DISEASE OF THE MONTH

Hypertension in Pregnancy

MARK S. PALLERUniversity of Minnesota, Minneapolis, Minnesota.

Notwithstanding its obvious benefits, pregnancy will remain a

risky business as we enter the next millennium ( 1 ). No doubt,

many of the historically significant adverse outcomes of preg-

nancy have been eliminated by modern medical care. For

example, acute renal failure occurring in pregnancy as a con-

sequence of septic abortion, abruptio pbacentae, and even pre-

eclampsia, has almost disappeared as a clinical entity. Never-

thebess, maternal death complicates childbirth in approximately

nine of I 00,000 deliveries. The three leading causes of mater-

nal death are pregnancy-induced hypertension, hemorrhage,

and pulmonary embolism. Hypertension complicates an esti-

mated 6 to 8% of all pregnancies. More importantly, hyper-

tension is responsible for approximately 15% of maternal

deaths. In addition, almost one-quarter of pregnant women

require hospitalization for complications before delivery, rep-

resenting a substantial health care burden. For the nephrobogist,

the impact of pregnancy on preexistent renal disease or chronic

hypertension will be encountered more often than new cases of

renal disease developing de novo during pregnancy. However,

pregnancy is often the first sustained contact between young

women and the health care system. Therefore, asymptomatic

renal disease or hypertension may be recognized initially dur-

ing a pregnancy.

Hypertension in PregnancyHypertension may be classified as chronic if it is recognized

before 20 weeks of gestation or as pregnancy-induced if it

occurs only in the second half of pregnancy. This separation is

clinically useful because almost all hypertension occurring in

the first half of pregnancy is a result of underlying chronic

hypertension (essential hypertension or secondary hyperten-

sion due to hyperaldosteronism or pheochromocytoma) or re-

nab disease. Hypertension developing in the second half of

pregnancy is more complex and is the result of either a preg-

nancy-specific process or a complex interplay of pregnancy

with renal disease or chronic hypertension resulting in exacer-

bation of hypertension.

Normal pregnancy is characterized by a decrease in periph-

eral vascular resistance and, to a lesser extent, a decrease in

blood pressure, which occur soon after conception. This de-

crease in vascular resistance is due to increased synthesis of

vasodilatory prostaglandins, particularly prostacyclin. and en-

Correspondence to Dr. Mark S. Paller. University of Minnesota. 420 DelawareStreet SE., Box 736. Minneapolis, MN 55455.

l()46-6673/0902-03 14$03.00/()

Journal of the American Society of Nephrology

Copyright tO 1998 by the American Society of Nephrology

dothelial-derived nitric oxide. These vasodilators also engen-

der resistance to circulating vasoconstrictors such as angioten-

sin II and norepinephrine, and to locally produced

vasoconstrictors such as endothelin. After an initial decrease in

blood pressure to average values of I 03 ± 1 1 mmHg systolic

and 56 ± 10 mmHg diastolic in the first trimester, blood

pressure begins to increase slightly after the 28th week of

gestation. Although 140/90 mmHg is a convenient criterion for

epidemiologic studies, perinatal mortality increases for each

increment in blood pressure, particularly when diastolic blood

pressure exceeds 85 mmHg. Similarly, perinatal mortality in-

creases when mean arterial pressure is greater than 82 mmHg

at mid-pregnancy or greater than 92 mmHg at the beginning of

the third trimester. Because a blood pressure of 1 20/80 mmHg

represents a mean arterial pressure of 93 mmHg, it is apparent

that blood pressure values during pregnancy must be inter-

preted differently than values in the nonpregnant state. Previ-

ously, the American College of Obstetrics and Gynecology

considered a pregnancy-related increase in systolic blood pres-

sure of 30 mmHg or pregnancy-related increase in diastolic

blood pressure of 15 mmHg as also representing hypertension

in pregnancy. These criteria have been abandoned because of

the considerable variability of blood pressure in normotensive

women.

Endothelial Cell Injury and Pregnancy-RelatedDiseases

A variety of diseases of relevance to the nephrologist whose

manifestations include consequences of diffuse endothelial cell

injury occur during pregnancy. Postpartum acute renal failure,

also known as postpartum hemolytic uremic syndrome, is one

such condition. This disease, characterized by hypertension

and coagulation abnormalities, including microangiopathic he-

molytic anemia, occurs 1 or 2 days to several months after

delivery. Its major manifestation is thrombotic microangio-

pathic acute renal failure. Postpartum acute renal failure has

many similarities to thrombotic thrombocytopenic purpura and

hemolytic uremic syndrome. Of great interest, preeclampsia,

the HELLP syndrome (hemolysis, elevated liver enzymes, low

platelets), and acute fatty liver of pregnancy also have features

consistent with endothelial injury. This suggests the possibility

of a continuum of disease resulting from endothelial cell injury

during pregnancy, perhaps initiated through distinct pathways.

