Early Human Development 174 (2022) 105669

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Early Human Development

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Preeclampsia: Maternal cardiovascular function and optimising outcomes☆

Natalie Dennehy a, Christoph Lees b, *
a
Imperial College Healthcare NHS Trust, Queen Charlotte's Hospital, Du Cane Road, London, United Kingdom of Great Britain and Northern Ireland
b
Department of Metabolism, Digestion and Reproduction, Imperial College London, United Kingdom of Great Britain and Northern Ireland

A B S T R A C T

Preeclampsia is associated with cardiac dysfunction, not only during the clinical phase of the disease, but also after delivery, with long term implications for both
maternal and neonatal cardiovascular health. An abnormal cardiovascular phenotype also precedes conception, indicating that pre-existing cardiovascular
dysfunction is associated with the development of preeclampsia. This review summarises the changes in cardiovascular function in preeclampsia, examining the
evidence for when cardiovascular dysfunction develops and presenting the evidence for two phenotypes – one associated with fetal growth restriction, low cardiac
output and high peripheral resistance, and a second associated with normal fetal growth, high cardiac output and low peripheral resistance. The presence of a
cardiovascular phenotype that precedes conception demonstrates the potential for prevention of preeclampsia through cardiovascular optimisation at this stage. The
two phenotypes mean therapy can be targeted to optimising cardiovascular function. The prevention and effective treatment of preeclampsia are essential aspects of
improving maternal and neonatal cardiovascular health in the long term.

1. Introduction in peripheral resistance, or increased peripheral resistance, with an

Preeclampsia is a multisystem disorder of pregnancy affecting 2–8 %
of pregnancies [1]. It is defined by the presence of new onset hyper­
tension and new onset proteinuria or fetal growth restriction. It is a
significant cause of preterm birth and fetal growth restriction, with
associated long-term consequences for infants and children. It is also
associated with a long-term impairment of cardiovascular function in
mothers, with women with preeclampsia at a significantly increased risk
of chronic hypertension, stroke, and cardiac failure, with a higher risk
for those with early onset preeclampsia [2].
2. Cardiovascular function in preeclampsia
Preeclampsia used to be thought of primarily as a placental condi­
tion, where poor placentation was thought to be the driver of hyper­
tension and proteinuria, to drive blood flow through the otherwise
poorly perfused placenta [3]. However, the application of non-invasive
methods to measure cardiovascular function to women with hyperten­
sive disorders of pregnancy, suggest that rather than the cardiovascular
changes of preeclampsia being driven by the placenta, preeclampsia
develops due to abnormal cardiovascular function (Fig. 1).
Blood pressure is determined by the cardiac output and peripheral
resistance, in accordance with Ohm's law. Thus hypertension is a result
of either increased cardiac output, with an inadequate compensatory fall
inadequate compensatory fall in cardiac output. Pregnancy is associated
with vasodilation to compensate for the increasing blood volume
required to attain an increased cardiac output [4].
Early studies of cardiovascular function in preeclampsia demon­
strated that women with preeclampsia had a high cardiac output [5] and
that these changes occurred prior to onset of hypertension and persisted
postnatally even once hypertension had resolved. This was contradicted
by later studies which demonstrated a significantly raised cardiac output
in pregnancy in women who would go on to develop preeclampsia
before hypertension had developed, but that cardiac output fell, and
peripheral resistance increased when the clinical syndrome developed
[6].
This seeming contradiction was consistent with the observation that
preeclampsia has different characteristics depending on its timing of
onset (early or late) and in the presence or absence of fetal growth re­
striction. Later studies stratified preeclampsia by timing of onset and the
presence of absence of fetal growth restriction. Valensise demonstrated
that preeclampsia developing before 34 weeks gestation was associated
with high peripheral resistance and low cardiac output, and later onset
preeclampsia was associated with low peripheral resistance and high
cardiac output [7]. These changes were present at 24 weeks, preceding
the development of hypertension and proteinuria. It was noted that
there were differences between the cohorts of women who went on to
develop early onset preeclampsia, who were of older age, and later onset

☆
Disclaimer: CCL is supported by the NIHR Biomedical Research Centre (BRC) based at Imperial College Healthcare NHS Trust and Imperial College London.
* Corresponding author.
E-mail address: c.lees@imperial.ac.uk (C. Lees).

