Expert Review ajog.

org

Preeclampsia has two phenotypes which require

different treatment strategies
Giulia Masini, MD; Lin F. Foo, BM, BSc (Hons), PhD, MRCOG; Jasmine Tay, BMedSci, BMBS, PhD, MRCOG;
Ian B. Wilkinson, MA, DM, FRCP, FAHA; Herbert Valensise, MD, PhD; Wilfried Gyselaers, MD, PhD;
Christoph C. Lees, MD, FRCOG

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 pre-
eclampsia. 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: arterial function, blood pressure, cardiac output, cardiovascular function, fetal growth restriction, hemodynamics, hyper-
tensive disease of pregnancy, preeclampsia, vascular resistance

Introduction
Classical obstetrical teaching character-
izes preeclampsia as a single pathophys-
iological entity with the defining features
of hypertension in association with pro-
teinuria,1 however, more recent defini-
tions also include presentation with acute
maternal kidney damage, abnormal liver
function, neurologic impairment, pul-
monary edema, hemolysis, thrombocy-
topenia, 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 associ-
ated with both vasoconstriction and
increased intravascular volume. From a

From the Fetal Medicine Unit, Careggi University Hospital, Florence, Italy (Dr Masini); Department of Metabolism, Digestion and Reproduction, Faculty of Medicine,
Imperial College London, London, United Kingdom (Dr Foo); Centre for Fetal Care, Queen Charlotte’s and Chelsea Hospital, Imperial College Healthcare, London,
United Kingdom (Drs Tay and Lees); Division of Experimental Medicine and Immunotherapeutics, Department of Medicine, University of Cambridge, Cambridge,
United Kingdom (Dr Wilkinson); Division of Obstetrics and Gynaecology, Department of Surgery, University of Rome, Policlinico Casilino, Tor Vergata, Rome, Italy
(Dr Valensise); Department of Obstetrics and Gynaecology, Ziekenhuis Oost Limburg, Genk, Belgium (Dr Gyselaers); Department of Physiology, Hasselt
University, Diepenbeek, Belgium (Dr Gyselaers); Institute for Reproductive and Developmental Biology, Department of Metabolism, Digestion and Reproduction,
Imperial College London, London, United Kingdom (Dr Lees); and Department of Development of Regeneration, Katholieke Universiteit Leuven, Leuven, Belgium
(Dr Lees).
Received Oct. 1, 2020; revised Oct. 27, 2020; accepted Oct. 31, 2020.
The authors report no conflict of interest.
This work was supported by the National Institute for Health Research Comprehensive Biomedical Research Centre at Imperial College Healthcare NHS
Trust and Imperial College London (C.C.L., J.T., and L.F.). The views expressed are those of the author(s) and not necessarily those of Imperial College,
the NHS, the NIHR or the Department of Health.
This paper is part of a supplement.
Corresponding author: Christoph C. Lees, MD, FRCOG. c.lees@imperial.ac.uk
0002-9378/$36.00
ª 2020 Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.ajog.2020.10.052

Click Video under article title in Contents at

S1006 American Journal of Obstetrics & Gynecology FEBRUARY 2022

ajog.org
mechanistic or physiological point of
view, these two abnormalities are un-
likely 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 evi-
dence since the early 2000s suggests that
preeclampsia may be caused by two
opposing mechanisms that are repre-
sented 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 cardiovas-
cular 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 car-
diac 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 intravas-
cular 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 cardiovas-
cular measurements were adjusted for
the gestational age at onset of the con-
dition, 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 pre-
eclampsia 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 condi-
tion is associated with FGR or not. These
findings have major implications for our
understanding of the condition and
FIGURE 1
Schematic representation of changes in the cardiac parameters and
arterial function in PE, FGR, or the combination of both complications5
FGR, fetal growth restriction; PE, preeclampsia.
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
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 condi-
tion of a woman with intravascular vol-
ume 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.
Lessons From Adult Hypertension
The fact that two phenotypes of pre-
eclampsia exist with diametrically oppo-
site cardiovascular characteristics may
not be so surprising when set against ev-
idence 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 un-
derlying essential hypertension are more
complex, and that it can be divided
broadly into 3 basic groups. Phenotypi-
cally, these groups differ in the age of
onset and the pattern of blood pressure
elevationeesystolic, diastolic, or systolic
and diastolic.8 The prevalence of hyper-
tension is strongly age-related, varying
from approximately 5% in patients under
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
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 pre-
sentation in young people and those aged
more than 60 years, whereas elevated
systolic and diastolic pressure (mixed
hypertension) predominates in the pa-
tients aged between 30 and 60 years.
Blood pressure is most commonly
considered to be the product of the car-
diac output and peripheral vascular
resistance and is presented as follows:
Mean arterial pressure¼cardiac out-
putperipheral vascular resistance
Detailed hemodynamic studies in the
1960s and 1970s9 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 remodel-
ing,10 and is effectively irreversible.
Conversely, the cardiac output is
normal or slightly low.
Young individuals with isolated sys-
tolic hypertension mainly have an
elevated cardiac output, with a low or
normal peripheral vascular resistance.11
Interestingly, Julius12 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,
S1007
Expert Review ajog.org

babies, and the converse also being true.

