1) The document discusses classifications of hypertensive disorders during pregnancy, including chronic hypertension, preeclampsia, gestational hypertension, and preeclampsia superimposed on chronic hypertension. 2) Preeclampsia is diagnosed based on new onset of high blood pressure and proteinuria after 20 weeks of gestation. Severe preeclampsia involves additional complications such as organ dysfunction. 3) Gestational hypertension is diagnosed when high blood pressure is found for the first time during pregnancy but without proteinuria, and is a provisional diagnosis until postpartum.

1. Chapter 35
Pregnancy-Related Hypertension
James M. Roberts, MD, and Edmund F. Funai, MD
mination. Because of the discrepancy between random protein deter-
minations and 24-hour urine protein values in women with
Classification of preeclampsia (which can be higher or lower),7-9 the diagnosis should
Hypertensive Disorders be based on a 24-hour urine specimen or on a timed collection
corrected for creatinine excretion if a 24-hour collection is not
Interpreting epidemiologic studies of the hypertensive disorders of feasible.3
pregnancy is difficult because the terminology is inconsistent.1 Several Preeclampsia occurs as a spectrum but is arbitrarily divided into
systems of nomenclature are in use around the world. The system mild and severe forms. This terminology is useful for descriptive pur-
prepared by the National Institutes of Health (NIH) Working Group poses but does not indicate specific diseases, nor should it indicate
on Hypertension in Pregnancy,2 although imperfect, has the advantage arbitrary cutoff points for therapy. The diagnosis of severe preeclamp-
of clarity and is available in published form for investigators through- sia is confirmed when any of the following criteria are met10:
out the world. The NIH system has four main classes: chronic hyper-
tension, preeclampsia and eclampsia, preeclampsia superimposed on Blood pressure of 160 mm Hg systolic or higher or 110 mm Hg
chronic hypertension, and gestational hypertension. diastolic or higher on two occasions at least 6 hours apart
while the patient is on bed rest
Proteinuria of 5 g or higher in a 24-hour urine specimen or 3+
Chronic Hypertension or greater on two random urine samples collected at least 4
Chronic hypertension is defined as hypertension that is observable hours apart
before pregnancy or that is diagnosed before the 20th week of gesta- Oliguria of less than 500 mL in 24 hours
tion. Hypertension is defined as a persistent blood pressure greater Cerebral or visual disturbances
than 140/90 mm Hg. Hypertension for which a diagnosis is confirmed Pulmonary edema or cyanosis
for the first time during pregnancy and that persists beyond the 84th Epigastric or right upper quadrant pain
day after delivery is also classified as chronic hypertension. Impaired liver function
Thrombocytopenia
Fetal growth restriction
Preeclampsia and Eclampsia
The diagnosis of preeclampsia is determined by increased blood pres- Eclampsia is the occurrence of seizures that cannot be attributed to
sure accompanied by proteinuria. The diagnosis requires a systolic other causes in a woman with preeclampsia.
pressure of 140 mm Hg or higher or a diastolic pressure of 90 mm Hg Edema occurs in too many normal pregnant women to be discrimi-
or higher. Diastolic blood pressure is defined as the Korotkoff phase V nant and has been abandoned as a marker in preeclampsia by the
value (i.e., disappearance of sounds). Gestational blood pressure eleva- National High Blood Pressure Education Program and by other clas-
tion should be determined by at least two measurements, with the sification schemes.11,12 Edema of the hands and face occurs in 10% to
repeat blood pressure performed in a manner that reduces the likeli- 15% of women whose blood pressure remains normal throughout
hood of artifact and patient anxiety.3 Absent from the diagnostic cri- pregnancy.13 Edema can be massive in women with severe preeclamp-
teria is the former inclusion of an increment of 30 mm Hg in systolic sia, rendering the patient virtually unrecognizable (Fig. 35-1).
or 15 mm Hg in diastolic blood pressure, even when absolute values
are below 140/90 mm Hg. This definition was excluded because avail-
able evidence shows that women in this group are not likely to suffer
Preeclampsia Superimposed on
increased adverse outcomes.4,5 Nonetheless, women who have an Chronic Hypertension
increase of 30 mm Hg in systolic or 15 mm Hg in diastolic blood pres- There is ample evidence that preeclampsia can occur in women who
sure warrant close observation, especially if proteinuria and hyperuri- are already hypertensive and that the prognosis for mother and fetus
cemia (i.e., uric acid ≥ 5.5 mg/dL)6 are also present.3 is much worse with both conditions than with either alone. Distin-
Proteinuria is defined as the urinary excretion of at least 300 mg of guishing superimposed preeclampsia from worsening chronic hyper-
protein in a 24-hour specimen. This usually correlates with 30 mg/dL tension tests the skills of the clinician. For clinical management, the
of protein (i.e., 1+ dipstick reading) or more in a random urine deter- principles of high sensitivity and unavoidable overdiagnosis are appro-

2. 652 CHAPTER 35 Pregnancy-Related Hypertension
A B
FIGURE 35-1 Facial edema in severe preeclampsia. Markedly edematous facies of this severely
preeclamptic woman (A) is especially evident when compared with her appearance 6 weeks after delivery
(B).
priate, especially with advancing gestational age. The suspicion of be assigned. If blood pressure elevation persists, the diagnosis is chronic
superimposed preeclampsia mandates close observation, with delivery hypertension. The diagnosis of gestational hypertension is used during
indicated by the overall assessment of maternal and fetal well-being pregnancy only until a more specific diagnosis can be assigned after
rather than by any fixed end point. The diagnosis of superimposed delivery.3
preeclampsia is highly likely with the following findings:
1. In women with documented hypertension and no proteinuria Problems with Classification
before 20 weeks’ gestation The degree of blood pressure elevation that constitutes gestational
New-onset proteinuria, defined as the urinary excretion of 0.3 g hypertension is controversial. Because average blood pressure in
of protein or more in a 24-hour specimen women younger than 30 years is 120/60 mm Hg, the standard defini-
2. In women with hypertension and proteinuria before 20 weeks’ tion of hypertension (i.e., blood pressure >140/90 mm Hg) is judged
gestation by some to be too high,14 resulting in the suggestion that women with
A sudden increase in proteinuria blood pressure increases greater than 30 mm Hg systolic or 15 mm Hg
A sudden increase in blood pressure in a woman whose blood diastolic should be observed closely even if absolute blood pressure has
pressure has previously been well controlled not exceeded 140/90 mm Hg.3
Objective evidence of involvement of multiple organ systems, Blood pressures measured in early pregnancy to diagnose chronic
such as thrombocytopenia (platelet count < 100,000/mm3), an hypertension are problematic. Blood pressure usually decreases early
increase in liver transaminases to abnormal levels,3 or sudden in pregnancy, reaching its nadir at about the time women often present
worsening of renal function for obstetric care (Fig. 35-2). The decrease averages 7 mm Hg for dia-
stolic and systolic readings. In some women, blood pressure may
decline by more than 7 mm Hg; in others, the early decline and sub-
Gestational Hypertension sequent return of blood pressure to pre-pregnant levels in late gesta-
A woman who has no proteinuria and a blood pressure elevation tion may satisfy criteria for a diagnosis of preeclampsia. Women with
detected for the first time during pregnancy is classified as having ges- hypertension before pregnancy have a greater decrease in blood pres-
tational hypertension. This is a provisional diagnosis that includes sure in early pregnancy than do normotensive women,15 and they are
women with preeclampsia who have not yet manifested proteinuria more likely to be misdiagnosed as preeclamptic according to blood
and women who do not have preeclampsia. The hypertension may be pressure criteria.
accompanied by other concerning signs or symptoms that can influ- The diagnosis of chronic hypertension based on the failure of blood
ence management. A final determination that the woman does not pressure to return to normal by 84 days after delivery can be in error.
have preeclampsia can be made only after delivery. If preeclampsia has In a long-range, prospective study by Chesley,16 many women who
not developed and blood pressure has returned to normal by 12 weeks remained hypertensive 6 weeks after delivery were normotensive at
after delivery, the diagnosis of transient hypertension of pregnancy can long-term follow-up. Neither proteinuria nor hypertension is specific

3. CHAPTER 35 Pregnancy-Related Hypertension 653
gresses at various rates. In most cases, progression is slow, and the
mm Hg
disorder may remain mild. In others, the disease can progress rapidly,
125 changing from mild to severe over days to weeks or, in fulminant cases,
Systolic progressing in days or hours.
120
PARA 0 In a series of eclamptic women analyzed by Chesley,18 25% had
evidence of only mild preeclampsia in the days preceding convulsions.
115 PARA 1+ For purposes of clinical management, overdiagnosis must be accepted
because prevention of the serious complications of preeclampsia and
110 eclampsia requires increased sensitivity and early treatment, primarily
through the timing of delivery. For this reason, studies of preeclampsia
75 are necessarily confounded by inclusion of women diagnosed as pre-
Diastolic eclamptic who have another cardiovascular or renal disorder.
70 PARA 0
65 PARA 1+
HELLP Syndrome
The pathophysiologic changes of preeclampsia can occur in the absence
60 of hypertension and proteinuria. This is not surprising, because the
16 20 24 28 32 36 40 traditional diagnostic criteria have more historical than pathophysio-
Gestational age (weeks) logic relevance.18 This situation presents a challenge to clinicians and
demands that they remain alert to the possibility of preeclampsia in
FIGURE 35-2 Blood pressure correlated with gestational age. The pregnant women with signs and symptoms that may be explained by
mean blood pressure was plotted against gestational age for 6000 reduced organ perfusion. One clear setting in which this occurs is the
white women between the ages of 25 and 34 years who delivered HELLP syndrome (hemolysis, elevated liver enzymes, and low plate-
singleton term infants. (From Christianson R, Page EW: Studies on
lets), a combination of findings that defines a reasonably consistent
blood pressure during pregnancy: Influence of parity and age. Am J
syndrome.19
Obstet Gynecol 125:509, 1976. Courtesy of the American College of
Obstetricians and Gynecologists.) For management purposes, it is appropriate to consider HELLP as
a variant of preeclampsia, but they may be different entities. Women
with HELLP are more often older, white, and multiparous than
TABLE 35-1 RENAL BIOPSY FINDINGS IN preeclamptic women. Not all women with HELLP have hypertension.20
PATIENTS WITH A CLINICAL From a pathophysiologic perspective, changes in the renin-angiotensin
DIAGNOSIS OF PREECLAMPSIA system characteristic of preeclampsia are not present in HELLP.21
Nonetheless, progression of the disease and its termination with deliv-
Primigravidas Multigravidas ery argue for an observation and management strategy similar to that
Biopsy Findings (n = 62) (n = 152) for preeclampsia.
Glomeruloendotheliosis with 70% 14%
or without nephrosclerosis
Normal histology
Chronic renal disease, chronic
5%
25%
53%
21%
Preeclampsia and Eclampsia
glomerulonephritis, or
chronic pyelonephritis
Epidemiology of Preeclampsia
Arteriolar nephrosclerosis 0% 12% and Eclampsia
Despite the difficulties in clinical diagnosis, there exists a disorder
Modified from McCartney CP: Pathological anatomy of acute
hypertension of pregnancy. Circulation 30(Suppl II):37, 1964; by unique to pregnancy characterized by poor perfusion of many vital
permission of the American Heart Association, Inc. organs (including the fetoplacental unit) that is completely rever-
sible with the termination of pregnancy. Pathologic, pathophysiologic,
and prognostic findings indicate that preeclampsia is not merely
to preeclampsia, and their presence in pregnancy can have other an unmasking of preexisting, underlying hypertension. Although the
explanations. unique nature of preeclampsia has been well documented for many
Renal biopsy specimens from women with preeclampsia demon- years, controversies in therapy persist because of management strate-
strate these diagnostic difficulties (Table 35-1).17 Of 62 women with a gies based on principles used to treat hypertension in nonpregnant
diagnosis of preeclampsia in their first pregnancies, 70% had a glo- individuals. The successful management of preeclampsia requires an
merular lesion believed to be characteristic of the disorder, but 24% understanding of the pathophysiologic changes in this condition and
had evidence of chronic renal disease that was not previously sus- recognition that the signs of preeclampsia (i.e., increased blood pres-
pected. Renal biopsy specimens of multiparous women with a clinical sure and proteinuria) are only signs and do not cause the other features
diagnosis of superimposed preeclampsia also demonstrate the uncer- of preeclampsia.
tainty of diagnosis. Of 152 subjects, only 3% had the characteristic
glomerular lesion, but 43% had evidence of preexisting renal or vas- Women at Risk
cular disease. Preeclampsia occurs in about 4% of pregnancies that continue past
Preeclampsia has a clinical spectrum ranging from mild to severe the first trimester. Nulliparity is the most common feature of women
forms. The illness in affected women does not begin with eclampsia or who develop preeclampsia. At least two thirds of cases occur in the
the severe manifestations of preeclampsia. Rather, the disease pro- first pregnancy that progresses beyond the first trimester. Other risk