Why the endothelium should be so susceptible to injury during

pregnancy remains unclear. A form of hemolytic uremic syn-

drome similar to postpartum acute renal failure occurs in

women receiving oral contraceptives. This finding suggests a

hormonal etiology for the endothelial susceptibility to injury.

Pregnancy: A Risky Business

The Shwartzman reaction that occurs after admission of endo-

toxin to experimental animals is enhanced when animals are

pregnant. A possible explanation for that phenomenon is an

impaired capacity of endothelial cells to synthesize nitric oxide

during pregnancy. Impaired endothelial synthesis of nitric ox-

ide and prostacyclin then predisposes to vasoconstriction and

coagulation.

PreeclampsiaPreeclampsia, a life-threatening illness specific to preg-

nancy, is poorly understood. Major manifestations of pre-

eclampsia include hypertension, edema, proteinuria, and sei-

zures. The disease is termed eclampsia when seizures occur,

but this distinction is not important because death due to

cerebral hemorrhage or cardiac failure can occur in the absence

of seizures. Preeclampsia is a fascinating disease because of its

association with first pregnancies and complicated pregnan-

cies. Depending on the population surveyed, preeclampsia

complicates between 5 and 22% of pregnancies. In addition to

nulliparity, other risk factors for the development of pre-

eclampsia include age greater than 40 years (advanced in terms

of reproductive age), familial history of pregnancy-induced

pregnancy hypertension, smoking, obesity, and diabetes mel-

litus. Pregnancies complicated by fetal hydrops. multiple ges-

tation, preexisting hypertension. antiphospholipid syndrome,

renal disease, and vascular disease are also at increased risk of

preeclampsia (Table 1 ). The relative risk of preeclampsia de-

veloping in women with chronic renal disease is 20 to 1 . and

the risk of preeclampsia developing in women with essential

hypertension is 10 to I . In these instances, preeclampsia affects

multiparous, as well as nulliparous, women. Moreover, pre-

eclampsia complicating these conditions may develop earlier

than 32 weeks of gestation, whereas “usual” preeclampsia

affecting nulliparous women develops in the third trimester

(usually after 32 weeks of gestation). One should be alert to the

possibility that preeclampsia occasionally presents as late as 48

hours postpartum.

The clinical manifestations of preeclampsia support the con-

tention that this is a systemic disease. Hypertension is the most

prominent feature of preeclampsia and may be severe. Hyper-

Table 1. Risk factors for the development of preeclampsia

Nulliparity

Age greater than 40 years (advanced age in reproductive

terms)

Familial history of pregnancy-induced pregnancy

hypertension

Obesity

Diabetes mellitus

Fetal hydrops

Multiple gestation

Hypertension

Renal disease

Antiphospholipid syndrome

Vascular disease

tension is caused by an increase in peripheral vascular resis-

tance and is associated with overactivity of the sympathetic

nervous system. Abnormalities in peripheral vascular reactivity

can be demonstrated before the development of overt hyper-

tension. Ordinarily in pregnancy there is a shift in production

of vasoactive substances by the endothelium, favoring vasodi-

bation. This increase in production of prostacyclin and nitric

oxide causes pregnant women to be less sensitive to the pressor

effects of substances such as angiotensin II. In women destined

to become preeclamptic in the third trimester. loss of this usual

resistance to the pressor effects of infused angiotensin II can be

demonstrated in mid-pregnancy when blood pressure is still

normal.

Vasoconstriction in preeclampsia may also cause a decrease

in cardiac output and a decrease in renal blood flow and GFR.

This decrease in renal blood flow is responsible for a rise in

plasma uric acid, which usually occurs in advance of any

changes in serum creatinine. Decreased urate clearance result-

ing in hyperuricemia is a useful clinical finding that can serve

to differentiate preeclampsia from other causes of hypertension

that may occur during pregnancy. Because of plasma volume

expansion that occurs during normal pregnancy, serum uric

acid bevels are between 2.5 and 4 mg/dl in pregnancy. A serum

uric acid level greater than 5.5 mg/dl is consistent with pre-

eclampsia. and values exceeding 6.0 mg/dl suggest more seri-

ous disease. Other manifestations of preeclampsia affecting the

kidney include proteinuria, increased serum creatinine, and in

severe preecbampsia oliguria. Although pregnancy causes a

small increase in the fractional excretion of albumin, 24-hour

urinary excretion of protein should not exceed 250 rng. Protein

excretion in excess of this amount suggests either renal disease

or preecbampsia (Table 2).

