been confirmed in several studies after the first results appeared almost 20 years ago
      • Vasapollo B.
      • Valensise H.
      • Novelli G.P.
      • et al.
      Abnormal maternal cardiac function and morphology in pregnancies complicated by intrauterine fetal growth restriction.
      • Vasapollo B.
      • Valensise H.
      • Novelli G.P.
      • Altomare F.
      • Galante A.
      • Arduini D.
      Abnormal maternal cardiac function precedes the clinical manifestation of fetal growth restriction.
      • Ferrazzi E.
      • Stampalija T.
      • Monasta L.
      • Di Martino D.
      • Vonck S.
      • Gyselaers W.
      Maternal hemodynamics: a method to classify hypertensive disorders of pregnancy.
      (Table 4, Figure 6), and opens potential therapeutic approaches that can be used to reduce the vascular resistance and increase the intravascular volume.
      Figure thumbnail gr6
      Figure 6Representation of the cardiac morphologic adaptation in pregnancies with normal fetal growth and in those with FGR
      Adapted from Vasapollo et at.
      • Vasapollo B.
      • Valensise H.
      • Novelli G.P.
      • et al.
      Abnormal maternal cardiac function and morphology in pregnancies complicated by intrauterine fetal growth restriction.
      AGA, appropriate for gestational age; CO, cardiac output; FGR, fetal growth restriction; LVMi, left ventricular mass index; TVR, total vascular resistance.
      Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.

      Implications for Research

      Personalized treatments have been shown to reduce the risk of severe hypertension and allows for the identification of the low cardiac output and high vascular resistance phenotype of preeclampsia.
      • Stott D.
      • Papastefanou I.
      • Paraschiv D.
      • Clark K.
      • Kametas N.A.
      Serial hemodynamic monitoring to guide treatment of maternal hypertension leads to reduction in severe hypertension.
      However, clinically impactful therapeutic studies in which the antihypertensive therapy and management has been chosen based on the maternal hemodynamic profile in preeclampsia have not yet been undertaken. This is a priority research area, especially given the abundance of lightweight, noninvasive devices, which makes studies of this type feasible.
      A combined approach to restore the optimal maternal cardiac performance has shown promise both in FGR without end diastolic flow in the umbilical artery
      • Valensise H.
      • Vasapollo B.
      • Novelli G.P.
      • et al.
      Maternal and fetal hemodynamic effects induced by nitric oxide donors and plasma volume expansion in pregnancies with gestational hypertension complicated by intrauterine growth restriction with absent end-diastolic flow in the umbilical artery.
      and in fetuses with less severe features of growth restriction.
      • Tiralongo G.M.
      • Pisani I.
      • Vasapollo B.
      • Khalil A.
      • Thilaganathan B.
      • Valensise H.
      Effect of a nitric oxide donor on maternal hemodynamics in fetal growth restriction.
      The approach for future therapeutic studies is to use an NO donor (eg, in transdermal patches) to reduce the vascular resistance and to modify the capacity of the venous system by increasing the heart rate and contractility of the myocardium. Transdermal glyceryl trintitrate patches that release NO are effective in increasing the availability of NO at the level of the tissues, which leads to vasodilatation. The increase in the plasma volume with oral or intravenous hydration adds to the pharmacologic effect, potentially restoring the cardiac output. Though these proof of principle studies show positive results, they are yet to be reported in larger phase 2 randomized studies.

      Conclusion

      There exists incontrovertible evidence that preeclampsia exists as two phenotypes, and that these have opposite presentations with respect to the cardiac output, vascular resistance, and intravascular volume. Although they are not entirely inaccurate, the terms early and late preeclampsia should be consigned in the future as the key discriminators of the two phenotypes, and it should be emphasized that the key discriminator is the absence or presence of FGR. FGR can occur at any gestational age although it is far more frequent in combination with preeclampsia that develops at an early gestational age.
      The “blind” management of hypertension in women with preeclampsia may achieve blood pressure control, but it ignores the effects on the maternal cardiovascular system and, more crucially, on the uteroplacental circulation with the associated downstream effects on the fetus. Comprehensive hemodynamic assessment of women with preeclampsia in addition to ultrasound and Doppler investigations of the fetus can guide a rational choice of antihypertensive and fluid management strategies in preeclampsia. The investigation and management of adult hypertension outside pregnancy has moved toward personalized management based on hemodynamic assessments. It is high time that obstetricians and physicians involved in obstetrical care reappraised their approach to preeclampsia management.

      Supplementary Data

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