4. 654 CHAPTER 35 Pregnancy-Related Hypertension
factors for preeclampsia are similar in nulliparous and parous Obesity is a risk factor for preeclampsia.28,51 In the National Insti-
women.22 tute of Child Health and Human Development (NICHD) study of
Although preeclampsia was thought to be more common among aspirin to prevent preeclampsia in low-risk pregnancies,31 the inci-
women of lower socioeconomic status, this impression may be a con- dence of preeclampsia increased with maternal body mass index. Even
sequence of the associations of preeclampsia with age, race, and parity. in women of normal weight, there is a linear relationship between
Studies of pregnant women in Scotland23 from Aberdeen,24 Finland,25 pre-pregnancy body mass index and the frequency of preeclampsia.52
and Israel26 found that preeclampsia was not related to socioeconomic The mechanism may be related to increased insulin resistance, because
status. Eclampsia, in contrast, is clearly more common in women of preeclampsia is more common in another setting of increased insulin
lower socioeconomic status,23,25,26 related to the lack of availability of resistance: gestational diabetes.53 With a threefold increased risk for
quality obstetric care for indigent women. Remarkably, preeclampsia obese women and with 35% to 50% of women of reproductive age in
and eclampsia were once thought to occur more frequently in women the United States being obese, obesity has become a major attributable
of higher socioeconomic status.18 risk factor for preeclampsia, which is associated with more than one
There is a relationship between the extremes of childbearing age third of cases of preeclampsia.
and the incidence of eclampsia and preeclampsia. Because most first Certain conditions of pregnancy increase the risk of preeclampsia.
pregnancies occur in young women, most cases of preeclampsia and The incidence is increased among parous and nulliparous women with
eclampsia occur in this age group, but the association with young multiple gestations, although to a larger degree in the latter.36,54 In a
maternal age is lost when parity is considered. In the studies cited,23,25,26 study of 34,374 pregnancies with singleton, twin, triplet, or quadruplet
a higher incidence of preeclampsia was found in older women inde- pregnancies, the incidence of preeclampsia increased with each addi-
pendent of parity. tional fetus. The incidences were 6.7%, 12.7%, 20.0%, and 19.6%,
The relationship of preeclampsia and eclampsia to race is compli- respectively.55 The disease process may be initiated earlier and may be
cated by the higher prevalence of chronic hypertension in African more severe in these cases.54
Americans and the difficulty in differentiating preeclampsia from Preeclampsia affects 70% of women with large, rapidly growing
unrecognized preexisting chronic hypertension. Some studies indicate hydatidiform moles and occurs earlier than usual during gestation.56
a relationship.26,27 In a small case-control study of carefully defined In cases of preeclampsia occurring before 24 weeks’ gestation, hyda-
preeclampsia, black race was a significant risk factor only in nullipa- tidiform mole should be suspected and sought.
rous women (odds ratio [OR] = 12.3; 95% confidence interval [CI], An interesting variant of preeclampsia is the mirror syndrome, in
1.6 to 100.8).28 Other studies support a more modest increased risk in which the mother’s peripheral edema mirrors the fetal hydrops. It
African-American women.29,30 Studies that include the more severe occurs with fetal hydrops, although not with erythroblastosis uncom-
forms of preeclampsia more often suggest an increased incidence plicated by hydrops. The incidence approaches 50% of pregnancies
among African-American women.28 complicated by hydrops. The mirror syndrome is not confined to
In contrast, the incidence of rigorously defined preeclampsia did hydrops resulting from isoimmunization. In one series, mirror syn-
not differ by race after other risk factors were controlled in two large, drome occurred in 9 of 11 pregnancies with hydropic infants of non-
prospective trials of medical prophylaxis that enrolled 294731 and immune origin.57 This condition can manifest early in pregnancy with
431432 nulliparous women. Maternal nonwhite race appears to be severe signs and symptoms of preeclampsia, and it has resolved with
related more to the severity than the incidence of disease. treatment of the underlying process.58-60 Proteinuria is massive, and
A diverse array of medical disorders that often coexist with preg- blood pressure elevation and edema are marked. Eclampsia occurs
nancy, including diabetes, chronic hypertension, chronic renal disor- rarely (see Chapter 26).
ders, and rheumatologic conditions, have been associated with
preeclampsia. The existence and severity of diabetes have been
associated with an increased risk for preeclampsia, and diabetic Short-Term Prognosis for Preeclampsia
microvascular disease further increases this risk. This relationship PERINATAL MORTALITY
has been found in Sweden33 and in the United States.34 Both The perinatal mortality rate is increased in infants of preeclamptic
studies33,34 demonstrated that the risk of preeclampsia was approxi- women.61-63 In a study that examined 10,614,679 singleton pregnancies
mately 20% and 21% in 491 and 462 pregnancies, respectively. This in the United States from 1995 to 1997 after 24 weeks’ gestation, the
estimate is far more modest than the 50% incidence reported in his- relative risk for fetal death was 1.4 for infants born to women with any
torical cohorts.18 The preeclampsia risk increased according to the of the gestational hypertensive disorders and 2.7 for those born to
severity of disease, with an 11% to 12% risk among women with class women with chronic hypertensive disorders compared with low-risk
B diabetes and 21% to 23% with class C and D diabetes. Microvascular controls. Causes of perinatal death are placental insufficiency and
disease increased this risk to 36% to 54% in diabetics with class F or abruptio placentae,64 which cause intrauterine death before or during
R disease.33,34 labor, and prematurity. Predictably, the mortality rate is higher for
Chronic renal insufficiency and hypertension are well-recognized infants of women with more severe forms of the disorder. At any level
risk factors. Of women with hypertension antedating pregnancy, 25% of disease severity, the perinatal mortality rate is greatest for women
develop preeclampsia.35,36 Renal insufficiency with33,37 and without dia- with preeclampsia superimposed on preexisting vascular disease.
betes38-40 also is an important risk factor.38,40 The stillbirth rate attributable to preeclampsia has declined dra-
Connective tissue disorders such as systemic lupus erythe- matically in the past 35 years. However, infants born of preeclamptic
matosus41,42 and antiphospholipid antibody syndrome43-45 have been pregnancies continue to have an approximately twofold increased risk
reported as risk factors for preeclampsia. With lupus, the risk is par- for neonatal death.65 Although neonatal survival rates have improved
ticularly elevated with hypertension or nephropathy.46,47 However, dramatically, delivery before 34 weeks’ gestation continues to be associ-
data concerning an association between isolated antiphospholipid ated with an increased risk of long-range neurologic disability (see
antibodies and preeclampsia have been conflicting, with some Chapter 58).
studies demonstrating no relationship48,49 and others confirming the Growth restriction is more common in infants born to preeclamp-
association.44,50 tic women (see Chapter 34) and more pronounced with increasing

5. CHAPTER 35 Pregnancy-Related Hypertension 655
severity and earlier diagnosis.66 As with perinatal mortality, intrauter- To determine the subsequent pregnancy outcomes of women who
ine growth restriction (IUGR) is more common in infants of chroni- clearly had preeclampsia, Chesley and colleagues74 followed 270 women
cally hypertensive women with superimposed preeclampsia.67 with eclampsia for more than 40 years; only two were lost to follow-up.
The dramatic decrease in perinatal mortality rate among infants of Among 187 women who had eclampsia in the first pregnancy, 33% had
preeclamptic women is the result in part of improved medical and a hypertensive disorder in any subsequent pregnancy. In most, the
obstetric management, including improved assessment of fetal well- condition was not severe, but 5% had recurrent eclampsia. Twenty
being in the antepartum and intrapartum periods. The primary effect women with eclampsia as multiparas had recurrent hypertension in
on the perinatal mortality rate, however, has come from improvements 50% of subsequent pregnancies.
in neonatal care. Women with a clinical diagnosis of preeclampsia have increased
risk for hypertensive disorders in subsequent pregnancies. The chances
MATERNAL MORTALITY of recurrence decrease as the likelihood of true preeclampsia increases.
Maternal death associated with preeclampsia predominantly re- If the condition does recur, it will usually not be worse, and if pre-
sults from complications of abruptio placentae, hepatic rupture, and eclampsia truly arose de novo, it probably will be less severe in subse-
eclampsia. Historically, the mortality rate of eclamptic women was quent pregnancies. Some women, however, are normotensive between
most effectively reduced by avoiding iatrogenic complications related pregnancies but have recurrent preeclampsia. The risk of such recur-
to overmedication and overzealous attempts at vaginal delivery. In rence is increased when preeclampsia occurs in the late second or
series from the late 19th century, when immediate delivery was the early third trimester.73 The recurrence of severe preeclampsia or
practice, the mortality rate of eclamptic women was 20% to 30%. eclampsia in one pregnancy predicts its likely recurrence in subsequent
Expectant management with profound maternal sedation with narcot- pregnancies.
ics and hypnotics in the early 20th century was associated with a 10%
to 15% mortality rate. The change to magnesium as the exclusive agent Preeclampsia and Cardiovascular Disease
in the 1920s and 1930s resulted in a maternal mortality rate of 5%. in Later Life
Although magnesium was undoubtedly helpful, the primary factor Evidence that preeclampsia is associated with long-term maternal
responsible for improved mortality was decreased maternal sedation.18 health consequences is based on the work of Chesley and coworkers,74
The currently used combination of magnesium sulfate (MgSO4) and who followed a cohort of white women with eclampsia in their first
antihypertensive drugs as sole pharmacologic agents, followed by pregnancy and reported no increased risk of subsequent chronic
timely delivery, has produced a maternal mortality rate of almost hypertension. However, mortality was twofold to fivefold higher over
zero68,69 because of an appreciation of the profound pathophysiologic the next 35 years among women with eclampsia in any pregnancy after
abnormalities of preeclampsia, careful cardiopulmonary monitoring, the first (Fig. 35-3). The findings of Chesley and colleagues74 led to
and limitation of unproven interventions. speculation that multiparous women with preeclampsia or eclampsia
were more likely to have had unrecognized underlying chronic hyper-
RECURRENCE IN SUBSEQUENT PREGNANCIES tension and that this, not preeclampsia, caused the subsequent increase
Data from classic series indicate that the likelihood of recurrent in mortality. Sibai and associates71 also found that women with recur-
preeclampsia is influenced by the certainty of the clinical diagnosis in rent preeclampsia were more likely to develop chronic hypertension.
the first pregnancy. Of 225 women with hypertension during preg- These studies are the basis for a statement by The National High Blood
nancy chosen for study without regard to parity, 70% had a recurrence Pressure Education Program’s Working Group on High Blood Pressure
of preeclampsia in their next pregnancy.70 In a study of primiparas with during Pregnancy that recurrent hypertension in pregnancy, pre-
severe preeclampsia, the recurrence rate was 45% .71 Because the diag- eclampsia in a multipara, and early-onset disease in any pregnancy may
nosis in these studies was based solely on clinical findings, these groups all herald increased future health risks.2
probably included patients with unrecognized preexisting blood pres- Women with idiopathic preeclampsia (i.e., preeclampsia occurring
sure elevation or underlying renal or cardiovascular disease. in nulliparous women without underlying renal or cardiovascular
Recurrence rates were reported in 2006 for 896 parous women in disease, including chronic hypertension) were not thought to have
Iceland according to standardized diagnostic criteria in both pregnan- increased risk of later vascular disease until a report from Norway75
cies (i.e., National High Blood Pressure Criteria3). The rates of recur- found modest (1.65-fold) increased cardiovascular mortality for nul-
rence differed substantially by the diagnosis in the first pregnancy, as liparous women with preeclampsia at term and an eightfold increased
seen in Table 35-2.72 risk when preeclampsia was severe enough to lead to preterm delivery.
TABLE 35-2 TYPE OF RECURRENT HYPERTENSION DURING THE SECOND PREGNANCY BY TYPE OF
HYPERTENSION IN THE FIRST PREGNANCY
Second Pregnancy*
Gestational Chronic Superimposed All
First Pregnancy Normal Hypertension Preeclampsia Hypertension Preeclampsia Recurrences
Gestational hypertension (n = 511) 153 (29.9%) 239 (46.8%) 25 (4.9%) 82 (16%) 12 (2.3%) 358 (70.1%)
Preeclampsia/eclampsia (n = 151) 63 (41.7%) 52 (34.4%) 17 (11.3%) 16 (10.6%) 3 (2%) 88 (58.3%)
Chronic hypertension (n = 200) 24 (12%) 69 (34.5%) 6 (3%) 91 (45.5%) 10 (5%) 176 (88%)
Superimposed preeclampsia (n = 34) 2 (5.9%) 10 (29.4%) 4 (11.8%) 14 (41.2%) 4 (11.8%) 32 (94%)
Total (N = 896) 242 (27%) 370 (41.3%) 52 (5.8%) 203 (22.7%) 29 (3.2%) 654 (73%)
*No women had eclampsia in the second pregnancy.
From Hjartardottir S, Leifsson BG, Geirsson RT, Steinthorsdottir V: Recurrence of hypertensive disorder in second pregnancy. Am J Obstet Gynecol
194:916-920, 2006.

