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Bn e f r o l o g i a. 2 0 2 3;4 3(3):269–280
Revista de la Sociedad Española de Nefrología
w w w.rev is tanef ro logia .com
eview
ardiovascular  and  renal  health:  Preeclampsia  as  a risk
arker
ecilia Villalaín Gonzáleza,b,c, Ignacio Herraiz Garcíaa,b,c, Leticia Fernández-Frierad,e,f,
ema  Ruiz-Hurtadob,f, Enrique Moralesb,g,∗, Jorge Solísb,f,h, Alberto Galindoa,b,c
Unidad de Medicina Fetal, Servicio de Obstetricia y Ginecología, Departamento de Salud Pública y Materno-Infantil, Hospital
niversitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain
Instituto de Investigación del Hospital 12 de Octubre (imas12), Madrid, Spain
Primary Care Interventions to Prevent Maternal and Child Chronic Diseases of Perinatal and Developmental Origin (RICORS network),
D21/0012/0024, Instituto de Salud Carlos III, Madrid, Spain
Hospital Universitario HM Montepríncipe-CIEC, Madrid, Spain
Centro Nacional de Investigaciones Cardiovasculares (CNIC), Madrid, Spain
Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Hospital Universitario 12 de Octubre, Madrid,
pain
Servicio de Nefrología, Departamento de Medicina, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid,
pain
Servicio de Cardiología, Hospital Universitario 12 de Octubre, Universidad Complutense de Madrid, Madrid, Spain
a  r  t  i  c  l  e  i  n  f  o
rticle history:
eceived 7 February 2022
ccepted 24 April 2022
eywords:
reeclampsia
ardiovascular
oman
revention
ypertension
a  b  s  t  r  a  c  t
Background: Cardiovascular (CVD) and chronic kidney disease (CKD) in women have unique
risk factors related to hormonal status and obstetric history that must be taken into account.
Pregnancy complications, such as preeclampsia (PE), can reveal a subclinical predisposition
for  the development of future disease that may help identify women who could benefit from
early  CVD and CKD prevention strategies.
Materials and methods: Review of PE and its association with future development of CVD and
CKD.
Results:  Multiple studies have established an association between PE and the development
of  ischemic heart disease, chronic hypertension, peripheral vascular disease, stroke and
CKD. It has not been sufficiently clarified if this relation is a causal one or if it is medi-k factors. Nevertheless, the presence of endothelial dysfunction andated by common risthrombotic microangiopathy during pregnancies complicated with PE makes us believe
that  PE may leave a long-term imprint. Early identification of women who have had a
pregnancy complicated by PE becomes a window of opportunity to improve women’s health
DOI of original article:
ttps://doi.org/10.1016/j.nefro.2022.04.010.
∗ Corresponding author.
E-mail address: emoralesr@senefro.org (E. Morales).
013-2514/© 2022 Sociedad Espan˜ola de Nefrologı´a. Published by Elsevier Espan˜a, S.L.U. This is an open access article under the CC
Y-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
270  n e f r o l o g i a. 2 0 2 3;4 3(3):269–280
through adequate follow-up and targeted preventive actions. Oxidative stress biomarkers
and  vascular ultrasound may play a key role in the early detection of this arterial damage.
Conclusions: The implementation of preventive multidisciplinary targeted strategies can help
slow  down CVD and CKD’s natural history in women at risk through lifestyle modifications
and  adequate blood pressure control. Therefore, we propose a series of recommendations
to  guide the prediction and prevention of CVD and CKD throughout life of women with a
history of PE.
© 2022 Sociedad Espan˜ola de Nefrologı´a. Published by Elsevier Espan˜a, S.L.U. This is an
open  access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/
by-nc-nd/4.0/).
