Review
Drug treatment of hypertension in pregnancy: a
critical review of adult guideline recommendations
Khalid A.J. Al Khaja a, Reginald P. Sequeira a, Alwaleed K. Alkhaja b, and Awatif H.H. Damanhori c
This review evaluates the guideline recommendations for
the management of hypertension in pregnancy as
presented by 25 national/international guidelines
developed for the management of arterial hypertension in
adults. There is a general consensus that oral
a-methyldopa and parenteral labetalol are the drugs of
choice for nonsevere and severe hypertension in
pregnancy, respectively. Long-acting nifedipine is
recommended by various guidelines as an alternative for
first-line and second-line therapy in nonsevere and severe
hypertension. The safety of b-blockers, atenolol in
particular, in early and late stages of pregnancy is
unresolved; their use is contraindicated according to
several guidelines. Diuretic-associated harmful effects on
maternal and fetal outcomes are controversial: their use is
discouraged in pregnancy. It is important to develop
specific guidelines for treating hypertension in special
groups such as adult females of childbearing age and
sexually active female adolescents to minimize the risk of
adverse effects of drugs on the fetus. In several guidelines,
the antihypertensive classes, recommended drug(s),
intended drug formulation, and route of administration are
not explicit. These omissions should be addressed in future
guideline revisions in order to enhance the guidelines’
utility and credibility in clinical practice.
Keywords: antihypertensive drugs, guidelines evaluation,
hypertension, hypertensive crisis, pregnancy, treatment
guidelines
Abbreviations: ACEIs, angiotensin-converting enzyme
inhibitors; ARBs, angiotensin II receptor blockers; CCBs,
calcium channel blockers
INTRODUCTION
H
ypertensive disorders are the most common
medical complications of pregnancy and are an
important cause of maternal and perinatal morbid-
ity and mortality worldwide [1,2]. According to population-
based data, approximately 1% of pregnancies are compli-
cated by preexisting hypertension, 5–6% by gestational
hypertension without proteinuria, and 1–2% by preeclamp-
sia [3]. It can be expected that these rates will increase given
the trend toward an older and more obese obstetric popu-
lation.
Hypertensive disorders of pregnancy should be classified
as preexisting or gestational hypertension on the basis of
454 www.jhypertension.com
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different diagnostic and therapeutic factors, and presence or
absence of preeclampsia. In women with preexisting hyper-
tension, preeclampsia should be defined as resistant hyper-
tension, new or worsening proteinuria. The term pregnancy-
induced hypertension is recommended to be abandoned, as
its meaning in clinical practice is unclear [4].
Antihypertensive drug treatment rationale in hyper-
tensive disorders of pregnancy represents a departure from
the nonpregnant adult in terms of diagnosis, severity of
hypertension, and the likely duration of treatment [5]. In this
setting, antihypertensive drugs are mainly used to prevent
and treat severe hypertension, to prolong pregnancy for as
long as safely possible, thereby maximizing the gestational
age of the newborn, and to minimize fetal exposure to
medications that may have adverse effects. During preg-
nancy, the challenge is in deciding when to use antihyper-
tensive medications and what level of blood pressure to
target. The choice of antihypertensives is less complex,
because only a small proportion of currently available
antihypertensives have been adequately evaluated in preg-
nant women, and many others are contraindicated [6].
Several national and international hypertension treatment
guidelines have addressed these therapeutic issues.
Guidelines are valuable tools with the potential to
improve care and patient outcomes in situations in which
science is incomplete, in which multiple therapies are
available, and when uncertainties exist – as in the case
of hypertension. Guidelines are a strategy to organize and
make accessible the best evidence that derives from labora-
tory, clinical, and epidemiologic science to support the
clinical decision-making process. Their publication is cul-
mination of both scientific and social processes intended to
include all relevant evidence as well as all appropriate
stakeholders. Their formulation needs judgment, com-
promise, and simplification to achieve consensus [7].
The euphoria associated with guideline production has
touched several societies and professional organizations
Journal of Hypertension 2014, 32:454–463
a
Department of Pharmacology & Therapeutics, College of Medicine & Medical
Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain, bQatar Foundation,
Doha, Qatar and cPrimary Care, Ministry of Health, Manama, Kingdom of Bahrain
Correspondence to Professor Khalid A.J. Al Khaja, PhD, Department of Pharmacology
& Therapeutics, Arabian Gulf University, PO Box 22979, Manama, Kingdom of
Bahrain. Tel: +973 39644642; fax: +973 17271090; e-mail: khlidj@agu.edu.bh
Received 9 April 2013 Revised 6 November 2013 Accepted 6 November 2013
J Hypertens 32:454–463 ß 2014 Wolters Kluwer Health | Lippincott Williams &
Wilkins.
DOI:10.1097/HJH.0000000000000069
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that become interested in developing them, and this ironi-
cally, fuels the problem by creating confusion to the pre-
scribing clinicians [8].
There is variation and a lack of clarity in many national
and international guidelines in terms of specific drug thera-
pies recommended for the management of hypertensive
disorders in pregnant women. In this study, we assessed the