6. 656 CHAPTER 35 Pregnancy-Related Hypertension
100 TABLE 35-3 SIGNS AND SYMPTOMS OF
PREECLAMPSIA OR ECLAMPSIA
90
Cerebral Blurred vision
Headache Amaurosis
80
Percentages surviving
Dizziness Gastrointestinal
Tinnitus Nausea
70 Drowsiness Vomiting
Change in respiratory rate Epigastric pain
60 Tachycardia Hematemesis
Fever Renal
50 Visual Oliguria
Diplopia Anuria
40 Scotomata Hematuria
Hemoglobinuria
30
dyslipidemia,92 altered angiogenic factors,93 and increased antibodies
10 20 30 40 45
to the angiotensin-2 receptor.94 These data may explain the common
Years
risk factors for preeclampsia and cardiovascular disease, but alternative
FIGURE 35-3 Eclampsia survivorship. Survival times are plotted
explanations, such as that preeclampsia causes vascular injury that
for women with eclampsia in the first pregnancy (solid line) and those increases cardiovascular risk or that normal pregnancies have a protec-
with eclampsia in a later pregnancy (dashed line). Survival of women tive effect, cannot be excluded.
with first-pregnancy eclampsia was not different from survival of a
control group. (From Chesley LC, Annitto JE, Cosgrove RA: The
remote prognosis of eclamptic women: Sixth periodic report. Am J Clinical Presentation
Obstet Gynecol 124:446, 1976, Courtesy of the American College of Preeclampsia can manifest with a wide spectrum of disease, ranging
Obstetricians and Gynecologists.) from life-threatening neurologic, renal, hepatic, and coagulation
abnormalities to mild findings of preeclampsia with minimal end-
organ involvement. The fetus may be severely compromised by the
Scottish investigators reported a fourfold increased risk of subsequent maternal condition and by extreme preterm delivery or only minimally
hypertension in nulliparous women with preeclampsia2,76,77 (OR = affected. These variations have puzzled clinicians and researchers for
3.98; CI, 2.82 to 5.61). Funai and colleagues78 described excess long- many years. An understanding of the pathophysiology of the disorder
term mortality in women with prior preeclampsia that was largely provides insight into the diverse clinical presentations.
attributed to a threefold increase in deaths due to cardiovascular
disease. Other reports support a link between preeclampsia and mater- Symptoms
nal ischemic heart disease,79,80 which is sometimes evident 20 years Most women with early preeclampsia are asymptomatic. The absence
after the preeclamptic pregnancy and coincident with the onset of of symptoms is the rationale for frequent obstetric visits in late preg-
menopause.78,80 A family history of cardiovascular disease increases the nancy. In most cases, signs such as increased blood pressure and pro-
association between preeclampsia and cardiovascular outcomes.81 teinuria antedate overt symptoms.
Obesity is a known risk factor for preeclampsia and cardiovascular The various symptoms associated with preeclampsia, especially
disease. Although controlling for obesity attenuates the increased risk preeclampsia of increasing severity, are listed in Table 35-3. Because
of death for postmenopausal women, this risk is not fully explained by preeclampsia is a disease of generalized poor perfusion, the diversity
obesity alone.82 of symptoms related to many organ systems is not surprising. Symp-
The relationships among obesity, insulin resistance, and preeclamp- toms suggesting hepatic, neurologic, and visual involvement are par-
sia are part of an interesting relationship of preeclampsia to the meta- ticularly worrisome. They include epigastric pain, “stomach upset,” and
bolic or insulin resistance syndrome.83 This syndrome predisposes to pain penetrating to the back. Headache and mental confusion indicate
cardiovascular disease in later life and consists of obesity, hypertension, poor cerebral perfusion and may be precursors of convulsions. Visual
dyslipidemia (i.e., increased low-density lipoprotein [LDL] cholesterol, symptoms ranging from scotomata to blindness indicate retinal arte-
decreased high-density lipoprotein [HDL] cholesterol, and increased rial spasm and edema. Symptoms suggesting congestive heart failure
triglycerides), and increased uric acid, all of which are found in women or abruptio placentae also represent significant complications of pre-
with preeclampsia.83 Other conditions predisposing to later-life cardio- eclampsia. Other symptoms, such as tightness of hands and feet and
vascular disease—including elevated levels of homocysteine,84 evidence paresthesias resulting from medial or ulnar nerve compression, may
of androgen excess (including polycystic ovarian syndrome),85 elevated alarm the patient but have little prognostic significance.
testosterone levels,86 male fat distribution (i.e., increased waist-to-hip
ratio),87 and lipoprotein lipase mutations88—are also linked to an Signs
increased risk for preeclampsia. Signs of preeclampsia usually antedate symptoms. The most common
Women who appear normal years after a preeclamptic pregnancy sequence is increased blood pressure followed by proteinuria.18
may nevertheless demonstrate subtle metabolic and cardiovascular
abnormalities. Compared with women with uncomplicated pregnan- BLOOD PRESSURE CHANGE
cies, formerly preeclamptic women have evidence of endothelial dys- An increase in blood pressure is required for the diagnosis of
function,89,90 higher blood pressures,89 increased insulin resistance,91 preeclampsia. Blood pressure variation in normal pregnancy can

7. CHAPTER 35 Pregnancy-Related Hypertension 657
lead to misdiagnosis. In clinical practice, the serious effects of pre- HYPERREFLEXIA
eclampsia on the mother and fetus warrant such overdiagnosis. The Although hyperreflexia is given much clinical attention and deep
primary pathophysiologic alteration, poor tissue perfusion resulting tendon reflexes are increased in many women before seizures, convul-
from vasospasm, is revealed more by blood pressure changes than by sions can occur in the absence of hyperreflexia,68 and many pregnant
absolute blood pressure levels. Although a diagnosis of preeclampsia women are consistently hyperreflexic without being preeclamptic.
is not made without absolute blood pressure increases to 140 mm Hg Changes, or lack thereof, in deep tendon reflexes are not part of the
systolic or 90 mm Hg diastolic, women who reach this level from a low diagnosis of preeclampsia.
early pregnancy value typically manifest more vasospasm than those
for whom 140/90 mm Hg represents a smaller increase. OTHER SIGNS
Although maternal and fetal risks rise with increasing blood pres- Other signs that occur less commonly in preeclampsia are indica-
sure,95 serious complications can occur in women who experience only tors of involvement of specific organs in the preeclamptic process.
modest blood pressure elevation. In two series, 20% of women with Women with marked edema may have ascites and hydrothorax, and
eclampsia never had a systolic blood pressure above 140 mm Hg.18,96 those with congestive heart failure display increased neck vein disten-
In a large, prospective study from the United Kingdom, there were 383 tion, gallop rhythm, and pulmonary rales. Hepatic capsular distention,
confirmed cases of eclampsia, of which 77% were hospitalized before manifested by hepatic enlargement and tenderness, is a particular
seizures occurred. Of these, 38% of the cases were not preceded by concern, as is disseminated intravascular coagulation (DIC) sufficient
documented proteinuria or hypertension.97 Others have noticed similar to cause petechiae or generalized bruising and bleeding.
findings.98,99
Laboratory Findings
PROTEINURIA Major changes revealed by laboratory studies occur in severe pre-
Among the diagnostic signs of preeclampsia, proteinuria in the eclampsia and eclampsia. In the patient with mild preeclampsia,
presence of hypertension is the most reliable indicator of fetal jeopardy. changes in most of these indicators may be minimal or absent.
In two studies of preeclampsia, the perinatal mortality rate tripled for
women with proteinuria,100 and the amount of proteinuria correlated RENAL FUNCTION STUDIES
with increased perinatal mortality rate and the number of growth- Serum Uric Acid Concentration and Urate Clearance. Uric
restricted infants.101 A later study demonstrated that the risk for acid is the most sensitive laboratory indicator of preeclampsia available
delivering a small-for-gestational-age fetus was higher in women with to clinicians. A decrease in uric acid clearance precedes a measurable
hypertension and proteinuria (52%) compared with women with new- decrease in the glomerular filtration rate (GFR). Hypertension with
onset gestational hypertension (15%) or chronic hypertension (12%). hyperuricemia but without proteinuria was associated with growth
The perinatal mortality rate was fourfold higher with proteinuria restriction as commonly as hypertension and proteinuria without ele-
and hypertension than in pregnancies complicated by hypertension vated uric acid in one series.105 Although increased serum uric acid
alone.102 concentration is often attributed to altered renal function, an alterna-
tive view favors increased production caused by oxidative stress.106 An
RETINAL CHANGES elevated uric acid level may itself have pathogenic effects.107 Table 35-4
Retinal vascular changes on funduscopic examination occur in shows normal uric acid levels during gestation and levels associated
retinal arterioles in at least 50% of women with preeclampsia, and they with preeclampsia.
are important because they correlate best with renal biopsy-proven Serum Creatinine Concentration and Creatinine Clearance.
changes of preeclampsia.103 Localized retinal vascular narrowing is Creatinine clearance is decreased in most patients with severe pre-
visualized as segmental spasm, and the generalized narrowing is indi- eclampsia, but it can be normal in women with mild disease. Serial
cated by a decrease in the ratio of arteriolar-venous diameter from serum creatinine determinations may indicate decreased clearance, but
the usual 3 : 5 to 1 : 2 or even 1 : 3. It can occur in all vessels or, in early single values are not helpful unless markedly elevated because of the
stages, in single vessels.104 Preeclampsia does not cause chronic arterio- wide range of normal values. The serum creatinine concentration
lar changes; the presence of arteriolar sclerosis detected by increased varies as a geometric function of creatinine clearance so that small
light reflex, copper wiring, or arteriovenous nicking indicates preexist- changes in glomerular filtration are best determined by measurements
ing vascular disease. of creatinine clearance.
TABLE 35-4 PLASMA URATE CONCENTRATIONS IN NORMOTENSIVE AND HYPERTENSIVE
PREGNANT WOMEN
Normotensive Patients Hypertensive Patients
Weeks of Gestation mmol/L SD* mg/dL mmol/L SD* mg/dL
24-28 0.18 (20%) 3.02 0.24 (20%) 4.03
29-32 0.18 (35%) 3.02 0.28 (25%) 4.7
33-36 0.20 (30%) 3.36 0.30 (20%) 5.04
37-40 0.26 (20%) 4.4 0.31 (23%) 5.28
41-42 0.25 (24%) 4.2 0.32 (12%) 5.38
*Each number in parentheses is the standard deviation given as a percentage of the mean values shown. Values for hypertensive and normotensive
women are statistically different at all gestational ages (P < .05).
Modified from Shuster E, Weppelman B: Plasma urate measurements and fetal outcome in preeclampsia. Gynecol Obstet Invest 12:162, 1981.