Salud  cardiovascular  y  renal  en  la  mujer:  la  preeclampsia  como  marcador
de  riesgo
Palabras clave:
Preeclampsia
Cardiovascular
Mujer
Prevención
Hipertensión
r  e  s  u  m  e  n
Antecedentes: La enfermedad cardiovascular (ECV) y renal en la mujer presentan factores
de  riesgo propios relacionados con el estatus hormonal y los antecedentes obstétricos que
deben tenerse en cuenta. Las complicaciones del embarazo, como la preeclampsia (PE),
pueden revelar predisposiciones subclínicas a padecer enfermedades futuras que ayuden
a  identificar a aquellas mujeres que puedan beneficiarse de nuevas oportunidades para la
prevención de la ECV y la enfermedad renal crónica.
Materiales y métodos: Revisión sobre la PE y su asociación con el desarrollo de ECV y renal
futuras.
Resultados: Múltiples estudios han establecido una asociación entre PE y el desarrollo de
cardiopatía isquémica, hipertensión crónica, enfermedad vascular periférica, accidente
cerebrovascular y enfermedad renal. No se ha aclarado suficientemente si esta relación es
de  causalidad o está mediada por la presencia de factores de riesgo comunes. Sin embargo,
la  demostración de fenómenos de disfunción endotelial y microangiopatía trombótica en los
embarazos que cursan con PE hace suponer que esta puede dejar una impronta a largo plazo.
La  identificación precoz de las mujeres que han padecido un embarazo complicado con PE es
una  ventana de oportunidad para mejorar la salud de la mujer, mediante su seguimiento y
la  adopción de medidas preventivas adecuadas. Los marcadores bioquímicos de dan˜o oxida-
tivo y la ecografía vascular pueden desempen˜ar un papel clave en la identificación precoz
de  este dan˜o arterial.
Conclusiones: La implantación de estrategias preventivas multidisciplinares y específicas
puede ayudar a frenar la historia natural de la ECV y renal en las mujeres de riesgo, a
través de la modificación de su estilo de vida y del adecuado control de la tensión arterial.
Para ello, proponemos una serie de recomendaciones para guiar el estudio de la predicción
y  prevención de la ECV tras la PE a lo largo de la vida de la mujer.
©  2022 Sociedad Espan˜ola de Nefrologı´a. Publicado por Elsevier Espan˜a, S.L.U. Este es un
artı´culo Open Access bajo la licencia CC BY-NC-ND (http://creativecommons.org/licenses/Introduction:  current  situation  of  cardiovascular
health  in  women
Cardiovascular disease (CVD) is the leading cause of death in
women, with a mortality rate of 49% in Europe, 16 times higher
than that of breast cancer (3%).1 This generates a great eco-
nomic and social burden, as well as significant physical and
psychological consequences for women and their families.
Although 80% of CVD events are preventable, it is estimated
that the mortality rate in women is increasing, especially at
younger ages.2 Despite this, the importance of CVD in women
is underestimated because of a lack of social awareness, due
to the erroneous perception that they are protected against it.by-nc-nd/4.0/).
Consequently, preventive resources for CVD in women are not
sufficiently prioritized.
There are several underlying reasons:
1) Traditionally, women have been excluded from clinical
trials, wrongly assuming that cardiovascular risk factors
(CVR) and recommendations should be similar for men  and
women.3
2) CVR stratification is inadequate. Most women younger
than 60 years are classified in the low-risk category for CVD,
even in the presence of high CVR factor burden.4
3) CVD risk in women is influenced by specific factors such as
early menopause or a history of pregnancy complications
n e f r o l o g i a. 2 0 2 3;4  3(3):269–280 271
Table 1 – Differential diagnosis of hypertensive disorders of pregnancy.
Chronic hypertension Gestational hypertension Preeclampsia
Diagnosed hypertension: New-onset hypertension after
20 + 0 weeks of pregnancy.
New-onset HTN after 20 + 0 weeks of pregnancy that
also associates one of the following:
Before pregnancy. No associated proteinuria or other
signs of PE
Proteinuria:
Before 20 + 0 weeks of
pregnancy.
