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TREATMENT OF CHRONIC
HYPERTENSION DURING
PREGNANCY

Brian McCullough, Pharm.D.


affecting 0.6-2.0% of women 18-29 years old
and 4.6-22.3% of women 30-39 years old,
chronic hypertension is a common disease in
pregnancy.' Despite a long history of treating hyper-
tension in pregnancy, few well designed studies exist
to guide treatment Instead, recommendations are de-
rived from expert opinion and experience rather than
standardized guidelines. Some trials have sought to
compare antihypertensives in pregnancy. However,
safe and effective treatment must be assessed on a
case by case basis because many of these trials are not
well designed or have unclear results. This article will
review the roles and studies evaluating safety of se-
lected antihypertensive therapies in the treatment of
chronic hypertension in pregnancy.

PREGNANCY CATEGORIES

All antihypertensive medications are listed as
Pregnancy Categories B, C, or D (definitions in Table
1), meaning that none have clearly shown freedom
from adverse events to the fetus. Although commonly
regarded as safe in pregnancy, medications classified
as Pregnancy Category B may still have risks to either
the mother or fetus. Therefore, each therapeutic op-
tion must be evaluated based on the patient's co-
morbid conditions, risk factors, gestational age, and
concomitant medications.


ETIOLOGY OF HYPERTENSION IN PREGNANCY

Chronic hypertension in pregnancy is defined as
systolic blood pressure above 140 mmHg or diastolic
blood pressure above 90 mmHg documented prior to
pregnancy or diagnosed prior to week 20 of gestation.
In contrast, pre-eclampsia is typically diagnosed after
the 20th week and is associated with proteinuria and/
or edema. Gestational hypertension, which is also di-
agnosed after the 20th week of gestation, is not accom-
panied by proteinuria. Pre-eclampsia and gestational
hypertension are treated differently from chronic hy-
pertension and will not be addressed in this article.
Women with mild pre-existent hypertension who
become pregnant are at increased risk of several com-
plications. First, pre-existent hypertension increases
the absolute risk of superimposed preeclampsia by 10
to 25%. Secondly, the absolute risk of abruptio placen-
tae is increased by 0.7 to 1.5%. Thirdly, a 12 to 34%
increased risk of preterm birth, which is defined as
delivery <37 weeks, is seen in pregnant mothers with
pre-existing hypertension. Fourthly, fetal growth re-
striction increases 8 to 16% compared to mothers
without pre-existing hypertension.3 Finally, fetal mor-
tality is also increased more than three-fold in women
with chronic hypertension.4






INSIDE THIS ISSUE:

TREATMENT OF CHRONIC HYPERTENSION
DURING PREGNANCY


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A Adequate and well-controlled studies have failed to demonstrate a risk to the fetus in the first trimes-
ter of pregnancy (and there is no evidence of risk in later trimesters).
Animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate
B
and well-controlled studies in pregnant women.
Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate
C and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant
women despite potential risks.

There is positive evidence of human fetal risk based on adverse reaction data from investigational or
D marketing experience or studies in humans, but potential benefits may warrant use of the drug in
pregnant women despite potential risks.

Studies in animals or humans have demonstrated fetal abnormalities and/or there is positive evidence
X of human fetal risk based on adverse reaction data from investigational or marketing experience. and
the risks involved in use of the drug in pregnant women clearly outweigh potential benefits.


INDICATIONS FOR TREATMENT

The time frame for initiating treatment in the man-
agement of chronic hypertension of pregnancy is not
agreed upon by all experts. Because of a natural de-
crease in blood pressure beginning at week 7 of gesta-
tion, many physicians are willing to wait until these
physiologic changes begin and assess if this alone
brings blood pressure within goal. In most pregnant
patients with mild to moderate hypertension, defined
as blood pressure of 140 to 160/90 to 100 mmHg no
clear evidence exists that initiation of treatment below
this value improves fetal or maternal outcomes.5 Con-
sequently, clinicians should consider delaying treat-
ment of mild to moderate hypertension.
A meta-analysis of seven randomized controlled
trials studying a total of 623 pregnant women with
mild chronic hypertension compared antihypertensive
treatment with no treatment The authors found a de-
crease in severe hypertension (defined as blood pres-
sure > 160/100 mmHg) and need for additional anti-
hypertensives, but found no difference in either mater-
nal or fetal outcomes including mortality.6 An upward
trend in the incidence of fetal growth restriction was
found, but failed to reach significance.
Several compelling indications may warrant anti-
hypertensive therapy (Table 2), because they put the
mother and fetus at high risk for adverse events. For
these patients, blood pressure above 140/90 mmHg
may be treated to a goal blood pressure of 120 to 140
mmHg/80 to 90 mmHg.