8. 658 CHAPTER 35 Pregnancy-Related Hypertension
LIVER FUNCTION TESTS
Although most tests of liver function are not highly predictive of
severity of preeclampsia,18 the association between microangiopathic
anemia and elevations in aspartate aminotransferase (AST) and alanine
aminotransferase (ALT) carries an especially disturbing prognosis for
the mother and infant.19,108 These findings usually correlate with the
severity of disease and, when associated with hepatic enlargement, may
be a sign of impending hepatic rupture.
COAGULATION FACTORS
Although overt DIC is rare, subtle evidence of activation of the
coagulation cascade occurs in many women with preeclampsia. The
average platelet count in the patient with mild preeclampsia is similar
to the platelet count in normal pregnant women.109 However, careful
platelet counts performed sequentially may reveal decreased platelets
in many patients.110 Highly sensitive indicators of activation of the
clotting system, reduced serum concentrations of antithrombin III,111
a decrease in the ratio of factor VIII bioactivity to factor VIII antigen,112
and subtle indicators of platelet dysfunction, including alteration of FIGURE 35-4 Hemorrhagic hepatic lesions in eclampsia.
turnover,6 activation,113 size,114 and content,115 exist in even mild pre- Hemorrhage into the periportal area occurred with crescentic
eclampsia and may antedate clinically evident disease. compression of liver cells. (From Sheehan HL, Lynch JB: Pathology of
Toxemia in Pregnancy. London, Churchill Livingstone, 1973.)
METABOLIC CHANGES
Preeclampsia is characterized by an increase in the insulin resis-
tance of normal pregnancy. Signs of the insulin resistance syndrome
are exaggerated.110 Levels of circulating lipids already elevated in
normal pregnancy116 are accentuated in women with preeclampsia.117
Triglycerides and fatty acid levels are elevated, changes that antedate
clinically evident disease by weeks to months.118,119 Levels of the car-
dioprotective HDL cholesterol are reduced in preeclamptic women,120
whereas levels of a variant of LDL cholesterol (i.e., small, dense cho-
lesterol that is strongly associated with cardiovascular disease) are
increased.121,122 These changes resolve after delivery.
Pathologic Changes in Preeclampsia
The pathologic changes found in organs of women dying of eclampsia
and in biopsy specimens from women with preeclampsia provide
strong evidence that preeclampsia is not merely an unmasking of
essential hypertension or a variant of malignant hypertension. These
findings also indicate that the elevation of blood pressure probably
does not have primary pathogenetic importance.
Brain FIGURE 35-5 Hepatic infarction in eclampsia. Hepatic infarction
caused by intense vasospasm manifests as small to large areas
Cerebral edema, once thought to be a common finding in women
beginning near the sinusoids and extending into the area near the
dying of eclampsia, was uncommon among postmortem examinations portal vessels. (From Sheehan HL, Lynch JB: Pathology of Toxemia in
performed within 2 to 3 hours of death.123 However, studies using Pregnancy. London, Churchill Livingstone, 1973.)
computed tomography again raised the possibility that cerebral edema
is an important pathophysiologic event in some women with pre-
eclampsia.124 Noninvasive studies of cerebral blood flow and resistance results from vasodilatation of arterioles, producing dislocation and
suggest that vascular barotrauma and loss of cerebral vascular auto- deformation of the hepatocytes in their stromal sleeves (Fig. 35-4).
regulation contribute to the pathogenesis of cerebral vascular pathol- Later, intense vasospasm causes hepatic infarction, ranging from small
ogy in cases of preeclampsia or eclampsia.125 to large areas beginning near the sinusoids and extending into the area
near the portal vessels (Fig. 35-5). Hemorrhagic changes are present in
Liver 66% and necrotic changes in 40% of eclamptic women and in about
Gross lesions of the liver are visible in about 60% of women dying of one half as many preeclamptic women. Hyalinization and thrombosis
eclampsia, and one third of the remaining livers are microscopically of hepatic vessels have been cited as evidence of DIC, but they may be
abnormal. Many early investigators thought that the hepatic changes the result of hemorrhage.
were pathognomonic for eclampsia,126 but similar changes have been
described in women dying of abruptio placentae.127 Kidney
Two temporally and etiologically distinct hepatic lesions have been The pathologic renal changes of preeclampsia and eclampsia are clearly
described.123 Initially, hemorrhage into the hepatic cellular columns different from those seen in other hypertensive or renal disorders.

9. CHAPTER 35 Pregnancy-Related Hypertension 659
EN
BM
R
FIGURE 35-6 Glomerular changes in preeclampsia are identified A
by light microscopy. The enlarged glomerulus completely fills
Bowman’s capsule. Diffuse edema of the glomerular wall is indicated Ep Cy
by the vacuolated appearance. The visible capillary loops are
extremely narrow, and there are virtually no red blood cells in the
capillary tuft.
En
Glomerular, tubular, and arteriolar changes have been described. The
glomerular lesion is considered by some to be pathognomonic of pre-
eclampsia and eclampsia, but identical changes have been seen in pla- BS R
cental abruption without evident preeclampsia.128 This change is not
En
seen in any other form of hypertension.
Ep
GLOMERULAR CHANGES
Changes seen by light microscopy in glomeruli that are character-
istic of preeclampsia include103 decreased glomerular size, with protru-
sion of the glomerular tuft into the proximal tubule. The diameter of P
the glomerular capillary lumen is decreased and contains few blood
cells. The endothelial-mesangial cells have increased cytoplasmic
B
volume and can contain lipoid droplets (Fig. 35-6).
Electron microscopic examination of glomeruli provides more evi- FIGURE 35-7 Electron photomicrographs of renal glomeruli.
dence that the primary pathologic change occurs in endothelial cells, A, Normal anatomy. B, Biopsy specimen from a preeclamptic woman.
which are greatly increased in size and can occlude the capillary lumen; Endothelial cells (En) are markedly enlarged, obstruct the capillary
their cytoplasm contains electron-dense material.129 The basement lumen, and contain electron-dense inclusions. The basement
membrane bordering the epithelial cell may be slightly thickened, and membrane (BM) is slightly thickened with inclusions, but the
it also contains electron-dense material. The epithelial cell podocytes epithelial foot processes (EP) are normal. BM, basement membrane;
are not altered (Fig. 35-7). These changes are collectively called glo- BS, Bowman’s space; Cy, cytoplasmic inclusions; EN, capillary
endothelial cells that line the glomeruli; Ep, renal epithelial cells; L,
merular capillary endotheliosis.
capillary lumen containing red blood cells; P, podocytes; R, red blood
Characteristic glomerular changes occur in 70% of primiparas
cell. (From McCartney CP: Pathological anatomy of acute
but in only 14% of multiparas with a diagnosis of preeclampsia.17 The hypertension of pregnancy. Circulation 30[Suppl II]:37, 1964. By
more likely the diagnosis of preeclampsia, the more common the glo- permission of the American Heart Association, Inc.)
merular lesion. As the clinical condition worsens, the magnitude of the
glomerular lesion increases. The glomerular lesions are reversible after
delivery and are not present in subsequent biopsy specimens obtained
5 to 10 weeks later.103 NONGLOMERULAR CHANGES
The glomerular changes correlate more consistently with protein- Pathologic changes in renal tubules include dilatation of proximal
uria than with hypertension, suggesting that proteins identified immu- tubules with thinning of the epithelium,123 tubular necrosis,103 enlarge-
nohistochemically may be trapped in the glomerulus. These staining ment of the juxtaglomerular apparatus,131 and hyaline deposition in
patterns are not found in other renal disorders with proteinuria. The renal tubules.123 Fat deposition in women with prolonged heavy pro-
glomerular changes of preeclampsia can be mimicked in animal studies teinuria has been reported.123 Necrosis of the loop of Henle, a change
by reducing the renal concentration of vascular endothelial growth that correlates with the degree of hyperuricemia, has also been
factor (VEGF), which usually exists in high concentration in this tissue described.131
by increasing the synthesis of the VEGF antagonist soluble Fms-like Thickening of renal arterioles may be seen in preeclampsia, espe-
tyrosine kinase 1 (sFlt1).130 cially in women with preexisting hypertension. Unlike the glomerular