FIGURE 2
The 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,18 early-onset preeclampsia,21 late-onset pre-
eclampsia type I (crossover),24 and late-onset preeclampsia type II (high-output).28 Adapted from
Gyselaers.29
PE, preeclampsia.
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
low-output cardiac state. Data from a
study by Lund-Johansen13 many years
before, support this transitional hy-
pothesis. 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 in-
dividuals with isolated systolic hyper-
tension is increased aortic stiffness14
rather than an elevated resistance or
cardiac output. The human aorta con-
tains 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 pressureyaortic stiffness-
stroke volume
The aorta progressively stiffens with
age15 owing to the mechanical degener-
ation of the elastin fibers and other
processes such as calcium deposition.
For reasons that are not fully under-
stood, this seems to be exaggerated or
accelerated in some individuals and gives
rise to a widened pulse pressure and thus
systolic hypertension.16
A Possible Latent Phase in
Preeclampsia
Pregnancy is a condition of physiological
expansion in the volume of noncircu-
lating 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.17 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.18 The change in cardiac
output during gestation has recently
been shown to be a strong determinant
of birthweight,19 with a higher cardiac
output being associated with larger
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 resis-
tance. Early-onset preeclampsia with
FGR presents with high peripheral
vascular resistance from the first
trimester onward,20 which is associated
with a failure to adequately increase the
cardiac output from the first to the sec-
ond trimester.20,21 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 pre-
eclampsia.22 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.20,23 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.24 During this crossover, a
short temporary state of “apparently
normal” cardiovascular function is pre-
sent. 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.25 Endothelial
dysfunction caused by intravascular
volume overload has been documented
in nonpregnant individuals during he-
modialysis26 and acute heart failure.27
For late-onset preeclampsia, frequently
seen in women with obesity, high-output
circulation is seen throughout all the
stages of pregnancy, including the clin-
ical stage of late-onset preeclampsia,
during delivery, and postpartum28
(Figure 2). The dual etiology of pre-
eclampsia suggested by these two

S1008 American Journal of Obstetrics & Gynecology FEBRUARY 2022

ajog.org
different evolutions of cardiovascular
function in the latent phases of the dis-
ease 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 age30 in women with
preeclampsia.
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 car-
diovascular system experiences major
changes in the different parameters, and
these modifications are the key for a
successful and uncomplicated preg-
nancy. 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 he-
modynamics, modifications in the car-
diac 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.31 Modification to
the central hemodynamics and in the
cardiac structure are strongly con-
nected with these changes.
Arguably the most informative he-
modynamic parameter is cardiac output,
which reflects the growing demand of
the cardiovascular system during gesta-
tion, and, as such, it starts to increase
soon after the beginning of pregnancy.32
The magnitude and trend of this increase
have been described recently in a meta-
analysis by Meah et al32 who showed
that the cardiac output increases by 15%
in the first trimester when compared
with the prepregnancy value, then peaks
Expert Review
FIGURE 3
The cardiovascular changes from before conception to postpartum
6.4 1,400
Scale on left axis
6.2 1,300
6 1,200
5.8 1,100
5.6 1,000
Scale on right axis
5.4 900
5.2 800
Pre-concep on First trimester Second trimester Third trimester Post-partum
Cardiac output (l/min) Peripheral vascular resistance (dyn·s/cm5)
90
85
80
75
70
65
Pre-concep on First trimester Second trimester Third trimester Post-partum
Mean arterial pressure (mmHg) Heart rate (beats/min)
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.40
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
in the early third trimester to 31% higher the peak of cardiac output (12e38 weeks
than the prepregnancy value (þ1.5 L/ of gestation).33e42 Our group, using
min), and then decreases by 6% in the different methodologies, recently re-
late third trimester. These results were ported that a rise in the peak cardiac
obtained from the analysis of both cross- output occurred earlier and more
sectional and longitudinal studies, but modestly than previously thought
most of them lacked prepregnancy (þ1.05 L/min or 17.5% above the pre-
measurements of the same subjects and pregnancy value at 15.2 weeks’ gestation
not all of them were performed using the as measured using the inert gas
same technique. Studies in which rebreathing technique; þ0.47 L/min or
women were recruited before pregnancy 7.7% above the prepregnancy value at
and subsequently followed throughout 10.4 weeks’ gestation as measured using
pregnancy generally included only a few the pulse wave velocity).42 As the prod-
subjects (8e69), and reported contrast- uct of stroke volume and heart rate, the
ing results about the magnitude of cardiac output increase is driven more by
change (17%e49% above the prepreg- the progressive rise in the heart rate,
nancy value) and the gestational age at which peaks in the third trimester (20%
FEBRUARY 2022 American Journal of Obstetrics & Gynecology S1009
Expert Review
FIGURE 4
Assessment of the carotid-femoral arterial pulse wave velocity
Carotid-femoral arterial pulse wave velocity calculated as the time delay between the pressure
waveforms (Dt) and divided by the distance (Dd) measured between the carotid and femoral arteries.
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
e24% higher than the prepregnancy
value), than stroke volume (13% in-
crease from the prepregnancy value in
the second trimester).32,40,43
The decrease in the peripheral
vascular resistance with gestational age is
associated with a reduction in the uterine
artery and fetal umbilical Doppler
impedance.44,45 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.32,40,41 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
S1010 American Journal of Obstetrics & Gynecology FEBRUARY 2022
shows a nadir in the second trimester
(9% from before the pregnancy) and a
gradual return to prepregnancy levels
near term32,36,40,46,47 (Figure 3).
As a consequence of these consider-
able hemodynamic changes during the
course of gestation, the maternal heart
experiences profound remodeling. A
progressive increase in the left ventricu-
lar mass has been reported widely, most
markedly in the third trimester (34%
above the prepregnancy values).32,47 The
left ventricular cavity dimension is
increased proportionally to the left ven-
tricular wall thickness, leading to
eccentric myocardial hypertrophy,
which reflects the increase in the preload
(owing to the maternal relative blood
volume overload).48 These changes are
comparable with the physiological hy-
pertrophy of an athlete who shares
several common characteristics such as
ajog.org
increased myocardial angiogenesis, the
absence of fibrosis, and reversibility.49
Changes in the large artery function
are predictors of cardiovascular risk in
nonpregnant subjects.50 The loss of the
elastic properties of the aorta and the
consequent rise in arterial stiffness cause
an increase in blood pressure, as previ-
ously discussed.51 In a normal preg-
nancy, 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.40,42,46,52,53
A gradual return to the prepregnancy
cardiovascular profile occurs postpartum,
with different parameters restoring at
different rates. The cardiac output re-
mains significantly higher than the pre-
pregnancy value for up to 1 year
postpartum (þ12% from the prepreg-
nancy 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.32,36,40 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 magni-
tude when compared with the observa-
tions in nulliparous women.36,54
Hemodynamic Measurements in
Pregnancy
Assessment of the cardiovascular func-
tion 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 gesta-
tional diabetes. Studies on cardiovascu-
lar function in association with
preeclampsia have largely focused on the
ajog.org Expert Review