recommendations for treatment of hypertension in preg-
nancy as presented by guidelines that were developed for
management of arterial hypertension in adults, particularly
in the backdrop of insights into drug safety for the fetus.
METHODS
Literature search
National and international guidelines for management of
hypertension were identified by searching PubMed Medical
Subject Heading (MeSH) terms: ‘guidelines’; ‘hypertension’.
The worldwide web via Google internet web search engine
as well as other effective search approaches was used with
following query: guidelines on management of hyperten-
sion followed by a specific name of a country (e.g. Bahrain,
Taiwan) or the name of well known organizations such as
NICE, ESH, NHLBI, and others. The search was performed
for January 2000 through June 2012 period. Based on
contact details obtained from the International Society of
Hypertension (ISH) website, emails were sent to several
ISH affiliated societies of Middle East, south-east Asia, and
Africa, requesting them to provide the worldwide websites
of their national guidelines for management of arterial
hypertension in adults, if available in English.
Inclusion and exclusion criteria
Guidelines written in English and published in 2000 onward
were included. However, guidelines written in languages
other than English, those prepared for elderly, and those
published prior to 2000, were excluded.
Types of outcome measures
The primary outcome measures were oral and parenteral
antihypertensives recommended by guidelines as first-line
and second-line therapies for nonsevere and severe hyper-
tension in pregnancy. The guidelines were also evaluated
based on the following criteria, as questions:
1. Does the guideline specify that antihypertensive(s)
with teratogenic potential are contraindicated in
women of childbearing age as a mandatory recom-
mendation?
2. Does the guideline specify that angiotensin-convert-
ing enzyme inhibitors (ACEIs) and angiotensin II
receptor blockers (ARBs) are to be used with extreme
caution in sexually active young females (teenage
girls)?
3. Does the guideline specify that women with chronic
hypertension who plan to conceive should not be
treated with ACEIs and ARBs?
4. Does the guideline emphasize that there is a need to
change the prescribed antihypertensive(s) to altern-
ative(s) with a better safety profile to hypertensive
women who wish to conceive or are pregnant?
Journal of Hypertension
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Hypertension in pregnancy
Validity assessment
Assessment of outcome measures was independently per-
formed by the first two authors of this review in a non-
blinded standardized manner. Any disagreements between
reviewers were resolved by the fourth author as consensus.
Operational definitions
In tables, the guidelines’ specifications pertaining to hyper-
tension in pregnancy if available or addressed are identified
(þ), and if not available or not addressed are identified (–).
Partially addressed guideline means that data pertaining to
pregnancy were mainly derived from tables that present
compelling and possible indications, contraindications, and
cautions for major classes of antihypertensive drugs. A
completely addressed guideline means that hypertension
in pregnancy as a category has been explicit or is addressed
as one of various headings under hypertension in special
patient groups. The definitions of mild (140–149/90–
99 mmHg), moderate (159–159/100–109 mmHg), and
severe (>160/>110 mmHg) hypertension were derived
from National Institute of Health and Clinical Excellence
(NICE) [9] for management of hypertension disorders
during pregnancy. We have considered terms such as
mild-to-moderate hypertension and nonsevere hyperten-
sion as equivalent.
RESULT
A total of 25 national and international clinical guidelines
fulfilled the inclusion criteria used in this review for out-
come measures. The recommendations related to the treat-
ment of hypertension in pregnancy were not addressed in
16%, partially addressed in 28%, and completely addressed
in 56%. Antihypertensives recommended for mild-to-mode-
rate (nonsevere) hypertension in pregnancy are shown
(Table 1). a-Methyldopa was the drug of choice recom-
mended almost uniformly by all partially and completely
addressed guidelines. Labetalol, calcium channel blockers
(CCBs) (neither specified as class nor as individual agent),
and nifedipine (nonspecified formulation) were also
recommended as first-line treatment by several guidelines,
in addition to a-methyldopa. Hydralazine, long-acting
(retard) nifedipine, and specified b-blockers such as
oxprenolol, metoprolol, and nonspecified ones were sec-
ond-line drugs. Atenolol and diuretics, deemed by several
guidelines as the recommended antihypertensives, remain
controversial due to their potential harmful effects on
maternal and fetal outcomes. ACEIs and ARBs are con-
sidered to be absolutely contraindicated by all partially and
completely addressed guidelines.
Antihypertensives recommended for acute hypertensive
crisis (severe hypertension) during pregnancy are shown
(Table 2). Intravenous labetalol (66.6%) followed by intra-
venous hydralazine (33.3%) were the first-line drugs. Sec-
ond-line and third-line therapy alternatives included
intravenous labetalol, oral nifedipine (mostly as nonspeci-
fied formulation), and oral a-methyldopa. Intravenous
hydralazine was contraindicated by two out of nine clinical
guidelines.
Intravenous infusion of glyceryl trinitrate for pulmonary
edema induced by preeclampsia, magnesium sulphate for
www.jhypertension.com 455
 TABLE 1. Guideline recommendations on oral antihypertensives for nonsevere hypertension in pregnancy

