Management of Hypertensive Disorders in Pregnancy

Consensus Document
Management of hypertensive disorders in

pregnancy: a Position Statement of the European
Society of Hypertension Working Group
‘Hypertension in Women’
Costas Thomopoulos a, Jana Brguljan Hitij b, Tine De Backer c, Eugenia Gkaliagkousi d,
Reinhold Kreutz e, Marilucy Lopez-Sublet f, Maria Marketou g, Anastasia S. Mihailidou h,i,
Agnieszka Olszanecka j, Antoinette Pechere-Bertschi k, Mariana Paula Perez l, Alexandre Persu m,
Federica Piani , Thenral Socrates , Katarzyna Stolarz-Skrzypek , and Renata Cıfkova
n o j
p,q
Hypertensive disorders in pregnancy (HDP), remain the HELLP, hemolysis, elevated liver enzymes, low platelets;
leading cause of adverse maternal, fetal, and neonatal i.v., intravenous; ICSI, Intra-Cytoplasmic Sperm Injection;
outcomes. Epidemiological factors, comorbidities, assisted ISSHP, International Society for the Study of Hypertension
reproduction techniques, placental disorders, and genetic in Pregnancy; IUGR, intrauterine growth restriction; IUI,
predisposition determine the burden of the disease. The intrauterine insemination; IVF, in-vitro fertilization; PIERS,
pathophysiological substrate and the clinical presentation of Preeclampsia Integrated Estimate of Risk; PLGF, placental
HDP are multifarious. The latter and the lack of well growth factor; PPGL, pheochromocytoma/paraganglioma;
designed clinical trials in the field explain the absence of sFlt-1, soluble fms-like tyrosine kinase-1; STRIDE-BP,
consensus on disease management among relevant Science and Technology for Regional Innovation and
international societies. Thus, the usual clinical management Development in Europe – Blood Pressure
of HDP is largely empirical. The current position statement
of the Working Group ‘Hypertension in Women’ of the
European Society of Hypertension (ESH) aims to employ the
current evidence for the management of HDP, discuss the
recommendations made in the 2023 ESH guidelines for the Journal of Hypertension 2024, 42:1109–1132
management of hypertension, and shed light on a
Department of Cardiology, General Hospital of Athens Laiko, Athens, Greece,
b
controversial issues in the field to stimulate future research. Department of Hypertension, University Medical Centre Ljubljana, Medical University
Ljubljana, Slovenia, cCardiovascular Center & Clinical Pharmacology, University Hos-
Keywords: assisted reproduction, cardiovascular risk, pital Gent, Belgium, d3rd Department of Internal Medicine, Papageorgiou Hospital
gestational hypertension, hypertension, hypertensive Faculty of Medicine, Aristotle University of Thessaloniki, Greece, eCharite-Univer-
sit€atsmedizin Berlin, Institute of Clinical Pharmacology and Toxicology, Berlin,
disorders in pregnancy, preeclampsia, pregnancy Germany, fAP-HP, Hopital Avicenne, Centre dExcellence Europeen en Hypertension
outcomes, pregnancy Arterielle, Service de Medecine Interne, INSERM UMR 942 MASCOT, Paris 13-Uni-
versite Paris Nord, Bobigny, FCRIN INI-CRCT (Cardiovascular and Renal Clinical
Abbreviations: ABPM, ambulatory blood pressure Trialists), gSchool of Medicine, University of Crete, Heraklion, Greece, hDepartment
monitoring; ACR, albumin to creatinine ratio; AIPE, Italian of Cardiology and Kolling Institute, Royal North Shore Hospital, St Leonards, iFaculty of
Medicine and Health Sciences, Macquarie University, Sydney, New South Wales,
Association of Preeclampsia; ART, assisted reproductive Australia, j1st Department of Cardiology, Interventional Electrocardiology, and Hy-
technology; ASPRE, Combined Multimarker Screening and pertension, Jagiellonian University Medical College, Krakow, Poland, kUniversity of
Geneva, Switzerland, lDepartment of Hypertension. Hospital de Agudos J. M. Ramos
Randomized Patient Treatment with Aspirin for Evidence- Mejıa, Buenos Aires, Argentina, mDivision of Cardiology, Cliniques Universitaires
Based Preeclampsia Prevention; BP, blood pressure; BUMP, Saint-Luc and Pole of Cardiovascular Research, Institut de Recherche Experimentale
Blood Pressure Monitoring in High-Risk Pregnancy to et Clinique, Universite Catholique de Louvain, Brussels, Belgium, nHypertension and
Cardiovascular Risk Research Center, Medical and Surgical Sciences Department,
Improve the Detection and Monitoring of Hypertension; Alma Mater Studiorum University of Bologna, Bologna, Italy, oMedical Outpatient and
CHAP, Chronic Hypertension and Pregnancy; CHIPS, Hypertension Clinic, ESH Hypertension Centre of Excellence University Hospital Basel,
Control of Hypertension in Pregnancy Study; CI, Basel, Switzerland, pCenter for Cardiovascular Prevention, Charles University in
Prague, First Faculty of Medicine and Thomayer University Hospital and qDepartment
confidence interval; CKD, chronic kidney disease; eGFR, of Medicine II, Charles University in Prague, First Faculty of Medicine, Prague, Czech
estimated glomerular filtration rate; ESH, European Society Republic
of Hypertension; FEIRI, European/International Correspondence to Costas Thomopoulos, MD, Head of Cardiology Department,
General Hospital of Athens Laiko; 17, Ag. Thoma Street, 11527 Athens, Greece.
Fibromuscular Dysplasia Registry; FET, frozen–thawed Tel: +30 2132061032; e-mail: [email protected]
embryo transfer; FIVET, Fertilization in Vitro and Embryo Received 25 March 2024 Accepted 25 March 2024
Transfer; FMD, fibromuscular dysplasia; FMF, Fetal J Hypertens 42:1109–1132 Copyright © 2024 Wolters Kluwer Health, Inc. All rights
Medicine Foundation; HBPM, home blood pressure reserved.
monitoring; HDP, hypertensive disorders in pregnancy; DOI:10.1097/HJH.0000000000003739
Journal of Hypertension www.jhypertension.com 1109
Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.

Thomopoulos et al.
INTRODUCTION based on office BP measurements [5,6]. The previous defi-

nition of a hypertensive emergency in pregnancy at levels at
H
ypertensive disorders in pregnancy (HDP) have an least 170/110 mmHg for SBP/DBP should be abandoned,
incidence of approximately 10% worldwide and and all women with new-onset confirmed severe hyper-
are a major cause of maternal, fetal, and neonatal tension should be hospitalized for immediate evaluation
morbidity and mortality [1]. Maternal risks include placental and treatment [7,8].
abruption, stroke, pulmonary edema, thromboembolic
events, renal failure, multiple organ failure, and dissemi- CLASSIFICATION OF HYPERTENSIVE
nated intravascular coagulation. The fetus is at high risk of
intrauterine growth restriction (IUGR; 25% of cases of DISORDERS IN PREGNANCY
preeclampsia), prematurity (27% of cases of preeclampsia), Considering pathophysiological, clinical, and manage-
and intrauterine death (4% of cases of preeclampsia). ment differences, HDP can be divided into two distinct
Premature newborns are also exposed to prolonged phenotypes [5]. The first is preexisting (chronic) hyper-
high-level neonatal care, postnatal death, and higher car- tension that precedes pregnancy or is diagnosed before
diovascular risk later in life [2]. the 20th week of pregnancy. It usually persists for more
The clinical management of HDP remains, by and large, than 6 weeks after delivery and, depending on the cause,
empirical because of scarce clinical research in the field and can be classified as essential or secondary hypertension.
the suboptimal outcome reporting across different studies For preexisting hypertension, based on discrepancies
[3]. Moreover, the expert opinion recommendations in between office and out-of-office BP values before or
different guidelines related to HDP are not only character- during the first half of pregnancy, we also recognize the
ized by areas of general agreement but also with significant importance of diagnosing or ruling out white-coat or
dissimilarities potentially associated with great variability in masked hypertension. The second phenotype is gestation-
decision-making [4]. Areas of major consensus between the al hypertension, which develops after 20 weeks of preg-
international guidelines for managing pregnancy-related nancy and usually resolves within 6 weeks after delivery.
hypertensive disorders include the use of automated blood Gestational hypertension also has two types: preeclamp-
pressure (BP) measurement with validated devices, imple- sia and transient hypertension (Table 1).
mentation of a dipstick to assess proteinuria followed by It should be noted that preexisting and gestational hy-
quantitative confirmation, adoption of the broader defini- pertension are conditions not clinically exclusive to each
tion of preeclampsia, clear recommendation for the use of other and, at times, may overlap. Thus, a woman with
aspirin to prevent preeclampsia in high-risk and moderate- preexisting hypertension may develop preeclampsia (i.e.
risk women, recognition that sustained hypertension in superimposed preeclampsia to preexisting hypertension).
pregnancy should be treated, irrespective of the severity, Among women with preexisting hypertension, almost 25%
the use of magnesium sulfate to prevent complications of will develop superimposed preeclampsia [9]. In these wom-
preeclampsia, prompt delivery for term preeclampsia, and en, the diagnosis is made when a de novo development of
acknowledgment of heightened future cardiovascular risk proteinuria is detected, or other maternal organ or utero-
in women with a history of preeclampsia. In contrast, areas placental dysfunctions develop after 20 weeks of gestation,
of major disagreement between the guidelines are the and it is usually associated with an abrupt or progressive BP
components of the broad definition of preeclampsia are elevation. Finally, we recognize antenatally unclassifiable
often unspecified, fetal manifestations or biomarkers are hypertension when BP is first recorded after 20 weeks of
not widely endorsed, the definition of severe preeclampsia gestation and hypertension is diagnosed. Thus, reassess-
remains controversial, the choice of drugs in mild or severe ment is necessary at or after 6 weeks postpartum. If hyper-
hypertension, as well as the thresholds to initiate treatment tension resolves, it should be retrospectively classified as
and the BP targets to achieve, remain unclear [4]. gestational hypertension, whereas if hypertension persists,
In the 2023 European Society of Hypertension (ESH) it should be retrospectively classified as one of the sub-
guidelines for managing hypertension [5], several important categories within HDP. We emphasize that the 20th week of
pregnancy-related issues were addressed, and new recom- pregnancy is the arbitrary limit to define HDP and should be
mendations were offered with their class of recommenda- used as an orientation point only, whereas a definite
tion and level of evidence. The present statement aims to diagnosis should be guided by clinical judgment and bio-
establish the willingness of the ESH Working Group ‘Hy- markers (see next sections). Classification of HDP is further
pertension in Women’ to shed light on practical problems hampered by the fact that maximum physiological reduc-
related to hypertension management during pregnancy by tion in blood pressure occurs at 16–22 weeks of pregnancy,
expanding on the pregnancy-related topic of the 2023 ESH with a return to prepregnancy BP values during the third
guideline recommendations [5]. trimester. Accordingly, a normal BP during the second
trimester without known prepregnancy or first-trimester
DEFINITION AND GRADING BP values may mask preexisting hypertension. Of note,
based on empirical observations, women with a diagnosis
Hypertension in pregnancy is defined as SBP at least of preexisting hypertension may enter pregnancy without
140 mmHg and/or DBP at least 90 mmHg. At variance with hypertensive BP levels and continue to have normal BP
BP grading in the general population, hypertension in during puerperium. Thus, the diagnosis of preexisting
pregnancy is classified as mild (SBP/DBP, 140–159/90– hypertension may be questioned after the end of puerperi-
109 mmHg) or severe (SBP/DBP at least 160/110 mmHg) um. Figure 1 presents an overview of HDP.
1110 www.jhypertension.com Volume 42 Number 7 July 2024

Hypertensive disorders in pregnancy
TABLE 1. Classification of hypertensive disorders in pregnancy screening for masked hypertension should not be routinely
A. Preexisting (chronic) hypertension performed because the prognostic value in pregnancy
Hypertension either preceding pregnancy or developing before 20 weeks remains uncertain [14–16].
gestation, usually persisting for more than 6 weeks postpartum, and may
be associated with proteinuria.
1. primary hypertension
2. secondary hypertension Preeclampsia: definition
3. white-coat hypertension Preeclampsia is a multifaceted disorder impacting both the
4. masked hypertension
B. Gestational hypertension mother and the fetus, highlighting the intricate interdepen-
Hypertension develops after 20 weeks gestation and usually resolves within dence of their physical conditions. It manifests abnormali-
6 weeks postpartum. ties in both maternal and fetal clinical conditions. We
Transient gestational hypertension
Usually detected in the clinic but then settles with repeated BP recommend using the broader definition of preeclampsia
measurements taken over several hours, it is associated with a 40% risk previously proposed by the International Society for the
of developing true gestational hypertension or preeclampsia in the
remainder of the pregnancy, thus requiring careful follow-up.
Study of Hypertension in Pregnancy (ISSHP) and endorsed
Preeclampsia is gestational hypertension accompanied by one or more of by the 2023 ESH guidelines [5,6]. Accordingly, preeclampsia
the following new-onset conditions at or after 20 weeks gestation: is gestational hypertension in the presence of one or more
– Proteinuria (urinary albumin excretion in a 24 h urine sample >0.3 g/day
or UACR in a random spot urine sample >30 mg/mmol (0.3 mg/mg) of the following new-onset conditions at or after 20 weeks
Other maternal organ dysfunction of gestation: significant proteinuria [albumin to creatinine
Acute kidney injury (serum creatinine 90 mmol/l; 1 mg/dl) ratio (ACR) at least 30 mg/mmol or albuminuria at least
Liver involvement (elevated ALT or AST >0.67 mkat/l; >40 U/l; with or
without right upper quadrant or epigastric abdominal pain) 300 mg/24 h], maternal organ dysfunction [i.e. acute kidney
– Neurological complications (e.g. eclampsia, altered mental status, injury (serum creatinine 1 mg/dl; 90 mmol/l); liver injury
blindness, stroke, clonus, severe headaches, persistent visual scotomata)
– Hematological complications (platelet count <150 000/ml, DIC, hemolysis)
(elevated transaminases >40 U/l) with or without right
– Uteroplacental dysfunction (fetal growth restriction, abnormal umbilical upper quadrant or epigastric pain; neurological manifes-
artery Doppler waveform analysis, or stillbirth) tations (convulsions, altered mental status, blindness, sco-
C. Preexisting hypertension plus superimposed preeclampsia
Preexisting hypertension associated with any of the above maternal organ toma or headache); hematological manifestations (platelet
dysfunctions consistent with preeclampsia or a further increase in BP with count <150 000/ml, disseminated intravascular coagulation,
new-onset proteinuria hemolysis)]; and uteroplacental dysfunction (i.e. IUGR,
D. Antenatally unclassifiable hypertension
When BP is first recorded after 20 weeks gestation, and hypertension is abnormal umbilical artery Doppler waves or stillbirth).
diagnosed, reassessment is necessary at or after 42 days postpartum. If The combination of hemolysis, thrombocytopenia, and
hypertension resolves, it should be reclassified as gestational
hypertension, whereas if hypertension persists, it should be reclassified as
elevated transaminases defines the HELLP syndrome, and
preexisting hypertension. therefore, additional features of preeclampsia should be
evaluated (Table 1) [5,6,17].
Modified from reference [5], with permission from Wolters Kluwer Health. ALT, alanine
aminotransferase; AST, aspartate aminotransferase; BP, blood pressure; DIC,
disseminated intravascular coagulation.
Preeclampsia: epidemiology
Preeclampsia occurs in 2–4% of pregnancies [18]. It is
associated with almost 50 000 maternal deaths and a 10
As in the general population, the diagnosis of hyperten- times higher number of fetal or neonatal deaths every year
sion in pregnancy should be based on repeated office BP worldwide [19]. Among risk factors for preeclampsia, so-
measurements, preferably complemented by out-of-office cioeconomic status plays a pivotal role as women from low-
BP measurements. White-coat hypertension is character- income or middle-income countries have a three to four-
ized by increased office BP and normal BP out-of-office. It is fold greater risk of preeclampsia compared with higher
more common in pregnancy than in the general population, income countries [20–22]. Regarding ethnic differences,
with a mean prevalence of 30% of pregnant women with Black and African-American, compared with Caucasian
elevated BP [6,10]. However, not to be underestimated, the women, are at a 60% higher risk for preeclampsia [22]. In
risk of preeclampsia and preterm birth is significantly addition, women with preexisting hypertension have five
higher in white-coat hypertension compared with normo- times greater rates of preeclampsia compared with pre-
tension [11], although maternal and neonatal prognosis pregnancy normotensive women [1]. At term, compared
seems to be better than in chronic hypertension [12]. with preterm, preeclampsia is two times more frequent, but
Transient gestational hypertension is usually detected in it is associated with lower rates of maternal or fetal and
the clinic and settles with repeated BP measurements taken neonatal complications [20]. Clinicians should always con-
over several hours. However, it is associated with a 40% risk sider preeclampsia as a serious disease with a rather unpre-
of developing true gestational hypertension or preeclamp- dictable prognosis. In clinical practice, it is no longer
sia in the remainder of the pregnancy, thus requiring close recommended to use the previous classification of pre-
clinical surveillance [10,13]. Masked hypertension refers to eclampsia based on clinical features such as mild or severe
women without antihypertensive treatment with elevated or the stage of pregnancy at the diagnosis [i.e. early preterm
BP values in out-of-office BP measurements associated with (<34 weeks), preterm (34–37weeks), term (37–39 weeks
normal office BP measurements. This form of hypertension, and post-term >39weeks)] [6]. Although many cases of at-
though difficult to detect, should be suspected in patients term preeclampsia may not lead to significant short-term
with kidney dysfunction or other hypertension-mediated complications for both the mother and newborn, consistent
organ damage diagnosed prepregnancy or in the first half with the adage ‘prompt delivery is the definitive treatment
of pregnancy [6]. In those high-risk women, out-of-office for preeclampsia,’ increased long-term cardiovascular dis-
BP measurements should be recommended; however, ease is a well known adverse consequence for women with