arterial function and circulatory hemo-

FIGURE 5
dynamics. These are described below.
Determinants of the arterial augmentation index (Aix)
Arterial function
Arterial function differs significantly in
cases of preeclampsia when compared
with gestational age-matched normo-
tensive controls.55 Arterial function is
quantified by studying the stiffening of
large vessels; vessel stiffness increases
with age, genetic predisposition, or dis-
ease 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
Aix (%) is calculated as (P2P1/PP)100, where P2 represents augmentation pressure and P1
and morbidity. There are no reported
represents forward wave.
normal limits for the pulse wave velocity
PP, pulse pressure.
in pregnancy, although a value of <10 Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
m/s is within the range for healthy,
nonpregnant women.56 The pulse wave
velocity increases with maternal weight
and age, but it is not influenced by parity. pulse pressure and is expressed as a measurement indicate overt endothelial
In women with a high risk for percentage (Figure 5). Significantly dysfunction.60 A reduced flow-mediated
preeclampsia, an increased pulse wave higher augmentation index levels have dilatation has been found in the first half
velocity provided a detection rate of 82% been observed in the subclinical stage of pregnancy in high-risk women who
with a 10% false-positive rate in pre- of preeclampsia,58 and the augmenta- subsequently develop preeclampsia
dicting early-onset preeclampsia, but tion index is proposed to be a useful when compared with controls,61 and an
only a 20% detection rate in predicting predictive marker for risk modeling increase in the flow-mediated dilatation
late-onset preeclampsia.57 when combined with other variables has been observed in the postpartum
The aortic pulse wave velocity is such as the central systolic blood period of preeclampsia cases,62 suggest-
considered the gold standard when pressure.59 The augmentation index is ing a reversal of the endothelial
determining arterial function, but the commonly estimated from either the dysfunction once preeclampsia has
carotid-femoral arterial pulse wave ve- radial or the brachial artery waveform, resolved. The devices and techniques to
locity is commonly used as a pragmatic using approaches such as tonometry or measure the arterial function in preg-
surrogate, because it covers the region oscillometric devices to assess the up- nancy is summarized in a consensus
that exhibits the greatest age-related per limb waveform (Table 1). This is statement from the International
stiffening (Figure 4). A variety of then transformed using an algorithm Working Group of Maternal Hemody-
noninvasive devices utilizing computer- to derive the aortic augmentation namics (Foo et al51).
ized oscillometry, applanation tonom- index.
etry, or Doppler have been utilized to Cardiac output
study the pulse wave velocity in preg- Endothelial function Early pregnancy is associated with sig-
nancy, because most devices have been The endothelial function is most nificant increases in the cardiac output,
validated against invasive testing in commonly assessed by studying upper- and a corresponding decrease in the pe-
nonpregnant cohorts.51 arm, flow-mediated dilatation or fore- ripheral vascular resistance (Figure 3).
The augmentation index is a mea- arm blood flow. Normal arteries dilate The magnitude of these changes during
sure of the arterial pressure waveform by 10% to 15% in response to blood pregnancy varies enormously among
and is quantified as the ratio of the flow. By definition, vasodilation mea- different studies and is probably reflec-
pressure difference in relation to the surements of <5% from the resting tone tive of the different measurement

FEBRUARY 2022 American Journal of Obstetrics & Gynecology S1011

Expert Review ajog.org

techniques, cohort designs, and refer-

ence points for the baseline and preg-
nancy data that were used. The cardiac

associated with distance estimation signals

Widely used in early studies; errors can be
output can be assessed using invasive
techniques (eg, pulmonary artery cath-
eterization either with direct Ficks or
thermodilution adjunct methods) but
these are mostly utilized in an intensive
care setting in critically unwell women.
Mechanotransducer

Most commonly, and universally un-

dertaken in obstetrical research settings,
minimally invasive (eg, pulse-contour or
transesophageal Doppler) or noninva-
sive (eg, cardiac magnetic resonance
imaging, transthoracic echocardiogra-
phy, and inert gas nonrebreathing)

Can be used with ultrasound machines that

techniques are utilized. The measure-
ment methodology and devices are

are already available; requires training

summarized in a consensus statement by
Bijl et al.63 Table 2 also summarizes some
of these methods. Once the cardiac
output and blood pressure are measured,
the peripheral vascular resistance can
Doppler ultrasound

be calculated by dividing the mean arte-

rial blood pressure by the cardiac output.