https://doi.org/10.1016/j.earlhumdev.2022.105669

Available online 15 September 2022

0378-3782/© 2022 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-
nc-nd/4.0/).
N. Dennehy and C. Lees
preeclampsia, who had a higher average BMI.
Higher body mass index is associated in particular with high cardiac
output, low resistance preeclampsia [8]. In fact, the patients enrolled in
Easterling's original study had a high mean BMI and this could have
contributed to the consistent finding of raised cardiac output [5].
Later studies questioned the importance of the timing of onset of
preeclampsia, rather highlighting the significance of the present of fetal
growth restriction. In preeclampsia with fetal growth restriction, pe­
ripheral vascular resistance was seen to be high and cardiac output low,
whereas preeclampsia without fetal growth restriction is associated with
a low vascular resistance and high cardiac output [9]. Tay et al.
demonstrated the key role of the rather the presence or absence of fetal
Fig. 1. Infographic, Painting Pixels Ltd, 2022: Low cardiac output + high peripheral resistance → poor placental function → hypertension and increased vascular
permeability.
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Early Human Development 174 (2022) 105669
growth restriction which separates the phenotype of preeclampsia with
growth restriction, high peripheral resistance and low cardiac output,
from preeclampsia with normal growth, low peripheral resistance and
high cardiac output [10]. Fetal growth restriction appears to be on the
same disease spectrum as preeclampsia, associated with raised periph­
eral resistance but preserved cardiovascular function. In these cases,
preeclampsia develops alongside associated with cardiovascular dia­
stolic dysfunction [11].
The evidence now suggests two phenotypes of preeclampsia – the
first associated with a high peripheral resistance and a failure of the
normal vasodilator response of pregnancy, which is associated with fetal
growth restriction and early onset hypertension [12]. The second
N. Dennehy and C. Lees
phenotype has high cardiac output with low or normal peripheral
resistance and is associated with late onset hypertension.
3. Onset of cardiovascular dysfunction
The classic description of the aetiology of preeclampsia is that the
failure of conversion of the spiral arteries of the placenta leads to a
consequent maladaptive cardiovascular response driving hypertension
and increased vascular permeability leading to proteinuria. However,
cardiovascular adaptation to pregnancy occurs in even in very early
pregnancy, preceding the development of the placenta. In healthy
pregnancies, augmentation index (a measure of arterial stiffness) and
blood pressure fall even within the first six weeks of pregnancy, long
before the placenta has formed [13,14]. It therefore is plausible that it is
in fact the impaired cardiovascular response to pregnancy that is pri­
mary and leads to abnormal placental blood flow, rather than the
reverse.
In fact, the cardiovascular changes described for preeclampsia not
only predate the development of hypertension, but they actually predate
pregnancy. Healthy women trying to conceive who subsequently
developed preeclampsia and fetal growth restriction had lower pre­
conception cardiac output and higher peripheral resistance [15]. This
small cohort excluded women with high BMI which could explain the
dominance of this low cardiac output phenotype.
The impact of antenatal cardiovascular function does not end with
determining whether a patient will develop preeclampsia. In healthy
pregnancies, the increase in cardiac output throughout pregnancy
positively correlates with fetal growth velocity and birth weight, and the
reduction in peripheral vascular resistance is associated with increased
birth weight [16]. This suggests that fetal growth restriction, which is
strongly associated with early onset preeclampsia, low cardiac output
and high peripheral resistance, is an extreme of a spectrum of fetal
growth determined by the function of the placenta in response to
varying cardiovascular responses to pregnancy which occur prior to the
formation of the placenta.
In healthy pregnancies, the cardiac output generally rises until the
second trimester and then falls approaching term, reaching a compara­
ble level to preconception in the postpartum period. Vascular resistance
falls in pregnancy with a nadir in the second trimester, returning to
normal levels in the post-partum period [14]. However, in women with
preeclampsia there is longstanding cardiovascular dysfunction seen in
the postpartum period. Women with early onset preeclampsia have
increased vascular resistance at one year postpartum, and women with
late onset preeclampsia have significantly higher cardiac output and
lower vascular resistance at one year postpartum [7]. This persistence of
cardiovascular abnormalities provides a potential mechanism for the
increased long term cardiovascular morbidity associated with pre­
eclampsia, including the increased risk of cardiac failure, ischaemic
heart disease and stroke [2].