Thomopoulos et al.
FIGURE 1 Overview of hypertensive disorders in pregnancy. BP, blood pressure; CV, cardiovascular; GH, gestational hypertension; PE, preeclampsia. Horizontal black arrows
indicate that preeclampsia may develop from approximately the 20th week of pregnancy or may develop de novo, usually, during the first days postpartum in a previously
normotensive pregnancy.
all forms of HDP and their offspring years and even decades immune system morbidities, preexisting hypertension, so-
after delivery [5]. cial determinants of poor health) determine endothelial
damage in the mother with preeclampsia development.
Preeclampsia: pathogenetic considerations The same pathophysiological substrate may adversely im-
Inadequate placentation, with a lack of spiral artery remod- pact fetoplacental health with emerging features such as
eling and poor villous development, represents the patho- fetal growth restriction, preterm birth (<37 weeks), low
genetic basis mostly observed in preterm preeclampsia and birth weight, small-for-gestational age (<10th percentile
determines a reduced uteroplacental blood supply pattern by sex), stillbirth, and placental abruption [20].
leading to IUGR [20]. A normal placentation accompanied Endothelial damage associated with placental dysfunc-
by either a multiple pregnancy, fetal macrosomia, or crowd- tion and a maternal high-risk factor profile contributes to BP
ing of intervillous space is more frequently observed in elevation, perpetuation of widespread vascular damage,
cases of at-term or postterm preeclampsia. It produces a and increased peripheral resistance. In the United Kingdom
condition of increased fetoplacental demands. However, a cohort of the ASPRE (Combined Multimarker Screening and
variable cause of intervillous crowding can also be associ- Randomized Patient Treatment with Aspirin for Evidence-
ated with a compromising uteroplacental blood flow. Re- Based Preeclampsia Prevention) trial, women underwent
duced uteroplacental blood supply, increased fetoplacental hemodynamic evaluation by a bioreactance system, and the
demands, or their combination result in a uteroplacental cardiac output, stroke volume, and peripheral resistance
mismatch that, in turn, increases placental stress-derived were registered during different pregnancy stages [23].
factors (e.g. pro-inflammatory cytokines) and promotes the Women at low risk of hypertensive complications ineligible
imbalance of angiogenic placental factors [e.g. proangio- for consequent randomization to aspirin or placebo partici-
genic placental growth factor (PLGF) and antiangiogenic pated in hemodynamic measures evaluation. Low-risk
soluble fms-like tyrosine kinase 1 (sFlt-1)]. Placenta-derived women had normal hemodynamic adaptations throughout
mediators alone or combined with factors conferring a pregnancy, at variance with high-risk women who pre-
maternal predisposition (e.g. obesity, diabetes mellitus, sented decreased cardiac output and stroke volume and

increased peripheral resistance. Moreover, the extent of widespread endothelial damage associated with pre-
hemodynamic derangement was similar between women eclampsia is extended to pulmonary microcirculation,
randomized to aspirin or placebo, suggesting that the and peripheral vascular resistance remains high despite
beneficial effects of aspirin on preeclampsia prevention antihypertensive treatment [26]. Preeclampsia is associated
might be independent of hemodynamics [23,24]. Inade- with activation of the coagulation system in a higher degree
quate cardiovascular adaptations during pregnancy, includ- than in a normal pregnancy. Thus, the risk of venous
ing increased arterial stiffness [25], maybe a marker of thromboembolism increases by two to three times in the
preeclampsia and should be further evaluated. peripartum period in women with preeclampsia compared
During pregnancy, the physiological increase in cardiac with those without preeclampsia [28]. Finally, in preeclamp-
output is associated with a 50–70% increase in renal blood sia, increased blood loss in combination with coagulation
flow [26]. Also, in an uncomplicated pregnancy, there is an derangement may promote disseminated intravascular co-
increase in glomerular filtration rate because of increased agulation with a high mortality rate, though the exact
renal flow and expanded plasma volume, with a subse- mechanism remains rather unclear [31].
quent decrease in serum creatinine levels by an average of
0.4 mg/dl (35 mmol/l) compared with prepregnancy. A Eclampsia
serum creatinine of 1.0 mg/dl (88 mmol/l), deemed normal Eclampsia is the most severe complication of preeclampsia
out-of-pregnancy, indicates kidney dysfunction in a preg- and, based on postmortem findings, is driven by
nant woman. In women with preeclampsia without preex- microscopic bleedings associated with increased perfusion
isting renal disease, the glomerular filtration rate is pressures that may exceed the cerebral circulation autor-
generally greater than 60 ml/min despite a 20% reduction egulatory capacity [27]. An eclamptic convulsion is life-
in renal blood flow compared with pregnant women with- threatening. Fortunately, the incidence of eclampsia has
out preeclampsia [26]. In preeclampsia, glomerular endo- been reduced with the advent of prompt management of
theliosis and loss of podocyte integrity contribute to preeclampsia. However, eclampsia may occur without
proteinuria development, with nephrotic levels reserved premonitory signs or symptoms of underlying preeclampsia
for severe cases [20]. during partum, delivery, or first days postpartum. In select-
ed cases, convulsions are preceded by imminent signs,
Preeclampsia: maternal complications including headache, visual disturbances, altered mental
Women with HDP, especially preeclampsia, are prone to state, and angina-like or epigastric pain [32].
develop cardiovascular complications [26]. The pivotal
three complications of cardiovascular interest are stroke, BLOOD PRESSURE MEASUREMENTS
pulmonary edema, and pulmonary embolism. Stroke dur- DURING PREGNANCY
ing pregnancy is a result of the development of severe
hypertension, typically established acutely during the third Precise measurement of BP during pregnancy is of major
trimester [27,28]. Pulmonary edema in women without a importance to provide the best obstetrical management,
history of underlying cardiac disease before pregnancy may allowing for the application of prevention and pharmaco-
develop in late pregnancy, during delivery or the first days logical intervention. However, BP evaluation may be
postpartum [29]. It may occur under two conditions: new- difficult in pregnant women because of physiological
onset systolic heart failure in the context of peripartum hemodynamic adaptations and most devices for BP mea-
cardiomyopathy, or heart failure with preserved ejection surement are inaccurate and lack validation by an estab-
fraction. Although peripartum cardiomyopathy may have a lished and recognized protocol adapted for pregnancy
sporadic epidemiological appearance in Western countries, [33].
it is more frequently, by almost four times, associated with
preeclampsia compared with normotensive pregnancies Auscultatory devices
[30]. In contrast, heart failure with preserved ejection frac- Noninvasive devices comprise auscultatory and oscillo-
tion can result from acute left ventricle decompensation metric methods. Korotkov sound V is preferred over
because of increased afterload in the context of pregnancy- sound IV for the auscultatory method, as it is closer to
mediated hypertensive disorders [29]. The mechanistic intra-arterial pressure and more reliably detected [34]. The
aspects of acute left ventricle decompensation are not auscultatory method is the initial gold standard for evalu-
different from those observed in nonpregnant women ating BP in pregnancy. However, mercury sphygmoman-
presenting with hypertension-mediated heart damage ometers have been proscribed because of mercury toxicity
and long-standing uncontrolled hypertension. The combi- and are now only recommended for the validation of
nation of the following five conditions forces intravascular devices. Auscultatory devices were replaced by aneroid
fluids to leak outside toward the alveoli: mobilization of devices that necessitate frequent recalibration and are
interstitial fluids into vessels, including uterus autotransfu- subjected to error greater than 3 mmHg compared with
sion effect during the first hours postpartum, fluid admin- mercury and automatic devices. An evaluation of the effect
istration during postpartum to accompany tocolytic or other of systematic imprecisions by 3 and 5 mmHg in measure-
intravenous treatments, drop of almost 30% in colloid ments of SBP would misjudge 24 and 43% of individuals
osmotic pressure in early postpartum because of volume with hypertension. It would wrongly comfort 19 and 30%,
expansion; in preeclampsia with clinically important pro- respectively, being falsely normotensive [35]. Automated
teinuria, the reduction of colloid osmotic pressure is higher oscillometric devices are now mainly used during preg-
because of the critically reduced plasma albumin levels, nancy to estimate the mean arterial BP; then, an algorithm

Thomopoulos et al.
extrapolates SBP by studying the shape of the arterial wall Home blood pressure self-monitoring during
vibration and, finally, DBP can be easily calculated from pregnancy
mean BP and SBP [33]. A properly validated device for home BP measurements in
pregnancy must be used, and appropriate instructions
Validation of devices should be given on when and how to use the device. A
Because of hemodynamic changes during pregnancy, devi- Japanese study provided provisional criteria for diagnosing
ces should be validated in pregnant women with or without hypertension in pregnancy using home BP monitoring
HDP, including preeclampsia. Compared with a normoten- (HBPM). Based on population distribution and regression
sive pregnancy, hemodynamic adaptations in preeclampsia with office BP values, home BP values corresponding to a
(i.e. increased peripheral resistance, decreased stroke ejec- clinical BP of 140/90 mmHg were 120.8/83.5, 126.0/85.2,
tion volume, reduced vascular compliance, and reduced and 136.3/89.3 mmHg in the first, second, and third trimes-
effective intravascular volume) may change the oscillomet- ters, respectively [41]. During pregnancy, home BP meas-
ric shape of the pulse wave, and validation against mercury urements define normal values at less than 135/85 mmHg,
sphygmomanometers is necessary. STRIDE-BP (Science corresponding to a mean ambulatory BP of 126/76 mmHg
and Technology for Regional Innovation and Development [42].
in Europe – Blood Pressure), an international nonprofit The advantages of HBPM are that it allows evaluation of
organization aiming to improve the accuracy of BP meas- BP during different stages of pregnancy and offers a better
urements, provides a list of validated devices for pregnant longitudinal follow-up based on a greater number of read-
women with different types of hypertensive disorders [36]. ings than office BP measurements. It can also detect white-
coat or masked hypertension [43]. According to the BUMP-1
Technique of blood pressure measurement (Blood Pressure Monitoring in High-Risk Pregnancy to
Properly assessing BP during pregnancy implies quiet Improve the Detection and Monitoring of Hypertension-
sitting for 5 min with feet flat on the ground, the arm 1) trial [44], HBPM did not lead to earlier clinic-based
supported at the level of the heart, and the back supported detection of hypertension among pregnant women at
before measurement. The left lateral lying position to avoid higher risk of preeclampsia. However, the BUMP-1 trial
abdominal venous compression by the gravid uterus is an also suggested that HBPM and office BP measurements may
alternative acceptable position in the third trimester or be used alternatively or in complement to diagnose HDP in
during the peripartum period. Using a cuff of an appropri- women at risk of preeclampsia. In the BUMP-2 trial [45],
ate size is mandatory [37]. With the auscultatory method, HBPM was not associated with better BP control among
ignoring the first measurement and considering the mean of pregnant women with preexisting or gestational hyperten-
the next two readings after 5 min of rest is advised. With sion compared with scheduled office BP measurements.
oscillometric devices, an average of two readings is consid- Again, the BUMP-2 trial suggested that BP control, accord-
ered reliable. Devices automatically measure three BP ing to HBPM, can be used alternatively or complementarily
values and provide the average BP, which can also be used. to office BP measurements because both methods achieved
similar rates of BP control. It has been shown that HBPM is
Blood pressure trajectory during pregnancy feasible and acceptable for women of different ethnicities
In normotensive pregnancy, SBP and DBP decrease com- or socioeconomic backgrounds [46].
pared with prepregnancy BP, attaining their maximum
reduction of about 4 mmHg in the early second trimester Ambulatory blood pressure monitoring during
with a gradual increase towards nonpregnant BP values in pregnancy
the last trimester. Healthy pregnancies seem to have lower Ambulatory BP monitoring (ABPM) seems to predict better
SBP and DBP than previously assumed, namely less than preeclampsia, IUGR, and adverse neonatal outcomes than
130/80 mmHg during the entire gestation, challenging the conventional BP measurements, partly because nocturnal
traditional, broader threshold for diagnosing gestational hypertension is associated with the future development of
hypertension [38]. In a hypertensive pregnancy, SBP values gestational hypertension and preeclampsia [47,48]. The
may not be remarkably higher in the first part of gestation indications of ABPM are confirming hypertension necessi-
and may only lack the physiological decrease observed in tating medical treatment or diagnosing white coat hyper-
normotensive pregnancy, and DBP may drop by 6 mmHg tension and thus mandating a close follow-up. In the
during the second trimester. However, in the third trimes- presence of hypertension-mediated organ damage, includ-
ter, SBP and DBP may be increased by almost 30 mmHg ing microalbuminuria, ABPM may reveal masked hyperten-
compared with BP values of the first trimester [38]. One sion. ABPM may increase the sensitivity of prediction tools
study demonstrated that BP categories with lower BP for preeclampsia, such as the Fetal Medicine Foundation
thresholds than those traditionally used to identify individ- algorithm [49], which currently includes the mean office
uals as hypertensive may inevitably result in the identifica- arterial pressure. However, including ABPM in the scores to
tion of more women at risk of preeclampsia and gestational predict preeclampsia deserves future studies. An earlier
hypertension [39]. Whether a lower BP threshold to define cross-sectional study that included 276 ambulatory BP
hypertension in pregnancy should be applied remains measurements defined the normal awake BP values for
unclear. Data confirming that intervention with pharmaco- pregnancy at different pregnancy stages [50]. A gradual rise
logical treatment introduced at a lower threshold (than in the awake SBP and DBP was observed from early
140/90 mm Hg) might be well tolerated are lacking [40]. pregnancy into the third trimester. Moreover, awake BP

was slightly higher than resting BP measured by a mercury of gestation), and 24 h urine analysis to detect those at a
sphygmomanometer [50]. When a valid device for pregnan- higher risk of gestational hypertension, preeclampsia,
cy has been used, normal values for 24 h ABPM in preg- and IUGR [5,6]. Laboratory exams that might be used to
nancy are fairly similar to those described in other predict at-term preeclampsia are reported in the following
populations (i.e. below 130/80 mmHg). However, before section.
22 weeks, 24 h BP values should be below 126/76 mmHg, a
threshold slightly below that for diagnosing hypertension in PREDICTION AND PREVENTION OF
nonpregnant women [50]. PREECLAMPSIA
LABORATORY EXAMS DURING High risk and moderate risk of preeclampsia
Available evidence allows us to distinguish women at high
PREGNANCY and moderate risk of developing preeclampsia. Clinical risk
Basic laboratory investigations for monitoring pregnant assessment for preeclampsia includes only risk factors that
hypertensive women include urine analysis, blood count, can be obtained from the medical history of pregnant
hematocrit, liver enzymes, serum creatinine, and serum women (Fig. 2) [5].
uric acid. Although uric acid is generally elevated in In a systematic review and meta-analysis of large cohort
clinically evident preeclampsia and identifies women at studies that evaluated the risk of preeclampsia using a
increased risk of adverse maternal and fetal outcomes common and generally accepted clinical risk factors
[6,51], it should not be used as a diagnostic criterion for assessed at 16 weeks or less of gestation, antiphospholipid
preeclampsia or to determine the timing of delivery. antibody syndrome, prior preeclampsia, chronic hyperten-
Determination of proteinuria in early pregnancy is rec- sion, pregestational diabetes, assisted reproductive tech-
ommended to detect preexisting renal disease and, in the nology (ART), and BMI greater than 30 kg/m2 were most
second half of pregnancy, to screen for preeclampsia. strongly associated with a high rate of preeclampsia [54].
However, proteinuria is no longer a ’sine qua non’ criteri- High-risk factors increased the risk of preeclampsia by at
on for diagnosing preeclampsia [5,6]. Occasionally, pro- least 2.5-fold. In addition to established risk factors for
teinuria may anticipate a subsequent rise of BP in the preeclampsia, there is an emerging number of factors that
natural course of preeclampsia. A dipstick test of at least may increase the risk, including high-normal prepregnancy
1þ should prompt evaluation of ACR in a single spot urine BP, white-coat hypertension, insulin resistance, primary
sample, and a value of less than 30 mg/mmol can reliably aldosteronism, overweight (25 BMI <30 kg/m2), gesta-
rule out proteinuria [52,53]. Other investigations to be tional diabetes, hyperthyroidism, and pregnancy with tri-
considered are: renal ultrasound if serum creatinine or somy 13 fetus. Other possible genetic risk factors for
any of the urine testing is abnormal, Doppler ultrasound of preeclampsia include a paternal family history of pre-
uterine and umbilical arteries (performed after 20 weeks eclampsia and oocyte donation [55]. A prediction model
FIGURE 2 Risk assessment for preeclampsia prediction based on clinical risk factors, Fetal Medicine Foundation risk model, and biomarkers. a, depending on the
manufacturer. FMF, Fetal Medicine Foundation; PE, preeclampsia; PLGF, placental growth factor; sFlt-1, soluble fms-like tyrosine kinase-1.