10. 660 CHAPTER 35 Pregnancy-Related Hypertension
Spinal
Endometrium
Basal
Radial
Arcuate
Myometrium
A
FIGURE 35-8 Schematic representation of uterine arteries. The
characteristic changes occur in the decidual vessels supplying the
placental site in a normal pregnancy. (From Okkels H, Engle ET:
Studies of the finer structure of the uterine vessels of the Macacus
monkey. Acta Pathol Microbiol Scand 15:150, 1938.)
lesion, it does not regress after delivery,103 suggesting that the arteriolar
change results from coincident disease, not preeclampsia.
B
Vascular Changes in the Placental Site FIGURE 35-9 Spiral arterial changes in normal pregnancy. A, In
The characteristic changes in the decidual vessels supplying the pla- the section of spiral arterioles at the junction of the endometrium and
cental site in normal pregnancy are depicted in Figure 35-8. In normal myometrium in a nonpregnant woman, notice the inner elastic lamina
pregnancy, the spiral arteries (Fig. 35-9) increase greatly in diameter.132 and smooth muscle. B, In a section of a spiral arteriole at the same
Morphologically, the endothelium is replaced by trophoblast, and the scale and from the same location during pregnancy, notice the
internal elastic lamina and smooth muscle of the media are replaced markedly increased diameter and absence of inner elastic lamina and
by trophoblast and an amorphous matrix-containing fibrin (see smooth muscle. (From Sheppard BL, Bonnar J: Uteroplacental
Fig. 35-9).133 These changes occur originally in the decidual portion of arteries and hypertensive pregnancy. In Bonnar J, MacGillivray I,
Symonds G [eds]: Pregnancy Hypertension. Baltimore, University Park
the spiral arteries but extend into the myometrium as pregnancy
Press, 1980, p 205.)
advances and can even involve the distal portion of the uterine radial
artery. The basal arteries are not affected. These morphologic changes
are considered to be a vascular reaction to the trophoblast, occurring
directly or humorally, that results in increased perfusion of the placen-
tal site.
In placental-site vessels of women with preeclampsia, the normal
physiologic changes do not occur, or they are limited to the decidual
portion of the vessels. Myometrial segments of spiral arteries retain the
nonpregnant component of intima and smooth muscle, and the diam-
eter of these arteries is about 40% that of vessels in normal preg-
nancy.134 Spiral arterioles in decidua and myometrium and basal and F
radial arterioles may become necrotic, with components of the normal
vessel wall replaced by amorphous material and foam cells, a change
called acute atherosis (Fig. 35-10).135 This lesion is best seen in the basal
arteries because they do not undergo the normal changes of pregnancy.
It is also present in decidual and myometrial spiral arteries and can
progress to vessel obliteration. The obliterated vessels correspond to
areas of placental infarction.
Failed vascular remodeling and atherotic changes may be seen
with fetal growth restriction in women without clinical evidence of
FIGURE 35-10 Atherosis. Numerous lipid-laden cells (L) and fibrin
preeclampsia. Atherotic changes occur in decidual vessels of some dia- deposition (F) are present in the media of this occluded decidual
betic women,136 and failed vascular remodeling is present in about vessel. (From Sheppard BL, Bonnar J: Uteroplacental arteries and
one third of women who experience preterm labor.137 It appears hypertensive pregnancy. In Bonnar J, MacGillivray I, Symonds G
that abnormal invasion may be necessary but is not sufficient to cause [eds]: Pregnancy Hypertension. Baltimore, University Park Press,
preeclampsia. 1980, p 205.)

11. CHAPTER 35 Pregnancy-Related Hypertension 661
Changes characteristic of preeclampsia have been observed in the hypertension. Second, the pathologic findings indicate that the primary
decidual vessels of one in seven primiparous women and in a lower pathology is poor tissue perfusion, not blood pressure elevation. The
percentage of multiparous women at the time of first-trimester abor- histologic data support the clinical impression that the poor perfusion
tion.138,139 These findings suggest that disordered placentation precedes results from profound vasospasm, which increases total peripheral
the clinical presentation of preeclampsia. The cause of the decidual resistance and blood pressure.
vascular lesions is unknown. The appearance of the atherotic vessels
resembles vessels in transplanted kidneys that have undergone rejec-
tion, suggesting an immunologic cause, which is consistent with find-
Pathophysiologic Changes
ings of a study that demonstrated components of complement (e.g., in Preeclampsia
C3) in decidual vessels with the lesion.140 Preeclampsia can cause changes in virtually all organ systems. Several
The vascular remodeling of spiral arteries supplying the intervillous organ systems are consistently and characteristically involved, and
space is intimately related to normal trophoblast invasion.141 The these are discussed in the following sections.
expression of adhesion molecules and their receptors that characterizes
implantation is abnormal in preeclampsia.142 The trophoblast that lines Cardiovascular Changes
the decidual vessels of normal pregnant women begins to express Blood pressure is the product of cardiac output and systemic vascular
molecules usually present only on endothelium,143 a phenomenon that resistance. Cardiac output is increased by up to 50% in normal preg-
does not occur in preeclampsia.144 Potential mechanisms responsible nancy, but blood pressure does not usually increase, indicating that
for the normal and abnormal changes include decidually produced systemic vascular resistance decreases. Blood pressure is lower in the
cytokines145-147 and local oxygen tension.148,149 There may be interac- first half of pregnancy than in the postpartum period, when cardiac
tions of specific molecules on trophoblast and maternal decidual cells output returns to nonpregnant levels (see Fig. 35-2). Some women
that drive invasion. Invasive cytotrophoblasts express a human leuko- destined to develop preeclampsia have a higher cardiac output before
cyte antigen (HLA) molecule (HLA-C) that is minimally hetero- clinically evident disease. However, cardiac output is reduced to pre-
geneous. Interaction of this molecule with a receptor on maternal pregnancy levels with the onset of clinical preeclampsia.157,158 Although
decidual cells, killer immunoglobulin receptors (KIRs), causes various some studies suggest increased cardiac output,159 most have found
degrees of activation of the trophoblast cell, depending on the combi- normal or slightly reduced cardiac output in women with untreated
nation of KIR and HLA-C subtypes. Mothers with the minimally acti- preeclampsia.160 Increased systemic vascular resistance is the mecha-
vating KIR subtype who have a fetus with a specific HLA-C subtype nism for the increase in blood pressure in clinical preeclampsia.
(HLA-C2) have an increased frequency of preeclampsia. This is not an There is substantial evidence that arteriolar narrowing occurs in
immune interaction because the relationship persists regardless of preeclampsia. Changes in the caliber of retinal arterioles correlate with
maternal HLA-C subtype. Researchers propose that this combination the clinical severity of the disorder and with renal biopsy-confirmed
does not favor trophoblast invasion and vascular remodeling. Popula- diagnosis of preeclampsia.103 Similar findings occur in vessels of the
tion studies indicate that populations in which HLA-C2 is common nail bed and conjunctiva. Measurements of forearm blood flow indi-
have a reduced frequency of the specific inhibitory KIR subtype and cate higher resistance in preeclamptic than in normal pregnant
vice versa.150 women.161,162 It is unlikely that this effect is determined by the auto-
nomic nervous system. Although normal pregnant women are exqui-
Placental Pathologic Changes sitely sensitive to the interruption of autonomic neurotransmission by
Ultrastructural examination of placentas from women with pre- ganglionic blockade and high spinal anesthesia, preeclamptic women
eclampsia reveals an abnormal syncytiotrophoblast containing areas of are less sensitive.163 This finding suggests that the arteriolar constric-
cell death and degeneration. Viable-appearing syncytiotrophoblast is tion of preeclampsia is not maintained by the autonomic nervous
also abnormal, with decreased density of microvilli, dilated endoplas- system and that humoral factors are implicated. The increased sympa-
mic reticulum, and decreased pinocytotic and secretory activity. The thetic activity in preeclampsia, however, raises questions about these
cells of the villous cytotrophoblast cells are increased in number and older findings.164 Assays of concentrations of recognized endogenous
have higher mitotic activity. The basement membrane of the tropho- vasoconstrictors are limited to determinations of catecholamines and
blast is irregularly thickened, with fine fibrillary inclusions.151 angiotensin II. Results suggest minimal or no change in catechol-
The changes may be caused by local hypoxia. Similar syncytiotro- amines, whereas circulating angiotensin II concentrations are lower in
phoblastic changes are present in placental segments maintained under preeclamptic women.165
hypoxic conditions in vitro.152 The cytotrophoblastic alterations are Levels of endothelin-1, a vasoconstrictor produced by endothelial
also consistent with hypoxia. The cytotrophoblasts comprise the stem cells, are increased in the blood of preeclamptic women166 at concen-
cells of the trophoblast and responds to damage by proliferation. The trations much lower than those necessary to stimulate vascular smooth
trophoblast of the preeclamptic placenta is characterized by increased muscle contraction in vitro. It is not clear whether these circulating
apoptosis and necrosis,153,154 possibly caused by hypoxia or hypoxia concentrations reflect endothelial production sufficient to stimulate
reperfusion injury,155 and this may be the origin of the increased cir- local vasoconstriction or low concentrations of endothelin potentiate
culating syncytiotrophoblast microparticles in preeclampsia.156 contractile responses to other agonists.
As indicated by the older term toxemia, early investigators sus-
Summary of Pathologic Changes pected that preeclampsia was caused by circulating humors. Early
in Preeclampsia reports suggesting etiologic agents such as pressor substances in blood,
Structural changes associated with preeclampsia and eclampsia lead to decidual extracts, placental extracts, and amniotic fluid of preeclamp-
two important conclusions. First, preeclampsia is not an alternate form tic patients have not been replicated. The explanation for the pressor
of malignant hypertension. The renal changes in preeclamptic and effects was, in some studies, normal endogenous pressors; in others,
eclamptic women and the structural changes in other organs of women the explanation was faulty methodology and failure to recognize the
dying of eclampsia differ from the alterations caused by malignant immunologic difference between the source of the extract and the

12. 662 CHAPTER 35 Pregnancy-Related Hypertension
50 50 Preeclampsia
Preeclampsia
Nonpregnant
Nonpregnant
40 Normal pregnancy
MBP, mm Hg
Normal pregnancy 40
MBP, mm Hg
30 30
20 20
10 10
5 10 15 25 50 100 200 5 10 15 25 50 100 200
Dose, ng/kg Dose, ng/kg
FIGURE 35-11 Mean dose-response graphs for norepinephrine. FIGURE 35-12 Mean dose-response graphs for angiotensin.
Women with preeclampsia have an increased sensitivity to all Preeclamptic women are much more sensitive to angiotensin II than
endogenous pressors. MBP, mean blood pressure. (From Talledo OE, normal pregnant and nonpregnant women. MBP, mean blood
Chesley LC, Zuspan FP: Renin-angiotensin system in normal and pressure. (From Talledo OE, Chesley LC, Zuspan FP: Renin-
toxemic pregnancies. III. Differential sensitivity to angiotensin II and angiotensin system in normal and toxemic pregnancies. III.
norepinephrine in toxemia of pregnancy. Am J Obstet Gynecol Differential sensitivity to angiotensin II and norepinephrine in toxemia
100:218, 1968. Courtesy of the American College of Obstetricians of pregnancy. Am J Obstet Gynecol 100:218, 1968. Courtesy of the
and Gynecologists.) American College of Obstetricians and Gynecologists.)
animals tested. In other experiments, no defect is obvious. The hypoth-
16
esis that arteriolar constriction of preeclampsia is caused by new cir-
culating pressors has largely been abandoned.18
A more compelling explanation for vasospasm in preeclampsia is
increased response to normal concentrations of endogenous pressors.
Women with preeclampsia have higher sensitivity to all the endoge- 12
nous pressors that have been tested. They are exquisitely sensitive to
ng/kg/min
vasopressin.167,168 Vasopressin can elicit marked blood pressure eleva-
tion, seizures, and oliguria in some patients.168 Sensitivity to epineph-
rine169 and norepinephrine170 is also increased (Fig. 35-11). The most 8 Nonpregnant mean
striking difference is seen in the sensitivity of the preeclamptic woman
to angiotensin II. Normal pregnant women are less sensitive to angio- P<.01
tensin II than nonpregnant women, requiring approximately 2.5 times P<.05 P<.1 P<.001
as much angiotensin to raise the blood pressure by a similar incre-
4
ment.171 In contrast, preeclamptic women are much more sensitive to 10 14 18 22 26 28 30 32 34 36 38 40
angiotensin II than are normal pregnant and nonpregnant women Weeks of gestation
(Fig. 35-12).170
In a classic study, angiotensin II sensitivity was significantly FIGURE 35-13 Angiotensin sensitivity throughout pregnancy. The
increased many weeks before the development of elevated blood pres- dose of angiotensin II necessary to increase diastolic blood pressure
sure (Fig. 35-13).172 Although resistance to angiotensin II does not 20 mm Hg in women who developed elevated blood pressure in late
decrease to nonpregnant levels until 32 weeks’ gestation, significant pregnancy (blue line, open circles) was compared with the dose for
those who remained normotensive (red line, solid circles). The graph
differences in sensitivity between women who later become hyperten-
demonstrates that a significantly lower dose was required in the
sive and those who remain normotensive have been observed as early former group as early as 10 to 14 weeks’ gestation. (From Gant NF,
as 14 weeks. However, a large British study did not confirm this classic Daley GL, Chand S, et al: A study of angiotensin II pressor response
finding,173 perhaps reflecting the heterogeneity of preeclampsia.174 throughout primigravid pregnancy. J Clin Invest 49:82, 1973. With
The decreased sensitivity of normal pregnant women to angioten- permission of the American Society for Clinical Investigation.)
sin II and the lower systemic vascular resistance in normal pregnancy
suggest that arteriolar narrowing in preeclamptic women may result
from decreased levels of circulating or local vasodilator substances, coagulation system manifests as the intravascular disappearance of
rather than from increased levels of circulating pressors. This attractive procoagulants, intravascular appearance of degradation products of
hypothesis, however, is not consistent with the unchanged sensitivi- fibrin, and end-organ damage from the formation of microthrombi.176
ties to norepinephrine, epinephrine, and vasopressin in normal In the most advanced form of DIC, procoagulants—especially fibrino-
pregnancy.168-170 gen and platelets—decrease to a degree sufficient to produce spontane-
ous hemorrhage. In milder forms, only highly sensitive indicators of
Coagulation Changes clotting system activation are present. Decreasing platelet concentra-
The syndrome of DIC occurs in preeclampsia and has been suggested tions is such a sign but may be evident only by serial observations.96
as a primary pathogenetic factor175 (see Chapter 40). Activation of the Sensitive indicators of intravascular coagulation, such as an elevated