456
Oral antihypertensive agentsb for nonsevere hypertension
(blood pressure >140/90 and <160/110 mmHg)
Acronym
(guidelines Controversial/
Al Khaja et al.

Organizations presentation) Year Ref.# First-line Second-line potentially harmful Contraindication

Africa
Egyptian Hypertension Society EHS (CA) 2004 [10] Methyldopa bBsMet, OX, Labetalol, bBa, Diuretics ACEIsAC, ARBsAC
NifedipineLA
Southern African Hypertension Society SAHS (PA) 2011 [11] Methyldopa NifedipineLA,Hydralazine, – bBa,PC, DiureticsPC,
Labetalol ACEIsCC, ARBsCC
Asia
Gulf Heart Association GHA (PA) 2010 [12] CCBsNS, Methyldopa, bBsNS – – –

www.jhypertension.com
Ministry of Health, Bahrain MOH, Bahrain (PA) 2008 [13] Methyldopa, LabetalolCRD bBsNS, CCBsNS, Hydralazine Diuretics ACEIsAC, ARBsAC
Ministry of Health, Malaysia MOH, Malaysia (CA) 2008 [14] Methyldopa, Labetalol NifedipineNS, AT bBa DiureticsPC, ACEIsC,
ARBsC
Ministry of Health, Singapore MOH, Singapore (PA) 2005 [15] Methyldopa Labetalol, bBOX, Hydralazine, bBa, Diuretics ACEIsC, ARBsC
NifedipineNS
Saudi Hypertension Management Society SHMS (CA) 2011 [16] Methyldopa, Labetalol NifedipineLA, AT bBa DiureticsPC, ACEIsCC,
ARBsCC
Taiwan Society of Cardiology TSC (CA) 2010 [17] Methyldopa, Labetalol, CCBsNS – bBa, Diuretics ACEIsC, ARBsC, DRIC
The Korean Society of Circulation KSC (NA) 2006 [18] – – – –
The Task Force on Conceptual and TFCPP-HK (NA) 2010 [19] – – – –
Preventive Protocols (Hong Kong)
Australia
Heart Foundation HF (CA) 2008 [20] Methyldopa, Labetalol – bBa,OX ACEIsC, ARBsC
Caribbean and Latin America
Latin America Society of LASH (CA) 2009 [21] Methyldopa Labetalol, NifedipineLA; bBa, RC, DiureticsRC
Hypertension Hydralazine ACEIsAC, ARBsAC
Pan America Health Organization/ PAHO/CHRC (PA) 2006 [22] Methyldopa (Hydralazine þ bBs) bBsS,LP – DiureticsC, ACEIsC,
Caribbean Health Res. Council ARBsC, aBsC
Europe
British Hypertension Society BHS (CA) 2004 [23] Methyldopa NifedipineLA, Hydralazine, bBsNS, Diuretics ACEIsCC, ARBsCC,
LabetalolTT
European Society of Hypertension/ ESH/ESC (CA) 2013 [24] Methyldopa, Labetalol, – bBNS DiureticsPC, ACEIsCC,
European Society of Cardiology NifedipineNS ARBsCC, DRIC
National Institute of Health and NICE (PA) 2011 [25] – – – ACEIsCC, ARBsCC
Clinical Excellence (UK)
Scottish Intercollegiate Guidelines Network SIGN (NA) 2007 [26] – – – –
International
WHO/International Society of Hypertension WHO/ISH/(PA) 2003 [27] – – – ACEIsAC, ARBsAC
WHO WHO (PA) 2007 [28] Methyldopa – – ACEIsCC, ARBsCC
North America
American Assoc. of Clinical Endocrinologists AACE (CA) 2006 [29] Methyldopa, bBsNS – ACEIsC, ARBsC
Hypertension Task Force NifedipineNS
Canadian Cardiovascular Society CCS (NA) 2011 [30] – – – –
Dept. of Veterans Administration/Dept. DVA/ DoD (PA) 2004 [31] – – – ACEIsC, ARBsC
of Defense (USA)
Institute of Clinical Systems Improvement (USA) ICSI (PA) 2010 [32] – – – ACEIsC, ARBsC
National Heart, Lung, Blood Institute (USA) NHLBI (CA) 2003 [5] Methyldopa, Labetalol bBsNS, CCBsNS, Diuretics. bBa ACEIsC, ARBsC
Registered Nurses Association of Ontario RNAO (PA) 2005 [33] – – – ACEIsC, ARBsC, CCBsC
a
, atenolol; AC, absolute contraindication; ACEIs, angiotensin-converting enzyme inhibitors; ARBs, angiotensin II receptor blockers; AT, add-on-therapy; C, contraindication; CA, completely addressed; CC, compelling contraindication; CCBs,
calcium channel blockers; CRD, chronic renal disease; DRIs, direct renin inhibitors; LA, long-acting (retard); LP, late pregnancy; Met, metoprolol; NA, not addressed; NS, nonspecified; OX, oxprenolol; PA, partially addressed; PC, possible
contraindication; RC, relative contraindication; S, specified; TT, third trimester; aBs, a-receptor blockers; bBs, b-blockers. ’–’ indicated no data are available.
b
Presented according to the sequence cited in guidelines’ text.