Thomopoulos et al.
based on high or intermediate clinical risk factors is sensi- preempt.obgyn.ubc.ca/home-page/past-projects/fullpiers/.

tive to preterm preeclampsia or term preeclampsia of 40 or [62–64]. Fetal health should also be assessed during any
35%, respectively. expectant strategy in women with preeclampsia to make sure
that delivery is safely postponed.
Multivariable prediction models
Alterations in angiogenic factors are recognized as a likely Prevention: the role of aspirin
consequence of abnormal placentation occurring in early Identification of a group at increased risk of developing
pregnancy. Increased sFlt-1, an antiangiogenic factor of preterm preeclampsia already at the beginning of pregnancy,
placental origin, counteracts proangiogenic factors such as many more weeks before the appearance of clinical symp-
PLGF and vascular endothelial growth factor, and this imbal- toms, allows for the implementation of prevention. Meta-
ance between antiangiogenic and proangiogenic factors analyses of randomized controlled trials showed that taking
contributes to BP increase and widespread vascular damage aspirin starting before the 16th week of pregnancy, that is,
[56]. An increased sFlt-1/PLGF ratio may be particularly before the end of the uterine spiral arteries remodeling,
pronounced in women with early (<34 gestational weeks) significantly reduces the risk of preeclampsia [65]. The results
preeclampsia. Measurements of angiogenic biomarkers have of the ASPRE multicenter trial confirmed the effectiveness of
been incorporated into risk stratification in several contem- aspirin in reducing the number of women with preeclampsia
poraneous trials for preeclampsia prevention [57,58] but are before 34 weeks of gestation by 80% and less than 37 weeks
not routinely used to guide clinical care in most countries. of gestation by 63% [57]. The postulated mechanisms of
Multivariable models have high detection rates when aspirin’s effect include the direct effect on apoptosis prolifer-
used at 11–13 weeks of gestation for preterm preeclampsia ation of trophoblast cells and antiplatelet prevention of
and at 35–36 weeks for term preeclampsia. The interna- placental infarctions [5]. As almost all the trials recruited
tionally validated FMF (Fetal Medicine Foundation) model women after 12 weeks of gestation, it is unclear whether
of maternal risk factors and biomarkers (i.e. BP, uterine– starting treatment before 12 weeks of gestation would have
artery pulsatility index as measured by Doppler ultrasonog- additional benefits without any increase in adverse effects.
raphy, and serum PLGF) identifies approximately 90% of The dose of aspirin used in most trials was 81–150 mg daily
women at 11–13 weeks of gestation in whom early preterm [6]. However, the higher dosages (i.e. 100–150 mg) of aspirin
preeclampsia (at <34 weeks) will develop and approxi- were associated with a greater reduction in the onset of
mately 75% of those in whom preterm preeclampsia (be- preeclampsia [23,66]. Moreover, up to one-third of pregnant
tween 34 and 37 weeks) will develop (Fig. 2) [59]. For the women proved to be aspirin-resistant (lack of platelet func-
90% of women identified as being at low risk for preterm tion response) at a dose of aspirin 81 mg [67]. To summarize,
preeclampsia at 11–13 weeks of gestation, rescreening 100–150 mg of aspirin once daily, preferentially at bedtime,
during the second and third trimesters can refine the risk should be recommended as the preventive measure in wom-
stratification and identify women who require closer moni- en at high or moderate risk of preeclampsia, starting between
toring. In a high-income setting, randomization to the 12 and 16 weeks of gestation until 36 weeks of gestation.
repeated measurement of PLGF and PLGF/sFlt-1 ratio in Aspirin therapy is indicated when at least one high or at least
women with suspected preterm preeclampsia (between two moderate risk factors are present (Table 2) [5,6,55].
22 weeks and 0 days’ gestation and 35 weeks and 6 days’ Whether treatment with low-dose aspirin can reduce the
gestation at the time of the initial PLGF-based test) or usual incidence of superimposed preeclampsia in women with
care with concealed repeat PLGF-based testing, was not chronic hypertension remains a subject of debate [68].
associated with improved perinatal outcomes [60]. Thus,
universal, routine repeat PLGF-based testing of all individ- Prevention: the role of calcium
uals with suspected preeclampsia may not be recom- supplementation
mended, and further studies are desirable. A single test A recent meta-analysis including 13 randomized controlled
in women with suspected preterm preeclampsia is still trials showed significant reductions in the risk of gestational
beneficial. However, the prediction of term preeclampsia hypertension and preeclampsia with high-dose calcium
is possible only at 35–36 weeks of gestation, with sFlt-1
making an independent contribution [61]; this screening TABLE 2. Indications for aspirin treatment based on clinical risk
approach at 35–36 weeks of gestation identifies 75–85% of assessment
women in whom term preeclampsia will develop (Fig. 2). High risk of preeclampsia includes any of the following:
1. Hypertensive disorders during a previous pregnancy
Prediction of preeclampsia complications 2. Chronic hypertension
3. Chronic kidney disease
Although the diagnosis of term preeclampsia mandates 4. Type 1 or type 2 diabetes mellitus
labor induction [5,6], in women with a diagnosis of preterm 5. Autoimmune diseases such as systemic lupus erythematosus or
preeclampsia, early delivery should be balanced against antiphospholipid syndrome
6. Assisted reproductive therapy in the current pregnancy
fetal prematurity and adverse maternal outcomes related to Moderate risk of preeclampsia includes two or more of the
underlying preeclampsia. Adverse maternal outcomes may following:
1. Nulliparity
be predicted by using the full-PIERS (Preeclampsia Inte- 2. Age 40 years or older
grated Estimate of Risk; components: gestational age, chest 3. Pregnancy interval of more than 10 years
pain or dyspnea, platelet count, serum creatinine, aspartate 4. BMI of 35 kg/m2 or more at the first visit
5. Family history of preeclampsia
or alanine aminotransferase, and oxygen saturation) model 6. Multifetal pregnancy
twice weekly, and an online calculator is available: https://

supplementation (1 g/day) versus placebo [69]. However, generally well tolerated and desirable with some modifica-
this effect was clear only for women with low baseline tion when needed. Pregnant women are encouraged to
calcium intake and greater for women at higher risk of continue or engage in physical activities because it controls
preeclampsia. No differences in severe preeclampsia were weight gain and may reduce the likelihood of hyperten-
observed [69,70]. Another meta-analysis, including 30 ran- sion-related disorders [79]. Overall, in women where no
domized controlled trials, confirmed that calcium supple- contraindication exists, physical activity is recommended
mentation decreases the incidence of preeclampsia by throughout pregnancy to prevent excessive weight gain
almost 50% [71]. The benefit exists regardless of the calcium and hypertension-related disorders. Reasonable advice
dose (low dose, 500 mg/day versus higher dose >1 g/day), would be to moderately exercise three to four times weekly
the baseline preeclampsia risk, vitamin D co-administra- in sessions of an average of 45 min.
tion, or the timing of calcium initiation. Importantly, calci-
um was ineffective among women with adequate baseline Prevention: additional measures
calcium intake [71]. Of note, no clear evidence on the timing Higher gestational weight gain has been considered a
of initiation of supplementation has been provided, with a potential risk factor for HDP, but data so far are limited
suggestion to start at the first antenatal care contact to and inconclusive. In a meta-analysis including 23 random-
improve compliance with the regimen. However, initiating ized controlled trials, increased gestational weight gain was
calcium supplementation during the second trimester of associated with a nonsignificant increase in the incidence of
pregnancy seems reasonable. Another issue is a lack of preeclampsia and gestational hypertension [80]. In a sub-
consensus definition for ‘low calcium intake’, which is sequent meta-analysis including 13 observational studies, it
usually considered at levels of less than 600–900 mg/day was found that excessive gestational weight gain was
[5,20,72]. Overall, calcium supplementation with at least associated with an increased incidence of preeclampsia
500 mg/day is recommended in pregnant women whose [81]. Finally, a meta-analysis of individual participant data,
calcium intake is less than 900 mg/day to reduce the risk of including 39 European, North American, and Australian
preeclampsia; a greater supplementation dose of 1–1.5 g/ cohorts, showed that a higher increase in gestational weight
day seems harmless. gain was associated with a significantly higher risk of
gestational hypertension and preeclampsia. Interestingly,
Prevention: the role of exercise prepregnancy obese mothers with high gestational weight
Epidemiological data from case–control studies have sys- gain had the highest risks of gestational hypertension and
tematically demonstrated that women who participate in preeclampsia [82]. Although weight reduction during preg-
regular physical activity in the prepregnancy period and nancy is not recommended to prevent HDP, antenatal
during pregnancy have a significantly reduced risk of counseling should include advice for achieving an ideal
developing pregnancy-related hypertensive disorders, par- body weight before pregnancy.
ticularly preeclampsia [73]. However, a recent pooled meta- The effect of sodium intake on BP response and hyper-
analysis including 17 randomized controlled trials found tension-associated complications in pregnant women
that women practicing aerobic exercise for about 30– remains a subject of investigation. Although there are a
60 min, two to seven times per week, during early preg- few studies that have shown a positive association between
nancy had a significantly lower incidence of gestational increased salt intake and a higher risk of gestational hyper-
hypertension but not preeclampsia [74]. Similar results tension and preeclampsia [83–85], no convincing data exist
favoring the impact of physical activity in reducing the demonstrating a relation between a low salt diet and a
incidence of gestational hypertension by 47%, but not lower incidence of hypertension-related pregnancy disor-
preeclampsia, were shown in the most recent analysis ders. The first multicenter randomized, controlled trial of a
derived from 23 systematic reviews, including 63 random- sodium-restricted diet during pregnancy evaluated 184
ized trials [75]. Interestingly, the most favorable impact was pregnant women given a low sodium diet (<50 mmol
observed in pregnant women who started light to moderate sodium/day) and a control group of 177 women given a
or moderate intensity exercise, with each session longer normal diet. No differences were found in the DBP between
than 45 min, in the first and second trimester of pregnancy groups, nor were there differences in the percentage of
[75]. At the same time, the evidence regarding the benefit of referrals and admissions to the hospital for hypertension or
physical exercise in overweight and obese pregnant wom- incidence of preeclampsia [86]. Overall, no evidence exists
en remains controversial [75–77]. The most recent meta- for a favorable effect of reduced salt intake during preg-
analysis involving 12 randomized controlled trials showed nancy in preventing or treating preeclampsia, and salt
that regular exercise (the duration and intensity of which consumption should remain a matter of personal prefer-
were different across the included studies) was associated ence [87]. However, it is reasonable that women with
with a decrease in the risk of developing gestational hyper- preexisting hypertension should continue pursuing a limit-
tension among overweight and obese pregnant women ed salt intake diet [88].
[78]. Additional studies are needed to clarify the potential Regarding timed birth, a trial involving greater than 6000
impact of certain types of exercise, the initiation time and low-risk nulliparous women showed that labor induction at
duration of exercise, and the level of intensity on pregnan- 39 weeks 0 days to 39 weeks 4 days of gestation, as com-
cy-related hypertensive disorders. Until then, assuming the pared with expectant care, reduced, though marginally, the
absence of obstetric or medical complications or contra- risks of the primary perinatal adverse outcome, lowered the
indications, physical activity in pregnancy is considered frequency of cesarean delivery and also reduced the rate of

Thomopoulos et al.
HDP [89]. Postterm preeclampsia ( 39 weeks) may be In secondary prevention or the presence of proteinuria,
prevented by prompt labor induction in low-risk nullipa- renin–angiotensin system blockers are used before preg-
rous women, but whether the results of the trial [89] can be nancy. However, withdrawal of these drugs is mandatory in
generalized to a different parity category or women at case of a suspected pregnancy (e.g. menses delay) because
higher risk is unknown. these drugs are associated with teratogenesis and renal
The role of candidate pharmacological agents with an failure of the fetus [5]. Thus, renin–angiotensin system
acceptable safety profile, such as pravastatin or metformin, blockers are contraindicated in the second and third tri-
in preventing HDP is currently being evaluated [20]. In a mester, especially after week 20 of pregnancy. However, if
German multicenter, double-blinded study of 1120 high- possible, they should also not be used in the first trimester.
risk women for term preeclampsia randomized to prava- If inadvertent treatment with these drugs early in pregnan-
statin 20 mg or placebo at 35 or 36 weeks of gestation, the cy, the pregnant woman should be switched to a lower risk
rates of term preeclampsia were not different between the antihypertensive agent [93–95]. A further obstetric exami-
groups [90]. The short interval between the intervention and nation by fetal ultrasounds may be offered to ensure fetal
outcome might be responsible for the neutral trial results. well being. In the event of exposure till after week 20,
treatment must be stopped immediately and switched, and
Prevention: the role of a multidisciplinary team oligohydramnios should be ruled out during the rest of
pregnancy. The kidney function of the newborn should be
Recognized guidelines on the management of HDP advo-
checked, an ultrasound examination of the kidneys should
cate the referral of women identified as high-risk for devel-
be carried out, and attention should be paid to possible
oping preeclampsia to specialized multidisciplinary teams,
hypotonia. Kidney structure, function, and BP levels should
from preconception to postpartum follow-up. These teams
also be monitored again in later childhood [96]. Overall,
should encompass obstetricians, cardiologists, and special-
throughout all trimesters of pregnancy, renin–angiotensin
ists in hypertension and obstetric medicine [55]. Although
system blockers are contraindicated.
preliminary, results from observational studies have shown
In women receiving drug classes other than renin–
a reduction in adverse pregnancy outcomes in women
angiotensin system blockers, drug discontinuation or treat-
undergoing multidisciplinary team follow-up during preg-
ment replacement should also be decided on an individual
nancy compared with standard care [91,92]. Adverse preg-
basis. The decision of treatment discontinuation or replace-
nancy outcomes in women diagnosed with HDP may be
ment should take into consideration the balance between
mitigated through risk stratification and a personalized
the risks of drug treatment during fetal organogenesis and
treatment approach elaborated by a multidisciplinary
the risks of inappropriate hemodynamic adaptations in
team. Future controlled studies are warranted to obtain
early pregnancy because of uncontrolled hypertension.
enough evidence to implement this strategy in usual clinical
The selection of alpha-methyl-DOPA as a first-line agent
practice.
in early pregnancy seems reasonable [97].
Which women with preexisting essential hypertension
CLINICAL MANAGEMENT: MILD are eligible to discontinue antihypertensive treatment with-
PREEXISTING ESSENTIAL out drug replacement? Although a definite answer is not
HYPERTENSION available because of different BP responses to treatment
withdrawal, some women may be selected for complete
The clinical history of women entering pregnancy with a first-trimester and early second-trimester drug discontinua-
previous diagnosis of essential hypertension is important tion [5]. The decision to discontinue antihypertensive treat-
for decision-making during pregnancy. The grade of hy- ment during this period should be individualized based on
pertension at the time of diagnosis (without on-treatment mild prepregnancy untreated BP levels (preexisting grade 1
drugs) and the estimated cardiovascular risk, including hypertension), controlled on-treatment early first trimester
assessment of hypertension-mediated organ damage, are BP values, the absence of hypertension-mediated organ
important and should be registered [5]. Another crucial set damage, and the perpetuation of well controlled BP levels
of relevant clinical factors in women with preexisting after a short-term trial of antihypertensive treatment with-
essential hypertension is the type and dose of drugs used drawal. Whenever complete drug discontinuation is decid-
before pregnancy and whether on-treatment SBP/DBP is ed, BP should be carefully monitored by office BP
controlled within the optimal BP target (i.e., usually <130/ measurements at least every 2 weeks and ideally comple-
80 mmHg). Although women are usually not at high risk mented by home BP measurements. In women with mod-
before pregnancy, there is a subset of women with a history erate or severe prepregnancy untreated BP levels
of cardiovascular disease or proteinuria under treatment (preexisting grade 2 or 3 hypertension); uncontrolled early
with renin–angiotensin system blockers. It is recom- on-treatment first trimester BP values; presence of hyper-
mended that hypertensive women at reproductive age, tension-mediated organ damage; and sustained BP eleva-
in primary prevention, and without proteinuria, should tion after a short-term trial of antihypertensive treatment
not be treated with renin–angiotensin system blockers withdrawal, drug replacement should be established. In this
unless they use reliable contraception [5]. Other drug clas- case, the potency of the initial antihypertensive treatment
ses (i.e. calcium channel blockers, beta-blockers, diuretics) monotherapy should be mild, and careful dose escalation
can and should be used in monotherapy or combinations should be attempted to control hypertension. In case of
(based on individual cardiovascular risk) to control hyper- uncontrolled hypertension with monotherapy at the maxi-
tension [5]. mum tolerated dose, a second antihypertensive agent may