13. CHAPTER 35 Pregnancy-Related Hypertension 663
level of fibrin degradation products; increased platelet turnover,6 thelium. Vessels from preeclamptic women and the umbilical vessels
volume,114 and activation177; reduced platelet content178; increased of their neonates generate less prostacyclin than similar vessels from
platelet content in plasma179; reduced levels of antithrombin III111; and normal pregnant women.202-204 If potent inhibitors preventing the syn-
a reduced ratio of factor VIII activity to factor VIII antigen,180 are thesis of all prostaglandins (including prostacyclin) are administered
common when concentrations of procoagulants remain normal. Subtle to pregnant women, the usual resistance to the vasoconstrictor effect
signs of platelet dysfunction,6,114,177-179 reduced antithrombin III,111 and of angiotensin II is abolished.205 Conversely, if aspirin is used as an
reduction in the ratio of factor VIII bioactivity to factor VIII antigen112 inhibitor of prostaglandin synthesis in a manner determined to specifi-
are present in women with mild preeclampsia and may precede its cally reduce contractile prostanoids (e.g., thromboxane A2) much more
clinical signs. than prostacyclin, the increased angiotensin II sensitivity of preeclamp-
Abnormalities of blood coagulation sufficient to make a diagnosis tic women is reduced.206
of DIC are present in approximately 10% of women with severe pre- Nitric oxide (NO) is another bioactive material produced by normal
eclampsia or eclampsia.181 Results of highly sensitive assays of coagula- endothelium.207 Its release is stimulated by several hormones and neu-
tion activation suggest, however, that abnormalities of the coagulation rotransmitters and by hydrodynamic shear stress. NO is quite labile
system are present in many patients with mild to moderate preeclamp- and acts synergistically with prostacyclin as a local vasodilator and
sia. Coagulation changes are thought to be secondary rather than inhibitor of platelet aggregation. Current thinking favors NO as an
primary pathogenetic factors182 because levels of procoagulants are endogenous vasodilator of pregnancy. Administration of inhibitors of
usually normal, and another early sign of preeclampsia—increased NO synthesis reduces blood flow much more strikingly in pregnant
serum uric acid—may precede changes in coagulation.110 than in nonpregnant women.208 Production of NO is reduced with
The cause of the change in coagulation factors is uncertain. Vascu- endothelial cell injury. Information about NO production in pre-
lar damage resulting from vasospasm may initiate DIC182 and probably eclampsia is conflicting,209-214 in part because of the use of blood con-
contributes to activation of the clotting system in severe preeclampsia. centrations of NO metabolites to determine production in the setting
Signs of endothelial dysfunction also antedate clinical disease,183 and of the reduced renal function of preeclampsia.215 Two studies have
activation of platelets and other components of the coagulation cascade documented reduced urinary NO excretion in preeclampsia,212,216 and
is a well-recognized consequence of endothelial dysfunction.184 Vascu- another found increased excretion.217 Perhaps the most compelling
lar changes in the implantation site that appear to antedate blood data are from estimates of the tissue concentrations of nitrotyrosine
pressure elevation may be pathogenetically important. (i.e., product of the interaction of NO and superoxide). Nitrotyrosine
Whether coagulation changes measured in preeclamptic patients residues are increased in the placenta218 and vessels219 of women with
represent true DIC or a localized consumption of procoagulants in preeclampsia. It is posited that the placenta directly or indirectly pro-
the intervillous space is not clear. Microthrombi and the presence of duces factors that alter endothelial function. Candidate molecules
fibrin antigen have been inconsistently observed in liver, placenta, and include the following:
kidney.185-187 Early coagulation changes such as factor VIII activity-
antigen ratios and platelet count correlate better with the fetal outcome Cytokines220 (with increasing evidence that endothelial
as measured by mortality and growth restriction rates than with the dysfunction is part of a generalized increased inflammatory
clinical severity of preeclampsia. Identical coagulation changes occur response221)
in normotensive women with growth-restricted fetuses,188 suggesting Placental fragments (i.e., syncytiotrophoblast microvillous
that localized coagulation in the intervillous space is important. Simi- membranes)222
larly, an increased concentration of fibrin antigen has been reported in Free radicals
the placentas of preeclamptic patients.185 Reactive oxygen species223
Endothelial Cell Dysfunction The latter hypothesis—that oxidative stress causes endothelial
There is increasing support for endothelial dysfunction as a patho- dysfunction—is especially interesting in view of the similarities of
physiologic component of preeclampsia.183,189,190 Alterations of glo- the lipid changes of preeclampsia to those of atherosclerosis,118 an
merular endothelial cells are a consistent feature of preeclampsia. endothelial disorder in which oxidative stress is thought to play a key
Levels of cellular fibronectin,191,192 growth factors,193 vascular cell adhe- role.224
sion molecule 1 (VCAM-1),194 factor VIII antigen, and peptides released The information available indicates that endothelial cell dysfunc-
from injured endothelial cells are increased in preeclamptic women tion can alter vascular responses and intravascular coagulation in a
before the appearance of clinical disease.112 Examination showed that manner consistent with the pathophysiologic abnormalities of pre-
the endothelial function of vessels of preeclamptic women was impaired eclampsia. Evidence is accumulating that endothelial injury may play
in vitro.195,196 a central role in the pathogenesis of preeclampsia.
The endothelium is a complex tissue with many important func-
tions. Prevention of coagulation and modulation of vascular tone have Renal Function Changes
special relevance to preeclampsia. Intact vascular endothelium is resis- Renal function changes characteristic of women with preeclampsia or
tant to thrombus formation.197 With vascular injury, endothelial cells eclampsia include decreased glomerular filtration and proteinuria.
can initiate coagulation by the intrinsic pathway (i.e., contact activa- Changes in components of the renin-angiotensin system probably
tion)198 or by the extrinsic pathway (i.e., tissue factor).199 Platelet adhe- differ from those of normal pregnancy. Sodium excretion is decreased,
sion can also occur after injury with exposure of subendothelial resulting in fluid retention and edema.
components, such as collagen200 and microfibrils.
Endothelium profoundly influences the response of vascular GLOMERULAR FUNCTIONAL CHANGES
smooth muscle to vasoactive agents. The response to some agents201 Glomerular Filtration Rate. Decreased glomerular filtration fre-
can change from dilation to constriction with the removal of endothe- quently complicates preeclampsia, and it is explained only partially by
lium. Prostacyclin, a highly potent vasodilator, is produced by endo- decreased renal plasma flow (RPF). The filtration fraction (GFR/RPF)

14. 664 CHAPTER 35 Pregnancy-Related Hypertension
may be decreased18 because of intrarenal redistribution of blood In summary, uric acid clearance changes earlier in preeclamptic
flow.225 A more obvious explanation is glomeruloendotheliosis, in pregnancy than does the GFR, suggesting a tubular rather than a glo-
which the occlusion of glomerular capillaries by swollen endothelial merular functional explanation. Although the exact mechanism for the
cells probably renders many glomeruli nonfunctional. urate clearance change is not established, the common feature in the
Protein Leakage. The pathogenesis of proteinuria in preeclamp- suggested mechanisms is decreased renal perfusion; however, increased
sia is primarily explained by glomerular changes. The normal absence production by poorly perfused tissue cannot be excluded.106,240
of protein in urine results from a relative impermeability of glomeruli Urinary Concentrating Capacity. Although the issue is not fully
to large protein molecules and from the tubular resorption of smaller settled, the tubular concentrating capacity is probably unchanged in
proteins that cross the glomeruli. As glomerular damage occurs, per- normal pregnancies.241 Assali and associates242 suggested that urinary
meability to proteins increases. As damage increases, so does the size concentrating ability is decreased in hypertensive women. The limita-
of the protein molecule that can cross the glomerular membrane. tions of these studies include the failure to account for parallel changes
Increased permeability results in decreased selectivity. With minimal in the concentrating capacity and GFR243 and the use of specific
glomerular damage or tubular dysfunction, only small protein mole- gravity—an unreliable estimate of osmolality—as the measure of
cules are excreted, but with greater damage, large and small proteins concentration.18
are present in urine. Normal pregnant women were found to have decreased capacity to
In women with preeclampsia, selectivity is low, indicating increased concentrate urine (measured as osmolar concentration and corrected
permeability and glomerular damage.226 The well-known clinical for the GFR) in response to vasopressin administration, a decrease
observation that the magnitude of proteinuria in preeclamptic women similar to that seen in pregnant women who were or later became
varies greatly over time was quantitated by Chesley,227 who noticed hypertensive.244 Conflicting study results suggesting that tubular con-
hourly variation in the urinary creatinine-to-protein ratio in women centrating capacity is unchanged in normal pregnancy are confounded
with preeclampsia that was not present in the urine of individuals with by a failure to correct for the increased GFR of normal pregnancy,
other proteinuric conditions. which concomitantly increases concentrating capacity.243
Because structural glomerular changes are constant, proteinuria in Excretion of Phenolsulfonphthalein. Because phenolsulfon-
preeclamptic women must in part depend on a varying functional phthalein is secreted by proximal tubular cells, its excretion can be used
cause (e.g., a variation in the intensity of the renal vascular spasm). as an indicator of proximal tubular function.235 However, phenolsul-
That vascular spasm can cause proteinuria has been demonstrated by fonphthalein excretion is altered independently of tubular secretory
measuring urinary excretion of protein in individuals subjected to the capacity with increased245 or decreased246 renal plasma flow or reduced
cold pressor test. Immersing a patient’s hand in ice water for 60 seconds GFR247 and with increased urinary dead space (a problem pertinent in
increases blood pressure by more than 16 mm Hg (systolic and dia- pregnancy). When these factors are controlled, reduced phenolsulfon-
stolic), and an increase in protein excretion almost invariably phthalein excretion precedes changes in the GFR and clinically evident
occurs.228 disease in women with preeclampsia.235
Renin-Angiotensin-Aldosterone System. The renin-angiotensin-
RENAL TUBULAR FUNCTIONAL CHANGES aldosterone system (RAAS) is important in pressure and volume regu-
Uric Acid Clearance. Three separate processes are involved in the lation in normal pregnancy (Fig. 35-14).248 Dramatic changes occur in
renal excretion of urate. Urate is completely filtered at the glomerulus. the RAAS during pregnancy.249 The following components are
It is not bound to plasma proteins under physiologic conditions,229 and increased:
glomerular urate concentration is equal to renal arterial plasma con-
centration. Urate is secreted and reabsorbed by renal tubules. Most Angiotensinogen (i.e., renin substrate)
urate (98%) is reabsorbed, and about 80% of excreted urate is accounted Plasma renin activity250
for by urate secretion. Both processes occur predominantly in the
proximal tubule. Reabsorption occurs to a greater extent than secre-
tion, and urate clearance is about 10% of creatinine clearance.230
Abnormalities of uric acid clearance have long been recognized as Juxtaglomerular
apparatus
a consistent phenomenon in preeclampsia231 and have been regarded
STIMULATION
as a function of decreased glomerular filtration.232 Several studies
have demonstrated the discrepancy between uric acid clearance and
both inulin clearance and creatinine clearance.233,234 Serial studies also Intravascular volume decreased
reveal that decreased uric acid clearance precedes decreases in the INHIBITION Sodium depletion
Renin
GFR.235
Urate clearance is decreased by hypovolemia, presumably as a result
of nonspecific stimulation of proximal tubular reabsorption.236 Plasma Sodium retention Renin substrate Angiotensin I
volume depletion is coincident with urate clearance changes,237 sug- Volume expansion
gesting that volume change may account for the abnormality in urate
clearance. However, the correlation between the degree of volume Angiotensin II
depletion and the decrease in urate clearance is poor.237
Stimulates Converting enzyme
Angiotensin II infusion decreases urate clearance even in the pres-
aldosterone secretion Pressor
ence of normal blood volume.238 The increase in angiotensin II sensi- effect
tivity seen in preeclampsia may account for the change in renal
function. Local effects of angiotensin II may also be important because FIGURE 35-14 Schematic representation of the renin-angiotensin
this substance can be produced locally,239 unassociated with increased system. The system regulates pressure and volume in normal
circulating angiotensin II. pregnancies, and abnormalities contribute to preeclampsia.