Cardiovascular Function Before

Conception
There is growing evidence that the pre-
pregnancy blood pressure values and
Affordable and noninvasive; not validated

early gestational changes relate to the

risk of developing new-onset gestational
hypertension disorders64,65 and other
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
Oscillometric fluid distention

complications such as fetal loss66 or

Methodologies commonly used to assess arterial function

placental malperfusion.67 This is true

against invasive devices

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.68 In the latter group,
low cardiac output and high vascular
resistance reflect temporary poor he-
modynamic function already before
Widely used in research studies; results

conception.23 Importantly, the relation-

ship between prehypertension and
can be affected by body habitus

gestational hypertension exists with or

without the use of aspirin65 and accounts
for all subtypes of gestational hyperten-
sion disorders.69 Physical exercise re-
stores the plasma volume and venous
compliance to near normal in formerly
Tonometry

preeclamptic women,70 improves arte-

TABLE 1

rial function, and reduces elevated blood

pressure before conception.71,72 These
effects are associated with improvements

S1012 American Journal of Obstetrics & Gynecology FEBRUARY 2022

 ajog.org
TABLE 2
Some of the methodologies commonly utilized to assess the maternal cardiac output
Inert gas rebreathing Continuous suprasternal Doppler Impedance cardiography Transthoracic echocardiography
FEBRUARY 2022 American Journal of Obstetrics & Gynecology

Minimal intraobserver variability, No ongoing cost and validated Can be performed in the supine position Machines and operators widely available;
but expensive and requires ongoing against echocardiogram and easy to operate findings operator dependent
consumable costs

Expert Review
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
S1013
Expert Review ajog.org

output, and low vascular resistance that

TABLE 3 are characteristic of preeclampsia
Examples of pharmacologic treatment choices based on the maternal without FGR, reduction of the cardiac
hemodynamic findings output and the systolic and diastolic
Low cardiac output and High cardiac output and blood pressures have been reported af-
Cardiovascular high vascular resistance low vascular resistance ter the administration of the loop
parameter phenotype phenotype
diuretic, furosemide.81 Diuretics are
Maternal heart rate <70 bpm >90 bpm rarely used in the management of pre-
Calcium channel blockers Alpha- and beta-blockers eclampsia; their use in a woman with
(eg, nifedipine), depleted intravascular volume could be
NO donors, and fluids (eg, alpha methyldopa, dangerous. In contrast, the use of
labetalol) preferred furosemide and hydrochlorothiazide in
Cardiac output <5 L/min >8 L/min pregnancies complicated by heart fail-
ure has shown no teratogenic effects
Calcium channel blockers Alpha- and beta-blockers
(eg, nifedipine), NO donors, (eg, alpha methyldopa, labetalol)
and only minor adverse effects such as
and fluids neonatal jaundice, thrombocytopenia,
imbalanced electrolytes, or clotting
(early-onset preeclampsia) (late-onset preeclampsia)
factors.82 This has stimulated interna-
Peripheral vascular >1400 dynes.s.cm5 <900 dynes.s.cm5 tional societies such as the European
resistance
Society of Hypertension/European
Calcium channel blockers Alpha- and beta-blockers Cardiology Society and the National
(eg, nifedipine), NO donors, (eg, alpha methyldopa, labetalol) High Blood Pressure Education Pro-
and fluids
gram Working Group on High Blood
(early-onset preeclampsia) (late-onset preeclampsia) Pressure in Pregnancy to openly ques-
Late preeclampsia, or that without FGR, is usually characterized by high cardiac output and low vascular resistances, whereas tion the general recommendation of
early preeclampsia, or preeclampsia associated with FGR, frequently shows low cardiac output and elevated peripheral vascular
resistances.
discouraging diuretic use during
bpm, beats per minute; FGR, fetal growth restriction; NO, nitric oxide.
pregnancy.50,83
Adapted from Vasapollo et al.85
The reduced cardiac output and
Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
increased vascular resistance linked to
the heart rate changes now consistently
found in clinical series studies on early
in the cardiac output and peripheral prolonged gestation in preeclampsia. preeclampsia, allow for pharmacologic
vascular resistance and are observed in This does, of course, require knowledge intervention to be directed toward
healthy or diseased individuals at all of not only the blood pressure but the restoring the maternal cardiovascular
ages.73e75 These effects are most efficient cardiac output and vascular resistance as status to optimal and to perfuse the
when physical exercise is embedded in a well. These parameters can be obtained peripheral tissues and placenta. The
program of patient education, stress in real time using a variety of relatively possibility of identifying a personalized
management, and lifestyle in- inexpensive Doppler tools or whole- targeted therapy on the basis of the
terventions.76 Despite good evidence body impedance devices as we have hemodynamic profile of a patient to
from mechanistic studies, none were described earlier. These devices are improve placental perfusion and fetal
sufficiently powered to show a reduction commonly used in operating theaters, growth has been investigated in early
in preeclampsia or the severity of pre- critical care units, and emergency stage studies. Reducing the vascular
eclampsia in a subsequent pregnancy. It departments. resistance and increasing the plasma
remains unclear whether pharmacologic In cases with a low blood volume, volume so as to try and restore the
interventions that tightly control blood low cardiac output, and high resistance maternal cardiovascular status by
pressure before conception or during circulation characteristically associated increasing the cardiac output is the
pregnancy improves the gestational with FGR, the use of nitric oxide (NO) main goal of the treatment. It is
outcome.77,78 donors, which is associated with plasma important to differentiate this inter-
volume expansion, has shown im- vention from the intervention required
Therapeutic Implications of Different provements in the end diastolic blood to treat late preeclampsia or, more
Preeclampsia Phenotypes flow velocity in the umbilical artery in correctly, preeclampsia that is not
The concept of different phenotypes of parallel with a reduction in the associated with FGR, which usually
preeclampsia, detectable by noninvasive maternal peripheral arterial resistance79 present with elevated cardiac output
technologies in the latent subclinical and a beneficial effect on the maternal and low vascular resistances,
stage of the disease,3,21 opens perspec- and neonatal outcomes.80 In the cases mandating a different pharmacologic
tives about targeted management and with a high blood volume, high cardiac approach.80