SELECTED THERAPEUTIC OPTIONS


Methyldopa
Methyldopa is a centrally acting a-adrenergic an-
tagonist used in the treatment of hypertension. Me-
thyldopa is Pregnancy Category B (Table 3) and has a
long, established track record in the treatment of hy-
pertension in pregnancy. Many studies have been con-
ducted in both humans and animals with no incidence
of serious adverse events to the fetus.7,8 While no con-
genital abnormalities have been observed, the use of
methyldopa is limited by its adverse events to the
mother, including somnolence, lethargy, and or-
thostatic hypotension. Methyldopa has been used
safely as an antihypertensive in pregnancy and is fre-
quently used by physicians based on its lack of docu-
mented fetal adverse effects.8

Labetalol
Labetalol has combined a- and P-adrenergic an-
tagonist activity and is one of the most frequently used
P-antagonists in the treatment of hypertension in
pregnancy. Labetalol is Pregnancy Category B. Unlike
other nonspecific 3-antagonists such as propranolol,
labetalol has not been found to increase respiratory
depression, fetal growth restriction, bradycardia, or
hypoglycemia.7 Possibly because of its combination of
a- and p-antagonism, labetalol is not associated with
decreased placental perfusion that can occur with pure
P-antagonists. Consequently, labetalol is a regularly
prescribed antihypertensive and may be a good option
if the mother cannot tolerate methyldopa.9 Because of


Pha rma Note Volume 25, Issue 8 I May 2010


Table 1. FDA Pregnancy Categories2


CATEGORY


DEFINITION


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Table 2. Risk Factors Associated with Antihypertensive Drug Use in Pregnancy3
SSecondary, rather than essential, hypertension (e.g., renal disease, collagen vascular disease, coarctation of the aorta)
SEnd-organ damage (e.g., ventricular dysfunction, retinopathy)
SDyslipidemia
. Maternal age over 40 years old
SMicrovascular disease
SHistory of stroke
. Previous perinatal loss
. Diabetes


potential adverse events, newborns of all mothers tak-
ing 3-blockers should be screened for lung function
and hypoglycemia postpartum.

p-antagonists with Intrinsic Sympathomimetic Activity
P-antagonists with intrinsic sympathomimetic ac-
tivity (ISA) such as pindolol (Pregnancy Category B)
may have advantages in pregnant women compared to
non-ISA agents. Pindolol has been found superior to b-
antagonists without ISA in pregnant patients. Head to
head studies with other 3-antagonists, including at-
enolol, found pindolol superior regarding fetal hemo-
dynamics10 and birth weight.11 3-antagonists with ISA
are associated with fewer adverse events than agents
without ISA and therefore may be a better choice for
the treatment of hypertension.

P-antagonists: Other Considerations
Unlike labetalol and pindolol which have data
documenting safety in pregnancy, some 3-antagonists
are likely harmful to the fetus based on available evi-
dence. Atenolol and propranolol are two agents that
increase the risk of adverse events to the fetus and
should not be used as antihypertensive therapy unless
the benefit clearly outweighs the risk to the fetus.
Atenolol decreases fetal birth weight compared to
placebo,12 labetalol,13 and 3-antagonists with ISA.11
Atenolol is also associated with neonatal bradycardia.
One study found a 39% incidence of bradycardia in
newborns of mothers treated with atenolol versus
10% with newborns of placebo-exposed mothers.14 In
addition to fetal risks while in the womb, atenolol may
cause harm in newborns. A case study found persis-
tent concentrations of atenolol in a newborn which the
authors associated with various adverse reactions in-
cluding bradycardia and hypotension.15 The increased
proportion of body water and the renal insufficiency
of newborns combined with the water-soluble nature
of atenolol put the fetus at risk for accumulation after
delivery. The long term effects of atenolol are largely
unknown, but with the availability of antihypertensive


agents with better safety data in pregnancy, atenolol
should be avoided.12
Propranolol is a non-specific 3-antagonist classi-
fied as Pregnancy Category C. Because of a number of
reports showing increased risk to the fetus, pro-
pranolol is best avoided during pregnancy. A pooled
analysis of 167 case reports of live-born infants born
to patients taking propranolol during pregnancy
showed a high number of newborns with intrauterine
growth restriction (14%), hypoglycemia (10%), bra-
dycardia (7%), respiratory depression (6%), and other
adverse events post delivery.7 However, the actual in-
cidence of adverse events may be less than reported
since this analysis was not a representative sample.
Nonetheless, patients should be carefully evaluated for
risk and benefit before initiating propranolol as a first
line agent7

Hydralazine
Hydralazine is a peripheral arterial vasodilator
that is Pregnancy Category C. No reports of congenital
defects have been associated with hydralazine, and it
is a commonly prescribed antihypertensive for preg-
nant women outside the United States.7 Adverse
events for the fetus, however, have been documented.
One case report describes a fetus that developed an
atrial arrhythmia in the womb while the mother was
taking hydralazine.16 The arrhythmia resolved 24
hours after discontinuing the medication. Aside from
risk of fetal harm, hydralazine therapy has the poten-
tial to cause adverse reactions in the mother including
orthostatic hypotension, peripheral edema, drowsi-
ness, and more serious adverse events such as blood
dyscrasias and a lupus-like syndrome. Practitioners
should carefully consider the potential risk of fetal and
maternal harm before a pregnant patient is treated
with hydralazine.