be used. In preexisting hypertension, the presence of 8–30%) and preterm birth for medical reasons by 27% (95%
intense antihypertensive treatment during the early second CI 11–40%). The prespecified composite maternal or neo-
trimester may promote a profuse DBP drop, potentially natal secondary outcomes were not different between
accompanied by miscarriage due to a synergistic effect with groups, including small-for-gestational-age newborns. Se-
the physiological second-trimester BP reduction. To sum- vere hypertension developed 18% less frequently in the
marize the above, a wise clinical attitude for women with active treatment group compared to the control group (95%
preexisting hypertension might be ‘go slow and avoid CI 0.74–0.90); however, no stroke event occurred in either
going too low’. study group during the trial. In light of the on-treatment BP
The optimal BP targets during pregnancy in women with values observed in CHIPS and CHAP trials (133/85 and 129/
preexisting hypertension largely remain unsettled. In 2015, 79 mmHg, respectively) [98,100], we suggest antihyperten-
a relatively small study, the Control of Hypertension in sive treatment should be restarted or potentiated in case of
Pregnancy Study (CHIPS) [98], evaluated whether less or BP increase to at least 140/90 mmHg at any gestational age.
more tight control of hypertension (i.e. achieved DBP Intensified BP-lowering should be avoided because of the
values less than 100 or 85 mmHg, respectively) was associ- potential risk of fetal hypoperfusion. Thus, a conservative
ated with different perinatal and maternal outcomes. In target of less than 140/90 mmHg seems reasonable. Labe-
CHIPS, 987 pregnant women with nonsevere and non- talol and alpha-methyldopa remain the first-choice drugs
proteinuric preexisting hypertension (75%) or gestational for BP control in women with preexisting hypertension
hypertension were enrolled at 14–33 weeks. The primary [5,55,98,100]. An alternative agent is extended-release ni-
outcome was a composite of pregnancy loss or substantial fedipine [5,55,98,100]. However, it should also be noted that
long-standing intensive neonatal care, with serious mater- the use of labetalol is not a choice in several countries in
nal complications as a secondary outcome. Both outcomes which it was removed from the market 30 years ago, mainly
were not different for an average DBP reduction difference because of hepatotoxicity, which may also occur when
of 4.6 mmHg between groups during follow-up. However, used in pregnancy [101]. Atenolol should be avoided during
as expected from previous evidence [99], the development pregnancy because of the increased risk of low birth weight
of severe hypertension, a nonprespecified secondary out- [102]. Bisoprolol may be well tolerated during the first
come, was 1.8-fold more frequent in the less tight compared trimester of pregnancy, whereas a potential adverse effect
with the tight DBP control group. Finally, in the subgroup of of prolonged bisoprolol exposure on fetal growth cannot
women with chronic hypertension, less tight BP control be ruled out [103]. Indeed, long-term intrauterine exposure
was associated with lower rates of small-for-gestational-age to metoprolol or bisoprolol (during the second and third
newborns than tight BP control. trimesters) may increase the risk of being born small for
In 2022, an open-label multicenter randomized trial, the gestational age, though without serious neonatal compli-
Chronic Hypertension and Pregnancy (CHAP), was pub- cations. It is still a matter of debate to which extent maternal
lished [100]. The CHAP trial addressed the outcomes and hypertension contributes to lower birth weight. Treatments
safety of antihypertensive drug treatment in singleton-preg- with metoprolol or bisoprolol are well tolerated treatment
nancy women with mild preexisting hypertension. Antihy- options, but a case-by-case decision on close neonatal
pertensive drug treatment with a target below 140/ monitoring is recommended [104].
90 mmHg (active-treatment group) was compared with a
conservative strategy of withholding or stopping such CLINICAL MANAGEMENT: MILD
treatment unless severe hypertension developed (control GESTATIONAL HYPERTENSION
group). The CHAP trial outcomes were preeclampsia with
severe features or preterm delivery or placental abruption In women with mild gestational hypertension, the prepreg-
or fetal/neonatal death (primary outcome); small-for-gesta- nancy or until early second-trimester BP values are well
tional-age newborn (safety outcome); and serious neonatal below 140/90 mmHg and many times below 120/70 mmHg.
or maternal complications or preeclampsia or preterm birth Often, these otherwise healthy women are at low cardiovas-
(secondary outcomes). The participants were enrolled be- cular risk and without comorbidities. The physiological drop
fore the 23rd week of gestation, and those at higher risk for in BP in the second trimester produces a further BP reduction
severe hypertension development (i.e. treated with more [5]. However, a small amount of these women will indeed
than one antihypertensive agent at baseline) were exclud- develop, for the first time, hypertension after the 20th week
ed. The preferred drugs were labetalol or extended-release of pregnancy with BP levels greater than 140/90 mmHg.
nifedipine, either used in 97% of participants. A combina- Earlier hypertension guidelines [105–107] have considered
tion drug treatment was only used after monotherapy dose the difference in BP between the first trimester and after the
escalation. During follow-up, the achieved SBP/DBP dif- 20th week to draft recommendations about antihypertensive
ference was 3.1/2.3 mmHg lower in the active treatment treatment initiation in mild gestational hypertension. In the
than in the control group. The composite primary outcome 1999 World Health Association/International Society of Hy-
occurred 18% less frequently in the active-treatment group pertension guidelines [108,109], a rise in BP from precon-
than in controls [95% confidence interval (CI) 8–27%]. In ception or first trimester levels (e.g. SBP rise 25 mmHg and/
subgroup analyses, placental abruption and fetal/neonatal or DBP rise 15 mmHg) defined gestational hypertension
deaths were not different between groups. However, both alternatively to BP greater than 140/90 mmHg. For example,
of the following primary outcome components were re- a woman with an early pregnancy BP of 100/60 mmHg and a
duced in the active treatment compared with the control BP at the 22nd week of 135/85 mmHg may have a significant
group: preeclampsia with severe features by 20% (95% CI hemodynamic deterioration that may produce complications

Thomopoulos et al.
for the mother and fetus. A less pronounced BP difference CLINICAL MANAGEMENT: SEVERE
during the same gestational timeframe may not be associated
with adverse hemodynamic adaptations [108,109].
HYPERTENSION
Previous, though more recent, hypertension guidelines Severe hypertension in pregnancy is defined as sustained
[8] suggested that treatment of mild gestational hyperten- SBP at least 160 mmHg and/or DBP at least 110 mmHg.
sion might be initiated from thresholds well above 140/ Despite having no evidence from large clinical trials, there
90 mmHg (e.g. >150/95 mmHg). This expert opinion-based is a consensus that severe hypertension in pregnancy
recommendation mainly stems from the notion that a mild- should be treated. Timely treatment (within 60 min of
to-moderate BP elevation in pregnancy may be seen as a diagnosis) is associated with a 72% reduction in the relative
counterbalancing mechanism to support inadequate hemo- risk of severe maternal morbidity [114]. The expected
dynamic adaptations or fetal perfusion such as a relatively delivery time determines the selection of antihypertensive
decreased cardiac output or increased peripheral resis- drugs and the route of administration.
tance, respectively, always related to the gestational age
[23]. Although the CHIPS trial [98] included a limited num- Severe hypertension before 20 weeks of
ber of women with gestational hypertension, secondary gestation
analyses did not indicate a differential outcome effect Preexisting (chronic) hypertension in pregnancy is rarely
between women with gestational and preexisting hyper- severe. However, in severe cases, secondary hypertension
tension, both for primary and secondary outcomes. To should be ruled out, particularly in the absence of a family
synthesize the pathophysiological considerations and the history of hypertension, obesity, or Black ethnicity, and if
limited available evidence from the CHIPS trial [98] related hypertension seems to be treatment-resistant. The patient
to women with mild gestational hypertension, treatment should be assessed in a specialized center. In addition to
initiation at values at least 140/90 mmHg appears to be basic laboratory tests, a hypertension-mediated organ
reasonable. At the same time, a DBP reduction to less than damage assessment should be performed. It includes
80 mmHg is not recommended. The same drugs recom- urinalysis, preferably albumin to creatinine ratio in a
mended for preexisting hypertension (see above) can be single spot urine sample, electrocardiogram, echocardi-
used in women with gestational hypertension. ography, and fundoscopy. In the absence of preeclamp-
sia, treatment of severe hypertension can be initiated with
CLINICAL MANAGEMENT: MATERNAL oral drugs: labetalol, methyldopa, or nifedipine extended-
HEMODYNAMICS-GUIDED THERAPY release [55]. BP control can usually be achieved within
several days.
Recent studies have explored the impact of the hemody-
namic profile of women with gestational hypertension in
the choice of the first-line antihypertensive agent. Before Severe hypertension after 20 weeks of
the clinical presentation of hypertension, around 24 ges- gestation
tational weeks, women who will develop preterm pre- Severe hypertension after 20 weeks can be due to
eclampsia demonstrated significantly higher systemic gestational hypertension, preeclampsia, or superimposed
vascular resistance and lower cardiac output compared gestational hypertension in women with preexisting hyper-
with normotensive pregnant women. On the contrary, tension or poorly controlled preexisting hypertension. For
women who later developed term preeclampsia had oral treatment, the same drugs (labetalol, methyldopa, or
lower systemic vascular resistance and higher cardiac nifedipine extended-release) can be used. If intravenous
output compared to normotensive pregnant women treatment is necessary, intravenous labetalol is the drug of
[110]. Based on current evidence, the Italian Association choice. Due to the number of adverse effects mostly related
of Preeclampsia (AIPE) recently proposed a classification to maternal hypotension, hydralazine intravenous should
into three maternal hemodynamic profiles: hypodynamic be used only when other drugs are ineffective or when
(>1300 dynes s/cm5), normodynamic, and hyperdynamic labetalol is contraindicated [115]. However, intravenous
(<800 dynes s/cm5) [111]. hydralazine is still widely used in North America. Recent
Administering antihypertensive treatment to hyperten- systematic reviews and meta-analyses found hydralazine
sive pregnant women based on their hemodynamic profile comparable to labetalol and nifedipine in safety and
substantially decreased the occurrence of severe maternal efficacy [116,117]. Urapidil intravenous can also be consid-
hypertension from 18 to 3.8% [112]. Furthermore, the re- ered, whereas sodium nitroprusside should be used as the
currence of preeclampsia was lower with treatment tailored last option because of an increased risk of fetal cyanide
to the hemodynamic profile compared with the standard of poisoning with prolonged use. Intravenous nitroglycerine
care [113]. Nifedipine and alpha-methyldopa may be more is the drug of choice if preeclampsia is associated with
effective in treating women with a ‘hypodynamic’ profile, pulmonary edema (starting with an infusion of 5 mg/min
namely those with high peripheral resistance and low with a subsequent gradual increase every 3–5 min to a
cardiac output. Beta-blockers may be more effective for maximum dose of 100 up to 200 mg/min) [118]. Occasion-
women with a ‘hyperdynamic’ profile characterized by high ally, short-acting nifedipine can be given orally to pregnant
cardiac output and low resistance [113]. Future randomized women if intravenous access is not available, with the
studies may clarify the best strategy and therapeutic option second dose given only after 30–60 min if severe hyperten-
for all subtypes of HDP. At present, we do not recommend sion persists. However, sublingual short-acting nifedipine
treatment decisions based on hemodynamic data. is contraindicated.

TABLE 3. Risk factors for hypertensive emergency during TABLE 5. Maternal early warning criteria needing immediate
pregnancy bedside evaluation
Preeclampsia SBP <90 or >160 mmHg
Cardiac disease DBP >100 mmHg
Chronic renal disease Heart rate <50 or >130 beats per minute
Concomitant use of recreational drugs or other BP-raising medication (e.g. Oxygen saturation on room air, at sea level, <95%
erythropoietin, anabolic steroids, and some herbal remedies) Oliguria (<35 ml/h for 2 h or more)
Noncompliance with antihypertensive drugs Maternal agitation, confusion, or unresponsiveness (changed mental status)
Use of utero-contractive drugs (e.g. ergonovine maleate, methyl-ergonovine Nonremitting headache in patients with hypertensive disease of pregnancy
maleate) for the prevention and treatment of postpartum hemorrhage Shortness of breath
caused by uterine atony
Non-Hispanic Black population Modified from reference [118], with permission from Oxford University Press.
Low socioeconomic status
Modified from reference [118], with permission from Oxford University Press. BP, blood
pressure.
than 38 may be used (Fig. 2) [60,119,120]. Assessment of

Hypertensive emergency during pregnancy fetal well being should be an integral part of the diagnostic
Hypertensive emergency in pregnancy is defined as pre- workup, particularly in the later phase of pregnancy and
eclampsia/eclampsia and SBP at least 160 mmHg and DBP peripartum. Table 5 lists maternal abnormal parameters
at least 110 mmHg or markedly elevated BP (DBP needing immediate bedside evaluation [121]. The immedi-
>120 mmHg) and progressive acute end-organ damage ate goal is to decrease mean BP by 15–25% to achieve SBP
(aortic dissection, acute myocardial infarction, pulmonary 140–150 mmHg and DBP 90–100 mmHg. Table 6 provides
edema, and respiratory failure). Several risk factors for the list of the most frequently used drugs for the treatment
hypertensive emergency in pregnancy have been identified of hypertensive emergencies in pregnancy. Intravenous
(Table 3). Patient history should include questions about administration of magnesium sulfate is recommended for
compliance/noncompliance with antihypertensive drugs, the prevention of eclampsia and treatment of seizures
use of recreational drugs, and other drugs potentially [122,123]. Concomitant use of calcium channel blockers
increasing BP (e.g. nonsteroid anti-inflammatory drugs, may induce hypotension because of potential synergism
steroids, sympathomimetics, utero-contractive drugs). [32]. Primary prevention of eclampsia is recommended by
Physicians should pay attention to emergency symptoms most guidelines in patients with severe preeclampsia and
such as headache, particularly when accompanied by visual persistent neurological symptoms such as severe headache,
disturbances, chest pain, dyspnea, neurological symptoms, visual disturbances, and hyperactive deep-tendon reflexes
nausea, or abdominal pain. Primary diagnostic workups during pregnancy and the postpartum period (4 g magne-
and specific tests in a suspected hypertensive emergency sium sulfate intravenous loading dose followed by contin-
during pregnancy are shown in Table 4. In women in whom uous infusion of 1 g/h until delivery for 24 h max, under
at-term preeclampsia is suspected, an sFlt-1:PLGF ratio less close monitoring of the mother) [5,124].
CLINICAL MANAGEMENT OF
PREEXISTING SECONDARY
TABLE 4. Diagnostic workups and specific tests in a suspected
hypertensive emergency during pregnancy
HYPERTENSION
Primary work-up In women of childbearing age, preexisting secondary hy-
Fundoscopy pertension remains a rare and heterogeneous group of
EKG
Hemoglobin, platelet count, fibrinogen diseases with unclear prevalence. According to the 2023
Serum creatinine, eGFR, electrolytes, LDH, haptoglobin ESH guidelines for the management of hypertension [5],
Urine: ACR
Urine microscopy: red cells, leukocytes, casts
abdominal ultrasound investigation may be considered in
Specific tests addition to basic laboratory tests in pregnant women with a
Troponin (acute chest pain) history suggestive of phaeochromocytoma/paraganglioma
NT-proBNP (heart failure)
Plasma or urinary fractionated metanephrines (to rule out (PPGL) and women at high risk of gestational hypertension,
pheochromocytoma) preeclampsia, or IUGR.
sFlt-1/PLGF (preeclampsia) In young women with unexplained preexisting hyper-
Echocardiography (aortic dissection, heart failure, or ischemia)
Brain CT or MRI tension, particularly in the absence of family history, over-
Renal ultrasound (renal parenchymal disease) and duplex renal artery weight, older age, or Black ethnicity, it is recommended to
Doppler (renovascular disease)
Urine drug screen (suspected methamphetamine or cocaine use)
rule out a secondary cause of hypertension before preg-
Assessment of fetal wellbeing nancy. This strategy allows us to implement an interven-
Electronic fetal heart monitoring tional treatment before pregnancy when required, to
Ultrasound examination for fetal growth
Amniotic fluid assessment evaluate the risk of subsequent fetomaternal complications,
Uterine artery Doppler velocimetry (mean pulsatility index >95th and to avoid workups involving irradiation during preg-
percentile in the second trimester and/or bilateral notching) nancy [9]. During pregnancy, secondary hypertension
Modified from reference [118], with permission from Oxford University Press. ACR, should be strongly considered in women with severe
albumin to creatinine ratio; CT, computed tomography; eGFR, estimated glomerular hypertension (including hypertensive emergencies) or
filtration rate; EKG, electrocardiogram; sFlt-1, soluble fms-like tyrosine kinase-1; LDH,
lactate dehydrogenase; NT-proBNP, N-terminal pro-brain natriuretic peptide; PLGF, underlying renal disease with persistent proteinuria
placental growth factor. (<20 weeks of amenorrhea) [118].

