177 Springer Science+Business Media New York 2015

K. Rosene-Montella (ed.), Medical Management of the Pregnant Patient,

DOI 10.1007/978-1-4614-1244-1_8
Chapter 8

Hypertensive Disorders of Pregnancy

Margaret

A.

Miller

and

Marshall

Carpenter

Background
Hypertensive disorders in pregnancy are a major cause of both maternal and fetal
morbidity and mortality and account for approximately one quarter of all antenatal
admissions to the hospital [ 1 ]. The spectrum of hypertensive disorders in
pregnancy
includes preexisting hypertension, new-onset hypertension in pregnancy, as well as
hypertension that may occur de novo in the postpartum period. Challenges in the
management of hypertension in pregnancy include choosing when to use antihypertensive medication, goals of antihypertensive therapy, and which drugs to
use.
Recent data also show that hypertensive disorders of pregnancy are associated with
long-term cardiovascular risks in women.
Denition
Hypertension in pregnancy is de ned as systolic blood pressure >140 mmHg OR
diastolic blood pressure >90 mmHg. Severe hypertension in pregnancy is de ned
as
systolic blood pressure >160 mmHg OR diastolic blood pressure >110 mmHg [ 2 ].

Hypertensive disorders of pregnancy include four distinct clinical disorders

including:

Chronic hypertension

Gestational hypertension

Superimposed preeclampsia

Preeclampsia

Table 8.1 outlines the common terminology used to describe the various clinical
presentations of hypertensive disorders in pregnancy.
Table 8.1

Common terminology describing hypertensive disorders in pregnancy

Chronic hypertension
Use of antihypertensive medication prior to pregnancy
New-onset hypertension <20 weeks gestation
Hypertension that presents initially in pregnancy, but does not resolve by 12
weeks postpartum is retrospectively diagnosed as chronic hypertension

Gestational hypertension
New-onset hypertension >20 weeks gestation without proteinuria or other
evidence of preeclampsia
Hypertension resolves by 12 weeks postpartum
Also referred to as transient hypertension of pregnancy or pregnancy- induced
hypertension

Preeclampsia
of the

SBP >140 mmHg OR DBP >90 mmHg >20 weeks gestation with any

following:
Proteinuria de ned as:
More than 300 mg protein in a 24-h urine
Urine protein/creatinine ratio >0.3
Elevated transaminases to twice normal
Platelets <100,000/ml
Creatinine > 1.1 mg/dl or doubling of baseline creatinine
Pulmonary edema
New-onset headache or visual disturbance

Superimposed preeclampsia
Underlying diagnosis of hypertension and >20 weeks gestation development of:

 Worsening hypertension PLUS

New-onset proteinuria or increase in preexisting proteinuria OR
Other signs and symptoms of preeclampsia

Other clinical terms

Severe preeclampsia
Preeclampsia with any of the following features
SBP >160 mmHg OR DBP >110 mmHg >20 weeks gestation on at least 2
occasions, at least 1 h apart, while patient is on bed rest PLUS:
Platelets < 100,000/ml
Transaminases elevated to twice normal, severe persistent RUQ
or epigastric pain unresponsive to treatment no alternate diagnosis
Serum creatinine > 1.1 or doubling of creatinine
Pulmonary edema
New-onset headache or visual disturbances

HELLP syndrome
Hemolysis, elevated liver enzymes, low platelets
HELLP is considered a severe form of preeclampsia

Eclampsia
Preeclampsia with seizure

Overall hypertensive disorders affect up to 8 % of pregnancies in the USA [ 3 ],

and up to 5 % of pregnancies are complicated by chronic hypertension [ 4

6 ].
Gestational hypertension is thought to occur in approximately 6 % of pregnancies,
and 37 % of all pregnancies are complicated by preeclampsia [ 1 , 7 ].

