European Heart Journal - Cardiovascular Pharmacotherapy (2021) 7, 346–351 REVIEW

doi:10.1093/ehjcvp/pvaa105 Hypertension

Management of pregnancy-related hypertensive

disorders in patients infected with SARS CoV-2:
pharmacological and clinical issues
Silvia Fogacci1, Federica Fogacci 1
, Elda Favari2, Peter P. Toth3, Claudio Borghi 1
,
and Arrigo F.G. Cicero 1*

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1
Hypertension and Cardiovascular Risk Research Group, Medical and Surgical Sciences Department, Alma Mater Studiorum University of Bologna, Bologna, Italy; 2Department of
Food and Drug, University of Parma, Parma, Italy; and 3CGH Medical Center, Sterling, IL, and Cicarrone Center for the Prevention of Cardiovascular Disease, Johns Hopkins
University School of Medicine, Baltimore, MD, USA

Received 17 July 2020; revised 20 August 2020; editorial decision 28 August 2020; accepted 31 August 2020; online publish-ahead-of-print 10 September 2020

Coronavirus-19 disease (COVID-19) continues to spread throughout the world. It is known that among patients with hypertension, dia-
betes, chronic respiratory disease, or cardiovascular diseases, COVID-19 is associated with greater morbidity and mortality compared
with patients without these conditions. This correlation is of great importance in pregnant women affected by COVID-19, since it usually
leads to the development of a serious clinical complication. In particular, managing hypertensive disorders in pregnancy can be problematic
because antihypertensive medications may interact pharmacologically with drugs used to treat COVID-19. This review focuses on the
safety of drug treatment for COVID-19 in pregnant women treated with antihypertensive medication. Several databases were searched to
identify relevant literature. A few antihypertensive drugs and antithrombotic treatments are known for having a beneficial effect in the
management of hypertension and hypertensive disorders in pregnancy. In this review, we focus on the expected drug–drug interactions
with the experimental agents most often used to treat COVID-19. The current indications for the management of hypertension-related
disorders in pregnancy maintain their validity, while the risk of pharmacological interaction with the currently tested anti-SARS-CoV-2
medications is relatively low.
...................................................................................................................................................................................................
Keywords SARS-CoV-2 • Coronavirus-19 • COVID-19 • Pregnancy • Hypertension • Antihypertensive treatment

..
Introduction ..
..
..
Coronavirus disease (COVID-19), caused by the highly transmissible ..
severe acute respiratory virus coronavirus 2 (SARS-CoV-2), contin-
..
..
ues to spread throughout the world.1 The virus is primarily spread ..
through close human contact via aerosolized droplets of saliva or
..
..
mucus secretions.2 Its main feature is infection of the respiratory sys- ..
..
tem in association with cough, fever, and typical changes in radio-
graphic studies that can lead to acute respiratory distress syndrome,
cardiovascular (CV) events such as myocardial infarction, myocardi-
tis, fulminant heart failure, and lethal arrhythmias, and neurovascular
events such as ischaemic stroke and encephalopathy. Pregnant
women are considered a high-risk group due to their altered im-
munological and physiological status.3–5 Viral respiratory illnesses fre-
quently develop during pregnancy; hence, pregnant women have
greater vulnerability for contracting a SARS-CoV-2 infection.6,7 As a
matter of fact, physiological hormonal changes in pregnant women,
such as the progesterone-mediated action on nasal mucosa, have
been demonstrated to increase the probability of contracting the dis-
ease compared with the general population.7
Very few studies are available concerning the effect of COVID-19
on pregnancy and foetal outcomes.8 The maternal–foetal interface
was analysed in different clinical settings, and no evidence of vertical
COVID-19 transmission was seen in pregnant women in the third tri-
mester of pregnancy.9–11 Due to limited scientific evidence regarding
..
... pregnancy and COVID-19, some official statements have been made
.. referring to SARS CoV-1.12 Some previous studies regarding SARS
..
.. suggest that women may need prioritized medical care since
.. COVID-19 infection during pregnancy may lead to maternal and foe-
..
.. tal complications, such as spontaneous miscarriage, preterm birth,
.. intrauterine growth restriction, premature rupture of membranes,
..
.. foetal tachycardia and foetal distress, multiple organ injury, and ad-
.. mission to intensive care units.10,12–14 Nevertheless, what is clear is
..
. that more studies are needed regarding COVID-19 and pregnancy,

