Expert Opinion on Pharmacotherapy

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Selecting emergency therapy for patients with pre-

eclampsia

Juan Tamargo

To cite this article: Juan Tamargo (2020) Selecting emergency therapy for patients
with pre-eclampsia, Expert Opinion on Pharmacotherapy, 21:10, 1119-1122, DOI:
10.1080/14656566.2020.1727444

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Published online: 05 Mar 2020.

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EXPERT OPINION ON PHARMACOTHERAPY
2020, VOL. 21, NO. 10, 1119–1122
https://doi.org/10.1080/14656566.2020.1727444

EDITORIAL

Selecting emergency therapy for patients with pre-eclampsia

Juan Tamargo
Department of Pharmacology and Toxicology, School of Medicine, Instituto De Investigación Sanitaria Gregorio Marañón, Universidad
Complutense, Madrid, Spain

ARTICLE HISTORY Received 1 October 2019; Accepted 5 February 2020

KEYWORDS Pregnancy; hypertension; preeclampsia; antihypertensive drugs; therapy

1. Introduction and mortality and to prolong the pregnancy for fetal benefit
as much as possible [2–9]. Severe systolic, rather than diastolic,
Preeclampsia (PE) is a life-threatening hypertensive disorder
hypertension is the most important predictor of maternal
affecting 2–8% of pregnancies and a leading cause of adverse
acute cerebrovascular complications (stroke, intracranial
maternal, fetal and neonatal outcomes [1]. Although the defi-
hemorrhage, hypertensive encephalopathy), end organ
nition of PE varies between guidelines, PE with severe features
damage and death, while DBP >110 mm Hg is associated
is a complex multisystem disorder characterized by severe
with an increased risk of placental abruption and intrauterine
hypertension [systolic/diastolic blood pressure (SBP/DBP)
growth restriction [2,5,6,10]. The goal is to reduce SBP to
≥160/110 mmHg on two occasions at least 4 h apart] in
<160/105 mmHg over minutes to hours and then to achieve
a previously normotensive woman or superimposed on pre-
a sustained BP of 140–150/90–100 mm Hg to prevent pro-
existing hypertension at or after 20 weeks gestation; protei-
longed exposure to severe systolic hypertension and the sub-
nuria (≥300 mg per 24 h; protein/creatinine ratio ≥0.3 mg/dL;
sequent loss of cerebral vasculature autoregulation, and
dipstick reading of 2+) and/or evidence of maternal organ
protect the pregnant woman from stroke and other end-
dysfunction: liver impairment (elevated transaminases: ALT or
organ damages, while maintaining utero-placental blood
AST>40 IU/L ± right upper quadrant or epigastric abdominal
flow to avoid fetal distress [5,6,9]. Lowering BP to ‘normal’
pain), acute kidney injury (serum creatinine >1.1 mg/dL or
ranges (<140/90 mmHg) does not confer additional benefit
a doubling of the serum creatinine concentration in the
but might lead to maternal end-organ hypoperfusion or affect
absence of other renal disease), hematological complications
placental perfusion and fetal growth [8–10]. Thus, close mater-
(thrombocytopenia: platelet count <150,000/μL, disseminated
nal and fetal monitoring is recommended to avoid hypoten-
intravascular coagulation, hemolysis), pulmonary edema, new-
sion following antihypertensive therapy. Blood pressure
onset headache unresponsive to medication or visual distur-
measurements should be performed every 15–30 min until
bances; and utero-placental dysfunction (e.g., fetal growth
BP is <160/110 mmHg; then, at least 4 times daily while the
restriction, abnormal umbilical artery Doppler wave form ana-
woman is an inpatient, depending on clinical circum-
lysis, or stillbirth) [2–7].
stances [7].
All women when first diagnosed of severe PE should all be
Severe hypertension in-hospital is treated with short-acting
assessed in hospital by a multidisciplinary team of experts in
drugs, including intravenous labetalol and hydralazine or
the management of hypertensive disorders of pregnancy.
immediate release-IR oral nifedipine (particularly when intra-
They should perform a fetal and maternal assessment to
venous access is not available), so that doses that can be
determine the affected organs, and planning delivery as it
repeated in 15–30 min if SBP/DBP persists ≥160/100 mmHg
remains the only cure of PE. Optimal timing of delivery is
[2–9]. In some guidelines, hydralazine is no longer a first-
based on gestational age, disease severity, and the balance
choice drug because it produces more perinatal adverse
between the benefits of delivery and the risks of conservative
effects than other drugs [3,7], but it can be used when nifedi-
management [1]. International Guidelines discuss the time of
pine or labetalol failed to achieve BP control. Oral methyldopa
delivery and recommend a single course of antenatal corticos-
is widely recommended because of its safety profile, but pre-
teroids to accelerate fetal lung maturation in women with
sents a slow onset of action and a mild antihypertensive effect,
severe PE receiving expectant management [2–7].
so that more women will not achieve BP goals in monother-
Once PE is diagnosed, control of blood pressure (BP) and
apy [8,9]. In a retrospective cohort study in 239,454 patients
seizures are the priority in the emergency setting. Acute-onset
with PE, the rate of patients receiving these antihypertensives
severe hypertension (SBP/DBP ≥160/110 mmHg) measured
increased from 37.8% in 2006 to 49.4% in 2015; during this
and confirmed within 15 min during pregnancy or postpartum
time period, the risk for stroke for severe PE significantly
represents an obstetrical hypertensive emergency for both
decreased from 13.5 per 10,000 deliveries in 2006–2008 to
mother and fetus and requires in-hospital care and immediate
6.0 in 2012–2014 [11].
BP reduction (within 30–60 min) to reduce maternal morbidity