Pathophysiology
In normal pregnancy, blood pressure drops beginning in the rst trimester
and
reaches a nadir by the end of the second trimester. The early drop in blood pressure
is due to a signi cant reduction in peripheral vascular resistance mediated by
endothelial production of vasodilating factors. During the third trimester, the blood pressure slowly rises back to the prepregnancy baseline. Because of this normal
physiologic drop in blood pressure, chronic hypertension may be masked in the rst
half of pregnancy. It is important that blood pressure values in the rst half of pregnancy are interpreted in the context of these known physiologic changes.
In the past 10 years, much has been learned about the pathophysiology of preeclampsia. Although the clinical manifestations of preeclampsia are not seen until
after 20 weeks gestation, the underlying pathology begins much earlier in pregnancy. Research has now shown that preeclampsia likely starts at the time of
placentation and is proposed to involve abnormal trophoblastic invasion of the maternal
spiral arteries leading to decreased perfusion of the placenta [ 8 , 9 ]. The ischemic
placenta then triggers release of mediators that leads to endothelial dysfunction
and
altered angiogenesis leading to the clinical manifestations of the disorder. While
hypertension and, previously, proteinuria are the hallmarks of the disease,
preeclampsia is a multisystem disease that can affect all organ systems.

Chronic Hypertension
Risk of Chronic Hypertension in Pregnancy
Most women with chronic hypertension will have normal healthy pregnancies,
especially if the hypertension is mild. Women with stage 1 hypertension (<160/100)
who have no evidence of end-organ damage and are otherwise healthy have
an
excellent prognosis for pregnancy. The primary risk for women in this category is
superimposed preeclampsia which occurs in approximately 20 % [ 5 ]. Women with
severe hypertension (>160/100) have a risk of preeclampsia of 50 %, and women
with the most severe disease including those who already have end-organ damage
or have a secondary cause of hypertension, have been reported to have a risk of
preeclampsia as high as 75 % [ 4 , 10 ]. The incidence of both maternal and fetal
adverse outcomes is related to the duration of disease, severity of disease,
and
whether or not the mother develops superimposed preeclampsia [ 11 ].

Maternal complications are primarily associated with preeclampsia and include

a vefold increase in maternal mortality, as well as an increased risk of maternal
cerebrovascular event, pulmonary edema, seizure, and renal failure [ 12 ].
Fetal complications include an increased risk of premature birth, intrauterine
growth restriction (IUGR), fetal demise, placental abruption, and cesarean delivery
[ 13 , 14 ]. Adverse fetal outcomes are also much more likely in women who
develop
superimposed preeclampsia [ 2 ].

Diagnosis

About 510 % of women enter pregnancy with a diagnosis of chronic hypertension

[ 5 ]. In addition, the overwhelming majority of women who have new-onset hypertension
chronic

prior

to

20

weeks

gestation

will,

ultimately,

be

diagnosed

with

hypertension. Ideally a woman with chronic hypertension should have a comprehensive evaluation prior to pregnancy. The evaluation of chronic hypertension
includes three components: (1) screening for secondary causes, (2) assessment for
target organ damage, and (3) a review of cardiovascular risk factors.

Essential hypertension accounts for 90 % of chronic hypertension and is more

common in African American women and women who have a family history of
hypertension, are obese, or are over 35 years old. If a woman has none of these risk
factors, then consideration of secondary causes is important. In addition, any
woman
with severe refractory hypertension, with sudden escalation of blood pressure, or
with speci c signs or symptoms should be evaluated for secondary causes
(Table 8.2 ). Although secondary hypertension is rare, it may pose signi cant risk
in
pregnancy if undiagnosed.

Target organs that are most commonly affected by chronic hypertension include
the heart, the brain, the kidneys, and the eye. Patients should be screened by symptoms, signs, or lab abnormalities (Table 8.3 ).