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 TABLE 2. Guideline recommendations on antihypertensives for acute/severe hypertensive crisis in pregnancy
Antihypertensive agentsa for acute/severe hypertensive crisis;
(Blood pressure >160/110 mmHg)b
Preeclampsia-induced Prevention of Refractory

Journal of Hypertension
Organizationsc Year Ref.# First-line Second-line Third-line Contraindication pulmonary edema eclampsia hypertension
Africa
EHS 2004 [10] Hydralazine i.v. Labetalol i.v. – – – Mg. sulfate i.v. Nitroprussided i.v.
SAHS 2011 [11] Labetalol i.v. NifedipineS PO – – – – –
Asia
GHA 2010 [12] – – – – – – –
MOH, Bahrain 2008 [13] Hydralazine i.v. Labetalol i.v. NifedipineNS PO – – – Nitroprussided i.v.
MOH, Malaysia 2008 [14] Labetalol i.v. Hydralazine i.v. NifedipineNS PO – Nitrates i.v. Mg. sulfate i.v. –
MOH, Singapore 2005 [15] Labetalol i.v. NifedipineNS PO Hydralazine i.v. – – – –
SHMS 2011 [16] Labetalol i.v. NifedipineNS PO Hydralazine i.v. – – – Nitroprussided i.v.
TSC 2010 [17] Labetalol i.v. Methyldopa PO NifedipineNS PO Hydralazine i.v. Nitroglycerin i.v. Mg. sulfate i.v. Nitroprussided i.v.
KSC 2006 [18] – – – – – – –
TFCPP-HK 2010 [19] – – – – – – –
Australia
HF 2008 [20] – – – – – – –
Caribbean and Latin America
LA
LASH 2009 [21] Labetalol i.v. Nifedipine PO – Hydralazine i.v. Nitroglycerin i.v. Mg. sulfate i.v. NitroprussidePP i.v.
PAHO/CHRC 2007 [22] – – – – – – –
Europe
BHS 2004 [23] – – – – – Mg. sulfate i.v. –
ESH/ESC 2013 [24] Labetalol i.v. Methyldopa PO NifedipineNS PO – Nitroglycerin – Nitroprussided i.v.
i.v./nitroprusside i.v.
NICE 2011 [25] – – – – – – –
SIGH 2007 [26] – – – – – – –
International
WHO/ISH 2003 [27] – – – – – – –
WHO 2007 [28] – – – – – – –
North America
AACE 2006 [29] – – – – – – –
CCS 2011 [30] – – – – – – –
DVA/DoD 2004 [31] – – – – – – –
ICSI 2010 [32] – – – – – – –
NHLBI 2004 [5] Hydralazine i.v. Labetalol i.v. NifedipineLA PO – – – Nitroprussided i.v.
RNAO 2005 [33] – – – – – – –

i.v., intravenous; LA, long-acting (retard); NS, not specified; PO, oral; PP, should be infused postpartum to avoid the risk of fetal thiocyanate intoxication; S, specified as not a slow-release tablet, should not be given sublingually, chewed,
bitten or used buccally. ’–’ indicated no data are available.
a
Presented according to the text sequence.
b
In case of preeclampsia and preeclampsia superimposed on chronic hypertension.
c
See Table 1 for details of acronyms.
d
Prolonged administration should be avoided because of the risk of fetal cyanide poisoning.