15. CHAPTER 35 Pregnancy-Related Hypertension 665
Plasma renin concentration Atrial Natriuretic Factor. Atrial natriuretic factor (ANF), a
Angiotensin II concentration250,251 peptide produced in response to atrial stretch with hypervolemia, regu-
Aldosterone252 lates intravascular volume by several mechanisms. ANF increases
sodium excretion and the egress of fluid from the intravascular com-
Abnormalities of the RAAS have been proposed as causal factors in partment. Although the reduced plasma volume of preeclampsia pre-
preeclampsia253 because angiotensin II is a potent vasoconstrictor, it dicts reduced ANF concentration, the concentration is increased,270
influences aldosterone secretion and consequent sodium retention, and the increase precedes clinical disease.271 The stimulus for this
and at high concentrations, it can cause proteinuria. Myometrium and increase is unclear, but the paradoxical finding of increased circulating
chorion can synthesize renin, which is stimulated in experimental ANF levels and reduced renin concentration with reduced plasma
animals by uterine ischemia.254 volume in preeclamptic women suggests that the reduced plasma
Most investigators agree that the angiotensinogen level remains volume is increased relative to the constricted vascular compartment.
elevated in preeclampsia.250,255 The plasma renin activity and plasma Changes in Sodium Excretion. Sodium retention has long been
renin concentration are reduced in preeclampsia compared with considered an integral part of the pathophysiology of preeclampsia.
normal pregnancy.256 In a prospective study of women with chronic Women with eclampsia and severe preeclampsia have very little chlo-
hypertension, plasma renin activity was lower when superimposed ride and sodium in the urine.272 After delivery, however, chloride
preeclampsia developed (i.e., diagnostic blood pressure increase and excretion increases dramatically. Infusion of hypertonic saline into
proteinuria) than in chronic hypertensive women without superim- preeclamptic women results in excretion of the infused sodium at
posed preeclampsia and in normal pregnant women. Concentrations about one half of the rate seen in normal pregnant women.167 Similar
were similar in early pregnancy in all groups and decreased only results occur in women with glomeruloendotheliosis identified on
slightly before the increase in blood pressure.257 renal biopsy.273 Most studies of exchangeable sodium have indicated an
The reduced renin activity in preeclampsia suggests suppression of increase in total body sodium in preeclamptic patients.274,275
renin release. This is puzzling in view of the reduced plasma volume The cause of sodium retention in preeclamptic women is difficult
that is characteristic of preeclampsia. There is no apparent nonphysi- to determine because of the enormous number of factors that influ-
ologic suppression of renin activity, because usual physiologic pertur- ence sodium excretion in normal pregnancy and because of the many
bations result in appropriately increased and decreased concentrations demonstrated anomalies of renal function in preeclampsia that can
of plasma renin activity (i.e., renin is increased with upright posture cause sodium retention (Table 35-5). Any or all of the demonstrated
and head-up tilt258 and falls with volume expansion259). Despite the changes in plasma volume, angiotensin sensitivity, and renal function
reduced content of the vascular compartment in preeclampsia, the may act on several of the factors listed in Table 35-5 to cause sodium
intense vasoconstriction characteristic of preeclampsia results in a retention.
physiologic perception of overfill, suppressing renin release. The Several investigators have considered the increased sodium reten-
reduced renin activity in preeclampsia results in reduced angiotensin tion to be a primary factor inciting the pathogenetic changes in pre-
II165 and aldosterone concentrations260 compared with concentrations
in normal pregnancy.
Attempts to test the role of the renin-angiotensin system (RAS) by TABLE 35-5 FACTORS AFFECTING SODIUM
using angiotensin II antagonists or by converting enzyme inhibitors BALANCE IN NORMAL
have not clarified this point. Administration of the angiotensin antago- PREGNANCY
nist (1-Sar-8-Ile-angiotensin II) to pregnant hypertensive women
increases blood pressure,261 and because this antagonist is a partial Factors Affecting Glomerular Filtration
Blood pressure in critical areas of the kidney
agonist, the increase in blood pressure may reflect the increased angio-
Relative tonus of afferent and efferent glomerular arterioles
tensin sensitivity of hypertensive pregnant women. The administration
Plasma oncotic pressure
of the angiotensin antagonist saralasin262 or the angiotensin-converting Intrarenal redistribution of blood flow
enzyme inhibitor SQ 20,881263 in the postpartum period did not have Central nervous system effects
significant effects on blood pressure in a mixed group of women with
hypertension. Factors Affecting Tubular Reabsorption
Interest in the role of the RAS in preeclampsia has increased as the Aldosterone
effects of angiotensin on responses other than blood pressure have Progesterone (an aldosterone antagonist)
been recognized.264 The activation of NADPH oxidase in several tissues Renal vascular resistance
by angiotensin II can generate oxidative stress.264-266 Hypoxia-inducing Perfusion pressure in peritubular capillaries
Oncotic pressure in peritubular capillaries
factors (HIFs) induce molecules responsible for many of the responses
Non-reabsorbable anions in the filtrate
to hypoxia. These factors are upregulated in the placenta of a woman Velocity of flow in tubules
with preeclampsia267 and can be activated by angiotensin II.268 Anti- Reabsorptive capacity of tubules
bodies to angiotensin II that activate angiotensin receptors and likely Estrogens (stimulate sodium reabsorption, possibly indirectly, by
increase the sensitivity of these receptors to angiotensin II are present effects on vascular permeability)
in women with preeclampsia.269 Plasma sodium concentration
Studies indicate that no simple relationship exists between compo- Hematocrit (viscosity effects)
nents of the RAS and preeclampsia. The significance, however, Changes of plasma volume
of reduced plasma renin activity, plasma renin concentration, and Angiotensin
angiotensin II concentration on blood pressure and sodium excretion Sympathetic nervous system
Possibly a natriuretic hormone (“third factor”)
in this group of women—who show apparent volume constriction
and who are exquisitely sensitive to angiotensin II—deserves Modified from Chesley LC: Hypertensive Disorders in Pregnancy. New
elucidation. York, Appleton-Century-Crofts, 1978.