A  25% may progress to PE Determination of ≥300 mg of proteinuria in 24 h urine.
Protein/creatinine ratio ≥0.3 mg/dl in a urine sample.
Finding of 2++ protein in an isolated urine sample.
Clinical or analytical maternal organ dysfunction:
Clinical
Neurological altration (persistent visual disturbances,
stupor, headache or clonus).
Epigastralgia or pain in the right hypochondrium.
Oliguria (<30–35 ml/h or <500 ml/24 h).
Lab results
Kidney failure (blood creatinine ≥90 mol/l or
1 mg/dl).
Elevation of transaminases doubling normal values.
Thrombocytopenia ≤100,000/l
Hemolysis (schistocytosis, elevated LDH > 600 UI/l,
increased bilirubin or decreased haptoglobin).
DIC (increased PT or D-dimer, decreased fibrinogen).
Uteroplacental dysfunction:
IUGR, defined as PFE < p3 for gestational age and/or
PFE < p10 with increased umbilical artery resistance
(Doppler pulsatility index > p95) and/or increased
uterine artery resistance (mean uterine artery
pulsatility index > p95).
th res
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aCID: disseminated intravascular coagulation; IUGR: intrauterine grow
EFW: estimated fetal weight; PT: prothrombin time; HTN: hypertensio
such as preeclampsia (PE), gestational diabetes, or preterm
delivery. These factors are not included in the traditional
CVR assessment.5
) The clinical manifestations of CVD in men and women
show differences that lead to the fact that cardiovascu-
lar disease and its severity are being under-recognized in
women.
Symptoms of CVD in women are often more  complex and
ultifactorial than in men,6 which, together with lack of
ducative information, leads to women to consulti at more
dvanced stages. In summary, all these observations highlight
he need for a female-oriented approach, including specific
isk factors and intervention programs. In this review, we  high-
ight the timing of pregnancy, and especially the development
f PE, as a marker of cardiovascular health.
regnancy  as  a  new  paradigm  for  the
dentification  of  cardiovascular  risk  in  women
regnant women, their families and health personnel usually
pproach pregnancy as a transitory situation. Once the new
other is discharged, the focus shifts to the newborn. If there
as a complication during pregnancy (e.g., PE), surveillances usually maintained until the signs and symptoms of ill-
ess disappear, with the expectation that this will restore the
oman’s health. Concerns about its impact on future health
re often limited to the potential effects on subsequent preg-triction; LDH: lactate dehydrogenase; p: percentile; PE: preeclampsia;
nancies, and its long-term influence is forgotten or unknown.7
However, as we  will see, PE affects a woman’s health for the
rest of her life.
PE and other hypertensive disorders of pregnancy (Table 1)
affect 10% of pregnant women. PE is at the top of the list of
causes of maternal mortality, accounting for approximately
1 in 6 deaths in pregnant women8 and the leading cause
of admission to intensive care units during the puerperal
period.9 Although hypertension and other clinical symptoms
usually resolve in the weeks following delivery, its biological
effects are maintained over time, predisposing to insulin resis-
tance, hypertension, endothelial dysfunction and, ultimately,
metabolic syndrome.10 PE forms part of some gestational alter-
ations that have been shown to be associated with future CVR
in women, such as other hypertensive states of pregnancy,
gestational diabetes or preterm delivery (Table 2). Of these,
the most consistent association is shown by PE.11 CVD and PE
share risk factors, such as hyperlipidemia, obesity and hyper-
tension itself, and PE may act as a factor reinforcing the high
baseline risk of these patients.12 PE has also been shown to
increase the risk of renal disease and complications in subse-
quent pregnancies. Table 3 summarizes its complications for
the mother in the short, medium and long term.
Indeed, in recent years the concept has spread that preg-
nancy complications, such as PE, may reveal subclinical
predispositions to future disease that help to identify those
women who may benefit from new opportunities for chronic
disease prevention.13 Pregnancy proves to be a cardiovascu-
272  n e f r o l o g i a. 2 0 2 3;4 3(3):269–280
Fig. 1 – Common pathways for the development of preeclampsia and cardiovascular disease.