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457
Hypertension in pregnancy
Al Khaja et al.
prevention of eclampsia and control of seizures, and sodium
nitroprusside for refractory cases of hypertension were
recommended by guidelines deemed complete (Table 2).
DISCUSSION
This systematic review comprehensively has analyzed
clinical guideline recommendations of various national/
international bodies for management of arterial hyperten-
sion in adults, particularly for pregnant hypertensive
women. For nonsevere hypertension in pregnancy,
a-methyldopa is universally recommended as a first-line
drug by all guidelines, whereas labetalol followed by nife-
dipine are second-line drugs. The general consensus on
a-methyldopa can be attributed to its long and extensive
use without any reported adverse maternal and fetal out-
comes [34–37].
CCBs were recommended in addition to a-methyldopa
by some guidelines as alternative first-line [12,17] or as
second-line [5,13] drugs for nonsevere hypertension in
pregnancy. However, the individual class of CCBs (dihy-
dropyridine/nondihydropyridine) and the specific drug
recommended have been equivocal in these guidelines;
several studies have investigated nifedipine [38], isradipine
[39], felodipine [40], nicardipine [41], and verapamil [42] for
hypertension in pregnancy. Therefore, neither it is clear
whether the guidelines’ intent was dihydropyridine or non-
dihydropyridine, nor the individual CCB drug intended.
Such ambiguity compromises the clarity of guidelines.
Nifedipine, without specifying the formulation, was
recommended by several guidelines: first-line alternative
[24,29] and second-line therapy [14,15] for nonsevere
hypertension (Table 1); and second-line [15,16] and
third-line therapy [13,14,17,24] for acute severe hyper-
tension in pregnancy (Table 2). The dihydropyridine nife-
dipine is available as long-acting (extended release,
prolonged action), short-acting (immediate release), and
sublingual formulations. Hence, the type of formulations
should have been precisely specified; short-acting nifedi-
pine has been reported to be associated with maternal
hypotensive episodes and fetal distress [43,44]. Moreover,
sublingual nifedipine, even in an emergency setting, is no
longer used in pregnancy-induced hypertension [5,43] or in
patients with essential hypertension [5,23]. Long-acting
nifedipine formulations (extended release, prolonged
action) have been specified in some guidelines as second-
line for treating nonsevere hypertension [10,11,16,21,23].
Such clarity is essential to promote the guidelines’ credibility.
Some clinical guidelines contraindicate the use of ate-
nolol during pregnancy [11,21], whereas others deem the
safety profile of b-blockers, particularly atenolol, contro-
versial, as these may be associated with adverse effects on
birth weight and fetal growth [5,10,14–17,20] (Table 1).
Contrary to these views, b-blockers are listed as first-line
[12] and second-line alternatives [5,13,29] for nonsevere
hypertension in pregnancy (Table 1). These national and
international guidelines have neither specified the individ-
ual b-blockers nor the pregnancy stages at which inter-
vention with b-blockers is appropriate. Although none
of the b-blockers are associated with teratogenicity [6],
atenolol should be avoided in early stages of pregnancy
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as its use has been associated with significantly lower birth
weight and significantly higher proportion of small-for-
gestational-age babies [45–47]. b-Blockers should also be
prescribed cautiously at the late stage of pregnancy as
infants whose mothers received b-blockers had a clinically
nonsignificant bradycardia [48] and were at increased risk
for respiratory distress syndrome, endocrine and metabolic
disturbances including neonatal hypoglycemia, perinatal
jaundice, digestive system disorders, and feeding problems
[49,50].
b-Blockers can be distinguished by several properties:
relative affinity to b1 and b2 receptors, intrinsic sympatho-
mimetic activity (ISA), blockade of a-receptor, differences
in lipid solubility, capacity to induce vasodilatation, and
pharmacokinetic parameters. b-Blockers with ISA would be
counterproductive to the therapeutic response expected
from a b-blockade, that is, prevent the bradycardia or
negative inotropic effect in a resting heart. Oxprenolol, a
b1-selective blocker with ISA, for instance, limits the
bradycardia seen with non-ISA b-blocker, maintains resting
cardiac output, and reduces the peripheral vascular resist-
ance, perhaps secondary to the ISA of this agent. This may
explain the potential benefit to fetal growth from treat-
ment with oxprenolol [34,51]. Moreover, oxprenolol-
related effects may justify its recommendation as a
second-line drug for nonsevere hypertension in late stages
of pregnancy by some guidelines [10,15]. Paradoxically,
oxprenolol was considered as potentially harmful agent
by Heart Foundation guidelines [20]. Unlike b1-selective
blockers that possess ISA, atenolol persistently reduces the
cardiac chronotropic and inotropic activity, which appears
to contribute to its antihypertensive effect and increases
the peripheral vascular resistance. This effect is perhaps
secondary to the lack of ISA and may explain association of
atenolol with fetal growth restriction as a result of utero-
placental blood flow reduction when used throughout
pregnancy.
Healthy normal pregnancy is associated with increased
circulating blood volume, whereas pregnancies compli-
cated by hypertension have been observed to have no
increase or even reduced circulatory blood volume as
compared with prepregnancy values [52]. Hence, to use
diuretics which would further reduce circulating volume in
these women is inappropriate. However, there is no evi-
dence that low-dose thiazide/thiazide-like diuretics are
harmful in women with preexisting hypertension [23]
and they may be continued through pregnancy. Diuretics
are well tolerated and have not been shown to increase
adverse perinatal effects [53]. More recently, NICE [9] guide-
lines for treatment of hypertensive disorders in pregnancy
have suggested that diuretics, particularly chlorothiazide,
should not be used as it may be associated with an
increased risk of congenital abnormalities and neonatal
complications such as neonatal thrombocytopenia, hypo-
glycemia, and electrolyte imbalances.
The use of diuretics in pregnancy has been considered
to be a possible or relative contraindication, notably by
European Society of Hypertension/European Cardiology
Society (ESH/ECS) 2013 guidelines [24] and by others
[11,14,16,21]. On the other hand, British Hypertension
Society (BHS) [23] and others [10,13,15,17] deemed the
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use of diuretics as a controversial issue associated with