Women with preeclarnpsia have symptoms that include ap-

prehension: vision problems: and headache and epigastric dis-

comfort related to neurologic and hepatic involvement, respec-

tively. Findings on physical examination in addition to

hypertension include segmental arteriolar narrowing on fundu-

scopic examination and rales and other physical findings con-

sistent with congestive heart failure. Signs of central nervous

system irritability include hyperactive deep tendon reflexes and

generalized seizures. Although peripheral edema at one time

was considered a requirement for the diagnosis of preeclamp-

sia, this finding has little predictive value. Up to 83% of

healthy. pregnant women develop localized edema at some

time during pregnancy. As many as 10% of pregnant women

develop generalized edema without other indications of dis-

ease. Therefore, edema does not predictably differentiate pre-

eclampsia from uncomplicated pregnancy or from pregnancy

complicated by chronic hypertension or renal disease.

Laboratory findings in preecbampsia, in addition to the ele-

vations in serum uric acid and creatinine discussed above,

include indicators of a microangiopathic hemolytic anemia.

These include fragmented red cells on peripheral smear, in-

creased lactate dehydrogenase, and thrombocytopenia. Hepa-

tocellular dysfunction can be recognized by an elevation in

liver enzymes. The HELLP syndrome (/iemolysis, elevated

liver enzymes, low platelets) is a clinical syndrome that rep-

3 16 Journal of the American Society of Nephrology

Table 2. Clinical features of hypertensive disorders in pregnancya

FeatureEssential Hypertension Renal Disease Preeclampsia

1st Half 2nd Half 1st Half 2nd Half 1st Half 2nd Half

Hypertension

Proteinuria

+1-

-

+

-

+1-

+

+

+

-

-

+

+

Microscopic

hematuria

- - +1- +1- - -

Increased - - +1- +1- - +1-

creatinine (>1.0

mg/dl)

Increased uric - - - - - +

acid (>4 mg/dl)

Coagulation

abnormalities

- - - - - +/-

a Women with essential hypertension or renal disease are at increased risk of developing superimposed preeclampsia with all of the

associated findings. - . usually absent: +, usually present: +/-. may be present.

resents one form of severe preeclampsia and occurs in 2 to I 2%

of cases of preeclampsia. As the severity of preeclampsia

increases, manifestations of endothelial cell injury are more

obvious. Thus, hypertension is more severe and coagubopathy

and liver function abnormalities are more prominent.

TherapyPrevention

The history of studies of prophylactic treatments for pre-

eclampsia is an engaging one. Initial small-scale, randomized,

controlled trials and meta-analyses of these trials were quite

promising. However. large-scale, randomized, controlled trials

have suggested either a more limited role for preventive ther-

apies (in the case of low-dose aspirin) or none at all (oral

calcium supplementation). Pregnancy trials have aptly demon-

strated the limitations of conclusions based on meta-analyses.

Low-dose aspirin was initially suggested to be an ideal

preventive treatment for preeclampsia predicated on the current

understanding of the pathophysiobogy of the disease. With

regard to prostaglandin production. preeclampsia is character-

ized by a shift away from the vasodilated state of normal

pregnancy. Therefore, in preeclampsia there is less production

of prostacyclin and prostaglandin E and greater production of

thromboxane compared with normal pregnancy, at least as

estimated from circulating levels of these vasoactive prosta-

glandins. It was reasoned that low-dose aspirin would reduce

platelet-derived production of thromboxane while not interfer-

ing with endothebial synthesis of prostacyclin and prostaglan-

din E. The net effect of low-dose aspirin therapy would be to

restore vascular tone toward a more vasodilated condition.

The earliest studies of low-dose aspirin to prevent pre-

eclampsia evaluated women with an increased risk of devel-

oping the disease. For example, in the 1989 study of Schiff et

al. women were selected for study by the presence of a positive

rollover test, a test that suggests increased sensitivity to angio-

tensin II and therefore a high risk of developing preeclampsia

(2). Other early studies were performed in cohorts at high risk

of developing preeclampsia because of a history of intrauterine

growth retardation, previous pregnancies with preeclampsia, or

the presence of chronic hypertension (3,4). These studies in-

dividually and a meta-analysis combining them suggested that

low-dose aspirin in women at risk for pregnancy-induced hy-

pertension reduced the occurrence of preeclampsia and severe

intrauterine growth retardation (5).