All women with hypertension should be screened for other cardiovascular risk
factors. In addition to hypertension, independent risk factors for cardiovascular disease in women include obesity (BMI > 30), sedentary lifestyle, hyperlipidemia, dia-

betes, smoking, end-stage renal disease, a history of gestational hypertension or

preeclampsia, and a family history of premature cardiovascular disease [ 15 ].
Although there is insuf cient evidence to suggest that lifestyle changes will affect
the outcome of the pregnancy, there is well-established long-term data showing
that
lifestyle changes can signi cantly reduce the likelihood of target organ damage.
Pregnant women are often motivated to make behavior changes, and with the frequency of prenatal visits, pregnancy provides an opportunity to provide important
education about healthy lifestyles.

The initial lab evaluation for a nonpregnant woman with new hypertension should
include CBC, creatinine, electrolytes, urinalysis, TSH, calcium, EKG, and fasting
blood sugar and fasting lipids. In pregnancy, the lipid panel may be deferred until 12
weeks postpartum as lipid levels may be affected by pregnancy, and an appropriate

screening test for diabetes in pregnancy should be done rather than the fasting
blood

sugar. Otherwise, this evaluation should be completed for all women with a new
diagnosis of hypertension, whether pregnant or not. Many clinicians also nd
it
helpful to document baseline preeclampsia labs in women at risk of preeclampsia.

Management
A careful review of both maternal and fetal risks and bene ts must be considered
in
the decision to use pharmacologic therapy in the treatment of hypertensive
disorders
of pregnancy. In women with systolic blood pressure >160 or diastolic blood pressure >110, there is good evidence that medications should be initiated to prevent
acute maternal end-organ damage, particularly stroke [ 16 ]. However, the bene t
of
antihypertensive therapy in mild to moderate hypertension (SBP 140159 or DBP
90109) has not been demonstrated in clinical trials. A 2007 meta-analysis showed
a 50 % reduction in the risk of severe hypertension, but no reduction in preeclampsia, perinatal mortality, preterm birth, or SGA infant [ 17 ]. In fact aggressive lowering of blood pressure in pregnancy may be associated with harm. A 2002 study
found that treatment of mild to moderate hypertension in pregnancy was associated
with a signi cant reduction in birth weight. This effect was consistent regardless of
etiology of hypertension or choice of medication [ 18 ]. International guidelines differ with respect to threshold for starting antihypertensive medications and blood
pressure goals in the management of hypertension in pregnancy, but most agree
that
mild to moderate hypertension over the course of 9 months of pregnancy is unlikely
to result in signi cant poor maternal or fetal outcomes [ 19 23 ].

Therefore, women with SBP < 160 AND

DBP < 110 mmHg are candidates for

non-pharmacologic management and should not be started on medications.

It is best to discuss plans for management of chronic hypertension before conception. Since 50 % of pregnancies are unplanned, women in their reproductive
years are best treated with a medication whose safety in pregnancy has
been
established. For women with chronic hypertension, it is likely that blood pressure
will drop in the rst half of gestation due to physiologic vasodilation. In women
with no target organ damage, it is reasonable to discontinue antihypertensive therapy in early gestation and monitor closely for rising BP. Medication should be
restarted if BP rises >160/100.

There are no large, randomized controlled trials to help guide decisions about
which antihypertensive medication to use in pregnant women. Head-to-head comparisons on speci c medications are limited, and well-designed trials evaluating
pregnancy outcome and fetal safety are inadequate. Drugs of rst choice in pregnancy are those with an acceptable safety pro le and include labetalol and methyldopa. Methyldopa has been used extensively in pregnancy and long-term safety has
been demonstrated [ 24 ]. However, its side effect pro le often limits dosing that is
adequate to achieve blood pressure control. Labetalol is a nonselective beta-blocker
with vascular alpha-blocking properties and has been postulated to preserve uteroplacental blood ow better than other beta-blockers. It has been found to be both
safe and effective [ 25 28 ] with fewer side effects than methyldopa and has
become
the rst choice for treatment of hypertension in pregnancy.