potential harmful effects on maternal and fetal outcomes.
Contrary to the above, the National Heart, Lung, Blood
Institute (NHLBI) [5] recommended diuretics, in addition to
b-blockers and CCBs, as an alternative second-line therapy
to a-methyldopa and labetalol. A conclusion, therefore,
cannot be drawn, although the overall trend is to discour-
age the use of diuretics in pregnant women.
Contrary to a-methyldopa, ACEIs and ARBs are absol-
utely contraindicated, particularly during the second and
third trimesters of pregnancy by all guidelines (Table 1).
Miscarriage, fetal death, fetal renal failure, and congen-
ital malformation have been observed with the use of
ACEIs and ARBs [54–57]. The cause of these defects
appears to be related to fetal hypotension, reduced renal
blood flow in fetus [57], and disruption of prenatal
development of the fetal uropoietic system as a result
of suppression of the fetal renin–angiotensin system
(RAS) [55]. It is likely that direct renin inhibitors might
be expected to have similar effects as ACEIs and ARBs
in pregnancy, an issue specifically addressed only by
ESH/ESC [24] and Taiwan Society of Cardiology [17]
among all guidelines.
A meta-analysis of 24 clinical trials [58], and a nonblinded
randomized trial [59] found no statistical significant differ-
ences between parenteral labetalol and hydralazine. The
authors of the meta-analysis concluded that there are
insufficient data to favor one agent over another in manag-
ing hypertension in pregnancy in terms of either effective-
ness to control hypertension or in terms of safety profile
[58]. Vigil-De Gracia et al. [59] concluded that both paren-
teral labetalol and hydralazine fulfill the criteria required for
an antihypertensive drug to treat severe hypertension in
pregnancy, although palpitation and maternal tachycardia
were significantly associated with patients treated with
hydralazine, and hypotension and bradycardia were sig-
nificantly more frequent in labetalol group. No statistical
changes in umbilical blood flow were observed as assessed
by Doppler ultrasound during acute severe hypertension in
pregnancy with the use of either parenteral labetalol or
hydralazine [60]. However, a meta-analysis [61] which eval-
uated hydralazine versus other antihypertensives (labetalol
and nifedipine) revealed that parenteral hydralazine was
more often associated with maternal hypotension, cesarean
sections, placental abruption, maternal oliguria, adverse
effects on fetal heart, and low Apgar scores than labetalol.
The authors concluded that their results do not support the
use of parenteral hydralazine as first line for treatment of
severe hypertension in pregnancy.
Five of the 10 completely addressed guidelines
[14,16,17,21,24] recommended the use of the parenteral
labetalol as the drug of choice for treatment of severe
hypertension in pregnancy (Table 2). However, the use
of parenteral hydralazaine is contraindicated by two
completely addressed guidelines [17,21]. The reason for
contraindication was attributed to the abrupt maternal
hypotension, which may impair placental perfusion result-
ing in fetal distress [61,62]. Parenteral labetalol as a drug of
choice followed by oral nifedipine and parenteral hydra-
lazine are the most commonly used antihypertensives
for treatment of severe hypertension in pregnancy as
Journal of Hypertension
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Hypertension in pregnancy
recommended by the Society of Obstetricians and Gyne-
cologists of Canada (SOGC) [63] and the Society of Obstetric
Medicine of Australia and New Zealand (SOMANZ) [64].
Recent NICE update published by Royal College of Obste-
tricians and Gynaecologists, UK [9] recommends parenteral
or oral labetalol as the first-line therapy, and parenteral
hydralazine or oral long-acting nifedipine as alternatives for
treatment of severe hypertension in pregnancy. The Euro-
pean Society of Cardiology guidelines on the management
of cardiovascular diseases recommend parenteral labetalol
or oral a-methyldopa or oral long-acting nifedipine as first-
line drugs for severe pregnancy hypertension; parenteral
hydralazine is no longer a drug of choice [65]. Based on
these international guideline recommendations and on
limited evidence-based data, it is apparent that there is a
trend to substitute hydralazine with labetalol. Whether
such a trend is going to be endorsed by the Eighth Joint
National Committee guidelines to be released soon is
awaited.
There is uniformity among guidelines (completely
addressed) with respect to the algorithms used for treat-
ment of pulmonary edema induced by preeclampsia, treat-
ment and prevention of eclampsia, and treatment of
refractory hypertension (hypertensive crisis) in pregnancy
(Table 2). In preeclampsia associated with pulmonary
edema, intravenous glyceryl trinitrate is the drug of
choice [14,17,21,24]. Intravenous magnesium sulfate is
the first-line drug for prevention of eclampsia and seizures
[10,14,17,21,23]. None of the guidelines have highlighted
the synergistic effect of nifedipine and magnesium sulfate
resulting in maternal hypotension and fetal hypoxia
[43,44,66] and marked hypocalcemia [67]. Awareness of
this synergism is important because nifedipine is being
used increasingly in pregnancy-related hypertension [66].
Despite this concern, these drugs are concomitantly admin-
istered without increased risks [68]. Intravenous infusion of
sodium nitroprusside remains the drug of choice for hyper-
tensive crisis, although its prolonged administration carries
an increased risk of fetal cyanide poisoning resulting from
nitroprusside biotransformation. This potential risk has
been emphasized by several guidelines [5,10,13,16,17,
21,24].
Inclusion of guideline recommendations for this review
has been carefully considered. The guideline specifications
were evaluated using author-determined survey questions
exploring whether the teratogenicity of ACEIs or ARBs has
been addressed by these guidelines (Table 3). Use of ACEIs
or ARBs during the second and third trimesters of preg-
nancy is contraindicated because of their association with
an increased risk of fetopathy [54,55]. Adverse birth out-
comes of these classes of antihypertensives are not only
confined to second and third trimesters, but their use
should be avoided even during the first trimester [55,56].
Cooper et al. [56] suggested that ACEIs should be avoided in
women who attempt to conceive and during the first
trimester of pregnancy. Alwan et al. [55] recommended that
ARBs should be substituted with an alternative antihyper-
tensive drug(s) as soon as pregnancy is confirmed. In USA,
the use of ACEIs in women of reproductive age has sig-
nificantly increased between 1995 and 2002 by 83% [69],
and many of these women may practice inadequate
www.jhypertension.com 459
Al Khaja et al.