CONTACT Juan Tamargo jtamargo@med.ucm.es

© 2020 Informa UK Limited, trading as Taylor & Francis Group
1120 J. TAMARGO
Two meta-analysis suggested that labetalol, hydralazine,
and nifedipine can achieve BP control in more than 70% of
women, although some differences may exist in their safety
profile [12,13]. A recent open-label, randomized controlled
trial compared oral labetalol, methyldopa, and nifedipine
retard for treating severe hypertension in pregnancy in low-
resource settings [14]. Nifedipine and labetalol, as single
drugs, were significantly more effective for lowering SBP/DBP
to 120–150/70–100 mmHg within 6 h than methyldopa, with-
out differences between nifedipine and labetalol. However,
more neonates born to women assigned to the nifedipine
group were admitted to the intensive care unit, primarily
because more low or very low birth weight babies were
born to mothers in the nifedipine group. Based on these
results, it was proposed to include these oral antihyperten-
sives for the treatment of severe hypertension in pregnancy.
However, until better evidence is available, the choice
between these antihypertensive drugs should be guided by
the physician’s experience with a particular drug, its safety
profile and patient´s characteristics (i.e. calcium-channel block-
ers should be selected in women of African or Caribbean
family origin) and preferences [7,9]. Table 1 summarizes the
first-/second-choice antihypertensive drugs recommended in
several international guidelines [2–6,15].
Intravenous nitroglycerin is the drug of choice when PE is
associated with pulmonary edema and/or coronary artery dis-
ease, and hydralazine and nitrates in the presence of hyper-
tension, severe left ventricular dysfunction and/or evidence of
congestion in decompensated heart failure [3]. Sodium nitro-
prusside is recommended in hypertensive crises when other
treatments have failed to control the BP and delivery is immi-
nent. However, it should be used for the shortest time possible
because of the risk of maternal/fetal cyanide and thiocyanate
toxicity, transient fetal bradycardia, and intracranial pressure
with potential worsening of cerebral edema in the mother.
Because plasma volume is reduced in PE, diuretics should be
best avoided and plasma volume expansion minimized, limit-
ing total fluids to 80–85 mL/h (1 mL/kg/h) unless there are
other ongoing fluid losses (hemorrhages).
Women with a hypertensive ‘urgency’ (SBP/DBP ≥160/
110 mmHg) without signs/symptoms of acute end-organ
damage may be treated with oral agents to produce an initial
BP reduction of less than 25% in the first hours of treatment,
and a more gradual decrease over hours thereafter. A faster BP
reduction may produce a fetal underperfusion, because the
feto-placental unit does not autoregulate blood flow [2–6,9].
Renin-angiotensin-aldosterone system inhibitors (i.e. angioten-
sin-converting enzyme inhibitors, angiotensin receptor block-
ers, aliskiren, sacubitril/valsartan, mineralocorticoid receptor
antagonists) are fetotoxic and contraindicated, while prazosin
and atenolol are not recommended during pregnancy [3,7,9].
Severe postpartum hypertension can be treated as already
described, but other antihypertensives (amlodipine, atenolol,
amlodipine, atenolol, captopril, enalapril, nifedipine retard,
quinapril) can be used [8,9]. Diuretics, methyldopa, or angio-
tensin receptor blockers should be avoided in breastfeeding
women [8,9]. Guidelines provide contradictory recommenda-
tions on the use of nonsteroidal anti–inflammatory drugs
Table 1. Antihypertensives recommended in different guidelines for the treat-
ment of acute-severe hypertension in pregnancy. Taken from Tamargo et al. [8].
Guideline [reference] Severe hypertension
ISSHP [2] 1. Definition: ≥160/110 mm Hg
2. Treatment:
● First line: labetalol (IV, oral), hydralazine (IV), nifedi-
pine-IR (oral)
● Second line: oral methyldopa, nifedipine-XL, oxpre-
nolol, prazosin
ESC [3] 1. Definition: ≥170/110 mmHg is an emergency
2. Treatment:
● First line: labetalol (IV), methyldopa (oral), nifedipine
(IR, oral)
● Second choice: hydralazine (IV), urapidil (IV)
● Hypertensive crisis: sodium nitroprusside (IV)
● Preeclampsia associated with pulmonary edema:
nitroglycerin (IV)
CANADIAN [4] 1. Definition: ≥160/110 mmHg
2. Treatment:
● First line: Labetalol (IV), hydralazine (IV), nifedipine-
IR (oral)
● Second line: clonidine (oral), labetalol (oral), nitro-
glycerin (IV infusion), methyldopa (oral); captopril
(oral) only post-partum
ACOG [5 6,] 1. Definition: ≥160/110 mm Hg
2. Treatment:
● First line: labetalol (IV, oral), hydralazine (IV), nifedi-
pine-IR* (oral)
● Second line: nicardipine or esmolol by infusion
pump
NICE [7] 1. Definition: ≥160/110 mmHg
2. Treatment:
● First line: labetalol (IV, oral), hydralazine (IV), nifedi-
pine-IR (oral)
● Second line: oral labetalol, nifedipine-XL and
methyldopa
SOMANZ [15] 1. Definition: ≥170/110 mmHg
2. Treatment:
● First line: diazoxide (IV), hydralazine (IV), labetalol
(IV), nifedipine-IR* (oral)
● Second line: oral clonidine, hydralazine, labetalol,
methyldopa, nifedipine-XL, oxprenolol, and prazosin
* It should be considered as first-line therapy, particularly when IV access is not
yet available; labetalol can be administered orally if immediate release oral
nifedipine is not available.
Drugs are presented in alphabetic order. ACOG: American College of
Obstetricians and Gynecologists. CANADIAN: Canadian Hypertensive
Disorders of Pregnancy Working Group. ESC: 2018 ESC Guidelines for the
management of cardiovascular diseases during pregnancy. IR: immediate
release. ISSHP: International Society for the Study of Hypertension in
Pregnancy. IV: intravenous. NICE: National Institute for Health and Care
Excellence in the United Kingdom. SOMANZ: Society of Obstetric Medicine
of Australia and New Zealand. XL: extended release.
(NSAIDs) for postpartum analgesia in women with PE. They
should be avoided when BP is difficult to control or there is
evidence of acute kidney injury. Postpartum thromboprophy-
laxis should be considered in women with PE, particularly in
the presence of other risk factors.
Antihypertensive therapy for mild-moderate hypertension
during pregnancy reduced the risk of severe hypertension, but
had little or no effect on the risk of PE, β-adrenergic blockers,
and calcium channel blockers being more effective than other
antihypertensives [16]. In pregnant women with hypertension
 EXPERT OPINION ON PHARMACOTHERAPY 1121

Table 2. Gaps in evidence and main challenges in the diagnosis and treatment of pre-eclampsia with severe features.
(1) PE is a complex syndrome with different risk factors, clinical presentations, pathophysiology, prognosis, and response to therapy
● Address pathophysiological mechanisms, rather than controlling BP and preventing seizures, is the best way to improve maternal and fetal outcomes
● A better understanding of the pathophysiology should be translated into a more rational design of new safer and more effective of PE
(2) Prediction of pre-eclampsia is challenging, because its clinical presentation is highly variable.
● Current standard criteria for PE diagnosis are suboptimal because they have low predictive value to detect adverse maternal and fetal outcomes
● There is a need of sensitive and specific predictive algorithms that can identify in early pregnancy women at risk of developing PE
● Models combining biomarkers, clinical, ultrasonographic, and laboratory parameters have been developed, but they remain investigational
(3) Antihypertensive therapy does not modify the pathophysiology and is empirically recommended when BP is above a certain threshold
● Current recommendations for antihypertensive therapy are not based on an assessment of maternal hemodynamics
● It is uncertain whether a hemodynamic-guided antihypertensive therapy can favorably modify maternal and fetal outcomes
● Large, long-term, head-to-head comparative RCTs between the first choice drugs are needed to confirm their efficacy and safety in women with acute-onset
severe hypertension
● Most trials are small and short term; with wide variations on how PE was defined, basal characteristics and comorbidities of the recruited population; and few
studies reported hard CV maternal and fetal outcomes (i.e. cardiovascular events or mortality) beyond BP control
● It is necessary to know the short-/long-term outcomes for women and babies after PE