Alternative beta-blockers include pindolol

and metoprolol. Other beta-blockers,

especially propranolol and atenolol, are best avoided due to individual reports of
M.A. Miller and M. Carpenter183
adverse outcomes such as preterm labor, neonatal bradycardia, and fetal growth
restriction [ 29 ]. Calcium channel blockers are considered a second-line drug for
hypertension
channel

in

pregnancy.

Nifedipine

is

the

most

widely

used

calcium

blocker in pregnancy and is not associated with teratogenic risk [ 30 ]. Data on ef cacy and long-term safety are limited. Amlodipine, used widely in the nonpregnant
population, has not been studied in pregnancy and is best avoided. Hydralazine is
most commonly used as an intravenous treatment of acute severe hypertension in
the setting of preeclampsia. A meta-analysis demonstrated a slightly increased rate
of adverse events with hydralazine compared to
not

labetalol

, but the evidence was

suf cient to make a de nitive recommendation for one drug over the other [ 31 ].
The
use of thiazide diuretics in pregnancy is controversial. Blood volume in pregnancy
increases by 50 %, and while studies have not shown an association between
diuretic
use and adverse pregnancy outcomes [ 3 ], there are data demonstrating that
diuretic
use counteracts this normal expansion of blood volume.

ACE inhibitor use in the rst trimester is associated with an increased risk of
congenital abnormalities [ 32 ]. In addition, fetal renal abnormalities have
been
reported with ACE inhibitor use in the latter half of pregnancy. ARBs, direct renin
inhibitors, while not studied in pregnancy, have a similar mechanism of action, so

may pose similar risk. These drugs are contraindicated in pregnant women
and
should be discontinued in women planning pregnancy [ 32 ]. Table 8.4 presents a
summary of antihypertensive medications in pregnancy.

Preeclampsia
Preeclampsia occurs in about 58 % of all pregnancies and is thought to be the
result of abnormal placentation, leading to poor placental perfusion and release of
factors that cause widespread endothelial dysfunction. It occurs almost exclusively
after 20 weeks gestation (although the underlying pathology likely starts earlier in
pregnancy) and can be life-threatening for both the mother and the baby. Risk factors for preeclampsia are listed in Table 8.5 .

Preeclampsia may affect multiple organ systems and is associated with both signi cant maternal and fetal morbidity and mortality (Table 8.6 ).

Diagnosis
The diagnosis of preeclampsia is made in a woman with new-onset hypertension
and either proteinuria or other end-organ dysfunction after 20 weeks gestation.
Criteria

for diagnosis include:

Systolic blood pressure >140 mmHg OR diastolic blood pressure >90 mmHg.
PLUS
Proteinuria >300 mg in 24-h urine OR protein/creatinine ratio >0.3 mg/dl
or >30 mg/mmol.
OR
Other end-organ dysfunction de ned as platelet <100,000/ml, serum creatinine
> 1.1 mg/dl, or doubling of the baseline creatinine and serum transaminases
twice the normal [ 7 ].

The diagnosis of preeclampsia in women with chronic hypertension or renal disease can be challenging but should be suspected if there is a worsening of blood
pressure or proteinuria in the second half of pregnancy, especially if it occurs
acutely.

In many cases, a woman will meet some but not all of the criteria as outlined

above. It is critically important that clinicians recognize that preeclampsia is a progressive and unpredictable disease. Women who present with some features of preeclampsia need to be frequently monitored to watch for evolving disease. Twice
weekly blood pressure checks and once weekly labs are recommended.

Management of Preeclampsia
Since preeclampsia is a disease of the placenta, it is only with delivery of the placenta that the disorder will start to resolve. Timing of the delivery can be
challenging
as the clinician must weigh the risk of fetal morbidity from preterm delivery with the
risk of both fetal and maternal morbidity in the face of worsening preeclampsia. The
administration of steroids for fetal lung maturity has been associated with improved
perinatal outcomes in women requiring delivery prior to 34 weeks gestation. In addition, treatment with intravenous magnesium is associated with a signi cant reduction in the risk of initial or recurrent eclamptic seizure and should be given to
women
with severe features of preeclampsia in the intrapartum period [ 33 ].