1122
TABLE 6. Most used drugs for the treatment of hypertensive emergencies in pregnancy
Onset of Duration Maximum Possible adverse
Drug Route action of action Starting dose Titration dose dose Perinatal concerns Contra-indications effects
Thomopoulos et al.
Labetalol i.v. (intermittent) 5–10 min 2–6 h 10–20 mg i.v. (over 20–80 mg 300 mg Fetal distress secondary II or III degree AV Bronchoconstriction
2 min) i.v. every 20– to abrupt maternal block; systolic heart (CAUTION in women
30 min hypotension; failure; asthma; with asthma); fetal
i.v. (infusion) neonatal bradycardia bradycardia bradycardia; postural
1–2 mg/min and hypoglycemia hypotension; sleep
Increase by 1 mg/ disturbances;
min every 10 min rebound
www.jhypertension.com
hypertension;
masking
hypoglycemia
Hydralazine i.v. (intermittent) 10 min 12 h 5 mg/i.v. or i.m. 5–10 mg i.v. every 30 mg Fetal distress secondary Headache; palpitations;
20–40 min to abrupt maternal tachycardia; nausea/
hypotension; vomiting; flushing;
caesarean section; hypotension; lupus-
abruption; APGAR like syndrome;
score <7 more CAUTION: side effects
common; rarely may mimic
neonatal worsening
thrombocytopenia preeclampsia
and neonatal lupus
Nifedipine short- Oral 5–10 min 2–4 h 10–20 mg Repeat in 30 min if 30 mg Fetal distress secondary Uncontrolled
acting needed to abrupt maternal hypotension (high
formulation hypotension; when combined with
increased liver magnesium sulfate);
clearance may stroke; maternal
require higher doses hypotension
(particularly when
given sublingually);
headache; flushing;
reflex tachycardia
Nitroglycerine i.v. (infusion) 1–5 min 3–5 min 5 mg/min Increase by 5 mg/ 200 mg/min headache; reflex
min every 5 min tachycardia
Esmolol i.v. (infusion) <1 min 15–30 min Bolus 500 mg/kg; Increase by 50 mg/ 300 mg/kg/min Fetal bradycardia; II or III degree AV First-degree heart
maintenance kg/min every resistant fetal block; systolic heart block; maternal
50 mg/kg/min 4 min beta-blockade failure; asthma; bradycardia; CHF;
bradycardia bronchospasm
Nicardipine i.v. (infusion) 1–5 min 4–6 h 5 mg/h Increase by 2.5 mg/ 15 mg/h liver failure Tachycardia; flushing;
h every 5–15 min headache
Urapidil i.v. (infusion) 3–5 min 4–6 h Bolus 12.5–25 mg; 40 mg/h
maintenance 5–
40 mg/h
Sodium i.v. (infusion) <1 min 2–3 min 0.25 mg/kg/min Increase by 0.25– 5 mg/kg/min Fetal cyanide and Nausea; vomiting

nitroprusside 0.5 mg/kg/min thiocyanide toxicity if
every 2–3 min used >4 h
Modified from reference [118], with permission from Oxford University Press. AV, atrioventricular; CHF, chronic heart failure; i.v., intravenous; i.m., intramuscular; NO, nitric oxide.
Volume 42 Number 7 July 2024

Fibromuscular dysplasia and renal artery is viable. Vaginal delivery with PPGL in-situ ablation is
stenosis probably as well tolerated as delivery by cesarean section
Fibromuscular dysplasia (FMD) is an idiopathic, segmental, [117,127,130]. Finally, it has been shown in an international
nonatherosclerotic, and noninflammatory disease of the multicenter study and systematic review of 249 pregnancies
musculature of the arterial walls [125]. It is probably one that both maternal and fetal outcomes were excellent when
of the main causes of secondary hypertension in women of catecholamine excess was treated. Alpha-adrenergic block-
childbearing age. Pregnancies in patients with known FMD ade therapy was associated with better outcomes. Howev-
are considered to be at increased risk, particularly in the er, several severe and even fatal events occurred, mainly in
case of previous cervical artery dissection, spontaneous patients with unrecognized PPGL [130]. Timely consider-
coronary artery dissection, or poorly controlled hyperten- ation and diagnosis of PPGL before or during pregnancy are
sion. Accordingly, in patients with FMD, an intensive fol- key features for an optimal outcome.
low-up is required each trimester throughout pregnancy, as
well as in the immediate postpartum. A delivery plan must Chronic kidney disease
be set up and adapted to the profile of the patient, espe- Chronic kidney disease (CKD) is probably the most com-
cially in those women with a history of arterial dissection or mon cause of secondary hypertension in nonobese, non-
aneurysms [125]. According to data collected from 534 diabetic young women and often remains undetected
pregnancies of 232 women subsequently diagnosed with [131,132]. Preexisting CKD is present in 3% of pregnancies
FMD and enrolled in the European/International FMD in high-income countries [55]. In pregnant women, a history
Registry (FEIRI), the risk of gestational hypertension, pre- of preeclampsia, advanced maternal age, assisted repro-
term birth, and, to a lesser extent, preeclampsia was higher duction, multiple pregnancies, Black race, or clinical find-
than in historical cohorts of normotensive or hypertensive ings such as masked hypertension, chronic uncontrolled
women. In an overwhelming proportion of cases (96%), hypertension, or intra-uterine growth restriction is associ-
FMD was diagnosed only after pregnancy. It is reasonable ated with an increased likelihood of CKD [10,54,55,133]. In
to hypothesize that timely diagnosis of renal FMD leading to women with renal insufficiency, the presence of either an
renal artery revascularization before pregnancy, wherever estimated glomerular filtration rate (eGFR) less than 40 ml/
appropriate, would have significantly limited the risk of min/1.73 m2 (<0.67 ml/s/m2) or proteinuria greater than
pregnancy-related complications [126]. The risk of preg- 1 g/day before conception predicts poor maternal and fetal
nancy-related complications associated with FMD in this outcomes [134]. Angiogenic markers may be particularly
cohort – admittedly including mostly patients with renal useful in pregnant women with CKD [10,135,136]. Monitor-
FMD and a low prevalence of aneurysms and dissection – ing the sFlt-1/PLGF ratio, starting at the 20th week, may
was much lower than in a genetic arteriopathy such as allow for anticipating placental ischemia syndromes [137].
vascular Ehlers–Danlos [126]. Therefore, pregnancies in Moreover, a small study [133] suggested that the sFlt-1 to
patients with FMD deserve a close follow-up but are PLGF ratio may help differentiate between the variable
not contraindicated. causes of increasing proteinuria, especially in CKD patients.
Indeed, a low ratio (i.e. <30) was associated with CKD
Phaeochromocytoma/paraganglioma alone, whereas a ratio of greater than 150 was less likely
Among secondary hypertension, PPGL remains a very rare compatible with CKD alone and deemed suggestive of
tumor (0.002% of all pregnancies) but with devastating preeclampsia [133]. Although several guidelines call for
consequences (maternal and fetal mortality is around more aggressive treatment in pregnant women with
50% if undiagnosed) [32,127]. The clinical presentation of CKD, the specific BP target to achieve remains unclear.
PPGL during pregnancy is not essentially different from that Diuretics can be used safely in case of reduced eGFR but
in nonpregnant patients. Factors independently associated perhaps at lower doses [55]. Women at high risk of pre-
with an antenatal diagnosis of PPGL are hypertension at eclampsia, including women with CKD, should be advised
admission, sweating, and admission because of a history of to take 100–150 mg of aspirin daily starting from weeks 12–
PPGL/gene mutation/adrenal mass. Preeclampsia remains a 16 until the end of week 35 [5,10].
factor independently associated with a postnatal diagnosis
of PPGL. Three main factors associated with adverse ma- Primary aldosteronism
ternal and fetal outcomes are PPGL discovered after preg- Ten percent of hypertensive pregnancies are due to primary
nancy, catecholamine excess at least 10 times the normal aldosteronism. There is very little data on primary aldoste-
levels, and no a-blockade during pregnancy [128]. Plasma- ronism and pregnancy. Given the changes in the renin–
free metanephrines or urinary fractionated metanephrines angiotensin system during pregnancy, the diagnosis of
are the first-choice screening tests for suspected PPGL. primary aldosteronism is difficult to establish during gesta-
While it avoids radiation exposure, MRI allows reliable tion. It may be suspected in hypertensive patients with
tumor localization (sensitivity >90%) [129]. If a PPGL is hypokalemia. A comprehensive literature review identified
diagnosed in the first 24 amenorrhea weeks, laparoscopic reports covering 40 pregnancies in patients suffering from
adrenalectomy after 10–14 days of medical pretreatment primary aldosteronism. Analysis of these cases shows them
with a-adrenergic blockade is recommended. Calcium to be high-risk pregnancies leading to maternal and fetal
channel blockers and magnesium sulfate may also be used. complications [138]. A recent case–control study of 59
If the tumor is diagnosed near the third trimester, the same women compared the management and outcome of preg-
protocol is proposed as surgical preparation until the fetus nancies in women with primary aldosteronism to a group of

Thomopoulos et al.
high-risk pregnant women without primary aldosteronism postpartum hypertension’, which appears weeks to
and to a group of low-risk pregnant women. Women with 6 months after delivery and usually resolves before the first
primary aldosteronism during pregnancy delivered earlier year postpartum [32]. The pathogenesis of this condition is
but at term and required longer hospitalization and more unknown, but one possibility is that the return of postpar-
antihypertensive drugs after delivery. There was no differ- tum menses increases BP through a spillover of the excess
ence in the rates of maternal or neonatal adverse events, of progesterone and activation of mineralocorticoid recep-
including neonatal death, compared with their high-risk tors. This mechanism seems similar to that documented in
nonprimary aldosteronism counterparts. Overall, this study patients with Geller syndrome, who exhibit exacerbated
showed that women with primary aldosteronism had better hypertension in the third trimester of pregnancy [32,144]. In
pregnancy outcomes than previously stated in the litera- a relatively small single-center trial, the combined self-
ture, including the risk of preeclampsia or preterm delivery monitoring and physician-guided drug titration was associ-
[139]. ated with lower BP and improvement of cardiac remodeling
In women with primary aldosteronism, pregnancy needs measures during the first 9 months postpartum compared
to be planned, and if the patient has a unilateral form with usual postnatal outpatient care [145,146]. Hyperten-
of primary aldosteronism, an adrenalectomy should be sion specialists may play a pivotal role in the postpartum
performed before conception. It is customary to stop spi- care of women with HDP, educating them about the im-
ronolactone before conception and to introduce antihyper- portance of ongoing BP monitoring, suggesting appropri-
tensive drugs that present no risk of teratogenicity, but this ate lifestyle changes, and prescribing the appropriate and
recommendation could change with more data [140]. In tailored medications to optimize BP control and overall
small studies, drugs such as eplerenone or amiloride have cardiovascular health.
shown no adverse effects during pregnancy, though be- All antihypertensive agents used during pregnancy may
cause of the scarcity of data, they should better be avoided be used during puerperium to achieve BP control. The use of
[55]. When conventional antihypertensive drugs used dur- angiotensin-converting enzyme inhibitors in the postpartum
ing pregnancy fail to control high blood pressure, diuretics, period should be reserved for women with cardiorenal
including potassium-sparing diuretics, may nevertheless be comorbidities except in cases of premature birth or renal
prescribed. Adrenalectomy may be considered during the failure in newborns. Renin–angiotensin system blockers are
second trimester of pregnancy, exclusively in cases of not recommended in healthy women with hypertensive
refractory hypertension [138]. disorders during puerperium [5,109]. Methyl-dopa should
be used with caution because of the risk of postpartum
POSTPARTUM HYPERTENSION (THE depression [5,147]. Different BP phenotypes during puerpe-
FOURTH TRIMESTER) rium are summarized in Supplemental Figure S1, http://links.
lww.com/HJH/C456 (online Data Supplement).
Postpartum BP elevation is common during the first week,
and 10% of normotensive women demonstrate a DBP ANTIHYPERTENSIVE MEDICATIONS
increase to levels greater than 100 mmHg after delivery AND LACTATION
[141]. Also, in women with a normotensive pregnancy, a
BP elevation during the first day postpartum is usually During the postpartum period, some drugs taken by the
associated with the use of vasoactive drugs to favor uterine nursing mother may have a greater effect on the neonate
contraction (oxytocin, methergine), blood transfusions, the compared with others [148]. It is especially evident for drugs
physiological uterine ’auto-transfusion phenomenon’ or an with a low distribution volume, small protein binding,
excessive intravenous fluid administration. In women with increased lipophilicity (because of the different pharmaco-
preeclampsia, a reduced diuresis during 12–36 h postpar- kinetic drug properties between the mother and newborn),
tum is observed because of a delayed fluid redistribution and electrical neutrality within normal pH levels [149]. The
associated with a greater colloid osmotic pressure drop amount of milk, the bioavailability, and the clearance of the
compared with a normal pregnancy [26]. In a small, ran- drug are additional factors that modulate drug effects on the
domized placebo-controlled trial in women with hyperten- neonate [148]. Although diuretics are not contraindicated,
sion during pregnancy, administration of furosemide 20 mg they may be associated with reduced milk production.
daily during the first 5 days postpartum prevented 1 woman Among beta-blockers, atenolol should be avoided, whereas
out of 13 from developing postpartum hypertension [142]. labetalol, bisoprolol, and propranolol may be used. How-
However, the wide use of furosemide postpartum needs ever, beta-blockers during breastfeeding may be accompa-
confirmation from larger studies. Finally, it should be noted nied by neonate low glucose levels. Verapamil and
that 70% of women with preeclampsia maintain hyperten- nifedipine are considered compatible with breastfeeding.
sive BP levels, even under antihypertensive treatment, for Alpha-methyl-dopa is also compatible with breastfeeding.
the first week after delivery [143]. However, it should be remembered that it may induce
During puerperium, BP levels usually normalize within depression in the mother. Finally, in women with a history
the first 6 weeks in women with gestational hypertension or of cardiovascular disease, angiotensin-converting enzyme
preeclampsia, but this arbitrary rule is not without excep- inhibitors, especially captopril and enalapril, should be
tions [5]. By contrast, women with preexisting hypertension used because they have the most safety data available.
or superimposed preeclampsia perpetuate elevated BP Angiotensin receptor blockers are not currently recom-
values beyond the 6 weeks of puerperium. A rare postpar- mended in lactating women because of limited safety
tum hypertension phenotype is the so-called ’late evidence [5]. A summary of the relative safety of

antihypertensive agents during lactation is provided in invasive and minimally invasive ART procedures and be-
Supplemental Table S1, http://links.lww.com/HJH/C456 tween FIVET and ICSI techniques. By contrast, IUI with
(online Data Supplement) [7]. donor sperm was shown to be associated with an increased
risk of preeclampsia or gestational hypertension compared
RISK OF HYPERTENSIVE DISORDER with IUI with partner sperm [158]. The immune system
RECURRENCE IN A SUBSEQUENT hypothesis suggests that previous long enough exposure to
the partner sperm induces an immune tolerance towards
PREGNANCY the partner, reducing the inflammatory response and thus
Women who have experienced a pregnancy complicated the likelihood of preeclampsia development [159]. Regard-
by hypertensive disorders are concerned about the recur- ing invasive procedures, heterologous IVF with oocyte
rence of the same disorder in a future pregnancy [150]. donation seems to increase the risk of preeclampsia up
Studies that evaluated the recurrence rate of HDP showed to three times compared with IVF with autologous oocytes
divergent results not only due to an important heterogene- [160]. Finally, frozen–thawed embryo transfer (FET) is
ity in pathophysiology and clinical presentation but also associated with an increased risk for preeclampsia com-
because of different study designs [151]. A meta-analysis pared with fresh embryo transfer, and programmed FET
including 99 415 women showed that the recurrence rate of cycles are at higher risk compared with other endometrial
pregnancy-related hypertensive disorders was 20.7% [152]. preparation protocols [157,161].
Recurrence manifested as preeclampsia in 13.8%, gestation- Although women who resort to ART may have additional
al hypertension in 8.6%, and HELLP syndrome in 0.2%. risk factors for preeclampsia, such as primiparity, preexist-
However, in most cases, HDP recurred in a milder form ing hypertension, and advanced maternal age, the hetero-
[152]. Along the same lines, earlier studies reported a geneity in preeclampsia risk for different ART techniques
recurrence rate of preeclampsia ranging from 5.9 to 25%, suggests that these preexisting maternal risk factors do not
with a weighted average rate of 14% [151]. One population- entirely explain the increased risk of developing hyperten-
based study in Norway demonstrated that women with sive disorders in ART pregnancies (Fig. 3). Thus, other
preterm preeclampsia in the first pregnancy had an early pathophysiological hypotheses have been proposed for
or late preterm preeclampsia recurrence rate of 39.4 and the association between ART and hypertensive risk. The
30.4%, respectively [153]. Similar rates were found in an- placental insufficiency hypothesis suggests that IVF-in-
other population-based study in Australia, with the reap- duced suboptimal endometrial preparation and generation
pearance of preeclampsia in 33.8% during the following of the trophoblast cells outside of the uterus lead to patho-
pregnancy [150]. Risk factors of a recurrent pregnancy- logical placentation and placental insufficiency, which in
related hypertensive disorder are early onset preeclampsia, turn causes systemic endothelial dysfunction [162]. Another
HELLP syndrome or delivery of small-for-gestational age, hypothesis sees the absence of a corpus luteum as a key
prematurity, chronic hypertension, increased body weight, factor for cardiovascular and renal maladaptation during
between-pregnancy interval longer than 5–10 years or pregnancy, which ultimately leads to the development of
short interbirth interval (<2 years), and thrombophilia hypertension. This hypothesis is corroborated by the results
[153–155]. In summary, the risk of recurrence of pregnan- of several studies on women undergoing different IVF
cy-related hypertensive disorders is higher with a previous cycles that demonstrated a protective role of one or multi-
hypertensive pregnancy than with a previous normotensive ple corpora lutea compared to the absence of a corpus
pregnancy. Regarding counseling, maternal and perinatal luteum [163]. Primary causes of infertility also play a role.
outcomes in the subsequent pregnancy seem less severe For example, polycystic ovary syndrome has been associ-
than in the previous pregnancy. However, concomitant risk ated with an increased risk for preeclampsia even after
factors are important to future pregnancy outcomes [150]. adjustment for age, race, obesity, recourse to ART, and
other maternal factors [164].
INFERTILITY TREATMENTS In conclusion, the 2023 ESH guidelines for the manage-
ment of hypertension [5] considered ART as an independent
According to the WHO, infertility is a global health issue risk factor for preeclampsia. Thus, they recommended the
affecting almost 15% of reproductive-age couples. ART initiation of low-dose aspirin in all women undergoing ART
procedures are expanding rapidly, with concerns for ma- before 16 weeks of pregnancy [5,6]. Future controlled studies
ternal and fetal health. Large meta-analyses of more than are warranted to identify additional preventive and thera-
eight million pregnancies have shown that any ART pro- peutic measures for women undergoing ART procedures.
cedure is associated with an approximately 1.5–2 times
higher risk of developing HDP compared with spontane- PREGNANCY-RELATED HYPERTENSIVE
ously achieved pregnancies [156,157]. However, distinc- DISORDERS AND FUTURE
tions do exist concerning the type of ART procedure. CARDIOVASCULAR OUTCOMES
Intrauterine insemination (IUI) is considered a noninvasive
or minimally invasive ART. In contrast, in-vitro fertilization Preeclampsia is associated with a poor future cardiovascu-
(IVF) techniques, including Fertilization in Vitro and lar outcome, as has been constantly shown in different
Embryo Transfer (FIVET) and Intra-Cytoplasmic Sperm longitudinal studies with a prospective or retrospective
Injection (ICSI), are considered invasive ART procedures. design after adjustment for known confounders [5,55]. All
No adequately powered studies exist to compare the risk types of cardiovascular outcomes were found to increase
of pregnancy-related hypertensive disorders between after preeclampsia compared with uneventful pregnancies