(4) There is a need for standardized, evidence-based, clinical guidelines for the prophylaxis and treatment of women with PE
● There are discrepancies between guidelines in the accepted standard of care for the management of acute-severe hypertension
● There is no consensus on the BP threshold at which antihypertensive therapy should be to started and to which levels BP should be maintained
(5) Women with a history of PE are at an increased risk of cardiovascular, renal, and diabetic complications later in life
● What interventions are more effective in preventing or reducing the risk of subsequent cardiovascular, renal, and diabetic burden remains unknown
BP: blood pressure. CV: cardiovascular. PE: pre-eclampsia with severe features. RCTs: randomized clinical trials.

during pregnancy, the CHIPS trial showed that the tight control
of maternal BP (target DBP 85 mmHg) reduced the risk of severe
maternal hypertension compared with less-tight control (target
DBP 100 mmHg), without differences in the risk of adverse
perinatal outcomes and serious maternal complications [17]. In
a post hoc analysis of this trial, severe hypertension was a risk
marker for adverse maternal and perinatal outcomes, indepen-
dent of BP control or PE development [18]. These findings
strongly suggest that women at high risk of the complications
of severe hypertension may benefit of a tight BP control.
Magnesium sulfate halves the risk of eclampsia and is the
drug of choice for the prophylaxis of seizures in women with PE
with severe features or severe hypertension in the intrapartum/
postpartum periods, but it is not routinely recommended in PE
without severe features [19]. Given prior to preterm birth mag-
nesium sulfate prevents cerebral palsy and reduces the com-
bined risk of fetal/infant death or cerebral palsy [20]. However,
guidelines provide contradictory recommendations on the safety
coadministration of magnesium sulfate and nifedipine [2–7].
2. Expert opinion
The present treatment of PE is based in controlling BP and
preventing eclamptic seizures without taking into consideration
the underlying pathophysiology of this complex syndrome
where many organ systems are involved. However, antihyperten-
sive therapy does not modify the pathophysiology of PE, is
empirically recommended if BP is above a certain threshold
(without consensus on what this should be) and few studies
reported hard cardiovascular maternal and fetal outcomes
beyond BP control [9]. In the next future, an improvement in
early diagnosis of women at high risk of PE with severe features
and the better understanding of the pathophysiology should be
translated into a more rational treatment to target directly the
maternal placental dysfunction leading to endothelial
dysfunction and multiorgan failure. Clinical trials using maternal
hemodynamics to guide the antihypertensive treatment should
help us to identify which drugs provide the safer and more
effective BP control and improve maternal and perinatal out-
comes [21]. Finally, because women with PE are at an increased
risk of cardiovascular, renal, and cerebrovascular diseases and
diabetes later in life [1,22], they should receive postnatal counsel-
ing regarding the management of future pregnancies and life-
style modification should be strongly encouraged to decrease
their cardiovascular risk [1,22]. Therefore, an improvement in
early detection, prevention, and physiopathology-guided man-
agement of PE with severe features hold the promise of improv-
ing the diagnosis and treatment of this multisystem disorder in
the coming years. Table 2 summarizes the gaps in evidence and
main challenges in the diagnosis and treatment of PE with severe
features.
Acknowledgments
We thank P Vaquero for her invaluable technical assistance.
Funding
This work was supported by grants from the Ministerio de Ciencia
e Innovación (SAF2017-88116-P), the Instituto de Salud Carlos III [PI16/
00398, CIBER-Cardiovascular (CB16/11/00303)] and the Comunidad de
Madrid (B2017/BMD-3738).
Declaration of interest
The author has no other relevant affiliations or financial involvement with
any organization or entity with a financial interest in or financial conflict
with the subject matter or materials discussed in the manuscript apart
from those disclosed.
1122 J. TAMARGO
Reviewer Disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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