Table 2 – Pregnancy-related cardiovascular risk factors
for which scientific evidence is at least level II-2.
Hypertensive disorders of
pregnancy
Gestational hypertension
Preeclampsia/HELLP syndrome
Eclampsia
Other disorders related to
placental dysfunction
Intrauterine growth restriction
Abruptio placentae
Preterm delivery Idiopathic cause (some of these
cases have been associated
with placental dysfunction).
Metabolic alterations Gestational diabetes
Excessive weight gain during
pregnancy
Lack of postpartum weight loss
HELLP: hemolysis syndrome, elevated transaminases and thrombo-
cytopenia.
Table 3 – Women’s health risks associated with the
development of preeclampsia.
Period Risk
Short-term (weeks–months) Directly associated mortality
Cesarean delivery
Prolonged of hospital stay
Hemorrhage and placental
abruption
Thromboembolic risk
Medium term (months–years) Complications in subsequent
pregnancies:
Recurrence of preeclampsia.
Preterm labor
Intrauterine growth
restriction/low birth weight.
Long-term (years–decades) Cardiovascular disease
Renal disease
Lower life expectancySource: Bellamy et al.12, Rich-Edwards et al.14 and Smith et al.62
lar stress test. Some pregnant women may exceed the limit
of vascular dysfunction and develop PE, which demonstrates
their vulnerability to recurrence of PE and later CVD. The fre-
quency with which a woman fails this exercise stress test
and the severity of this failure marks the future risk of CVD
(Fig. 1). Following this argument, if we  can identify these
women at risk after a first complicated pregnancy with a PE, we
can implement early screening programs to modify lifestyle
habits or initiate treatments that can mitigate the risks in
subsequent pregnancies and also for long-term cardiovascular
health.14 Therefore, we are faced with the possibility of con-
verting a problem into a real window of opportunity to improve
women’s health.Source: Shih et al.63
Concept  of  placental  dysfunction  and  its
pathogenic  relationship  with  short-  and
long-term  endothelial  injury
In recent years there have been significant advances in the
understanding of the pathogenesis of placental dysfunction,
which is responsible of multiple closely linked complications
of pregnancy, especially EP, constrained intrauterine growth
and abruptio placentae. In addition, it is also associated with
preterm delivery and intrauterine death.15
The etiology of placental dysfunction is multifactorial.
There are involved various genetic, environmental and
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In short, PE is a major risk factor for the developmentn e f r o l o g i a. 2 0 
mmunological factors, most CVR factors (dyslipidemia,
ypertension, obesity, diabetes mellitus) and other abnormal-
ties such as systemic lupus erythematosus, thrombophilias
nd nephropathies. Apart from its ultimate origin, it is
resently established as “angiogenic hypothesis” that links
lacental dysfunction with the damage that appears in the
aternal endothelia through an imbalance in the processes
f angiogenesis. Thus, in response to situations of placen-
al hypoperfusion or hypoxia, the placenta releases into the
aternal circulation an excess of the anti-angiogenic factor
nown as the soluble form of tyrosine kinase-1 similar to
ms  (sFlt-1, for soluble fms-like tyrosine kinase-1), which blocks
he endothelial regenerating action of proangiogenic factors
uch as placental growth factor (PlGF) and vascular endothelial
rowth factor. This angiogenic imbalance triggers a generalized
ndothelial dysfunction in the pregnant woman that causes
he onset of hypertension, and cause damage to the fenes-
rated endothelia of the target organs affected by PE, such as
he brain, liver and kidney.16
In the second half of pregnancies complicated by placen-
al dysfunction, an elevated sFlt-1/PlGF ratio can be detected
n maternal serum at least one month before the first clin-
cal signs and symptoms appear. Moreover, the sFlt-1/PlGF
lteration is greater in the most severe and early cases. Its
ain clinical application is to guide in situations of sus-
ected preterm PE, with a high negative predictive value for
he appearance of PE in the following week (99%) and in the
ollowing 4 weeks (94%) when the sFlt-1/PlGF ratio is ≤38.17
owever, when the pregnancy is at term (37–42 weeks), PE
sually presents with milder forms and with less alteration
f the angiogenic balance.18,19 In these cases of late PE, pla-
ental abnormalities are is less marked and frequent. On the
ontrary, its onset is usually the result of a combination of
aternal predisposing factors and worse cardiovascular func-
ion secondary to the cardiovascular overload of pregnancy,
hich reaches its peak at this time. This ultimately compro-
ises placental perfusion, finally leading to the onset of PE.20
According to this model, 2 different hypotheses can be
ut forward to justify the endothelial damage and predispo-
ition to CVD and renal disease in women who have suffered
 gestational complication related to placental dysfunction.