Subsequent, randomized, prospective trials evaluated much

larger numbers of women and those at low or minimal risk of

developing preeclampsia. For example, the 1993 study by Sibai

et al. evaluated 3 1 35 women in their first pregnancy but

without other risk factors for the development of preeclampsia

(6). That study showed that overall, low-dose aspirin had a

small but significant effect in reducing the incidence of pre-

eclampsia. A subgroup analysis showed that women whose

initial systolic blood pressure was greater than 120 mmHg had

a more dramatic reduction in the incidence of preeclampsia of

53%. The CLASP study of 9364 women found no significant

reduction in the incidence of preeclampsia in women who were

treated with 60 mg of aspirin beginning between the 12th and

32nd weeks ofgestation (7). The ECPPA study of 1009 women

in Brazil used a similar protocol and found no benefit of

low-dose aspirin to prevent preeclampsia (8).

Several trends show why the initial enthusiasm for low-dose

aspirin has waned. The earliest studies of low-dose aspirin

were used in women at moderate-to-high risk of developing

preeclampsia. In general, these studies used doses of aspirin

greater than 60 mg per day (75 to I 50 mg daily), and aspirin

therapy was initiated before 20 weeks of gestation. More recent

studies used lower doses of aspirin, enrolled women at lower

risk for preeclampsia, and initiated therapy as late as 32 weeks

of gestation. Currently, several large-scale trials are under way

that will evaluate the use of low-dose aspirin in women at high

risk of developing preeclampsia. Until these studies are com-

pleted. the following seems to be a conservative recommenda-

tion for the use of aspirin. Women at the highest risk of

developing preeclampsia can be treated with low-dose aspirin

Pregnancy: A Risky Business 317

in the hope of preventing preeclampsia using doses �100 mg

daily. The safety of low-dose aspirin in these women is no

longer contested. Several of the recent large-scale trials eval-

uated safety very carefully and found no increased incidence of

bleeding, abruptio placentae, or other adverse effects, contrary

to anecdotal reports from earlier small studies (9,10). Because

high-risk women may develop early-onset preeclampsia (be-

fore 30 weeks gestation) if low-dose aspirin is used, it should

be initiated between 10 and 14 weeks of gestation. Women

considered at high risk for preeclampsia include those who

have chronic renal disease, particularly with hypertension,

proteinuria, or renal insufficiency, as well as women who have

a history of previous multiple pregnancies complicated by

intrauterine growth retardation or preeclampsia.

Calcium supplementation for prophylaxis of preeclampsia

has a similar history of diminished expectations. Original stud-

ies suggested that 2 grams of elemental calcium daily would

reduce the incidence of preeclampsia. In 1991, Belizan et al.

reported beneficial effects of calcium in 1 194 nulliparous

women (1 1). Calcium was administered beginning the 20th

week of pregnancy. Several additional small-scale studies, as

well as a meta-analysis combining all studies performed before

May 1994, suggested that calcium supplementation reduced

the risk of preeclampsia by 62% (12). Unfortunately, the most

recent large-scale trial of calcium supplementation in 4589

nulliparous women reported by Levine et al. revealed no

beneficial effects of calcium (13). Again, these findings seem

most secure for women at low risk of developing preeclampsia.

It is possible that previous small studies performed at a single

center had evaluated women at moderate or high risk for the

development of preeclampsia. In the absence of clues as to

which women should receive calcium supplementation, cal-

cium cannot be recommended for prophylaxis of preeclampsia

at this time.

Management

The time-tested, definitive treatment for preeclampsia is

delivery. For women at term, this does not represent a major

problem. When preeclampsia occurs between the 32nd and

34th weeks of gestation, obstetricians have some flexibility.

Because long-term fetal outcome is likely to be good, delivery

still remains a feasible option. However, if preeclampsia is not

severe, conservative therapy consisting of bed rest and antihy-

pertensive therapy can be undertaken. Fetal outcome is less

well guaranteed at 28 to 34 weeks of gestation. If preeclampsia

occurs at this time, it is reasonable to attempt medical man-

agement. It must be noted that experience with such an ap-

proach is limited. Conservative management between 1 8 and

28 weeks of gestation has been debated, with some studies

suggesting termination of pregnancy at the expense of the life

of the fetus to prevent maternal morbidity and others suggest-

ing that an initial attempt at conservative management will

occasionally result in prolongation of pregnancy with an ulti-

mately acceptable outcome. Most would agree that pregnancy

should be terminated if preeclampsia develops before the 18th

week of gestation.