4. Optimising cardiovascular function in preeclampsia
The identification of the cardiovascular changes in pregnancy which
precede the development of the clinical syndrome (i.e., a latent phase)
raises the possibility that therapy at this stage might prevent or postpone
the development of the clinical syndrome.
As cardiovascular function appears to determine the risk of devel­
oping preeclampsia, this is also a target for preventative therapy. Ex­
ercise therapy has been shown to improve markers of metabolic
syndrome including endothelial function, vascular wall thickness and
autonomic control in women who have previously had preeclampsia,
who are at increased risk of recurrence in future pregnancies [17]. It is
unclear whether the cardiovascular dysfunction seen in these women is
cause or consequence of preeclampsia, or a combination of the two.
Exercise therapy played a role in normalising the biomarkers of car­
diovascular function, although further research is needed into whether
3
Early Human Development 174 (2022) 105669
this could prevent preeclampsia. BMI optimisation also has a role to play
in the prevention of preeclampsia, with significant interpregnancy
weight loss in overweight and obese women being shown to reduce the
incidence of preeclampsia in subsequent pregnancies, and weight gain to
significantly increase the risk [18].
There is good evidence that low dose aspirin commenced in the first
or early second trimester of pregnancy is associated with a decreased
risk of preeclampsia in women who are high risk [19]. This has long
been ascribed to the affect of aspirin at a placental level, decreasing
thromboxane and lipid peroxidases and enhancing trophoblast invasion
and fms-like tyrosine kinase 1 production [20,21]. However, aspirin
demonstrably optimises cardiovascular function and has a role in the
prevention of myocardial infarction and stroke, and so its preeclampsia
modifying effect could have a similar mechanism [22].
Therapy for preeclampsia has typically involved various strategies to
lower blood pressure, including triggering vasodilation, and decreasing
cardiac output and these treatments are used variably with respect to the
timing of onset of preeclampsia and the presence of fetal growth re­
striction. The two phenotypes of preeclampsia, as defined by associated
cardiovascular change, therefore provide a potential opportunity for
targeted antihypertensive therapy that seeks to compensate for the un­
derlying cardiovascular deficit. Previous studies have shown that vaso­
dilator therapy in fetal growth restriction can improve birth weight and
growth velocity [23]. More studies are required to identify if targeting
therapy in this way in preeclampsia achieves better blood pressure
control or improved obstetric outcomes.
5. Neonatal cardiovascular function
The cardiovascular consequences of preeclampsia outlast pregnancy
not only for the mother, but also for the neonate. The association be­
tween preeclampsia and impaired cardiovascular function is multifac­
torial and related to the increased incidence of prematurity and fetal
growth restriction. Preeclampsia is associated with a significantly
increased chance of preterm birth, with the associated increase in car­
diovascular risk [24]. This increased cardiovascular risk is longstanding,
and the effect may be cross-generational, with the children and grand­
children of infants born preterm demonstrating an increased risk of
ischaemic heart disease in adulthood [25]. Preeclampsia is also associ­
ated with fetal growth restriction, which has profound cardiovascular
consequences. Infants with lower birth weight have a higher risk of
cardiovascular events in adulthood [26]. Fetal reduced growth velocity,
which suggests placental dysfunction, is associated with an increased
risk of ischaemic cardiac events even if it does not result in low birth
weight [27]. There is limited evidence for preeclampsia having neonatal
effects beyond these two factors, however the offspring of mothers with
preeclampsia themselves have a higher systolic blood pressure [28].
Strokes in adulthood are also more common in the offspring of mothers
with preeclampsia [29]. Thus preeclampsia, particularly early onset
preeclampsia which is more commonly associated with preterm delivery
and fetal growth restriction, contributes significantly to the neonate's
long-term risk of developing cardiovascular disease.
6. Conclusion
Increasing understanding of cardiovascular adaptation in healthy
pregnancies, has led to a better understanding of the aetiology of pre­
eclampsia. This presents a unique opportunity to develop and improve
therapy for preeclampsia, with a potential for prevention of pre­
eclampsia and targeted therapy. Optimising cardiovascular function
prior to pregnancy may be the key to the prevention of preeclampsia.
The prevention and effective and timely treatment of preeclampsia is
also essential to improve the long-term cardiovascular health of mothers
and their offspring.
N. Dennehy and C. Lees Early Human Development 174 (2022) 105669

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