Thomopoulos et al.
FIGURE 3 Why assisted techniques are related to an increased risk of hypertensive disorders? The mosaic of hypotheses. Order of gestation refers to the number of fetuses
in each pregnancy.
(i.e. heart failure, acute coronary syndromes, stroke, pulmo- vascular event of variable intensity centered on spiral arteries
nary embolism, valvular heart disease) [165–168], as well as a and the placenta [173]. Indeed, spiral arteries from pre-
five-fold increased risk of end-stage kidney disease com- eclamptic decidual tissue demonstrate histopathological
pared with parous women with no preeclampsia [169]. A forms of acute atherosis, with lipid-laden foam cells in the
meta-analysis of cohort studies showed that preeclampsia vessel wall lining the subendothelial area and occasionally a
with more severe features was associated with a higher lumen thrombus [174]. Whether vascular alterations were
incidence of future disease compared with preeclampsia preexistent to pregnancy (as a consequence of a subclinical
with less severe features [170]. A genome-wide genetic atherosclerotic process in the mother) or developed during
association study using Mendelian randomization provided pregnancy (as a consequence of preeclamptic systemic
genetic evidence supporting an association between preg- vascular dysfunction) remains unclear. By summarizing
nancy-related hypertensive disorders and a higher risk of the above, in women who have experienced HDP, lifestyle
coronary heart disease or stroke, which is only partially modifications are indicated to reduce the risk of complica-
mediated by cardiometabolic factors [171]. Although the tions in subsequent pregnancies as well as to reduce cardio-
association between preeclampsia and future cardiovascular vascular risk in general [175,176]. Regular visits for
events is consistently shown in most of the observations so cardiovascular risk assessment and frequent home BP meas-
far [165–168], we acknowledge that studies suffer from urements are recommended [176]. After delivery and hospital
unmeasured confounding before or after the preeclamptic discharge, the role of telemonitoring in women with HDP
pregnancy, that in many studies, the term ‘pregnancy-in- should be investigated in future trials to confirm the already
duced hypertension’ was used instead of preeclampsia or published promising evidence [145,146].
gestational hypertension [172]. Finally, it remains unknown
whether some cases of preeclampsia were complicated by CONCLUDING REMARKS AND FUTURE
subclinical myocardial injury, as in the case of overlapping DIRECTIONS
peripartum cardiomyopathy [30]. Because preeclampsia is
highly prevalent among women with high-risk profiles, it can Pregnancy-related hypertensive disorders continue to be a
be assumed that the development of preeclampsia may major cause of maternal, fetal, and neonatal morbidity and
further re-stratify these women at very high cardiovascular mortality worldwide. About 10% of pregnancies are com-
risk. Also, it cannot be ignored that preeclampsia represents a plicated by hypertension, and these rates are likely to rise

because of the increasing age and prevalence of obesity in hypertension and stroke later in life [183]. Additionally,
pregnant women. Moreover, ART procedures, regardless of preeclampsia was found to be associated with an increase
the type of treatment, are associated with an increased risk in heart failure, coronary heart disease, and cardiovascular
of developing HDP, with the highest risk being docu- death. Although the absolute risk of end-stage renal disease
mented in FET and OD pregnancies [157]. It is estimated in women who have had preeclampsia is low, preeclampsia
that about 2–6% of children in high-income countries are is a marker for an increased risk of subsequent kidney
conceived using assisted reproductive technology [177]. deterioration [184]. Women with a history of HDP may
There is an alarming fact that maternal death in some subsequently develop hypertension and premature cardio-
developed countries, such as the United States of America, vascular disease. They are now recognized as high-risk
has been steadily increasing over the past 30 years. This individuals. However, recommendations on systematic
phenomenon may be partly because of more sensitive and checkups are still lacking, and doctors in their usual practice
accurate reporting or to an increase in chronic comorbid- often forget to ask about that when taking history. BP
ities such as diabetes and obesity, renal disease, and sys- monitoring in the early postpartum period is strongly
temic vascular disease in pregnant women. Each of these advised, using BP self-measurement if feasible, with BP
comorbidities increases the risk of developing preeclamp- values directly reported to the attending doctors. In con-
sia. We are not predicting preeclampsia well, which is an clusion, several aspects of hypertension in pregnancy
important area for future research. Early detection of pre- should be further tested to ensure their future inclusion
eclampsia improves outcomes; however, no reliable in the guidelines.
screening test can predict its development during the
second or early third trimester [178]. The lack of reliable ACKNOWLEDGEMENTS
testing in HDP opens prospects for investigating endothe-
lial dysfunction by measuring blood and urine biomarkers Figure 3 was created with BioRender.com with permission.
(e.g. proteomics), not only for diagnostic purposes but also
to target personalized therapy [179]. Conflicts of interest
A low dose of aspirin, when initiated before 16 weeks of C.T. reports Honoraria for consultancy or lectures from
gestation, can substantially reduce the risk of preeclampsia. Menarini, Astra Zeneca, Krka, Servier, Sanofi, and Med-
Despite the evidence for the protective effect of a low dose tronic; R.K. reports personal Honoraria for consultancy,
of aspirin, it is still not adequately used. The CHAP trial in lectures or support for research from Bayer, CinCor
chronic hypertension in pregnancy showed that only 44.6% Pharma, Merck, Menarini Group, ProMed, PolPharma,
of women were taking a low dose of aspirin [100], suggest- and Servier; and T.S. reports material support from
ing that preconception counseling is inadequate or that this Roche Diagnostics.
issue was not discussed. Some promising data for statins
shows that they might be beneficial in preventing pre- REFERENCES
eclampsia; however, further studies are needed to draw 1. Thomopoulos C, Brguljan J, Cıfkova R, Persu A, Kreutz R. Mild chronic
definitive conclusions [180,181]. hypertension in pregnancy: to treat or wait? Blood Press 2022; 31:121–
124.
Based on the results of the CHIPS and CHAP trials 2. Backes CH, Markham K, Moorehead P, Cordero L, Nankervis CA,
[1,98,100], most guidelines have reduced the threshold Giannone PJ. Maternal preeclampsia and neonatal outcomes. J Preg-
for initiating drug treatment in pregnancy to at least 140/ nancy 2011; 2011:214365.
90 mmHg. However, the target DBP is still unclear, and the 3. Duffy J, Cairns AE, Richards-Doran D, van ’t Hooft J, Gale C, Brown M,
2023 ESH guidelines suggest not reducing BP 80 mmHg or et al., International Collaboration to Harmonise Outcomes for Pre-
eclampsia (iHOPE). A core outcome set for preeclampsia research: an
less [5]. Future clinical trials should address the optimal BP international consensus development study. BJOG 2020; 127:1516–
targets and their effects on maternal and fetal/neonatal 1526.
outcomes. The role of maternal hemodynamics seems 4. Scott G, Gillon TE, Pels A, von Dadelszen P, Magee LA. Guidelines-
promising for the future management of HDP [111]. similarities and dissimilarities: a systematic review of international
clinical practice guidelines for pregnancy hypertension. Am J Obstet
In general, for hypertension in pregnancy, there is still a Gynecol 2022; 226:S1222–S1236.
lack of evidence from large clinical trials, which are quite 5. Mancia G, Kreutz R, Brunstr€ om M, Burnier M, Grassi G, Januszewicz
difficult to organize for several reasons. Firstly, there might be A, et al. 2023 ESH Guidelines for the management of arterial hyper-
ethical problems. Secondly, pregnant women are not interest- tension The Task Force for the management of arterial hypertension
ed in participating in clinical trials, at least partly because of the European Society of Hypertension: endorsed by the Interna-
tional Society of Hypertension (ISH) and the European Renal Associ-
pregnant women are unaware of the association between ation (ERA). J Hypertens 2023; 41:1874–2071.
pregnancy complications and cardiovascular disease [182]. 6. Brown MA, Magee LA, Kenny LC, Karumanchi SA, McCarthy FP, Saito
Finally, there has been minimal effort from pharma companies S, et al. The hypertensive disorders of pregnancy: ISSHP classification,
for testing antihypertensive drugs in pregnancy. Therefore, diagnosis & management recommendations for international practice.
Pregnancy Hypertens 2018; 13:291–310.
the only substances that have been tested in large clinical 7. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, Blomstrom-
outcome trials in pregnancy are methyldopa, labetalol, and Lundqvist C, Cifkova R, De Bonis M, et al., ESC Scientific Document
long-acting nifedipine, and they are all recommended by the Group. 2018 ESC Guidelines for the management of cardiovascular
2023 ESH guidelines [5]. Additional substances need to be diseases during pregnancy. Eur Heart J 2018; 39:3165–3241.
tested in large clinical outcome trials, and till then, clinical 8. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M,
et al. 2018 ESC/ESH Guidelines for the management of arterial hyper-
experiences will guide the recommendations. tension: the Task Force for the management of arterial hypertension
Women with a history of gestational hypertension, and of the European Society of Cardiology and the European Society of
preeclampsia in particular, have a higher risk of developing Hypertension: the Task Force for the management of arterial

Thomopoulos et al.
hypertension of the European Society of Cardiology and the Europe- 29. Sciscione AC, Ivester T, Largoza M, Manley J, Shlossman P, Colmorgen
an Society of Hypertension. J Hypertens 2018; 36:1953–2041. GH. Acute pulmonary edema in pregnancy. Obstet Gynecol 2003;
9. Seely EW, Ecker J. Chronic hypertension in pregnancy. Circulation 101:511–515.
2014; 129:1254–1261. 30. Bello N, Rendon ISH, Arany Z. The relationship between preeclamp-
10. Magee LA, Brown MA, Hall DR, Gupte S, Hennessy A, Karumanchi SA, sia and peripartum cardiomyopathy: a systematic review and meta-
et al. The 2021 International Society for the Study of Hypertension in analysis. J Am Coll Cardiol 2013; 62:1715–1723.
Pregnancy classification, diagnosis & management recommendations 31. Erez O, Othman M, Rabinovich A, Leron E, Gotsch F, Thachil J. DIC in
for international practice. Pregnancy Hypertens 2022; 27:148–169. pregnancy - pathophysiology, clinical characteristics, diagnostic
11. Johnson S, Liu B, Kalafat E, Thilaganathan B, Khalil A. Maternal and scores, and treatments. J Blood Med 2022; 13:21–44.
perinatal outcomes of white coat hypertension during pregnancy: a 32. Lindheimer MD, Taler SJ. Cunningham FG; American Society of
systematic review and meta-analysis. Hypertension 2020; v76:157– Hypertension. ASH position paper: hypertension in pregnancy. J Clin
166. Hypertens 2009; 11:214–225.
12. Bellomo G, Narducci PL, Rondoni F, Pastorelli G, Stangoni G, Angeli 33. Hurrell A, Webster L, Chappell LC, Shennan AH. The assessment of
G, et al. Prognostic value of 24-h blood pressure in pregnancy. JAMA blood pressure in pregnant women: pitfalls and novel approaches.
1999; 282:1447–1452. Am J Obstet Gynecol 2022; 226:S804–S818.
13. Lee-Ann Hawkins T, Brown MA, Mangos GJ, Davis GK. Transient 34. Ashworth DC, Maule SP, Stewart F, Nathan HL, Shennan AH, Chappell
gestational hypertension: not always a benign event. Pregnancy LC. Setting and techniques for monitoring blood pressure during
Hypertens 2012; 2:22–27. pregnancy. Cochrane Database Syst Rev 2020; 8:CD012739.
14. Espeche WG, Salazar MR, Minetto J, Leiva Sisnieguez CE, Cerri G, 35. Turner MJ, Baker AB, Kam PC. Effects of systematic errors in blood
Balbın E, et al. Hypertension arising after 20 weeks of gestation: pressure measurements on the diagnosis of hypertension. Blood Press
gestational hypertension or masked chronic hypertension? J Hum Monit 2004; 9:249–253.
Hypertens 2023; 37:813–817. 36. Stergiou GS, O’Brien E, Myers M, Palatini P, Parati G, STRIDE BP
15. Nuckols VR, Stroud AK, Armstrong MK, Brandt DS, Santillan MK, Scientific Advisory Board. STRIDE BP: an international initiative for
Santillan DA, et al. Postpartum ambulatory and home blood pressure accurate blood pressure measurement. J Hypertens 2020; 38:395–399.
monitoring in women with history of preeclampsia: diagnostic agree- 37. Kho CL, Brown MA, Ong SL, Mangos GJ. Blood pressure measure-
ment and detection of masked hypertension. Pregnancy Hypertens ment in pregnancy: the effect of arm circumference and sphygmo-
2022; 29:23–29. manometer cuff size. Obstet Med 2009; 2:116–120.
16. Salazar MR, Espeche WG, Leiva Sisnieguez CE, Juliano PL, Vulcano 38. de Haas S, Mulder E, Schartmann N, Mohseni Z, Abo Hasson F,
MV, Sanchez Caro L, et al. Masked hypertension and Alsadah F, et al. Blood pressure adjustments throughout healthy
neonatal outcome in high-risk pregnancies. J Hum Hypertens 2023; and hypertensive pregnancy: a systematic review and meta-analysis.
37:36–41. Pregnancy Hypertens 2022; 27:51–58.
17. Botero JP, McIntosh JJ. Labor and delivery: DIC, HELLP, preeclampsia. 39. Hauspurg A, Parry S, Mercer BM, Grobman W, Hatfield T, Silver RM,
Hematology Am Soc Hematol Educ Program 2023; 2023:737–744. et al. Blood pressure trajectory and category and risk of hypertensive
18. GBD 2015 Maternal Mortality Collaborators. Global, regional, and disorders of pregnancy in nulliparous women. Am J Obstet Gynecol
national levels of maternal mortality, 1990-2015: a systematic analysis 2019; 221:e1–e8.
for the Global Burden of Disease Study 2015. Lancet 2016; 388:1775– 40. Porcelli BA, Diveley E, Meyenburg K, Woolfolk C, Rosenbloom JI,
1812. Raghuraman N, et al. A new definition of gestational hypertension?
19. GBD 2015 Child Mortality Collaborators. Global, regional, national, New-onset blood pressures of 130 to 139/80 to 89 mm Hg after
and selected subnational levels of stillbirths, neonatal, infant, and 20 weeks of gestation. Am J Obstet Gynecol 2020; 223:e1–e7.
under-5 mortality, 1980-2015: a systematic analysis for the Global 41. Mikami Y, Takai Y, Era S, Ono Y, Saitoh M, Baba K, et al. Provisional
Burden of Disease Study 2015. Lancet 2016; 388:1725–1774. criteria for the diagnosis of hypertension in pregnancy using home
20. Magee LA, Nicolaides KH, von Dadelszen P. Preeclampsia. N Engl J blood pressure measurements. Hypertens Res 2017; 40:679–684.
Med 2022; 386:1817–1832. 42. Brown MA. Is there a role for ambulatory blood pressure monitoring
21. Kim MK, Lee SM, Bae SH, Kim HJ, Lim NG, Yoon SJ, et al. Socioeco- in pregnancy? Clin Exp Pharmacol Physiol 2014; 41:16–21.
nomic status can affect pregnancy outcomes and complications, 43. Dougall G, Franssen M, Tucker KL, Yu LM, Hinton L, Rivero-Arias O,
even with a universal healthcare system. Int J Equity Health 2018; 17:2. et al. Blood pressure monitoring in high-risk pregnancy to improve
22. Ross KM, Dunkel Schetter C, McLemore MR, Chambers BD, Paynter the detection and monitoring of hypertension (the BUMP 1 and 2
RA, Baer R, et al. Socioeconomic status, preeclampsia risk and trials): protocol for two linked randomised controlled trials. BMJ Open
gestational length in black and white women. J Racial Ethn Health 2020; 10:e034593.
Disparities 2019; 6:1182–1191. 44. Tucker KL, Mort S, Yu LM, Campbell H, Rivero-Arias O, Wilson HM,
23. Ling HZ, Jara PG, Bisquera A, Poon LC, Nicolaides KH, Kametas NA. et al., BUMP Investigators. Effect of self-monitoring of blood pressure
Maternal cardiac function in women at high risk for preeclampsia on diagnosis of hypertension during higher-risk pregnancy: the
treated with 150 mg aspirin or placebo: an observational study. BJOG BUMP 1 Randomized Clinical Trial. JAMA 2022; 327:1656–1665.
2020; 127:1018–1025. 45. Chappell LC, Tucker KL, Galal U, Yu LM, Campbell H, Rivero-Arias O,
24. Li LN, Li XD, Du J. The effect of aspirin on uterine arterial blood flow et al., BUMP 2 Investigators. Effect of self-monitoring of blood
and endometrium in moderate and severe intrauterine adhesion after pressure on blood pressure control in pregnant individuals with
transcervical resection of adhesion: a systematic review and meta- chronic or gestational hypertension: the BUMP 2 Randomized Clinical
analysis. J Matern Fetal Neonatal Med 2023; 36:2209818. Trial. JAMA 2022; 327:1666–1678.
25. Osman MW, Nath M, Breslin E, Khalil A, Webb DR, Robinson TG, 46. Pealing LM, Tucker KL, Mackillop LH, Crawford C, Wilson H, Nickless
Mousa HA. Association between arterial stiffness and wave reflection A, et al., OPTIMUM-BP Investigators. A randomised controlled trial of
with subsequent development of placental-mediated diseases during blood pressure self-monitoring in the management of hypertensive
pregnancy: findings of a systematic review and meta-analysis. J pregnancy. OPTIMUM-BP: a feasibility trial. Pregnancy Hypertens
Hypertens 2018; 36:1005–1014. 2019; 18:141–149.
26. Thomopoulos C, Makris T. Iatrogenic aspects of hypertension in 47. Brown MA, Davis GK, McHugh L. The prevalence and clinical
pregnancy. In: Gussak IB, Kostis JB, editors. Iatrogenicity: causes significance of nocturnal hypertension in pregnancy. J Hypertens
and consequences of iatrogenesis in cardiovascular medicine. New 2001; 19:1437–1444.
Brunswick: Rutgers University Press; 2018. pp. 143–155. 48. Brown MA, Mangos G, Davis G, Homer C. The natural history of white
27. Cipolla MJ. Cerebrovascular function in pregnancy and eclampsia. coat hypertension during pregnancy. BJOG 2005; 112:601–606.
Hypertension 2007; 50:14–24. 49. O’Gorman N, Wright D, Poon LC, Rolnik DL, Syngelaki A, de Alvarado
28. Ros HS, Lichtenstein P, Bellocco R, Petersson G, Cnattingius S. M, Carbone IF, et al. Multicenter screening for preeclampsia by
Pulmonary embolism and stroke in relation to pregnancy: how can maternal factors and biomarkers at 11-13 weeks’ gestation: compari-
high-risk women be identified? Am J Obstet Gynecol 2002; 186:198– son with NICE guidelines and ACOG recommendations. Ultrasound
203. Obstet Gynecol 2017; 49:756–760.