Hypertension complicating pregnancy represents a risk for

both the mother and the fetus, both of whom must be consid-

ered when selecting therapy. Hypertension should be treated to

prevent maternal morbidity and mortality due to causes such as

cerebral hemorrhage. The effect of antihypertensive therapy on

fetal outcome is less clear, and there is considerable debate as

to how aggressively blood pressure should be treated. Arguing

against aggressive antihypertensive therapy is the fear that

uteroplacental blood flow will be compromised if maternal

blood pressure falls too quickly because of a limited ability of

the placenta to autoregulate blood flow. Diastolic blood pres-

sure goals have ranged from 90 to 1 10 mmHg, denoting the

lack of unanimity of opinion. The number and size of prospec-

live, randomized, controlled trials of antihypertensive therapy

for women who develop hypertension in the third trimester are

actually quite limited. Most studies do suggest that fetal mor-

bidity and mortality can be reduced when treatment is provided

for diastolic blood pressures >90 mmHg. The outcomes that

can be expected by treating hypertension in the third trimester

include reduction in the incidence of prematurity, intrauterine

growth retardation, and perinatal death. For example, Phippard

et al. aggressively treated pregnancy-induced hypertension in

women with previously normal blood pressure whose mean

blood pressure rose to 1 26/82 mmHg with either clonidine (and

hydralazine if needed) or placebo ( 14). Antihypertensive ther-

apy reduced third trimester complications and prematurity by

80%. Those studies that have demonstrated improved fetal

outcome have instituted antihypertensive therapy in the second

or third trimester of pregnancy. Results may not be comparable

when antihypertensive therapy is begun in the first trimester

(see below).

Treatment of mild hypertension (diastolic blood pressure

<95 mmHg) usually commences with bed rest. One needs to

ascertain that there is no evidence of serious disease such as

proteinuria (>500 mg/24 h), renal function impairment (cre-

atinine > 1 .0 mg/dl), or hyperuricemia. Development of these

or other complications is an indication for delivery, especially

when pregnancy is at or beyond 32 weeks of gestation. Mod-

erate hypertension (diastolic blood pressure 95 to I 00 mmHg)

should lead to the use of any one of several suitable antihy-

pertensive agents if delivery is not desirable because of pre-

maturity (Table 3).

Methyldopa has been used extensively in pregnancy and is

often the agent of first choice. Although this agent has been

largely abandoned for general use in essential hypertension

because of the side effects of orthostatic hypotension and

fatigue, methyldopa is both safe and effective in pregnancy. In

a trial of methyldopa versus placebo to treat hypertension in

pregnancy by Redman et al. , methyldopa effectively controlled

blood pressure (15). Methyldopa therapy also yielded better

fetal outcome (fewer mid-pregnancy abortions), but had no

effect in preventing preeclampsia. An initial concern was that

infants born to mothers who had received methyldopa had

smaller head circumference for gestational age. When these

infants were evaluated at 1 year, all head sizes were normal

( 1 6). More importantly, infants born to women who had re-

ceived placebo scored worse on the Denver Developmental

Screening Test than did infants whose mothers received active

3 18 Journal of the American Society of Nephrology

Table 3. Antihypertensive agents in pregnancy

First choice

methyldopa

atenobol, metoprobol

labetabol

hydralazine

hydrochborothiazidea

Also useful

cbonidine

nifedipine

isradipine

prazosi n

Contraindicated

angiotensin-converti ng enzyme inhibitors

angiotensin receptor blockers

Parenteral agents for severe hypertension

hydralazine

labetalol

magnesium sulfate

sodium nitroprussidea

a See text for specific guidelines.

therapy (methyldopa). These infants were evaluated again at 4

years of age ( I 7). In developmental tests. the mean score for

treated children was consistently higher than for children

whose mothers received placebo. The authors suggested that

maternal hypertension is associated with mild developmental

delays in early childhood and that methyldopa reduced this

adverse effect of hypertension in pregnancy. Other studies

have not so intensively evaluated long-term fetal outcome, but

have focused on maternal and fetal health during and imme-

diately after pregnancy.