ccording to a first hypothesis, this risk would be condi-
ioned by the sequelae of angiogenic imbalance produced
uring pregnancy and could affect women without pregesta-
ional risk factors. Angiogenic imbalance not only cause an
ndothelial alteration, but also other immunoinflammatory
bnormalities that play a long-term role in the cardiovascular
ealth of women, and it is not clear whether this is a per-
anent condition in the mother (and even in her children)
r whether it can be reversed over the years.21,22 Addition-
lly, sympathetic hyperactivity, decreased plasma volume
nd decreased baroreflex sensitivity, which have also been
bserved in the postpartum period, have been postulated as
utonomic alterations that may be the cause of subsequent
rterial hypertension.23 In the second hypothesis, both pla-
ental dysfunction and future CVD would be conditioned by
re-existing CVR factors, without the influence of angiogenic
mbalances in pregnancy.24 It is expected that new long-term
ollow-up and intervention studies, which take into account
he role of angiogenic imbalance in pregnancy, will clarify the(3):269–280 273
true causal relationship between placental dysfunction and
CVD.
Long-term  risks  following  preeclampsia  and
other  complications  related  to  placental
dysfunction
Cardiovascular  complications
It has been known since the 1960s that PE is a risk factor for
the development of chronic hypertension,25 but its associa-
tion with long-term CVR has not been specifically evaluated
until the last decade.26 In 2011, the American Heart Associa-
tion included in its cardiovascular prevention guidelines the
evaluation of women’s obstetric history, where the presence
of hypertensive disorders of pregnancy is a major factor in
CVR, recommending close follow-up in these women.27
Multiple studies have established a clear association
between PE and CVD, however, the origin of PE is still unclear.28
Both PE and atherosclerosis include in their pathophysiol-
ogy the activation of monocytes and inflammatory factors
that result in endothelial dysfunction. Within pregnancy itself,
there are also a series of factors that modulate the risk of sub-
sequent development of CVD, with a higher risk in women in
whom PE develops at a younger gestational age, has a more
severe course, and has at least one normal first pregnancy,
with a cumulative risk.7
The reported impact of PE on CVD varies across studies, as
follow-up periods differ and different definitions are used for
both PE and the set of entities that comprise CVD. In Appendix
A, the Supplementary Table 1 summarizes the main studies.
The relative risk (RR) of developing chronic hypertension in
the future varies between 3.1 and 3.7,12 with a mean follow-
up after delivery of 14 years. Women who have had PE in 2
or more  pregnancies have up to a 10-fold increased risk of
requiring antihypertensive medication in the future.29
The risk of CVD and infarction in women with a history
of PE has been confirmed in multiple epidemiological studies.