50. Brown MA, Robinson A, Bowyer L, Buddle ML, Martin A, Hargood JL, 69. Hofmeyr GJ, Lawrie TA, Atallah ÁN, Torloni MR. Calcium supplemen-
et al. Ambulatory blood pressure monitoring in pregnancy: what is tation during pregnancy for preventing hypertensive disorders and
normal? Am J Obstet Gynecol 1998; 178:836–842. related problems. Cochrane Database Syst Rev 2018; 10:CD001059.
51. Schmella MJ, Clifton RG, Althouse AD, Roberts JM. Uric acid determi- 70. Sammour MB, El-Kabarity H, Fawzy MM, Schindler AE. Prevention
nation in gestational hypertension: is it as effective a delineator of risk and treatment of preeclampsia and eclampsia. J Steroid Biochem Mol
as proteinuria in high-risk women? Reprod Sci 2015; 22:1212–1219. Biol 2005; 97:439–440.
52. Chappell LC, Shennan AH. Assessment of proteinuria in pregnancy. 71. Woo Kinshella ML, Sarr C, Sandhu A, Bone JN, Vidler M, Moore SE,
BMJ 2008; 336:968–969. et al. Calcium for preeclampsia prevention: a systematic review and
53. Waugh J, Hooper R, Lamb E, Robson S, Shennan A, Milne F, et al. Spot network meta-analysis to guide personalised antenatal care. BJOG
protein-creatinine ratio and spot albumin-creatinine ratio in the 2022; 129:1833–1843.
assessment of preeclampsia: a diagnostic accuracy study with deci- 72. Institute of Medicine (US) Committee to review dietary reference
sion-analytic model-based economic evaluation and acceptability intakes for vitamin D and calcium. In Ross AC, Taylor CL, Yaktine AL,
analysis. Health Technol Assess 2017; 21:1–90. Del Valle HB, editors. Dietary reference intakes for calcium and
54. Bartsch E, Medcalf KE, Park AL, Ray JG; High Risk of Preeclampsia vitamin D. Washington (DC): National Academies Press (US); 2011.
Identification Group. Clinical risk factors for preeclampsia deter- 73. Kasawara KT, Nascimento SLDo, Costa ML, Surita FG, E Silva JLP.
mined in early pregnancy: systematic review and meta-analysis of Exercise and physical activity in the prevention of preeclampsia:
large cohort studies. BMJ 2016; 353:i1753. systematic review. Acta Obstet Gynecol Scand 2012; 91:1147–1157.
55. Garovic VD, Dechend R, Easterling T, Karumanchi SA, McMurtry 74. Magro-Malosso ER, Saccone G, Di Tommaso M, Roman A, Berghella
Baird S, et al., American Heart Association Council on Hypertension; V. Exercise during pregnancy and risk of gestational hypertensive
Council on the Kidney in Cardiovascular Disease, Kidney in Heart disorders: a systematic review and meta-analysis. Acta Obstet Gynecol
Disease Science Committee; Council on Arteriosclerosis, Thrombosis Scand 2017; 96:921–931.
and Vascular Biology; Council on Lifestyle and Cardiometabolic 75. Martınez-Vizcaıno V, Sanabria-Martınez G, Fernandez-Rodrıguez R,
Health; Council on Peripheral Vascular Disease; and Stroke Council. Cavero-Redondo I, Pascual-Morena C, Álvarez-Bueno C, Martınez-
Hypertension in pregnancy: diagnosis, blood pressure goals, and Hortelano JA. Exercise during pregnancy for preventing gestational
pharmacotherapy: a scientific statement from the American Heart diabetes mellitus and hypertensive disorders: An umbrella review of
Association. Hypertension 2022; 79:e21–e41. randomised controlled trials and an updated meta-analysis. BJOG An
56. Rana S, Lemoine E, Granger JP, Karumanchi SA. Preeclampsia: patho- Int J Obstet Gynaecol 2023; 130:264–275.
physiology, challenges, and perspectives. Circ Res 2019; 124:1094– 76. Xing Y, Wang X, Zhang W, Jiang H. The effect of exercise on maternal
1112. complications and birth outcomes in overweight or obese pregnant
57. Rolnik DL, Wright D, Poon LC, O’Gorman N, Syngelaki A, de Paco women: a meta-analysis. Ann Palliat Med 2020; 9:4103–4112.
Matallana C, et al. Aspirin versus placebo in pregnancies at high risk 77. Muhammad HFL, Pramono A, Rahman MN. The safety and efficacy of
for preterm preeclampsia. N Engl J Med 2017; 377:613–622. supervised exercise on pregnant women with overweight/obesity: a
58. Duhig KE, Myers J, Seed PT, Sparkes J, Lowe J, Hunter RM, et al., systematic review and meta-analysis of randomized controlled trials.
PARROT Trial Group. Placental growth factor testing to assess women Clin Obes 2021; 11:e12428.
with suspected preeclampsia: a multicentre, pragmatic, steppedwedge 78. Xie E, Tao H, Liu M, Li C, Zhao Q. The effect of exercise on the
cluster-randomised controlled trial. Lancet 2019; 393:1807–1818. prevention of gestational hypertension in obese and overweight
59. Wright D, Wright A, Nicolaides KH. The competing risk approach for pregnant women: an updated meta-analysis. Front Public Health
prediction of preeclampsia. Am J Obstet Gynecol 2020; 223:12.e7–23.e7. 2022; 10:923161.
60. Hurrell A, Webster L, Sparkes J, Battersby C, Brockbank A, Clark K, 79. Physical activity and exercise during pregnancy and the postpartum
et al., PARROT-2 trial group. Repeat placental growth factor-based period: ACOG Committee Opinion, Number 804. Obstet Gynecol
testing in women with suspected preterm preeclampsia (PARROT-2): 2020; 135:e178–e188.
a multicentre, parallel-group, superiority, randomised controlled trial. 80. Ruifrok AE, Van Poppel MNM, Van Wely M, Rogozińska E, Khan KS,
Lancet 2024; 403:619–631. De Groot CJM, et al. Association between weight gain during preg-
61. D€obert M, Wright A, Varouxaki AN, Mu AC, Syngelaki A, Rehal A, et al. nancy and pregnancy outcomes after dietary and lifestyle interven-
STATIN trial: predictive performance of competing-risks model in tions: a meta-analysis. Am J Perinatol 2014; 31:353–364.
screening for preeclampsia at 35-37 weeks’ gestation. Ultrasound 81. Ren M, Li H, Cai W, Niu X, Ji W, Zhang Z, et al. Excessive gestational
Obstet Gynecol 2022; 59:69–75. weight gain in accordance with the IOM criteria and the risk of
62. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton Pipkin F, hypertensive disorders of pregnancy: a meta-analysis. BMC Pregnan-
et al. Prediction of adverse maternal outcomes in preeclampsia: cy Childbirth 2018; 18:281.
development and validation of the fullPIERS model. Lancet 2011; 82. Santos S, Voerman E, Amiano P, Barros H, Beilin LJ, Bergstr€
om A, et al.
377:219–227. Impact of maternal body mass index and gestational weight gain on
63. Ukah UV, Payne B, Karjalainen H, Kortelainen E, Seed PT, Conti- pregnancy complications: an individual participant data meta-analysis
Ramsden FI, et al. Temporal and external validation of the fullPIERS of European, North American and Australian cohorts. BJOG 2019;
model for the prediction of adverse maternal outcomes in women 126:984–995.
with preeclampsia. Pregnancy Hypertens 2019; 15:42–50. 83. Yılmaz ZV, Akkaş E, T€ urkmen GG, Kara Ö, Y€ucel A, Uygur D. Dietary
64. Ukah UV, Payne B, Hutcheon JA, Ansermino JM, Ganzevoort W, sodium and potassium intake were associated with hypertension,
Thangaratinam S, et al. Assessment of the fullPIERS Risk Prediction kidney damage and adverse perinatal outcome in pregnant women
Model in Women With Early-Onset Preeclampsia. Hypertension 2018; with preeclampsia. Hypertens Pregnancy 2017; 36:77–83.
71:659–665. 84. Birukov A, Andersen LB, Herse F, Rakova N, Kitlen G, Kyhl HB, et al.
65. Roberge S, Nicolaides K, Demers S, Hyett J, Chaillet N, Bujold E. The Preeclampsia ALDOSTERONE, SALT, AND POTASSIUM INTAKES AS
role of aspirin dose on the prevention of preeclampsia and fetal PREDICTORS OF PREGNANCY OUTCOME, INCLUDING PRE-
growth restriction: systematic review and meta-analysis. Am J Obstet ECLAmpsia. Hypertension 2019; 74:391–398.
Gynecol 2017; 216:110.e6–120.e6. 85. Arvizu M, Bjerregaard AA, Madsen MTB, Granstr€ om C, Halldorsson TI,
66. Bujold E, Roberge S, Nicolaides KH. Low-dose aspirin for prevention Olsen SF, et al. Sodium intake during pregnancy, but not other diet
of adverse outcomes related to abnormal placentation. Prenat Diagn recommendations aimed at preventing cardiovascular disease, is
2014; 34:642–648. positively related to risk of hypertensive disorders of pregnancy. J
67. Caron N, Rivard GÉ, Michon N, Morin F, Pilon D, Moutquin JM, Rey E. Nutr 2020; 150:159–166.
Low-dose ASA response using the PFA-100 in women with high-risk 86. Knuist M, Bonsel GJ, Zondervan HA, Treffers PE. Low sodium diet and
pregnancy. J Obstet Gynaecol Can 2009; 31:1022–1027. pregnancy-induced hypertension: a multicentre randomised con-
68. Richards EMF, Giorgione V, Stevens O, Thilaganathan B. Low-dose trolled trial. Br J Obs Gynaecol 1998; 105:430–434.
aspirin for the prevention of superimposed preeclampsia in women 87. Duley L, Henderson-Smart DJ. Reduced salt intake compared to
with chronic hypertension: a systematic review and meta-analysis. Am normal dietary salt, or high intake, in pregnancy. Cochrane Database
J Obstet Gynecol 2023; 228:395–408. Syst Rev 2000; 1999:CD001687.

Thomopoulos et al.
88. Webster K, Fishburn S, Maresh M, Findlay SC, Chappell LC, Guideline 109. Meinert F, Thomopoulos C, Kreutz R. Sex and gender in hypertension
C, Guideline Committee. Diagnosis and management of hypertension guidelines. J Hum Hypertens 2023; 37:654–661.
in pregnancy: summary of updated NICE guidance. BMJ 2019; 366: 110. McLaughlin K, Scholten RR, Kingdom JC, Floras JS, Parker JD. Should
l5119. maternal hemodynamics guide antihypertensive therapy in pre-
89. Grobman WA, Rice MM, Reddy UM, Tita ATN, Silver RM, Mallett G, eclampsia? Hypertension 2018; 71:550–556.
et al., Eunice Kennedy Shriver National Institute of Child Health and 111. Vasapollo B, Zullino S, Novelli GP, Farsetti D, Ottanelli S, Clemenza S,
Human Development Maternal–Fetal Medicine Units Network. Labor et al. Maternal hemodynamics from preconception to delivery: re-
induction versus expectant management in low-risk nulliparous search and potential diagnostic and therapeutic implications: position
women. N Engl J Med 2018; 379:513–523. statement by Italian Association of Pre-Eclampsia and Italian Society
90. D€obert M, Varouxaki AN, Mu AC, Syngelaki A, Ciobanu A, Akolekar R, of Perinatal Medicine. Am J Perinatol 2024; doi: 10.1055/a-2267-3994.
et al. Pravastatin versus placebo in pregnancies at high risk of term 112. Stott D, Papastefanou I, Paraschiv D, Clark K, Kametas NA. Serial
preeclampsia. Circulation 2021; 144:670–679. hemodynamic monitoring to guide treatment of maternal hyperten-
91. Magun E, DeFilippis EM, Noble S, LaSala A, Waksmonski C, D’Alton sion leads to reduction in severe hypertension. Ultrasound Obstet
ME, Haythe J. Cardiovascular care for pregnant women with cardio- Gynecol 2017; 49:95–103.
vascular disease. J Am Coll Cardiol 2020; 76:2102–2113. 113. Mulder EG, Ghossein-Doha C, Cauffman E, Lopes van Balen VA,
92. Piani F, Degli Esposti D, Agnoletti D, Borghi C, Bologna HDP Study Schiffer VMMM, Alers RJ, et al. Preventing recurrent preeclampsia by
Group. Does a multidisciplinary team involving internists specialized tailored treatment of nonphysiologic hemodynamic adjustments to
in hypertension and obstetric medicine improve pregnancy out- pregnancy. Hypertension 2021; 77:2045–2053.
comes? Eur J Intern Med 2023; 117:148–150. 114. Gupta M, Greene N, Kilpatrick SJ. Timely treatment of severe maternal
93. Moretti ME, Caprara D, Drehuta I, Yeung E, Cheung S, Federico L, hypertension and reduction in severe maternal morbidity. Pregnancy
Koren G. The fetal safety of angiotensin converting enzyme inhibitors Hypertens 2018; 14:55–58.
and angiotensin II receptor blockers. Obstet Gynecol Int 2012; 115. Magee LA, Cham C, Waterman EJ, Ohlsson A, von Dadelszen P.
2012:658310. Hydralazine for treatment of severe hypertension in pregnancy:
94. Hoeltzenbein M, Tissen-Diabate T, Fietz AK, Zinke S, Kayser A, meta-analysis. BMJ 2003; 327:955–960.
Meister R, et al. Pregnancy outcome after first trimester use of 116. Antza C, Dimou C, Doundoulakis I, Akrivos E, Stabouli S, Haidich AB,
angiotensin AT1 receptor blockers: an observational cohort study. et al. The flipside of hydralazine in pregnancy: a systematic review
Clin Res Cardiol 2018; 107:679–687. and meta-analysis. Pregnancy Hypertens 2020; 19:177–186.
95. Hoeltzenbein M, Tissen-Diabate T, Fietz AK, Zinke S, Kayser A, 117. Sridharan K, Sequeira RP. Drugs for treating severe hypertension in
Meister R, et al. Increased rate of birth defects after first trimester pregnancy: a network meta-analysis and trial sequential analysis of
use of angiotensin converting enzyme inhibitors - Treatment or randomized clinical trials. Br J Clin Pharmacol 2018; 84:1906–1916.
hypertension related? An observational cohort study. Pregnancy 118. Cıfkova R, Johnson MR, Kahan T, Brguljan J, Williams B, Coca A, et al.
Hypertens 2018; 13:65–71. Peripartum management of hypertension: a position paper of the ESC
96. Weber-Schoendorfer C, Kayser A, Tissen-Diabate T, Winterfeld U, Council on Hypertension and the European Society of Hypertension.
Eleftheriou G, Te Winkel B, et al. Fetotoxic risk of AT1 blockers Eur Heart J Cardiovasc Pharmacother 2020; 6:384–393.
exceeds that of angiotensin-converting enzyme inhibitors: an obser- 119. Zeisler H, Llurba E, Chantraine F, Vatish M, Staff AC, Sennstr€ om M,
vational study. J Hypertens 2020; 38:133–141. et al. Predictive value of the sFlt-1:PlGF ratio in women with sus-
97. Hoeltzenbein M, Beck E, Fietz AK, Wernicke J, Zinke S, Kayser A, et al. pected preeclampsia. N Engl J Med 2016; 374:13–22.
Pregnancy outcome after first trimester use of methyldopa: a pro- 120. Verlohren S, Brennecke SP, Galindo A, Karumanchi SA, Mirkovic LB,
spective cohort study. Hypertension 2017; 70:201–208. Schlembach D, et al. Clinical interpretation and implementation of the
98. Magee LA, von Dadelszen P, Rey E, Ross S, Asztalos E, Murphy KE, sFlt-1/PlGF ratio in the prediction, diagnosis and management of
et al. Less-tight versus tight control of hypertension in pregnancy. N preeclampsia. Pregnancy Hypertens 2022; 27:42–50.
Engl J Med 2015; 372:407–417. 121. El Farra J, Bean C, Martin JN Jr. Management of hypertensive crisis for
99. Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive the obstetrician/gynecologist. Obstet Gynecol Clin North Am 2016;
drug therapy for mild to moderate hypertension during pregnancy. 43:623–637.
Cochrane Database Syst Rev 2018; 10:CD002252. 122. Altman D, Carroli G, Duley L, Farrell B, Moodley J, Neilson J, et al. Do
100. Tita AT, Szychowski JM, Boggess K, Dugoff L, Sibai B, Lawrence K, women with preeclampsia, and their babies, benefit from magnesium
et al., Chronic Hypertension and Pregnancy (CHAP) Trial Consortium. sulphate? The Magpie Trial: a randomised placebo-controlled trial.
Treatment for mild chronic hypertension during pregnancy. N Engl J Lancet 2002; 359:1877–1890.
Med 2022; 386:1781–1792. 123. Duley L, G€ ulmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium
101. Whelan A, Izewski J, Berkelhammer C, Walloch J, Kay HH. Labetalol- sulphate and other anticonvulsants for women with preeclampsia.
induced hepatotoxicity during pregnancy: a case report. AJP Rep Cochrane Database Syst Rev 2010; 2010:CD000025.
2020; 10:e210–e212. 124. Shields LE, Wiesner S, Klein C, Pelletreau B, Hedriana HL. Early
102. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension standardized treatment of critical blood pressure elevations is associ-
during pregnancy. BMJ 1990; 301:587–589. ated with a reduction in eclampsia and severe maternal morbidity. Am
103. Hoeltzenbein M, Fietz AK, Kayser A, Zinke S, Meister R, Weber- J Obstet Gynecol 2017; 216:415.e1–415.e5.
Schoendorfer C, Schaefer C. Pregnancy outcome after first trimester 125. Gornik HL, Persu A, Adlam D, Aparicio LS, Azizi M, Boulanger M, et al.
exposure to bisoprolol: an observational cohort study. J Hypertens First International Consensus on the diagnosis and management of
2018; 36:2109–2117. fibromuscular dysplasia. Vasc Med 2019; 24:164–189.
104. Kayser A, Beck E, Hoeltzenbein M, Zinke S, Meister R, Weber- 126. Pappaccogli M, Prejbisz A, Ciurică S, Bruno RM, Aniszczuk-Hybiak A,
Schoendorfer C, et al. Neonatal effects of intrauterine metoprolol/ Bracalente I, et al., European/International Fibromuscular Dysplasia
bisoprolol exposure during the second and third trimester: a cohort Registry and Initiative (FEIRI) and the Working Group ‘‘Hypertension
study with two comparison groups. J Hypertens 2020; 38:354–361. and the Kidney’’ of the ESH. Pregnancy-related complications in
105. WHO Expert Committee on Arterial Hypertension & World Health patients with fibromuscular dysplasia: a report from the European/
Organization. Arterial hypertension: report of a WHO expert commit- International Fibromuscular Dysplasia Registry. Hypertension 2020;
tee [meeting held in Geneva from 13 to 21 March 1978]. Geneva: 76:545–553.
World Health Organization; 1978. 127. Lenders JW. Pheochromocytoma and pregnancy: a deceptive con-
106. Guidelines for the treatment of mild hypertension. Memorandum nection. Eur J Endocrinol 2012; 166:143–150.
from a WHO/ISH meeting. Hypertension 1983; 5:394–397. 128. Langton K, Tufton N, Akker S, Deinum J, Eisenhofer G, Timmers H,
107. WHO. 1986 guidelines for the treatment of mild hypertension: et al. Pregnancy and phaeochromocytoma/paraganglioma: clinical
memorandum from a WHO/ISH meeting. J Hypertens 1986; 4:383– clues affecting diagnosis and outcome - a systematic review. BJOG
386. 2021; 128:1264–1272.
108. Guidelines Subcommittee. 1999 World Health Organization-Interna- 129. Lenders JWM, Langton K, Langenhuijsen JF, Eisenhofer G. Pheochro-
tional Society of Hypertension Guidelines for the Management of mocytoma and pregnancy. Endocrinol Metab Clin North Am 2019;
Hypertension. J Hypertens 1999; 17:151–183. 48:605–617.