S1014 American Journal of Obstetrics & Gynecology FEBRUARY 2022

ajog.org Expert Review

Treatment of hypertension
There is no consensus on the relative TABLE 4
efficacy and safety of the medications Summary of the principal hemodynamic findings of the maternal
used to treat severe hypertension in cardiovascular adaptation in a normal pregnancy and in FGR
pregnancy, and the most recent Parameter Normal fetal growth FGR
Cochrane review found insufficient data Heart rate [ Y
to recommend a specific drug.84 The
Cardiac output [[ YY
current drug choice in the obstetrical
practice is empirical and simplistic and Vascular resistance YY [[
often linked to the experience and fa- Ventricular mass [[ YY
miliarity of the clinician with the drug, FGR, fetal growth restriction; [, increased; Y, decreased.
and it is therefore not based on the car- Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
diovascular profile of the patient. Phar-
macologic agents have different
mechanisms of action, but they are often reduction in the increase in the maternal Implications for Research
used interchangeably. The major cate- heart rate, a reduced cardiac output, and Personalized treatments have been
gories are alpha- and beta-blockers an increased vascular resistance have shown to reduce the risk of severe hy-
(labetalol), which have a negative effect been confirmed in several studies after pertension and allows for the identifi-
on the cardiac output, calcium channel the first results appeared almost 20 years cation of the low cardiac output and high
blockers, which have a predominantly ago86e88 (Table 4, Figure 6), and opens vascular resistance phenotype of pre-
vasodilator mode of action, and centrally potential therapeutic approaches that eclampsia.89 However, clinically im-
acting antihypertensive agents such as can be used to reduce the vascular pactful therapeutic studies in which the
alpha-methyldopa. The gold standard resistance and increase the intravascular antihypertensive therapy and manage-
aim of the medical treatment is to ach- volume. ment has been chosen based on the
ieve blood pressure control, but this is
usually administered “blindly” without FIGURE 6
considering the maternal hemodynamic Representation of the cardiac morphologic adaptation in pregnancies
profile. with normal fetal growth and in those with FGR
Therefore, a possible “intelligent”
therapeutic approach to treat hyperten-
sive disorders in pregnancy based on the
maternal cardiovascular hemodynamic
parameters is presented in Table 3.85 To
optimize rational antihypertensive ther-
apy without jeopardizing the uteropla-
cental circulation for cases in which
hemodynamic assessments can be un-
dertaken, 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 pharmaco-
logic 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.
Adapted from Vasapollo et at.86
Treatment of fetal growth restriction
AGA, appropriate for gestational age; CO, cardiac output; FGR, fetal growth restriction; LVMi, left ventricular mass index; TVR, total
The findings that the maternal cardiac vascular resistance.
adaptation in cases of isolated FGR is Masini. The two phenotypes of preeclampsia and differential treatments. Am J Obstet Gynecol 2022.
linked with reduced ventricular mass, a