Once a woman has been diagnosed with preeclampsia, the next step is to determine the severity of disease. Severe features of preeclampsia include:

SBP >160 mmHg OR DBP >110 mmHg >20 weeks gestation on at least two

occasions, at least 1 h apart while patient is on bed rest.

Platelets <100,000/ml.

Transaminases elevated to twice the normal, severe persistent RUQ, or

epigastric
pain unresponsive to treatment and no alternate diagnosis.

Serum creatinine > 1.1 or doubling of creatinine.

Pulmonary edema.

New-onset headache or visual disturbances.

Box 8.1 outlines an algorithm for the management of women with preeclampsia,
but with none of these severe features. Box 8.2 presents an algorithm for the management of women with severe features of preeclampsia.
Acute, severe elevations of blood pressure in women with preeclampsia should
be treated as a hypertensive emergency. Severe systolic hypertension is the most
important predictor of cerebral hemorrhage and stroke which is the most common
cause of maternal death in preeclampsia [ 16 ]. Systolic blood pressure greater than

160 mmHg and/or diastolic blood pressure greater than 110 mmHg for more than
15 min requires urgent treatment. Severe hypertension should be stabilized prior to
delivery and/or intubation. The goal of treatment is to achieve a systolic blood pressure between 140 and 160 and diastolic blood pressure between 90 and 100 mmHg.
First-line medications for the treatment of acute severe hypertension to a maximum
of 300 mg per day. YTC in pregnancy include intravenous labetalol and hydralazine
(see Table 8.7 ). Rapid successive doses of either of these drugs should be administered followed by the second drug if BP goals are still not achieved. Labetalol is
initiated at 20 mg IV over 2 min, and the dose should be doubled every 10 min up
to 80 mg IV if BP goal is not achieved to a maximum of 300 mg per day. Hydralazine
can be started at either 5 or 10 mg IV over 2 min with a second 10 mg dose given
after 20 min if BP goals are still not achieved. If both of these medications fail to
improve blood pressure, emergent consultation with obstetric medicine, maternal
fetal medicine, or critical care specialist is recommended. Sodium nitroprusside is
reserved for extreme emergencies as it may be associated with fetal thiocyanate

toxicity. Magnesium sulfate is used for seizure prophylaxis, and is not an effective
antihypertensive medication.

Postpartum
Postpartum hypertension may occur as a result of preexisting chronic hypertension,
persistent gestational hypertension, or preeclampsia which can continue into or
occur
de novo in the postpartum period [ 34 , 35 ]. For women with hypertension during
pregnancy, blood pressure is expected to peak at about 36 days postpartum [ 36 ].
Resolution
of hypertension is unpredictable and may occur in just a few days or may take as
long
as 6 months.
important.

Therefore,

close

monitoring

of

the

postpartum

woman

is

Factors that may contribute to persistent or even new-onset hypertension in the

postpartum period include uids, NSAIDs, and other vasoconstricting medications such
as
ergots that may be given for uterine atony. Women presenting with new-onset
hypertension should be screened for preeclampsia. If other symptoms are present such as
tachycardia, shortness of breath, headache, or neurologic ndings, secondary
causes
of hypertension such as pheochromocytoma, peripartum cardiomyopathy, or stroke
should be ruled out. The approach to treatment of hypertension in the postpartum
period is much the same as during pregnancy. Severe hypertension should be
treated
urgently and aggressively. Both labetalol and nifedipine are effective medications
and

may be used safely in breastfeeding. Nifedipine, compared to labetalol, has

been
shown to improve renal blood ow leading to improved diuresis and is the drug of
choice in women with volume overload [ 35 ,
safe in

37 ]. ACE inhibitors are also

breastfeeding and may be used in postpartum women [ 36 ].