130. Bancos I, Atkinson E, Eng C, Young WF Jr, Neumann HPH, Interna- 152. van Oostwaard MF, Langenveld J, Schuit E, Papatsonis DN, Brown
tional Pheochromocytoma and Pregnancy Study Group. Maternal and MA, Byaruhanga RN, et al. Recurrence of hypertensive disorders of
fetal outcomes in phaeochromocytoma and pregnancy: a multicentre pregnancy: an individual patient data metaanalysis. Am J Obstet
retrospective cohort study and systematic review of literature. Lancet Gynecol 2015; 212:624.e1–624.e17.
Diabetes Endocrinol 2021; 9:13–21. 153. Ebbing C, Rasmussen S, Skjaerven R, Irgens LM. Risk factors for
131. Cabiddu G, Mannucci C, Fois A, Maxia S, Chatrenet A, Osadolor S, recurrence of hypertensive disorders of pregnancy, a population-
et al. Preeclampsia is a valuable opportunity to diagnose chronic based cohort study. Acta Obstet Gynecol Scand 2017; 96:243–250.
kidney disease: a multicentre study. Nephrol Dial Transplant 2022; 154. Cnattingius S, Wikstr€om AK, Stephansson O, Johansson K. The impact
37:1488–1498. of small for gestational age births in early and late preeclamptic
132. Filali Khattabi Z, Biolcati M, Fois A, Chatrenet A, Laroche D, Attini R, pregnancies for preeclampsia recurrence: a cohort study of successive
et al. Chronic kidney disease in preeclamptic patients: not found pregnancies in Sweden. Paediatr Perinat Epidemiol 2016; 30:563–
unless searched for-Is a nephrology evaluation useful after an episode 570.
of preeclampsia? J Nephrol 2019; 32:977–987. 155. Ohamadike O, Lim SL, Siegel A, Zemtsov G, Kuller JA, Dotters-Katz S.
133. Rolfo A, Attini R, Tavassoli E, Neve FV, Nigra M, Cicilano M, et al. Is it Hypertensive disorders of pregnancy: common clinical conundrums.
possible to differentiate chronic kidney disease and preeclampsia by Obstet Gynecol Surv 2022; 77:234–244.
means of new and old biomarkers? A prospective study. Dis Markers 156. Chih HJ, Elias FTS, Gaudet L, Velez MP. Assisted reproductive tech-
2015; 2015:127083. nology and hypertensive disorders of pregnancy: systematic review
134. Imbasciati E, Gregorini G, Cabiddu G, Gammaro L, Ambroso G, Del and meta-analyses. BMC Pregnancy Childbirth 2021; 21:449.
Giudice A, Ravani P. Pregnancy in CKD stages 3 to 5: fetal and 157. Thomopoulos C, Salamalekis G, Kintis K, Andrianopoulou I, Micha-
maternal outcomes. Am J Kidney Dis 2007; 49:753–762. lopoulou H, Skalis G, et al. Risk of hypertensive disorders in preg-
135. Bramham K, Seed PT, Lightstone L, Nelson-Piercy C, Gill C, Webster P, nancy following assisted reproductive technology: overview and
et al. Diagnostic and predictive biomarkers for preeclampsia in meta-analysis. J Clin Hypertens (Greenwich) 2017; 19:173–183.
patients with established hypertension and chronic kidney disease. 158. Pohjonen EM, S€ oderstr€om-Anttila V, Bergh C, Loft A, Magnusson Å,
Kidney Int 2016; 89:874–885. Pinborg A, et al. Obstetric and perinatal risks after the use of donor
136. Perni U, Sison C, Sharma V, Helseth G, Hawfield A, Suthanthiran M, sperm: a systematic review and meta-analysis. Eur J Obstet Gynecol
August P. Angiogenic factors in superimposed preeclampsia: a lon- Reprod Biol 2022; 274:210–228.
gitudinal study of women with chronic hypertension during preg- 159. Kyrou D, Kolibianakis EM, Devroey P, Fatemi HM. Is the use of donor
nancy. Hypertension 2012; 59:740–746. sperm associated with a higher incidence of preeclampsia in women
137. Kwiatkowski S, Bednarek-Je˛drzejek M, Kwiatkowska E, Cymbaluk- who achieve pregnancy after intrauterine insemination? Fertil Steril
Płoska A, Torbè A. Diagnosis of placental insufficiency independently 2010; 93:1124–1127.
of clinical presentations using sFlt-1/PLGF ratio, including SGA 160. Blazquez A, Garcıa D, Rodrıguez A, Vassena R, Figueras F, Vernaeve
patients. Pregnancy Hypertens 2021; 25:244–248. V. Is oocyte donation a risk factor for preeclampsia? A systematic
138. Landau E, Amar L. Primary aldosteronism and pregnancy. Ann review and meta-analysis. J Assist Reprod Genet 2016; 33:855–863.
Endocrinol (Paris) 2016; 77:148–160. 161. Busnelli A, Schirripa I, Fedele F, Bulfoni A, Levi-Setti PE. Obstetric and
139. Downie E, Shanmugalingam R, Hennessy A, Makris A. Assessment perinatal outcomes following programmed compared to natural
and management of primary aldosteronism in pregnancy: a case- frozen-thawed embryo transfer cycles: a systematic review and
control study. J Clin Endocrinol Metab 2022; 107:e3152–e3158. meta-analysis. Hum Reprod 2022; 37:1619–1641.
140. Liszewski W, Boull C. Lack of evidence for feminization of males 162. Manna C, Lacconi V, Rizzo G, De Lorenzo A, Massimiani M. Placental
exposed to spironolactone in utero: a systematic review. J Am Acad dysfunction in assisted reproductive pregnancies: perinatal, neonatal
Dermatol 2019; 80:1147–1148. and adult life outcomes. Int J Mol Sci 2022; 23:659.
141. Walters BN, Thompson ME, Lee A, de Swiet M. Blood pressure in the 163. Pereira MM, Mainigi M, Strauss JF. Secretory products of the corpus
puerperium. Clin Sci (Lond) 1986; 71:589–594. luteum and preeclampsia. Hum Reprod Update 2021; 27:651–672.
142. Lopes Perdigao J, Lewey J, Hirshberg A, Koelper N, Srinivas SK, 164. Mills G, Badeghiesh A, Suarthana E, Baghlaf H, Dahan MH. Polycystic
Elovitz MA, Levine LD. Furosemide for accelerated recovery of blood ovary syndrome as an independent risk factor for gestational diabetes
pressure postpartum in women with a hypertensive disorder of and hypertensive disorders of pregnancy: a population-based study
pregnancy: a randomized controlled trial. Hypertension 2021; on 9.1 million pregnancies. Hum Reprod 2020; 35:1666–1674.
77:1517–1524. 165. Lykke JA, Langhoff-Roos J, Sibai BM, Funai EF, Triche EW, Paidas MJ.
143. Walters BN, Walters T. Hypertension in the puerperium. Lancet 1987; Hypertensive pregnancy disorders and subsequent cardiovascular
2:330. morbidity and type 2 diabetes mellitus in the mother. Hypertension
144. Geller DS, Farhi A, Pinkerton N, Fradley M, Moritz M, Spitzer A, et al. 2009; 53:944–951.
Activating mineralocorticoid receptor mutation in hypertension ex- 166. M€annist€o T, Mendola P, V€a€ar€asm€aki M, J€arvelin MR, Hartikainen AL,
acerbated by pregnancy. Science 2000; 289:119–123. Pouta A, Suvanto E. Elevated blood pressure in pregnancy and
145. Kitt J, Fox R, Frost A, Shanyinde M, Tucker K, Bateman PA, et al. Long- subsequent chronic disease risk. Circulation 2013; 127:681–690.
term blood pressure control after hypertensive pregnancy following 167. Honigberg MC, Zekavat SM, Aragam K, Klarin D, Bhatt DL, Scott NS,
physician-optimized self-management: the POP-HT Randomized et al. Long-term cardiovascular risk in women with hypertension
Clinical Trial. JAMA 2023; 330:1991–1999. during pregnancy. J Am Coll Cardiol 2019; 74:2743–2754.
146. Kitt J, Krasner S, Barr L, Frost A, Tucker K, Bateman PA, et al. Cardiac 168. Inversetti A, Pivato CA, Cristodoro M, Latini AC, Condorelli G, Di
remodeling after hypertensive pregnancy following physician-opti- Simone N, et al. Update on long-term cardiovascular risk after
mized blood pressure self-management: the POP-HT Randomized preeclampsia: a systematic review and meta-analysis. Eur Heart J
Clinical Trial Imaging Substudy. Circulation 2024; 149:529–541. Qual Care Clin Outcomes 2024; 10:4–13.
147. Wiciński M, Malinowski B, Puk O, Socha M, Słupski M. Methyldopa as 169. Khashan AS, Evans M, Kublickas M, McCarthy FP, Kenny LC, Sten-
an inductor of postpartum depression and maternal blues: a review. vinkel P, et al. Preeclampsia and risk of end stage kidney disease: a
Biomed Pharmacother 2020; 127:110196. Swedish nationwide cohort study. PLoS Med 2019; 16:e1002875.
148. Podymow T, August P. Update on the use of antihypertensive drugs in 170. Grandi SM, Filion KB, Yoon S, Ayele HT, Doyle CM, Hutcheon JA,
pregnancy. Hypertension 2008; 51:960–969. et al. Cardiovascular disease-related morbidity and mortality in wom-
149. Breitzka RL, Sandritter TL, Hatzopoulos FK. Principles of drug transfer en with a history of pregnancy complications. Circulation 2019;
into breast milk and drug disposition in the nursing infant. J Hum Lact 139:1069–1079.
1997; 13:155–158. 171. Rayes B, Ardissino M, Slob EAW, Patel KHK, Girling J, Ng FS.
150. Seeho SK, Algert CS, Roberts CL, Ford JB. Early-onset preeclampsia Association of hypertensive disorders of pregnancy with future car-
appears to discourage subsequent pregnancy but the risks may be diovascular disease. JAMA Netw Open 2023; 6:e230034.
overestimated. Am J Obstet Gynecol 2016; 215:785.e1–785.e8. 172. Wu P, Haththotuwa R, Kwok CS, Babu A, Kotronias RA, Rushton C,
151. Giannubilo SR, Landi B, Ciavattini A. Preeclampsia: what could et al. Preeclampsia and future cardiovascular health: a systematic
happen in a subsequent pregnancy? Obstet Gynecol Surv 2014; review and meta-analysis. Circ Cardiovasc Qual Outcomes 2017; 10:
69:747–762. e003497.

Thomopoulos et al.
173. Roberts JM, Hubel CA. The two stage model of preeclampsia: varia- 178. MacDonald TM, Walker SP, Hannan NJ, Tong S, Kaitu’u-Lino TJ.
tions on the theme. Placenta 2009; 30:S32–S37. Clinical tools and biomarkers to predict preeclampsia. EBioMedicine
174. Staff AC, Dechend R, Pijnenborg R. Learning from the placenta: acute 2022; 75:103780.
atherosis and vascular remodeling in preeclampsia-novel aspects for 179. Nguyen TPH, Patrick CJ, Parry LJ, Familari M. Using proteomics
atherosclerosis and future cardiovascular health. Hypertension 2010; to advance the search for potential biomarkers for preeclampsia: a
56:1026–1034. systematic review and meta-analysis. PLoS One 2019; 14:e0214671.
175. Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, 180. Smith DD, Costantine MM. The role of statins in the prevention of
et al., ESC Scientific Document Group. 2021 ESC Guidelines on preeclampsia. Am J Obstet Gynecol 2022; 226:S1171–S1181.
cardiovascular disease prevention in clinical practice. Eur Heart J 181. Vahedian-Azimi A, Karimi L, Reiner Ž, Makvandi S, Sahebkar A.
2021; 42:3227–3337. Effects of statins on preeclampsia: a systematic review. Pregnancy
176. Parikh NI, Gonzalez JM, Anderson CAM, Judd SE, Rexrode KM, Hlatky Hypertens 2021; 23:123–130.
MA, et al., American Heart Association Council on Epidemiology and 182. Aldridge E, Pathirana M, Wittwer M, Sierp S, Roberts CT, Dekker GA,
Prevention; Council on Arteriosclerosis, Thrombosis and Vascular Arstall M. Women’s awareness of cardiovascular disease risk
Biology; Council on Cardiovascular and Stroke Nursing; and the after complications of pregnancy. Women Birth 2023; 36:e335–
Stroke Council. Adverse pregnancy outcomes and cardiovascular e340.
disease risk: unique opportunities for cardiovascular disease preven- 183. Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM,
tion in women: a scientific statement from the American Heart Hannaford P, Smith WC. Hypertensive diseases of pregnancy and risk
Association. Circulation 2021; 143:e902–e916. of hypertension and stroke in later life: results from cohort study. BMJ
177. Yang H, Kuhn C, Kolben T, Ma Z, Lin P, Mahner S, et al. Early life 2003; 326:845.
oxidative stress and long-lasting cardiovascular effects on offspring 184. Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM. Preeclamp-
conceived by assisted reproductive technologies: a review. Int J Mol sia and the risk of end-stage renal disease. N Engl J Med 2008;
Sci 2020; 21:E5175. 359:800–809.

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Management of hypertensive disorders in

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INTRODUCTION based on office BP measurements [5,6]. The previous defi-

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based on high or intermediate clinical risk factors is sensi- preempt.obgyn.ubc.ca/home-page/past-projects/fullpiers/.

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than 38 may be used (Fig. 2) [60,119,120]. Assessment of

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