FEBRUARY 2022 American Journal of Obstetrics & Gynecology S1015

Expert Review
maternal hemodynamic profile in pre-
eclampsia 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 ar-
tery79 and in fetuses with less severe
features of growth restriction.90 The
approach for future therapeutic studies
is to use an NO donor (eg, in trans-
dermal 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 ran-
domized 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 intra-
vascular 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 hyper-
tension 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 circula-
tion with the associated downstream ef-
fects on the fetus. Comprehensive
S1016 American Journal of Obstetrics & Gynecology FEBRUARY 2022
hemodynamic assessment of women
with preeclampsia in addition to ultra-
sound and Doppler investigations of the
fetus can guide a rational choice of
antihypertensive and fluid management
strategies in preeclampsia. The investi-
gation and management of adult hyper-
tension 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 preeclamp-
sia management. -
REFERENCES
1. Perry IJ, Beevers DG. The definition of pre-
eclampsia. Br J Obstet Gynaecol 1994;101:
587–91.
2. Brown MA, Magee LA, Kenny LC, et al. Hy-
pertensive disorders of pregnancy: ISSHP
classification, diagnosis, and management rec-
ommendations for international practice. Hy-
pertension 2018;72:24–43.
3. Valensise H, Vasapollo B, Gagliardi G,
Novelli GP. Early and late preeclampsia: two
different maternal hemodynamic states in the
latent phase of the disease. Hypertension
2008;52:873–80.
4. Melchiorre K, Sutherland GR, Liberati M,
Thilaganathan B. Preeclampsia is associated
with persistent postpartum cardiovascular
impairment. Hypertension 2011;58:709–15.
5. Easterling TR, Benedetti TJ, Schmucker BC,
Millard SP. Maternal hemodynamics in normal
and preeclamptic pregnancies: a longitudinal
study. Obstet Gynecol 1990;76:1061–9.
6. 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 re-
striction, cardiac output is low: insights from a
prospective study. Am J Obstet Gynecol
2018;218:517.e1–12.
7. 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). Ultrasound Obstet
Gynecol 2013;42:400–8.
8. Franklin SS, Gustin W 4th, Wong ND, et al.
Hemodynamic patterns of age-related changes
in blood pressure. The Framingham Heart
Study. Circulation 1997;96:308–15.
9. Frohlich ED, Ulrych M, Tarazi RC, Dustan HP,
Page IH. A hemodynamic comparison of
essential and renovascular hypertension. Car-
diac output and total peripheral resistance: su-
pine and tilted patients. Circulation 1967;35:
289–97.
10. Folkow B. Structure and function of the ar-
teries in hypertension. Am Heart J 1987;114:
938–48.
ajog.org
11. McEniery CM, Yasmin WS, Wallace S,
et al. Increased stroke volume and aortic
stiffness contribute to isolated systolic hyper-
tension in young adults. Hypertension 2005;
46:221–6.
12. Julius S. Transition from high cardiac output
to elevated vascular resistance in hypertension.
Am Heart J 1988;116:600–6.
13. Lund-Johansen P. Hemodynamics in early
essential hypertension. Acta Med Scand
1967;181(Suppl482):1–5.
14. Yasmin, McEniery CM, Wallace S, et al.
Matrix metalloproteinase-9 (MMP-9), MMP-2,
and serum elastase activity are associated
with systolic hypertension and arterial stiff-
ness. Arterioscler Thromb Vasc Biol 2005;25:
372.
15. Avolio AP, Deng FQ, Li WQ, et al. Effects
of aging on arterial distensibility in populations
with high and low prevalence of hypertension:
comparison between urban and rural com-
munities in China. Circulation 1985;71:
202–10.
16. McEniery CM, Wilkinson IB. The pressures
of aging. Hypertension 2013;62:823–4.
17. Melchiorre K, Sharma R, Khalil A,
Thilaganathan B. Maternal cardiovascular func-
tion in normal pregnancy: evidence of malad-
aptation to chronic volume overload.
Hypertension 2016;67:754–62.
18. Andreas M, Kuessel L, Kastl SP, et al. Bio-
impedance cardiography in pregnancy: a longi-
tudinal cohort study on hemodynamic pattern
and outcome. BMC Pregnancy Childbirth
2016;16:128.
19. Mahendru AA, Foo FL, McEniery CM,
Everett TR, Wilkinson IB, Lees CC. Change in
maternal cardiac output from preconception to
mid-pregnancy is associated with birth weight in
healthy pregnancies. Ultrasound Obstet Gyne-
col 2017;49:78–84.
20. Rang S, van Montfrans GA, Wolf H. Serial
hemodynamic measurement in normal preg-
nancy, preeclampsia, and intrauterine growth
restriction. Am J Obstet Gynecol 2008;198:519.
e1–9.
21. Gyselaers W, Vonck S, Staelens AS,
et al. Gestational hypertensive disorders
show unique patterns of circulatory deterio-
ration with ongoing pregnancy. Am J Physiol
Regul Integr Comp Physiol 2019;316:
R210–21.
22. Gyselaers W, Vonck S, Staelens AS, et al.
Body fluid volume homeostasis is abnormal in
pregnancies complicated with hypertension
and/or poor fetal growth. PLoS One 2018;13:
e0206257.
23. Foo FL, Mahendru AA, Masini G, et al. As-
sociation Between prepregnancy cardiovascu-
lar function and subsequent preeclampsia or
fetal growth restriction. Hypertension 2018;72:
442–50.
24. Bosio PM, McKenna PJ, Conroy R,
O’Herlihy C. Maternal central hemodynamics in
hypertensive disorders of pregnancy. Obstet
Gynecol 1999;94:978–84.
ajog.org
25. Vonck S, Lanssens D, Staelens AS, et al.
Obesity in pregnancy causes a volume overload
in third trimester. Eur J Clin Investig 2019;49:
e13173.
26. Mitsides N, Cornelis T, Broers NJH, et al.
Extracellular overhydration linked with endo-
thelial dysfunction in the context of inflam-
mation in haemodialysis dependent chronic
kidney disease. PLoS One 2017;12:
e0183281.
27. Colombo PC, Onat D, Sabbah HN. Acute
heart failure as ”acute endothelitis”—interaction
of fluid overload and endothelial dysfunction. Eur
J Heart Fail 2008;10:170–5.