The risk of recurrence of preeclampsia in subsequent pregnancies varies with the
severity and the time of onset of the initial episode. Women diagnosed with earlyonset preeclampsia (prior to 32 weeks) have a risk as high as 2565 % of recurrence
in a subsequent pregnancy. Women who had non-severe preeclampsia have a much
lower risk (57 %) [ 38 , 39 ].

Prevention
The majority
healthy

of

women

with

chronic

hypertension

will

have

normal,

pregnancy. Preconception evaluation is important to address blood pressure control

and choice of antihypertensive medication prior to pregnancy. Much research has
focused on the prevention of preeclampsia, but, to date, no effective interventions
to
prevent preeclampsia have been clearly established.

Smaller, older studies found that low-dose aspirin was associated with a reduced
risk of preeclampsia, but a larger RCT did not nd this same effect [ 40 ]. A recent
metaanalysis concluded that low-dose aspirin is not bene cial in low-risk women but
may
be effective in high-risk women in reducing the risk of preeclampsia [ 41 ].
Therefore,

it is reasonable to recommend low-dose aspirin (81100 mg daily) to women with

risk
factors for preeclampsia (most commonly women <18 years old, with multiple pregnancy, preexisting
preeclampsia).

hypertension,

renal

disease,

diabetes,

or

previous

Calcium supplementation of at least 1 g/day has been associated with a reduced

risk of preeclampsia in women with poor dietary calcium intake [ 42 ].

Conclusive studies have found that antioxidants such as vitamin C and vitamin E
do not reduce the risk of preeclampsia and should not be recommended [ 43 45 ].
Control of blood pressure is also not associated with a reduction in the risk of
preeclampsia, so antihypertensive therapy cannot be recommended solely for preeclampsia prevention.

There is insuf cient evidence to make a recommendation about the usefulness of

a heart healthy diet and exercise to reduce the risk of preeclampsia, but since these
interventions are associated with many other positive health outcomes, it is always
worthwhile to recommend.

Early data suggests that exercise may be effective in preventing preeclampsia;

however, further studies are needed to con rm these ndings [ 46 ,
Preeclampsia
is more common
recommend

in

obese

women,

so

it

is

certainly

47 ].

reasonable

lifestyle changes to achieve a healthy weight prior to conception.

Long-Term Risk
Women who develop gestational hypertension or preeclampsia have an increased

to

risk of hypertension, stroke, and cardiovascular disease later in life. Numerous epidemiologic studies have shown that women with a history of preeclampsia have
approximately twice the risk of ischemic heart disease [ 48 , 49 ]. In women with
preeclampsia with premature delivery or low birth weight baby, the relative risk
may be as high as eight to ninefold [ 50 52 ]. In their 2011 guidelines for the
prevention of cardiovascular disease in women, the American Heart Association sites preeclampsia as an important risk factor for women [ 15 ]. Therefore, women with a
history of preeclampsia should be counseled postpartum about the importance of
lifestyle modi cations, adequate BP control, and control of metabolic factors to
prevent cardiovascular disease [ 53 ].
Even in the absence of gestational diabetes, both gestational hypertension and
preeclampsia have been associated with a twofold increased risk of diabetes later in
life. In women with GDM, the diagnosis of either gestational hypertension or preeclampsia increases the risk of future diabetes from a 13-fold increased risk
to
1618-fold [ 50 , 54 , 55 ]. Preeclampsia has been associated with an increased risk
of
end-stage renal disease in later life, but the absolute risk is small [ 56 ].

Summary
Chronic hypertension in pregnancy is associated with both acute and long-term
adverse
maternal and fetal outcomes. Women with severe hypertension or advanced
disease
with end-organ damage are at a higher risk. Poor
common in

outcomes are more

women with severe hypertension or advanced disease with end-organ damage or

those

who develop
threatening

superimposed

preeclampsia.

Preeclampsia

is

potentially

to both mother and baby, and early recognition is critical to improved outcomes.

life-