The RR of ischemic heart disease is 1.5–2.2, after 10 years of
delivery.30
It has also been observed that surrogate markers of CVD,
such as the coronary artery calcification index, are signifi-
cantly elevated in women with a history of PE when compared
to healthy women 30 years after the index pregnancies.31,32
Additional components of CVD, such as heart failure,
peripheral artery disease, and CVD mortality, double their
risk,33 with a significant increase in death from stroke also
observed in patients with a history of PE.34 Likewise, a his-
tory of PE increases the risk of death in patients with coronary
revascularization, with an adjusted RR of 1.6.35
The risk of developing diabetes mellitus in women with
a history of PE is as much as double,36 which may further
increase the CVR of these patients.of ischemic heart disease, chronic hypertension, peripheral
vascular disease, stroke and diabetes mellitus and this is
underestimated in routine clinical practice.
 0 2 3
ease that, once identified, should lead to early intervention to274  n e f r o l o g i a. 2
Renal  complications
PE has been defined as a disease with transient and reversible
renal involvement within 3 months after delivery. In addition,
women with chronic kidney disease (CKD) have a significantly
increased risk of developing PE. PE nephropathy is considered
to be a glomerular endotheliosis that can lead to glomeru-
lar dysfunction expressed as proteinuria and podocyturia.37
It is usually unknown whether the endothelial lesions that
develop during PE reverse after delivery; certainly a renal
biopsy is usually not performed after delivery. It is also
unknown whether sFlt-1 levels, and other markers that are
altered in PE, such as inflammatory cytokines and angiotensin
II type 1 receptor agonist autoantibodies, remain altered to any
degree after delivery. On the other hand, the imbalance in the
organization of the podocyte cytoskeleton could also cause a
loss of podocytes in the urine and compensatory glomerular
hypertrophy, which leads to changes in the glomerular base-
ment membrane, an increase in the extracellular matrix and
the development of focal glomerulosclerosis that ends up in
the appearance of proteinuria and CKD.38–40
There is little information in the literature on the risk
of developing CKD after PE.41 A systematic review of retro-
spective studies highlighted the association between PE and
persistent microalbuminuria after delivery. After a median
follow-up of 7.1 years after delivery, 31% of women with PE
developed microalbuminuria compared to 7% of women with
uncomplicated pregnancies. Women with severe PE had an
8-fold increased risk of developing microalbuminuria. There
were no differences in serum creatinine values or renal
glomerular filtration rate.42 However, the inclusion criteria of
this study required a minimum follow-up of only 6 months
after delivery, which is too short a period to assess the risk of
CKD or advanced chronic kidney disease (ACKD). The results
reported by other studies with longer-term follow-up have
been more  contradictory. Classic studies directly linked PE
with a 4-fold increased risk of developing ACKD within 10
years after pregnancy.43 However, the Dutch Prevention of Renal
and Vascular End-stage Disease – PREVEND – study, which ana-
lyzed renal function in women with a history of hypertensive
disorders during pregnancy, did not observe increased protein-
uria or incidence of CKD.44
To better assess the long-term renal risk of PE, Covella
et al. conducted a systematic review including studies with a
follow-up of at least 4 years. This review highlighted that the
RR of developing ACKD was significantly higher40 in 110,803
women with PE compared to 2,680,929 women as a control
group. However, they were unable to elucidate whether the
risk of ACKD was related to the presence of underlying dis-
eases that might predispose to the development of PE or to
the severity of PE itself. In parallel to what happens with other
CVD, there are important limitations in these retrospective
studies to identify the phenotype of the patient with PE who
is more  at risk of developing ACKD, since the risk factors for
CKD and PE overlap.45–47
Finally, in recent years several studies have shown asso-
ciation of pregnancy with various forms of thrombotic
microangiopathy, including atypical hemolytic uremic syn-
drome. These describe a new view of the involvement of
dysregulation of the alternative complement pathway in the;4 3(3):269–280
etiopathogenesis of atypical hemolytic uremic syndrome and
a form of PE known as hemolysis, elevated transaminases and
thrombocytopenia syndrome (HELLP). In this sense, comple-
ment should be considered as a new protagonist in vascular
disease due to its direct involvement with the endothelium,
and thus, its alterations should be considered as a new CVR
factor in pregnant women.48,49
Early  detection  of  subclinical  atherosclerosis
and  preventive  strategies  in  women  with  a
history  of  preeclampsia
Atherosclerosis remains one of the most important public
health problems for women in the western world. Atheroscle-
rosis is influenced by the presence of CVR factors, including
PE, and it is critical to identify strategies for its prevention
and early diagnosis. Imaging can play a key role by iden-
tifying atherosclerotic plaques at early stages. According to
clinical practice guidelines, the most appropriate techniques
are coronary calcium quantification by CT and vascular ultra-
sound. The latter makes it possible to identify the presence
of atherosclerotic plaques in the vascular wall in a sim-
ple, non-invasive and rapid manner. It has also been shown
that ultrasound detection of plaque is associated with the
occurrence of CVD,50 with the same accuracy as coronary cal-
cification detected by CT.