28. Easterling TR, Benedetti TJ. Preeclampsia:
a hyperdynamic disease model. Am J Obstet
Gynecol 1989;160:1447–53.
29. Gyselaers W. Preeclampsia is a syndrome
with a cascade of pathophysiologic events.
J Clin Med 2020;9:2245.
30. 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. Ultrasound Obstet Gyne-
col 2014;44:293–8.
31. Longo LD. Maternal blood volume and car-
diac output during pregnancy: a hypothesis of
endocrinologic control. Am J Physiol 1983;245:
R720–9.
32. Meah VL, Cockcroft JR, Backx K, Shave R,
Stöhr EJ. Cardiac output and related haemo-
dynamics during pregnancy: a series of meta-
analyses. Heart 2016;102:518–26.
33. Atkins AFJ, Watt JM, Milan P, Davies P,
Crawford JS. A longitudinal study of cardiovas-
cular dynamic changes throughout pregnancy.
Eur J Obstet Gynecol Reprod Biol 1981;12:
215–24.
34. Capeless EL, Clapp JF. Cardiovascular
changes in early phase of pregnancy. Am J
Obstet Gynecol 1989;161:1449–53.
35. Robson SC, Hunter S, Boys RJ, Dunlop W.
Serial study of factors influencing changes in
cardiac output during human pregnancy. Am J
Physiol 1989;256:H1060–5.
36. Clapp JF 3rd, Capeless E. Cardiovascular
function before, during, and after the first and
subsequent pregnancies. Am J Cardiol
1997;80:1469–73.
37. Spaanderman MEA, Meertens M, van
Bussel M, Ekhart THA, Peeters LLH. Cardiac
output increases independently of basal
metabolic rate in early human pregnancy.
Am J Physiol Heart Circ Physiol 2000;278:
H1585–8.
38. 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. Am J Clin Nutr
2005;81:678–85.
39. Ogueh O, Brookes C, Johnson MR.
A longitudinal study of the maternal
cardiovascular adaptation to spontaneous and
assisted conception pregnancies. Hypertens
Pregnancy 2009;28:273–89.
40. Mahendru AA, Everett TR, Wilkinson IB,
Lees CC, McEniery CM. A longitudinal study of
maternal cardiovascular function from precon-
ception to the postpartum period. J Hypertens
2014;32:849–56.
41. Petersen JW, Liu J, Chi YY, et al. Compari-
son of multiple non-invasive methods of
measuring cardiac output during pregnancy re-
veals marked heterogeneity in the magnitude of
cardiac output change between women. Physiol
Rep 2017;5:e13223.
42. Masini G, Foo LF, Cornette J, et al. Cardiac
output changes from prior to pregnancy to post
partum using two non-invasive techniques.
Heart 2019;105:715–20.
43. Osman MW, Nath M, Khalil A, Webb DR,
Robinson TG, Mousa HA. Longitudinal study to
assess changes in arterial stiffness and cardiac
output parameters among low-risk pregnant
women. Pregnancy Hypertens 2017;10:
256–61.
44. Tay J, Masini G, McEniery CM, et al. Uterine
and fetal placental Doppler indices are associ-
ated with maternal cardiovascular function. Am J
Obstet Gynecol 2019;220:96.e1–8.
45. Masini G, Tay J, McEniery CM, et al.
Maternal cardiovascular dysfunction is associ-
ated with hypoxic cerebral and umbilical Doppler
changes. J Clin Med 2020;9:2891.
46. Poppas A, Shroff SG, Korcarz CE, et al.
Serial assessment of the cardiovascular system
in normal pregnancy. Role of arterial compliance
and pulsatile arterial load. Circulation 1997;95:
2407–15.
47. Valensise H, Novelli GP, Vasapollo B, et al.
Maternal cardiac systolic and diastolic function:
relationship with uteroplacental resistances. A
Doppler and echocardiographic longitudinal
study. Ultrasound Obstet Gynecol 2000;15:
487–97.
48. Melchiorre K, Sharma R, Thilaganathan B.
Cardiac structure and function in normal preg-
nancy. Curr Opin Obstet Gynecol 2012;24:
413–21.
49. Chung E, Leinwand LA. Pregnancy as a
cardiac stress model. Cardiovasc Res
2014;101:561–70.
50. 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 Eu-
ropean Society of Hypertension (ESH) and of the
European Society of Cardiology (ESC). Eur Heart
J 2013;34:2159–219.
51. Foo FL, McEniery CM, Lees C, Khalil A;
International Working Group on Maternal He-
modynamics. Assessment of arterial function
in pregnancy: recommendations of the Inter-
national Working Group on Maternal Hemo-
dynamics. Ultrasound Obstet Gynecol
2017;50:324–31.
52. Iacobaeus C, Andolf E, Thorsell M, et al.
Longitudinal study of vascular structure and
FEBRUARY 2022 American Journal of Obstetrics & Gynecology
Expert Review
function during normal pregnancy. Ultrasound
Obstet Gynecol 2017;49:46–53.
53. Khalil A, Jauniaux E, Cooper D,
Harrington K. Pulse wave analysis in normal
pregnancy: a prospective longitudinal study.
PLoS One 2009;4:e6134.
54. Ling HZ, Guy GP, Bisquera A, Poon LC,
Nicolaides KH, Kametas NA. The effect of
parity on longitudinal maternal hemody-
namics. Am J Obstet Gynecol 2019;221:249.
e1–14.
55. Hausvater A, Giannone T, Sandoval YH,
et al. The association between preeclampsia
and arterial stiffness. J Hypertens 2012;30:
17–33.
56. Baulmann J, Schillings U, Rickert S, et al.
A new oscillometric method for assessment of
arterial stiffness: comparison with tonometric
and piezo-electronic methods. J Hypertens
2008;26:523–8.
57. Katsipi I, Stylianou K, Petrakis I, et al. The
use of pulse wave velocity in predicting pre-
eclampsia in high-risk women. Hypertens Res
2014;37:733–40.
58. Savvidou MD, Kaihura C, Anderson JM,
Nicolaides KH. Maternal arterial stiffness in
women who subsequently develop pre-
eclampsia. PLoS One 2011;6:e18703.
59. Khalil A, Garcia-Mandujano R, Maiz N,
Elkhouli M, Nicolaides KH. Longitudinal changes
in maternal hemodynamics in a population at risk
for pre-eclampsia. Ultrasound Obstet Gynecol
2014;44:197–204.
60. Celermajer DS, Sorensen KE, Gooch VM,
et al. Non-invasive detection of endothelial
dysfunction in children and adults at risk of
atherosclerosis. Lancet 1992;340:1111–5.
61. Noori M, Donald AE, Angelakopoulou A,
Hingorani AD, Williams DJ. Prospective study of
placental angiogenic factors and maternal
vascular function before and after preeclampsia
and gestational hypertension. Circulation