Beta-adrenergic blockers are useful alternatives to methyl-

dopa. Atenobol and metoprolol are the beta-blockers for which

there is the largest body of experience and the greatest enthu-

siasm for use in pregnancy. The combined alpha- and beta-

blocker labetabol has also been used frequently. Despite con-

cerns about beta-blocker-induced fetal bradycardia, this

complication has not been detected in most studies. Several

studies using beta-blockers have noted decreases in birth

weight compared with infants whose mothers received pla-

cebo. An equal number of studies have failed to find any effect

of beta-blockers on fetal development. Rubin and colleagues

showed that atenobol reduced perinatal mortality when used to

treat hypertension that developed in the third trimester ( 1 8). On

the other hand, this same group found that atenolol was asso-

ciated with intrauterine growth retardation (lower birth weights

and lower placental weights) when initiated at the end of the

first trimester in women with chronic hypertension ( I 9). From

these studies, it is difficult to know whether the differences in

outcome are related solely to the timing of antihypertensive use

( 1 st versus 3rd trimester) or whether the nature and chronicity

of the hypertension explain these divergent results. Because of

this uncertainty. physicians treating hypertensive women have

often proceeded cautiously in the application of antihyperten-

sive drugs.

Centrally acting adrenergic agents such as clonidine, the

alpha-adrenergic antagonist prazosin. and dihydropyridine cab-

cium-channel blockers such as nifedipine have also been suc-

cessfully used to treat moderate hypertension in pregnancy.

Phenylalkylamine and benzothiazepine calcium-channel

blockers (verapamil and diltiazern), unlike dihydropyridines,

may slow labor and should be avoided in the immediate prepar-

turn period. For more severe hypertension. combinations of

agents can be used. For example, hydralazine. which also has

a long history of safe use in pregnancy, can be added to any of

these agents.

Diuretics are adjuncts in the treatment of preeclampsia be-

cause the fundamental pathophysiologic abnormality is not

sodium retention but vasoconstriction. At one time, thiazides

were administered prophylactically to prevent preeclampsia. A

nieta-analysis suggested that thiazide diuretics were effective

for this purpose. but this practice has been appropriately aban-

doned because the effect was small and fears of causing vol-

ume depletion in vasoconstricted women were great (20).

Nevertheless, that experience suggests that thiazides can be

used safely during pregnancy when volume excess is present or

when combination antihypertensive therapy is required.

When preeclampsia is severe, renal sodium retention does

develop as a result of impaired renal blood flow and decreased

GFR. In these women, edema becomes more problematic and

pulmonary edema can become a life-threatening complication.

In preecbampsia, pulmonary capillary wedge pressure is ele-

vated in approximately one-third of the women studied. The

majority of women with pulmonary edema have elevated pul-

monary capillary wedge pressure. Therefore, it is appropriate

to use diuretics in patients who have symptoms of congestive

heart failure or volume excess.

Severe hypertension (diastolic blood pressure > 100 mmHg)

requires urgent treatment. Of the parenteral antihypertensive

agents available, hydralazine and labetalol are most frequently

used. Hydralazine has reflux tachycardia as a major side effect,

which may limit its effectiveness: addition of a beta-blocker

reduces the severity of this problem. Oral nifedipine has been

successfully used when parenterab agents were not convenient.

The most severe hypertension can be treated with sodium

nitroprusside infusion if delivery is imminent. Sodium nitro-

prusside will effectively lower blood pressure and can be

accurately titrated. Because of the risk of fetal cyanide toxicity,

sodium nitroprusside is reserved for hypertensive emergencies

and is used for less than a few hours. Magnesium sulfate has

weak antihypertensive effects that are of benefit in severe

preeclampsia. More importantly, magnesium sulfate prevents

seizures in preeclamptic women and has been found to be

superior to phenytoin for that purpose. As alternatives for

seizure prevention and treatment, phenytoin and diazepam can

be used. Because hypermagnesemia results in respiratory pa-

ralysis, magnesium sulfate must be administered carefully. The

dose of continuous infusions must be reduced in women with

impaired renal function. Muscular and respiratory paralysis is

treated with intravenous calcium.

Pregnancy: A Risky Business 319

Outcome

Preeclampsia is associated with an increase in perinatal

morbidity and mortality. A major feature of preeclampsia is

decreased uteroplacental blood flow because of vasoconstric-

tion. Pathologic changes are most apparent in the spiral arteries

of the placenta, a consequence of impaired prostaglandin pro-

duction by trophoblasts. Impaired uteroplacental perfusion

leads to intrauterine growth retardation. Fetuses are also at risk

in preeclampsia because of an increased incidence of abruptio

placenta.