A population-based study The Progression of Early Subclin-
ical Atherosclerosis – PESA – has been studying for the past
10 years more  than 4000 individuals aged 40–54 years with
imaging techniques to evaluate the presence and progres-
sion of atherosclerosis in early stages. It has been observed
that nearly 50% of women aged 40–54 years have subclini-
cal atherosclerosis, and 25% have 2 or more  affected arterial
territories.51 Even in the absence of CVR factors, 40% of the
participants had subclinical disease.52 However, all of them
were at low risk according to the European SCORE. This lack
of accuracy of the scores in predicting CVD in women could be
related to the lack of analysis of their specific CVR factors.
There is ample evidence demonstrating the benefit of CVD
prevention at early stages. However, it has not been system-
atically implemented, which contrasts with the widespread
development of breast cancer screening, despite the fact that
CVD mortality in women is much higher than breast cancer.
Significant progress has been made in raising awareness of
the importance of CVD in American women through initia-
tives such as Go Red for Women, or the Mujeres por el Corazón
campaign of the Spanish Society of Cardiology, whose main
objective is to raise awareness among women about CVD pre-
vention and promote healthy habits.
Proposal  for  the  comprehensive  care  of  women
who  have  suffered  preeclampsia
As has been explained, PE is a risk factor of CV and Renal dis-halt the development and progression of these diseases. As a
starting point, it is essential to highlight the importance of a
correct identification of those women who develop PE during
n e f r o l o g i a. 2 0 2 3;4  3(3):269–280 275
Fig. 2 – Three-step strategy for cardiovascular risk reduction after a pregnancy complicated by preeclampsia.
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eregnancy. To this end, it is necessary to insist on correct blood
ressure (BP) measurement during obstetric visits, often lim-
ted by lack of time, lack of appropriate equipment or incorrect
ractices (such as, for example, the use of incorrectly sized
uffs, BP measurement in the recumbent position, or taking
nly one measurement). Particular attention should be paid
o blood pressure values, comparing them whenever possible
ith the references from the first trimester and their trajec-
ory throughout gestation.53 If an increasing trend is observed,
igns or symptoms of PE should be monitored, and protein-
ria should be determined (an isolated determination with
rotein/creatinine index is valid). However, it is very impor-
ant to bear in mind that PE does not always present with
ypertension and proteinuria, but sometimes has more  het-
rogeneous forms of presentation. It is therefore essential to
lways maintain a high degree of suspicion,54 and in these
ases the angiogenic biomarkers sFlt-1-PlGF can be used to
onfirm or rule out the diagnosis of PE.
We propose a follow-up strategy that begins in the postpar-
um period and will accompany the woman throughout her
ife. It is based on the one we  have implemented in recent years
or the follow-up of cases of early PE, involving obstetricians,
ephrologists and cardiologists (Fig. 2).