2010;122:478–87.
62. Kuscu NK, Kurhan Z, Yildirim Y, Tavli T,
Koyuncu F. Detection of endothelial dysfunction
in preeclamptic patients by using color Doppler
sonography. Arch Gynecol Obstet 2003;268:
113–6.
63. Bijl RC, Valensise H, Novelli GP, et al. Inter-
national Working Group on Maternal Hemody-
namics. Methods and considerations
concerning cardiac output measurement in
pregnant women: recommendations of the In-
ternational Working Group on Maternal Hemo-
dynamics. Ultrasound Obstet Gynecol 2019;54:
35–50.
64. Wen SW, Tan H, Retnakaran R, et al. Pre-
gravid predictors of new onset hypertension in
pregnancy—results from a pre-conception
cohort study in China. Eur J Obstet Gynecol
Reprod Biol 2017;214:140–4.
65. Nobles CJ, Mendola P, Mumford SL, et al.
Preconception blood pressure and its change
Into early pregnancy: early risk factors for pre-
eclampsia and gestational hypertension. Hy-
pertension 2020;76:922–9.
S1017
Expert Review
66. Nobles CJ, Mendola P, Mumford SL, et al.
Preconception blood pressure levels and
reproductive outcomes in a prospective cohort
of women attempting pregnancy. Hypertension
2018;71:904–10.
67. Atlass J, Menke M, Parks WT, Catov JM.
Pre-conception blood pressure and evidence of
placental malperfusion. BMC Pregnancy Child-
birth 2020;20:25.
68. Li N, An H, Li Z, et al. Preconception blood
pressure and risk of gestational hypertension
and preeclampsia: a large cohort study in China.
Hypertens Res 2020;43:956–62.
69. Egeland GM, Klungsøyr K, Øyen N, Tell GS,
Næss Ø, Skjærven R. Preconception cardio-
vascular risk factor differences between gesta-
tional hypertension and preeclampsia: Cohort
Norway Study. Hypertension 2016;67:
1173–80.
70. Scholten RR, Hopman MT, Lotgering FK,
Spaanderman ME. Aerobic exercise training in
formerly preeclamptic women: effects on
venous reserve. Hypertension 2015;66:
1058–65.
71. Scholten RR, Thijssen DJ, Lotgering FK,
Hopman MT, Spaanderman ME. Cardiovascular
effects of aerobic exercise training in formerly
preeclamptic women and healthy parous control
subjects. Am J Obstet Gynecol 2014;211:516.
e1–11.
72. Hürter H, Vontelin van Breda S, Vokalova L,
et al. Prevention of pre-eclampsia after infertility
treatment: preconceptional minimalisation of risk
factors. Best Pract Res Clin Endocrinol Metab
2019;33:127–32.
73. Chan E, Giallauria F, Vigorito C, Smart NA.
Exercise training in heart failure patients with
preserved ejection fraction: a systematic review
and meta-analysis. Monaldi Arch Chest Dis
2016;86:759.
74. Larsen MN, Madsen M, Nielsen CM,
et al. Cardiovascular adaptations after
S1018 American Journal of Obstetrics & Gynecology FEBRUARY 2022
10 months of daily 12-min bouts of intense
school-based physical training for 8e10-
year-old children. Prog Cardiovasc Dis
2020 [Epub ahead of print].
75. Buttery AK. Cardiac rehabilitation for frail
older people. Adv Exp Med Biol 2020;1216:
131–47.
76. Rasouli M, Pourheidari M, Hamzeh
Gardesh Z. Effect of self-care Before and During
pregnancy to prevention and control pre-
eclampsia in high-risk women. Int J Prev Med
2019;10:21.
77. Lu Y, Chen R, Cai J, Huang Z, Yuan H. The
management of hypertension in women plan-
ning for pregnancy. Br Med Bull 2018;128:
75–84.
78. Reddy S, Jim B. Hypertension and preg-
nancy: management and future risks. Adv
Chronic Kidney Dis 2019;26:137–45.
79. Valensise H, Vasapollo B, Novelli GP, et al.
Maternal and fetal hemodynamic effects
induced by nitric oxide donors and plasma vol-
ume expansion in pregnancies with gestational
hypertension complicated by intrauterine growth
restriction with absent end-diastolic flow in the
umbilical artery. Ultrasound Obstet Gynecol
2008;31:55–64.
80. Vasapollo B, Novelli GP, Gagliardi G, et al.
Medical treatment of early-onset mild gestational
hypertension reduces total peripheral vascular
resistance and influences maternal and fetal
complications. Ultrasound Obstet Gynecol
2012;40:325–31.
81. 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. Int J Gynecol Obstet 2017;136:
87–90.
82. Halpern DG, Weinberg CR, Pinnelas R,
Mehta-Lee S, Economy KE, Valente AM. Use of
medication for cardiovascular disease during
ajog.org
pregnancy: JACC state-of-the-art review. J Am
Coll Cardiol 2019;73:457–76.
83. Report of the National High Blood Pressure
Education Program Working Group on High
Blood Pressure in Pregnancy. Am J Obstet
Gynecol 2000;183:S1–22.
84. Duley L, Meher S, Jones L. Drugs for treat-
ment of very high blood pressure during preg-
nancy. Cochrane Database Syst Rev
2013;2013:CD001449.
85. Vasapollo B, Novelli GP, Valensise H. He-
modynamic guided treatment of hypertensive
disorders in pregnancy: is it time to change our
mind? J Matern Fetal Neonat Med 2019 [Epub
ahead of print].
86. Vasapollo B, Valensise H, Novelli GP, et al.
Abnormal maternal cardiac function and
morphology in pregnancies complicated by in-
trauterine fetal growth restriction. Ultrasound
Obstet Gynecol 2002;20:452–7.
87. Vasapollo B, Valensise H, Novelli GP,
Altomare F, Galante A, Arduini D. Abnormal
maternal cardiac function precedes the
clinical manifestation of fetal growth restric-
tion. Ultrasound Obstet Gynecol 2004;24:
23–9.
88. Ferrazzi E, Stampalija T, Monasta L, Di
Martino D, Vonck S, Gyselaers W. Maternal he-
modynamics: a method to classify hypertensive
disorders of pregnancy. Am J Obstet Gynecol
2018;218:124.e1–11.
89. Stott D, Papastefanou I, Paraschiv D,
Clark K, Kametas NA. Serial hemodynamic
monitoring to guide treatment of maternal hy-
pertension leads to reduction in severe hyper-
tension. Ultrasound Obstet Gynecol 2017;49:
95–103.
90. Tiralongo GM, Pisani I, Vasapollo B, Khalil A,
Thilaganathan B, Valensise H. Effect of a nitric
oxide donor on maternal hemodynamics in fetal
growth restriction. Ultrasound Obstet Gynecol
2018;51:514–8.