Calcium Channel Antagonists
Dihydropyridine calcium channel antagonists such
as nifedipine have been used to treat hypertension in


Pha rma Note Volume 25, Issue 8 I May 2010


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pregnant women; however all dihydropyridines are
Pregnancy Category C. Animal studies in rats and rab-
bits have shown teratogenicity at doses well above the
maximum human dose, but these findings have not
been substantiated in humans. In a study of 23 women
receiving slow release nifedipine, the authors found no
evidence of fetal harm.17 However, almost all babies
born were "small-for-dates." The authors attributed
this finding to the complicated patients enrolled in the
study and their respective disease states. Given the
limited data, nifedipine is considered a second line
agent to be used only when the benefit outweighs the
potential risks.3
The non-dihydropyridine calcium channel antago-
nists diltiazem and verapamil are rarely used in preg-
nancy as antihypertensives and are Pregnancy Cate-
gory C. Diltiazem causes teratogenic effects on the
skeletal system in high dose animal studies,18 but tera-
togenicity has not been found in humans.7,19 A chart
review of 229,101 completed pregnancies showed 27


newborns exposed to diltiazem.7 Of these, four
(14.8%) had major birth defects, of which two were
cardiovascular defects (7.4%). Based on the small
sample size, the significance of these findings is un-
clear, but it is possible that fetuses exposed to dilti-
azem may be at increased risk of cardiovascular ab-
normalities. This possible association is reason
enough to be wary of the use of diltiazem for treating
hypertension during pregnancy.
Verapamil is not often used as an antihypertensive
due to its relatively weak action on the vasculature.
One case study has demonstrated efficacy in the treat-
ment of fetal tachycardia in combination with di-
goxin.20 However, the authors of this case study could
not conclude that the resolution of tachycardia was
due to digoxin, verapamil, or the combination of the
two. Despite documented safety in some pregnancies,
one case report has shown a possible association with
fetal AV block and death (in combination with di-
goxin).21 No reports have demonstrated teratogenicity,


Table 3. Antihypertensive Therapeutic Options in Pregnancy
PREGNANCY COMPATIBLE W/
MEDICATION STARTING DOSE MAXIMUM DOSE
CATEGORY BREASTFEEDING?

Methyldopa
a B 250mg PO BID 3g/day PO Yes
(Aldomet)

Labetalol
Labetaelol C 100mg PO BID 2400 mg/day PO Yes
(Trandatel, Normodyne)

Pindolol
Pindsn B 5mg PO TID 40mg/day PO No'
(Visken )

Propranolol
ndranl) C 40mg PO BID 640mg/day PO Yes
(Inderall)

Hydralazine
Hydralazine C 10mg 2-4 times daily 300mg/day PO Yes
(Apresoline)

Nifedipine
Nifedipe C 30mg XL PO daily 90mg/day PO (XL) Yes
(Procardia 1)

Diltiazem (CD)
(Cardiz Tiazec, Di ) C 120-240mg PO daily 480mg/day PO Yes
(Cardizem, Tiazac, Dilacor")

Verapamil 80mg PO TID (IR) 480mg/day PO (IR)
(Calan IR, Isoptin, Verelan SR) 240mg daily (Verelan) 480mg/day PO (Verelan)

Hydrochlorothiazide
(Hydrod Mcrozide, o ) B 12.5-25mg PO daily 50mg/day PO Yes
(Hydrodiurill, Microzide*, others)
Clonidine
Clo neC 0.1mg BID 2.4mg/day PO Weigh Risk/Benefit'
(Catapres)
XL = extended release; CD = Controlled dose (once daily); IR = Immediate Release; PO = By mouth.
* According to American Association of Pediatrics Committee on Drugs 2001
t According to manufacturer's recommendations

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but because of verapamil's inferior blood pressure
control, other options may be more beneficial in treat-
ing hypertension uncomplicated by arrhythmias or
tachycardia during pregnancy.