First, unified strategies for the management of hyperten-
ion and thromboembolic risk in the puerperium should be
stablished. Obstetricians, nephrologists, and primary care
hysicians should carefully follow women presenting with
ostpartum hypertension and be familiar with both anti-
ypertensive treatments compatible with breastfeeding and
he need for thromboprophylaxis. In general, it is recom-
ended to introduce antihypertensive medication whenever
ostpartum BP is >140/90 mmHg,55,56 and drugs such as
nalapril, nifedipine or labetalol can be used in the firstline, avoiding alfamethyldopa because of its association with
puerperal depression. Close ambulatory monitoring of BP
evolution should be carried out, which in most cases will
allow the gradual withdrawal of antihypertensive medication.
Those postpartum women in whom hypertension persists
despite the use of antihypertensive drugs at maximum doses
will require complementary studies and a multidisciplinary
approach with nephrologists, anesthesiologists and endocri-
nologists to establish a differential diagnosis. The risk of
venous thromboembolism is increased in the puerperium
(0.3/1000 pregnancies) and even more  after PE (1.2/1000
pregnancies).57 There is no consensus among the different
clinical guidelines on how to perform thromboprophylaxis.
Our proposal is to use low molecular weight heparin in pro-
phylactic doses during the first 2 weeks of puerperium after
EP and increase to 6 weeks in the case of early EP (before 34
weeks) or after EP and cesarean section.58
Secondly, it is advisable to offer preconception counsel-
ing within the first year after the EP episode or when the
patient requests it, since many  women who have had an
EP often have doubts and uncertainty regarding their repro-
ductive future. The risk of recurrence of PE in subsequent
pregnancies is approximately 15%, although it may be higher
if it has occurred in more  than one pregnancy, if it resulted
in preterm delivery, or if there are predisposing conditions.59
Although these figures may be discouraging, it should be
emphasized that in most subsequent pregnancies PE does not
occur or does not manifest severely and that the prophylactic
use of low-dose aspirin (150 mg/d taken at night between 12
and 36 weeks of gestation) prevents more  than 60% of early
forms of PE.60 In those women with a history of early PE it is
advisable to perform a thrombophilia study in case they could
also benefit from prophylactic anticoagulation. Although it
 0 2 3
r
1
1
1
1276  n e f r o l o g i a. 2
has been proposed to prevent PE recurrence through lifestyle
changes, there are still important gaps in knowledge about
their possible benefit.61 Nevertheless, it seems reasonable to
recommend healthy lifestyle habits and referral to a specialist
if CVR factors such as hypertension, obesity, smoking, diabetes
or dyslipidemia are detected.
Finally, the challenge of long-term CVD prevention needs
to be addressed. Given that CVD can take decades to manifest
after PE, the question is: when should screening and interven-
tion be initiated? In our opinion, up to the age of 50 years,
an opportunistic approach could be taken by primary care
physicians and obstetrician-gynecologists, taking advantage
of visits for other causes to evaluate CVR factors. After the age
of 50 years, it is advisable to carry out a specific assessment
of CVR and renal disease, implement appropriate prophylactic
or therapeutic measures, and establish annual or case-specific
follow-up visits (Fig. 2).
Conclusions
Pregnancy is a cardiovascular stress test that provides valuable
information on the woman’s future CVR. Although no clear
causality has been established between PE or other situations
of placental dysfunction and the development of ischemic
heart disease, chronic hypertension, peripheral vascular dis-
ease, stroke, or kidney disease, the association between them
is undeniable. Therefore, it is essential to raise awareness
among both patients and professionals of the future risks and
to support the creation of multidisciplinary programs for the
adequate follow-up and prevention of CVD and renal disease
in women with this obstetric history.
Financing
The present work has been funded by the Instituto de Salud
Carlos III with the project “Cardiovascular health in women
with a history of early preeclampsia” (grant PI19/01579), and by
the Spanish Society of Cardiology, through a Grant for Trans-
lational Research Projects in Cardiology (grant TP18/0308).
Conflict  of  interest
The authors declare that they have no conflicts of interest.
Appendix  A.  Supplementary  dataSupplementary material related to this article can be found,
in the online version, at doi:https://doi.org/10.1016/j.nefroe.
2022.04.009.
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