TABLE 3. Profile of partially and completely addressed guidelines in terms of research questions
Research questions
Organizationsa Year Ref.# Q1 Q2 Q3 Q4
Africa
EHS 2004 [10]    
SAHS 2011 [11]    
Asia
GHA 2010 [12]    
MOH, Bahrain 2008 [13]    
MOH, Malaysia 2008 [14]   þ þ
MOH, Singapore 2005 [15]    
SHMS 2011 [16]    
TSC 2010 [17] þ  þ 
Australia
HF 2008 [20]    
Caribbean and Latin America
LASH 2009 [21]  þ  
PAHO/CHRC 2006 [22]    
Europe
BHS 2004 [23]   þ 
ESH/ESC 2013 [24] þ  þ 
NICE 2011 [25]    
International
WHO/ISH 2003 [27]    
WHO 2007 [28]    
North America
AACE 2006 [29]    
DVA/DoD 2004 [31]    
ICSI 2010 [32]    
NHLBI 2003 [5]  þ þ þ
RNAO 2005 [33]    
Rate of research questions addressed (%) 9.5 9.5 23.8 9.5

Q1, Does the guideline specify that antihypertensive(s) with teratogenic potential are contraindicated in women of childbearing age as a mandatory recommendation?; Q2, Does the
guideline specify that ACEIs and ARBs are to be used with extreme caution in sexually-active young females (teenage girls)?; Q3, Does the guideline specify that women with chronic
hypertension who plan to conceive should not be treated with ACEIs and ARBs ?; Q4, Does the guideline emphasize that there is a need to change the prescribed antihypertensive(s) to
alternative(s) with a better safety profile to hypertensive women who wish to conceive or are pregnant?. ’þ’ indicates that the data are available; ’–’ indicated no data are available.
a
See Table 1 for acronym details.