* Corresponding author: Medical and Surgical Sciences Department, Sant’Orsola-Malpighi University Hospital, U.O. Medicina Interna Borghi, Via Albertoni 15, 40138 Bologna,
Italy.Tel: þ39 512142224, Fax: þ39 51391320, Email: arrigo.cicero@unibo.it
C The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.
Published on behalf of the European Society of Cardiology. All rights reserved. V
Hypertensive pregnants and COVID-19
..
considering the fact that it affects the well-being of mothers and their
babies.6 For this reason, accurate hygiene and social information
must be guaranteed to pregnant women and their families in order to
prevent SARS-CoV-2 infection.2
It is known that among patients with hypertension, diabetes,
chronic respiratory disease, or CV diseases, SARS-CoV-2infection is
associated with greater morbidity and mortality compared with
patients without these conditions.11,15 This correlation is of great im-
portance in pregnant women affected by COVID-19, since it usually
leads to the development of a serious clinical complication.6
Regarding hypertensive disorders in pregnancy, there are very few
drugs available with a controversial security profile, that sometimes
pharmacologically interact with the drugs tested to treat COVID-
19.16 In particular, the anti-COVID-19 medications for which there is
currently more evidence are low molecular weight heparin
(LMWH), lopinavir/ritonavir, hydoxychloroquine, and
chloroquine.7,15
The purpose of the current review is to highlight the safety of drug
treatment for COVID-19 in pregnant women treated with antihyper-
tensive medications.
Materials and methods
For the purpose of this review, the authors identified trials in both
MEDLINE (National Library of Medicine, Bethesda, Maryland, MD, USA;
January 1980 to July 2020) and the Cochrane Register of Controlled
Trials (The Cochrane Collaboration, Oxford, UK). The terms ‘SARS-
CoV-2’, ‘severe acute respiratory syndrome’, ‘Coronavirus disease’,
‘COVID-19’, ‘lopinavir/ritonavir’, ‘chloroquine’, ‘hydroxychloroquine’, ‘as-
pirin’, ‘methyldopa’, ‘hydralazine, ‘beta-blockers’, ‘labetalol’, ‘metoprolol’,
‘atenolol’, ‘pindolol’, ‘calcium channel blockers’, ‘diltiazem’, ‘nifedipine’,
‘verapamil’, ‘magnesium sulfate’, ‘low molecular weight heparin’, ‘LMWH’,
‘hypertension’, ‘pre-eclampsia’, ‘preeclampsia’, ‘clinical trial’, and ‘human’
were incorporated into an electronic search strategy. The references of
the identified studies and review articles were reviewed to look for add-
itional studies of interest. The authors reviewed all of the citations
retrieved from the electronic search to identify potentially relevant
articles for this review.
Results
A few antihypertensive drugs and antithrombotic treatments are
known to have a beneficial effect in the management of hypertension
and hypertensive disorders in pregnancy. In this review, we focus on
the expected drug–drug interactions with the experimental agents
most often used to treat SARS-CoV-2 infection (Figure 1).
Aspirin
In accordance with the European Society of Cardiology (ESC) guide-
lines for the management of CV diseases during pregnancy, 100–150
mg/day acetylsalicylic acid (aspirin) should be recommended to preg-
nant women with a high or moderate risk of developing pre-
eclampsia (class I; level of evidence A).17 Similarly, the American
College of Obstetricians and Gynecologists (ACOG) recommends
that these patients take 81 mg/day of aspirin (level of evidence A).18
In the general population, non-steroidal anti-inflammatory drugs
(NSAIDs), such as ibuprofen, are reported to negatively affect the
347
.. lungs, worsening a pre-existing pulmonary infection.19,20 For this rea-