Women who develop preeclampsia in a first pregnancy but

who are normotensive in subsequent pregnancies have no

long-term morbidity or mortality related to the initial episode

of preeclampsia. Epidemiologic studies have found that these

women have no increased prevalence of hypertension and have

a normal life expectancy. In marked contrast, women who

develop preeclampsia in a second pregnancy or in multiple

pregnancies have an increased prevalence of hypertension and

greater mortality than age-matched control subjects. When

women with multiple episodes of preeclampsia were evaluated

20 to 40 years after their initial pregnancy, the prevalence of

hypertension was approximately twice that of the control pop-

ulation. Hypertension is believed to be the cause of the excess

vascular disease and premature death in such women. This

observation is consistent with our current understanding of

preeclampsia. “Idiopathic” or “primary” preeclampsia is a dis-

ease that occurs in nulliparous women. Major risk factors for

recurrent or “secondary” preeclampsia are chronic hyperten-

sion, renal disease, and diabetes. These diseases persist long

after pregnancy has ended, and their associated morbidity and

mortality accrues. When preeclampsia occurs in the first half of

pregnancy, it is more likely to be secondary to one of these

diseases (21,22). For such women, there are long-term health

risks. Women who develop preeclampsia late in a first preg-

nancy and who have no evidence of hypertension or renal

disease between and during subsequent pregnancies can be

reassured of a favorable long-term outcome.

Hypertension Complicating Renal DiseaseDiagnosis

Renal disease is one manifestation of preeclampsia. On the

other hand, renal disease predisposes to the development of

superimposed preeclampsia. This distinction is made more

difficult if a woman has not been evaluated before pregnancy

or early in gestation. Even subtle renal disease may predispose

to the development of preeclampsia. For example, women with

a history of reflux during childhood but with normal renal

function have an increased incidence of preeclampsia and

perinatal complications. Urinary abnormalities in the first tn-

mester should suggest underlying renal disease. Although the

fractional excretion of albumin increases during pregnancy,

protein excretion is usually not greater than 250 mg/24 h.

Protein excretion in excess of this amount can be caused by

either intrinsic renal disease or preeclampsia. Hematunia is not

a usual finding in preeclampsia and suggests glomerubonephri-

tis. Table 2 outlines those findings that help to differentiate

preeclampsia from chronic hypertension or hypertension asso-

ciated with renal disease.

Pregnancy Outcome

Fetal loss, intrauterine growth retardation, and prematurity

are the major fetal consequences of maternal renal disease. The

most important risk factor for these undesirable fetal outcomes

is hypertension, although renal insufficiency and high-grade

proteinunia also portend a less favorable outcome. With severe

hypertension (> 175/1 10 mmHg). fetal loss rates greater than

60% have been reported. The risk of developing superimposed

preeclampsia during pregnancy in women with renal disease

varies between 20 and 40%. For this reason, it seems reason-

able to begin low-dose aspirin early in pregnancy in women

with renal disease in expectation of preventing preeclampsia.

Renal Outcome: Testing the Hvpeifiltration Hypothesis

Pregnancy is a potential test of the hyperfiltration hypothe-

sis, originally articulated by Hostetter, Brenner, and col-

leagues, proposing that an increase in glomerular capillary

hydrostatic pressure is a central factor in the inexorable pro-

gression of chronic renal diseases. Pregnancy might be partic-

ularly risky in this regard because renal vasodilation is char-

actenistic of pregnancy. In the presence of systemic

hypertension, a greater portion of systemic blood pressure

would be transmitted into the glomerulus, potentially exacer-

bating injury. To test this hypothesis, one would first need to

ascertain whether pregnancy results in an irreversible detenio-

ration in renal function in women with chronic renal insuffi-

ciency. Although the general answer to that question is yes

with the following provisos, it has not been possible to study

mechanisms of injury in women. Pregnant rats have been

studied, but may not be a suitable model for the human expe-

nience. For example, the spontaneously hypertensive rat does

not develop the expected afferent arteriolar vasodilatation of

pregnancy, does not experience the usual pregnancy-induced

increase in GFR, and also does not develop increased intraglo-

merular pressure during pregnancy or progressive renal failure.

On the other hand, in experimental gbomerulonephnitis pro-

duced by injecting rats with Adriamycin, systemic hyperten-

sion did exacerbate proteinuria. possibly indicating irreversible

renal injury.

Women with renal disease who have normal GFR, normal

blood pressure, and no proteinunia do not suffer renal impair-

ment during pregnancy. In contrast, approximately one-third of

women who have renal insufficiency when they become preg-

nant suffer an irreversible, accelerated deterioration in renal

function (23,24). Hypertension has often been found to be an

additional risk factor for this deterioration during pregnancy.

The hyperfiltration hypothesis has not been fully tested, how-

ever, because there has been no adequate demonstration (or

lack thereof) that aggressively treating hypertension to prevent

intraglomerular hypertension necessarily prevents irreversible

deterioration of renal function during pregnancy in these high-

risk women.