contraception [70]. Such exposure may increase the fetal
exposure to ACEIs or ARBs, when used during the first
trimester of pregnancy [56]. Moreover, the prevalence and
rate of diagnosis of hypertension in children and adoles-
cents appear to be increasing, in part, due to increasing
prevalence of childhood obesity as well as growing public
awareness [71]. Our analysis of the guidelines revealed that
contraindication of potentially teratogenic antihyperten-
sives such as ACEIs and ARBs in women of child-bearing
age was specified only as a mandatory recommendation by
ESH/ESC guidelines [24] and Taiwan guidelines [17]; Latin
American Society of Hypertension (LASH) [21] and NHLBI
[5] guidelines specified that ACEIs and ARBs are to be used
with extreme caution in sexually active young females
(adolescents) at risk of pregnancy; approximately one
fourth of the guidelines [5,14,17,23,24] have specified that
women with chronic hypertension who plan to conceive
should not be treated with ACEIs or ARBs; and less than
10% of overall assessed guidelines [5,14] have emphasized
the importance of changing the prescribed antihyperten-
sive(s) to alternative(s) with better safety profile for hyper-
tensive women who wish to conceive or are already
pregnant.
Most of the current guidelines do not provide adequate
guidance to clinicians despite clear evidence of poten-
tial harm in pregnancy that could result from many
antihypertensives, in particular those which interfere with
RAS. Similarly, guidelines also do not emphasize the
dangerous interactions between nifedipine and magnesium
sulfate. The preference for particular antihypertensive
drugs is not very important in the absence of robust
evidence for superiority of any drugs. Hence, at a local
level, a consensus about standard treatment guidelines is
needed, keeping in mind the principle ‘not to reduce blood
pressure too rapidly and too far’.
In conclusion, it is evident that hypertension treatment
guidelines developed for adults during the last decade have
variable recommendations regarding the treatment of
hypertension in special groups such as adult females of
childbearing age and sexually active adolescents. In some
of these guidelines, the antihypertensive classes, recom-
mended drug(s), intended drug formulation, and route of
administration do not conform to evidence-based criteria. It
is apparent that antihypertensive-associated teratogenic
risk has not been adequately addressed by many guide-
lines. We suggest that these important therapeutic issues
need to be addressed in future revisions of guidelines. The
recently revised ESH/ESC guidelines have addressed some
of these therapeutic issues. Well designed randomized
clinical trials and meta-analysis of published randomized
data are needed to resolve controversial issues related to
the management of arterial hypertension in pregnant and

460 www.jhypertension.com Volume 32
Number 3
March 2014

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child-bearing age group women. With the advent of newer
antihypertensive drugs being introduced, the need for
evaluating efficacy and safety of such drug therapies in
women acquires a greater magnitude of importance.
ACKNOWLEDGEMENTS
The authors acknowledge the assistance given to them by
Mrs Radha Raghavan in preparing this article.
Conflicts of interest
This article has not been submitted or presented elsewhere
and has not been financially supported in any form by any
drug companies or organization.
There is no conflict of interest to be declared.
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Reviewers’ Summary Evaluations
Reviewer 1
The aim of the manuscript is to critically review 25 national
and international guidelines for the management of arterial
hypertension in pregnancy.
There is a discrimination bias because only English-
language guidelines were included into the analysis, which
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applies mostly to national guidelines, as international
guidelines are mostly written in English anyway.
In my opinion, the ESC guidelines on the management of
cardiovascular disease during pregnancy (Eur Heart J
2011;32 : 3147–97) should be listed in the tables under
Europe and not only mentioned in the Discussion section.
It is strange these guidelines were not included (search was
performed for the January 2000 through June 2012 period).
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March 2014
 Hypertension in pregnancy

On the other hand, the 2013 ESH-ESC hypertension guide-
lines were included.
Reviewer 2
The strengths of this study are that it brings together all the
published guidelines on the management of hypertension
in pregnancy and draws out the areas of certainty and
uncertainty in clinical practice. The weakness is that the
authors do not make judgements as to which is the best
guideline to follow in the development of local working
practice; this is inevitably going to be influenced by local
availability of drugs.

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