.. son, some investigators brought into question the safety of aspirin
..
.. treatment in pregnancy during the COVID-19 pandemic.21 Taking
.. into account that significant data about aspirin intake and aggravation
..
.. of COVID-19 symptoms in pregnancy are lacking, the same authors
.. agree that the benefits of aspirin prophylaxis in women at high risk
..
.. for hypertensive disorders outweigh the potential dangers posed by
..
.. the virus.21 In this perspective, it is also worth pointing to a possible
.. effect of NSAIDs on induction of mitogen-acivated protein kinase
..
.. phosphatase 1, leading to the inhibition of inflammatory gene expres-
.. sion.22 Moreover, we have also to consider a possible interaction ef-
..
.. fect between aspirin and LMWH on risk of bleeding.23 On the other
.. hand, there is no evidence that aspirin interacts with medications cur-
..
.. rently being evaluated for treating SARS-CoV-2 infection.24
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..
..
.. Methyldopa
.. Methyldopa is an alpha-2 adrenergic agonist with both central and
..
.. peripheral nervous system effects. Together with labetalol and cal-
..
.. cium antagonists, methyldopa is one of the drugs of choice recom-
.. mended by the ESC for the treatment of hypertension in pregnant
..
.. women (class I; level of evidence B).17 In accordance with the
.. American Heart Association (AHA) recommendations,25 methyl-
..
.. dopa should only be prescribed in cases of severe hypertension dur-
.. ing pregnancy, considering potential maternal and foetal side effects
..
.. (class I; level of evidence A).
.. In vitro, chloroquine and hydroxychloroquine are aminoquinolone
..
.. derivatives that have antiviral activity against SARS-CoV-2;26–29 how-
.. ever, efficacy data in humans are still preliminary. Compared with
..
.. chloroquine, hydroxychloroquine has a much better safety profile,30
..
.. and has demonstrated promising capacity to prevent pre-eclampsia.31
.. In clinical practice, methyldopa is often prescribed to women affected
..
.. by systemic lupus erythematosus treated with hydroxychloroquine
.. to prevent flares.32 The co-administration of methyldopa and
..
.. hydroxychloroquine is considered to be safe in hypertensive preg-
.. nant women infected with SARS-CoV-2.
..
..
.. Beta-blockers
..
.. Among beta-adrenergic receptor blockers, the ESC recommends the
..
.. use of labetalol as first-line therapy in pregnant women with hyper-
.. tension (class I; level of evidence C),17 while the AHA suggests aten-
..
.. olol (class III; level of evidence B), pindolol, metoprolol, and labetalol
.. as first-line therapies (class IIa; level of evidence B).25 The ACOG rec-
..
.. ommends labetalol therapy in urgent blood pressure control in
.. pregnancy.18Third-generation beta-blockers have also been shown
..
.. to prevent bronchial asthma attacks and respiratory dysfunction. The
.. release of nitric oxide, antioxidant action, and other mechanisms
..
.. underlying the vasodilating action of these drugs may be responsible
.. for their beneficial therapeutic effects.33 However, these agents have
..
.. never been tested in pregnant women.
..
.. In pregnant women, the combination of beta-blockers and LMWH
.. is the recommended treatment for atrial fibrillation.34 In this context,
..
.. we can reasonably expect the combination of beta-blockers and hep-
.. arin to be safely administered in hypertensive-treated pregnant
..
.. women infected by SARS-CoV-2. This is certainly of great interest,
.. since LMWH seems to mitigate the pulmonary coagulopathy often
..
. promulgated by the virus.35,36 In contrast, the simultaneous
348 S. Fogacci et al.