Clonidine
Clonidine (Pregnancy Category C) is a centrally
acting a2-adrenergic agonist used as adjunct therapy
to treat hypertension in the general population. Data
in pregnancy, however, is limited. No congenital de-
fects have been reported with clonidine although one
retrospective analysis found a possible association
with sleep disturbances and hyperactivity with chil-
dren whose mothers had taken clonidine during preg-
nancy.22 Clonidine therapy is often limited by an in-
creased incidence of somnolence, dizziness, and leth-
argy which may be intolerable for the mother. Because
of a lack of data, clonidine should not be used as first
line therapy, but may be appropriate for adjunct ther-
apy in severe hypertension if other antihypertensive
options are limited.

Thiazide and Thiazide-like Diuretics
Thiazides and thiazide-like diuretics include
chlorothiazide, hydrochlorothiazide (HCTZ), chlortha-
lidone, indapamide, and metolazone. All are FDA Preg-
nancy Category B except chlorothiazide which is Cate-
gory C, though all have very similar pharmacologic
profiles. Thiazide diuretics create imbalances in serum
electrolytes, especially potassium. Electrolyte distur-
bances caused by thiazide diuretics have not been
linked to fetal harm, but the true risk is unknown. Thi-
azide diuretics also decrease plasma volume expan-
sion that occurs naturally as pregnancy progresses.
One study found that patients treated with diuretics
had only an 18% increase in plasma volume versus
52% in those receiving placebo.23 However, no differ-
ences were observed in fetal or maternal adverse out-
comes.
Since thiazide diuretics contract volume early in
therapy, pregnant mothers should be evaluated for
indications to continue a thiazide if she has been on
this medicine for a long period of time. Unfortunately,
no well designed trials have evaluated the feasibility of
this option. Most practitioners consider thiazide diu-
retics as Pregnancy Category D and avoid their use due
to theoretical complications from limited plasma vol-
ume expansion and electrolyte disturbances. Prospec-
tive trials evaluating the safety of thiazide diuretics
should be performed since they have been shown to
possess mortality benefit to non-pregnant patients24
and are well tolerated in the treatment of hyperten-
sion in the general population.


ACE-Inhibitors and ARBs
Angiotensin-Converting Enzyme (ACE) Inhibitors
and Angiotensin Receptor Blockers (ARBs), while
widely used in the general population, are Pregnancy
Category D and should not be used in pregnancy. A
review of Tennessee Medicaid patients found that in-
fants exposed to ACE inhibitors in the first trimester
were at increased risk for malformations of the cardio-
vascular system (RR, 3.72; 95% CI, 1.89 to 7.30) and
the central nervous system (RR, 4.39; 95% CI, 1.37 to
14.02).25 Fetal complications of oligohydramnios, re-
nal failure, and in-utero death are associated with ACE
-I and ARB exposure in the second and third trimes-
ter.26
While the fetal harm caused by ACE-Is and ARBs is
well documented, a 2008 retrospective cohort study of
Tennessee Medicaid patients found an alarming trend
of increased usage of ACE-Is and ARBs in pregnant fe-
males from 1986 to 2003.27 The incidence rose from
11.2 per 10,000 pregnancies during 1986-1988 to
58.9 per 10,000 pregnancies in 2003. Disturbingly, the
rates of usage in the second and third trimester nearly
tripled despite a black box warning issued by the FDA
in 1992, warning of the fetal harm caused by these
medications. The application of this study to all preg-
nancies may be questioned, but it shows that prescrib-
ers should be more vigilant in discontinuing ACE-Is
and ARBs as soon as pregnancy is discovered to avoid
the potential for fetal adverse events.

SUMMARY

Antihypertensive therapy is best initiated when
blood pressure exceeds 160/100 mmHg in pregnant
women with chronic hypertension without additional
risk factors of fetal harm. Women with secondary hy-
pertension, end organ damage, dyslipidemia, greater
than 40 years old, microvascular disease, previous
stroke, previous perinatal loss, and/or diabetes melli-
tus should be treated for any blood pressure above
140/90 mmHg with a goal systolic pressure of 120 to
140 mmHg and goal diastolic pressure of 80-90
mmHg. Methyldopa, labetalol, and pindolol are the
best choices for first line therapy whereas b-
antagonists without ISA, hydralazine, calcium channel
antagonists, thiazide diuretics, and clonidine are best
reserved for second line or adjunct therapy. ACE-Is
and ARBs have no place in the treatment of hyperten-
sion in pregnancy as they lead to congenital defects
and are no more effective than other classes of anti-
hypertensives. Ultimately, the choice of antihyperten-
sive therapy should be individualized regarding each
patient's risk factors.


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The PharmaNote is Published by:
The Department of Pharmacy
Services, UF Family Practice Medical
Group, Departments of Community
Health and Family Medicine and
Pharmacotherapy and Translational
Research
University of Florida



John G. Gums Editor
PharmD, FCCP

R. Whit Curry, MD Associate Editor

Steven M. Smith Assistant Editor
PharmD


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