320 Journal of the American Society of Nephrology

Management

Current practice is to continue antihypertensive therapy

when pregnancy develops, but the exact goal for blood pres-

sure control has not been established. Too low maternal blood

pressure potentially puts the fetus at risk, whereas too high

blood pressure endangers both mother and child. As noted

above, there is a wide range of antihypertensive agents that can

be safely used during pregnancy. An important exception to the

rule of continuing current therapy when pregnancy develops is

the use of angiotensin-converting enzyme inhibitors (ACEI).

ACE! have been associated with increased fetal loss in exper-

imental animals and with fetal renal tubular dysplasia, perinatal

acute renal failure, and other congenital anomalies. The moth-

ers of these unfortunate infants have all consumed ACE! in the

second or third trimester of pregnancy, or both. A recent

post-marketing survey of ACE! in the United States, Canada,

and Israel revealed no adverse fetal outcomes because of use of

ACE! in the first trimester only (25). Therefore, when women

receiving ACE! become pregnant, they should be switched to

other antihypertensive agents. However, when exposure is

limited to the first trimester, it does not appear necessary to

intentionally terminate the pregnancy. One must assume that

angiotensin I! receptor blockers are similarly contraindicated

for use during pregnancy. Angiotensin type 2 (AT2) receptors

are involved in development of the fetal kidney. It is not clear

whether blocking only type 1 receptors (AT,) would also put

the fetus at risk, but with the large number of acceptable

alternatives these agents should not be used.

Chronic HypertensionEssential Hypertension

Essential hypertension is a major risk factor for the devel-

opment of superimposed preeclampsia. Some women with

essential hypertension fail to have the decrease in blood pres-

sure that is a manifestation of vasodilatation in early preg-

nancy. When blood pressure determinations before pregnancy

are not available, the early lack of a decrease in blood pressure

will be missed and the diagnosis of chronic hypertension

sometimes may not be certain until postpartum follow-up.

Hypertension due to preeclampsia resolves within 7 days after

delivery. Some women with essential hypertension will have

resolution of hypertension immediately after delivery but will

develop hypertension in later years or during a subsequent

pregnancy. Table 2 highlights the clinical features of hyper-

tensive disorders and demonstrates how essential hypertension

can sometimes be differentiated from the other causes of hy-

pertension in pregnancy.

Women already receiving antihypertensive therapy are usu-

ally continued on their medication during pregnancy. This

includes continuation of a diuretic when it is part of the usual

regimen. ACE! and angiotensin !I receptor blockers should be

discontinued as soon as pregnancy is recognized. The devel-

opment of mild hypertension, even early in pregnancy, presents

a more controversial issue. Small elevations in blood pressure

are not likely to be harmful to mother or fetus. However, more

severe elevations in blood pressure are risky to both the mother

and fetus. Maternal risks are largely related to cerebral hem-

orrhage. Fetal risks include intrauterine growth retardation and

death. Most practitioners would agree with starting antihyper-

tensive therapy when diastolic blood pressure exceeds 100

mmHg. Because fetal mortality is increased when blood pres-

sure exceeds 85 to 90 mmHg, some would argue for the

initiation of antihypertensive therapy at these levels of blood

pressure. However, prospective, randomized, controlled trials

have not consistently demonstrated maternal or fetal benefit for

treatment of mild hypertension in pregnancy (14,26). Many

epidemiologists have argued that the reported studies have

been too small to demonstrate small beneficial effects of anti-

hypertensive therapy. However, many studies are also too

small to demonstrate possible infrequent detrimental effects of

too aggressive antihypertensive therapy. The reader should be

reminded that the debate centers mostly on therapy of mild

hypertension. Experts now recommend the use of antihyper-

tensive therapy for moderately severe hypertension complicat-

ing pregnancy (27).

Secondary Hypertension

Secondary causes of hypertension occasionally present in-

teresting problems in pregnancy. Progesterone has the capabil-

ity of antagonizing the kaliuretic effect of mineralocorticoids.

In women with hyperaldosteronism, the antagonism of miner-

alocorticoids by progesterone during pregnancy is variable.

Some women with primary hyperaldosteronism have reversal

of potassium wasting and less hypertension during pregnancy.

In others, hypertension due to sodium retention is exacerbated

by pregnancy and occasionally results in severe hypertension.

Pheochromocytoma is notable for its ability on rare occa-

sions to have a dramatic presentation during pregnancy with

fatal or near-fatal complications. Unrecognized, maternal and

fetal mortality in pheochromocytoma approaches 25%. With

appropriate use of aipha-adrenergic blockers, maternal mortal-

ity can be prevented, although some risk to the fetus persists.

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