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Figure 1 Interaction of antihypertensive drugs with anti-COVID-19 medications. LMWH, low molecular weight heparin; NSAIDs, non-steroidal
anti-inflammatory drugs.

..
administration of beta-blockers and hydroxychloroquine (or chloro- .. lopinavir/ritonavir in non-pregnant women, we can reasonably ex-
quine) requires close electrocardiographic monitoring due to the risk .. pect a toxic effect in pregnancy as well.44
..
of QT prolongation.37 ..
..
..
Hydralazine ..
Hydralazine hydrochloride is a hydrazine derivative vasodilator drug.
.. Low molecular weight heparin
.. LMWH has been shown to prevent pre-eclampsia in high-risk preg-
In light of the ACOG recommendations, hydralazine is one of the
drugs used for urgent blood pressure control in pregnancy.18 The
AHA also recommends it in hypertensive-treated women (class III;
level of evidence B).25 To date, there is a lack of validated studies eval-
uating the interaction between hydralazine and investigational drugs
used for treating SARS-CoV-2 infection, while NSAIDs could reduce
its efficacy by inhibiting prostacyclin-related vasodilation.38
Calcium channel blockers
Calcium channel blockers (CCBs) are another group of antihyperten-
sive drugs recommended by the ESC (level of evidence C)17 and the
AHA (class I; level of evidence A),25 whereas the ACOG advises ni-
fedipine administration only in the setting of hypertensive urgency.18
During the current pandemic, questions have been raised about
potential drug–drug interactions with treatments for SARS-CoV-2 in-
fection. A variety of antiretroviral therapies are being tested to treat
COVID-19.3,39–41 The co-administration of nifedipine and lopinavir/
ritonavir is potentially toxic, linked to their common cytochrome
P450 3A4-related metabolism,42,43 occasionally causing serious sides
effects such as tachycardia, hypotension, headache, and peripheral
oedema.43 Considering the safety profile of combining nifedipine and
..
.. nant women by improving endothelial function in the vasculature.45,46
.. Moreover, LMWH inhibits endothelial inflammation,47 making it po-
..
.. tentially useful for treatment of SARS-CoV-2 infection.
... In accordance with the latest ESC guidelines for the management
..
.. of CV disease during the COVID-19 pandemic, drug–drug interac-
.. tions should be considered before administering azithromycin in
..
.. patients treated with LMWH,37 despite possible beneficial effects of
.. azithromycin in patients infected with SARS-CoV-2.48 In contrast,
..
.. chloroquine, hydrochloroquine, and lopinavir/ritonavir do not have
.. any clinically significant interactions with LMWH.37
..
..
..
..
..
.. Magnesium sulfate
.. Intravenous magnesium sulfate is recommended for preventing
..
.. eclampsia and treating seizures, as suggested by the ACOG (level of
..
.. evidence A)18 and the ESC17 guidelines. According to a case–control
.. study, its co-administration with LMWH shows better results than
..
.. magnesium sulfate alone in treating severe pre-eclampsia.49 There
.. are no contraindications to combined treatment in hypertensive
..
. pregnant women infected with SARS-CoV-2.50
Hypertensive pregnants and COVID-19 349

..
Vitamins
Though vitamin D supplementation is not recommended by inter-
national guidelines, a recent meta-analysis shows it may prevent pre-
eclampsia in pregnancy.51 From the COVID-19 point of view, it
seems to have a role in the pre-clinical phase in strengthening the im-
mune system, especially in cases of deficiency.52 Furthermore, several
studies have shown antiviral effects of vitamin D, which can interfere
directly with viral replication, but also can act in an immunomodula-
tory and anti-inflammatory way.53 So far, low serum levels of vitamin
D have been linked to increased morbidity and mortality in COVID-
19 patients.54,55 Ahmed et al. have reported the case of a 29-year-
woman with diabetes and vitamin D deficiency who died from throm-
botic complications during SARS-CoV-2 infection.56
.. appropriate treatment, though the choice is in some respects
.. understandable.
..
.. Future research should focus on drugs protecting the endothelium
.. from the damage induced by SARS-CoV-2 infection.68 In particular,
..
.. cell adhesion molecules (CAMs), including CD209L/L-SIGN and
.. CD209/DC-SIGN, could have a relevant role in infection with SARS-
..
.. CoV-2 and other related viruses, consequently being possible thera-
.. peutic targets.69 Inhibition of interleukin-6 (IL-6) and the Janus kinase/
..
.. signal transducer and activator of transcription (JAK/STAT) pathway
..
.. could be also favourable targets.70
.. To date, the only safe medical care showing benefit in treating the
..
.. virus in pregnant patients is pressurized air enriched with oxygen,
.. intravenous hydration, nutritional support, and electrolyte balance,
..
.. which are believed to help and improve the oxygenation in patients

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In addition to vitamin D, vitamin C is not included in international .. with a very compromised respiratory system.29 For this reason, peo-
recommendations, though its deficiency has been associated with an ..
increased risk of pre-eclampsia.57 Its role in preventing hypertensive
.. ple, and in particular pregnant women, with a weak immune system
.. should take into account preventive measures to protect their health.6
disorders in pregnancy is still unclear and needs to be further investi- ..
..
gated.58 In the course of the SARS-CoV-2 pandemic, vitamin C serum ..
levels are reported to decrease during infection and the requirement ..
.. Conclusions
for supplementation increases accordingly.59 A number of ongoing ..
clinical trials will provide additional information on the impact of vita- .. In conclusion, despite the scarcity of available data, current recom-
..
min administration as a component of supportive care in SARS-CoV- .. mendations for the management of hypertension-related disorders in
2 infection.60,61 .. pregnancy remain valid since the risk of pharmacological interaction
..
.. with currently tested anti-SARS-CoV-2 medications is relatively low.
..
.. Conflict of interest: none declared.
Discussion ..
..
The general advice for pregnant women is to avoid pharmacological ..
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