16. 666 CHAPTER 35 Pregnancy-Related Hypertension
eclampsia. Although this possibility cannot be definitely excluded, it is feature of normal pregnancy, with further increases in women with
not likely for several reasons: mild preeclampsia and significant elevations observed in women with
severe preeclampsia.289
1. Angiotensin sensitivity precedes obvious fluid retention by Another hypothesis about the immunologic cause of preeclampsia
months. is that vascular changes in the spiral arterioles of the placental implan-
2. Thiocyanate space, an indicator of sodium space, does not reliably tation site are the result of an allograft rejection between mother and
predict preeclampsia.276 fetus. However, who is rejecting whom?286 Should the spiral arteries
3. Restriction of dietary sodium or increasing sodium excretion with lined with trophoblast be thought of as fetal vessels, with the fetus
diuretics does not affect the occurrence of preeclampsia.277-279 rejecting the mother, or as maternal vessels, with the mother rejecting
the fetus?
SUMMARY OF RENAL FUNCTION CHANGES If preeclampsia represents a rejection of the fetus by the mother,
Renal function changes in preeclampsia are consistent and charac- the protective effect of previous exposure to antigen indicates that the
teristic. Changes in tubular function precede the more widely appreci- preeclamptic mother has a deficit of blocking antibodies or of suppres-
ated changes in glomerular function. These functional changes return sor cell function. The recognition of a unique HLA antigen, HLA-G,
to normal within weeks to months after the conclusion of pregnancy. on the trophoblast290 suggests other possible causes of rejection of the
Prospective, sequential studies of renal function indicate that some of fetus. HLA-G is a class I antigen present almost exclusively on the
these changes antedate the clinical diagnosis of preeclampsia, but they cytotrophoblast with minimal heterogeneity. Unlike classic HLA anti-
do not necessarily antedate other indicators of preeclampsia such as gens, which exhibit numerous epitopes, fetal HLA-G in the trophoblast
changes in coagulation and plasma volume. They are therefore unlikely is likely to be identical in most fetuses, and the fetus would exhibit the
to be causal abnormalities. Although the cause of renal functional same antigen as that expressed by the mother during her fetal life.
changes is not clear, they may be explained by systemic or regional Because an immune cell (i.e., natural killer lymphocyte) found in
abnormalities of renal perfusion. maternal decidua in high numbers is postulated to destroy cells not
bearing HLA antigens, a reduced level of HLA-G may render the fetus
Immunologic Changes and Activation of a target for these cells. Unusual epitopes of HLA-G also can activate
Inflammatory Responses maternal immune defenses. Although there are suggestions that poly-
Epidemiologic and laboratory observations suggest that fetal-maternal morphisms of HLA-G may be more common in preeclampsia,291 the
immunologic interactions may be etiologically important in the patho- data are minimal, and findings are not universally accepted.292
genesis of preeclampsia. The increased incidence of preeclampsia in If preeclampsia represents a rejection of the mother by the fetus,
first pregnancies and the protective effect even of miscarriage suggest the preeclamptic mother would have to be deficient in the capacity
that maternal exposure to fetal antigens may be protective, an effect to destroy fetal immune cells. These alternative hypotheses—one
that appears to be lost if the father is not the same man who fathered requiring active intervention and the other passive intervention by the
the prior pregnancy.280,281 The increased risk of preeclampsia with a maternal immune system—should give disparate results in in vitro
new father is affected by the interpregnancy interval, which tends to testing of maternal immune function. The experimental evidence
be longer in pregnancies with new fathers. This finding is compatible available is not consistent enough to confirm or to contradict either
with an immunoprotective effect of antigen exposure, which is also lost hypothesis.
when antigen exposure is minimal for a prolonged period.282 Exposure The innate immune response system may also play a role.293 Normal
to paternal components of fetal antigen through sexual activity with pregnancy is associated with an activation of inflammatory response
the potential father before the first pregnancy is also associated with that is similar to that seen in sepsis. This inflammatory response is
reduced risk of preeclampsia.283,284 The pathologic changes in decidual further increased in preeclampsia.294 Materials released from the pla-
vessels at the placental site in preeclampsia are similar to the vascular centa, perhaps microvillus particles associated with aponecrosis, inter-
changes of acute immunologic rejection.140 act with maternal immune cells to produce inflammatory activation.295
Several immunologic mechanisms have been suggested.285,286 Pre- Increased release of these materials in preeclampsia is posited to
eclampsia may be an immune complex disease. There is an efflux of augment the immune response with secondary pathogenetic effects of
fetal antigen into the maternal circulation during pregnancy. If the this inflammatory activation.
maternal antibody response is adequate, the complexes are cleared by An immunologic cause of preeclampsia is consistent with much
the reticuloendothelial system, and no damage occurs. If the antibody that is known about the disorder. Increased delineation of the changes
response or clearance mechanisms are inadequate,287 the pathologic in the immunologic activity in preeclampsia may provide insight into
immune complexes formed can cause vasculitis, glomerular damage, the cause of preeclampsia and normal fetal-maternal compatibility
and activation of the coagulation system. An inadequate maternal anti- during pregnancy.
body response also can be suggested by HLA typing that demonstrates
an increased concordance of the major histocompatibility antigens in Oxidative Stress
maternal-paternal pairs that result in preeclamptic pregnancies.286 Oxidative stress occurs when there is an excess of active oxygen prod-
However, preeclampsia is less common in consanguineous marriages, ucts beyond the capacity of buffering mechanisms, antioxidants, and
a finding incompatible with this concept.288 Alternatively, the maternal antioxidant enzymes. This phenomenon can occur with excess produc-
antibody system may be overwhelmed by an excess of fetal antigen, a tion of reactive oxygen products or with deficiency of antioxidant
theory supported by the increased incidence of preeclampsia when mechanisms.296 Reactive oxygen products can damage proteins, lipids,
trophoblastic tissue is increased (e.g., twins, hydatidiform mole, and DNA, and the endothelium is particularly vulnerable. Levels of
hydropic placenta). Few data support this concept. lipid markers of oxidative stress are increased in women with pre-
Actual measurements of immune complexes in women with pre- eclampsia.297,298 Lipid oxidation products, protein products of oxida-
eclampsia are inconsistent because of broadly different methodologies tion, protein carbonyls,299 and nitrotyrosine are present in the
and definitions of preeclampsia. Increased immune complexes are a circulation, blood vessels,219 and placenta218 of preeclamptic women

17. CHAPTER 35 Pregnancy-Related Hypertension 667
and their fetuses. Reduced levels of antioxidants300,301 and increased Although these and other studies325 support the genetic heterogeneity
levels of antibodies to oxidized LDL cholesterol302 are found in excess of preeclampsia,174 the literature may be underpowered and subject to
in women with preeclampsia. These changes are not likely the result publication bias.326
of preeclampsia, because reduced antioxidants and increased lipid In the Genetics of Preeclampsia study of 1000 paternal, maternal,
peroxidation products are present in women destined to develop and fetal triads, none of the usual candidates was related to preeclamp-
preeclampsia.303,304 sia.326 The results of linkage analyses to perform hypothesis-free testing
The excess oxidative species relevant to preeclampsia have several of genetic associations have varied. Associations of preeclampsia have
origins. Transition metals such as iron catalyze the formation of reac- been found with loci on chromosomes 2p,327,328 2q,327,328 4q,325,329 9,329
tive oxygen species, and free iron and redox active copper305 are and 10330 in different populations. A novel study from the Nether-
increased in the blood of women with preeclampsia.306 Reduced tissue lands330 combined physical localization of a candidate gene with a
perfusion sufficient to result in hypoxia and followed by restored per- search for functionally relevant genes in this chromosomal region. This
fusion and reoxygenation leads to the formation of reactive oxygen methodology identified STOX1, a paternally imprinted gene involved
species.307 This mechanism is compatible with pregnancy and pre- in trophoblast differentiation. As a paternally imprinted gene, STOX1
eclampsia. Uterine and placental blood flow is not privileged, and flow is active only when coming from the mother. A mutated version of this
is reduced when blood is shunted to other organs during exercise, gene was consistently present in affected sisters in preeclamptic pedi-
eating, and other normal activities. In late pregnancy, uterine and pla- grees. Although STOX1 was localized to chromosome 10 in the
cental blood flow is reduced profoundly by postural effects on uterine Netherlands study, a paralogue of this gene, STOX2, is located on
perfusion. All of these changes are reversible and are followed by chromosome 4q, close to the suggestive region identified in genome-
restored perfusion. In normal pregnancy, reduced placental perfusion wide searches in Finland and Australia. The use of high-throughput
as described is not sufficient to generate free radicals. In preeclampsia, genetic and gene expression and proteomic studies is just beginning to
however, free radicals are generated in the intervillous space.218,308 be applied to the study of preeclampsia.326
Reduced placental perfusion may result in maternal systemic disease
as the products of oxidative stress are transferred to the maternal
circulation.309 Management of Preeclampsia
Philosophy of Management
Genetics of Preeclampsia The optimal philosophy of management is a product of the current
The tendency of preeclampsia and eclampsia to occur in daughters and knowledge about the pathophysiologic changes of and prognosis for
sisters of women with preeclampsia is frequently overlooked. In Aber- preeclampsia. Three principles can be applied.
deen, Scotland, the incidence of proteinuric preeclampsia was increased First, delivery is always appropriate therapy for the mother but may
fourfold among sisters of women who had preeclampsia in their first not be so for the fetus. Because we do not understand its cause, attempts
pregnancy compared with sisters of women who did not.310 The inci- to prevent preeclampsia by conventional medical approaches have
dence of preeclampsia was 15% among mothers but only 4% among been understandably unsuccessful. The primary goal of therapy is to
mothers-in-law of preeclamptic women.311 Chesley and Cooper312 prevent maternal morbidity and mortality. Preeclampsia is progressive
evaluated preeclampsia in the first pregnancy of sisters, daughters, at variable rates, and careful antepartum observation can identify the
granddaughters, and daughters-in-law of women who had been woman at risk. Preeclampsia is completely reversible and begins to
eclamptic. The incidence of preeclampsia was 37% among sisters, 26% abate with delivery. If only maternal well-being were considered, deliv-
among daughters, and 16% among granddaughters. The incidence was ery of all preeclamptic women, regardless of severity of process or stage
6% among daughters-in-law. The fetal genome is also related to the of gestation, would be appropriate. Expectant management is appro-
occurrence of preeclampsia. Men who have fathered preeclamptic priate in some circumstances to attain an optimal outcome for the
pregnancies are more likely to father preeclamptic pregnancies with fetus. The goal of any therapy for preeclampsia other than delivery
new partners than are men who have never been fathers in preeclamp- must be improved rates of perinatal and long-term mortality and
tic pregnancies.313 Men born to preeclamptic pregnancies are more morbidity for the fetus, infant, and child.
likely to be fathers of preeclamptic pregnancies than are men who are Second, the signs and symptoms of preeclampsia are not pathoge-
born of non-preeclamptic pregnancies.314 netically important. The pathologic and pathophysiologic changes of
What is inherited in preeclampsia? Possibilities include immuno- preeclampsia indicate that poor perfusion, caused at least in part by
logic differences, features that compromise implantation, and an vasospasm, is the major factor leading to the derangement of maternal
increased response to the systemic insult caused by reduced placental physiologic function and ultimately leading to perinatal mortality and
perfusion. Examinations of candidate genes support all possibilities. In morbidity. This same abnormality causes increased total peripheral
some populations, certain HLA types are more common in the mother resistance, with subsequent elevation of blood pressure and decreased
and the fetus from preeclamptic pregnancies.315,316 A variant of the renal perfusion leading to sodium retention and edema. The protein-
angiotensinogen gene—reported to be more common in some uria of preeclampsia is at least partially explained by vasospasm and
studies317-319—is speculated to influence blood pressure and spiral by reversible glomerular damage. Attempts to treat preeclampsia by
artery remodeling.320 Gene variants potentially leading to aberrations of natriuresis or by lowering blood pressure do not alleviate the impor-
endothelial function are more common in preeclamptic women.321-323 tant pathophysiologic changes. Natriuresis may be counterproductive
Mutations leading to increased risk factors for later-life cardiovascular and may adversely affect fetal outcome because the plasma volume is
disease, including function-perturbing mutations of lipoprotein lipase already reduced in preeclamptic women.
genes88 and methylene tetrahydrofolate reductase (MTHFR, an enzyme Third, the pathogenic changes of preeclampsia are present long
abnormality associated with increased circulating homocysteine),322 before clinical criteria for diagnosis are evident. Changes in vascular
are associated with preeclampsia. As is common in studies of genetic reactivity, plasma volume, and renal function antedate—in some cases
polymorphisms, the results vary according to the population studied.324 by months—the increases in blood pressure, protein excretion,

18. 668 CHAPTER 35 Pregnancy-Related Hypertension
and sodium retention. Irreversible changes affecting fetal well-being is possible. Magnesium sulfate may reduce fetal heart rate variability,335
therefore may be present before the clinical diagnosis is made. but if normal variability was never evident, fetal scalp blood sampling
This likely explains the failure of dietary, pharmacologic, and may be necessary to ensure that decreased variability is not related to
postural therapy instituted after the recognition of clinical disease to fetal compromise. For the woman with marked hepatic capsular dis-
reduce perinatal morbidity and mortality. The only rationale for tention, cesarean delivery is indicated if vaginal delivery is not immi-
therapy other than immediate delivery is to palliate the maternal nent. Even several extra hours can threaten the life of the mother, and
condition to allow fetal maturation, and even this rationale is liver rupture is difficult to predict and to treat. In some cases of severe
controversial. preeclampsia, especially those with HELLP syndrome, rapidly worsen-
ing thrombocytopenia or other signs of maternal instability may pre-
Delivery clude a trial of labor.
Delivery is the definitive treatment for preeclampsia. Regional anesthesia offers its usual advantages for vaginal and
cesarean delivery but does carry the possibility of extensive sympa-
DELIVERY REMOTE FROM TERM tholysis with consequent decreased cardiac output, hypotension, and
Delivery in the setting of severe preeclampsia usually is chosen for impairment of already compromised uteroplacental perfusion. This
the maternal and fetal indications described previously. Fetal indica- problem can be avoided by meticulous attention to anesthetic tech-
tions for intervention include the following: nique and volume expansion. Regional anesthesia is not a rational
means of lowering blood pressure because it does so at the expense of
Non-reassuring fetal test results cardiac output. Similarly, although analgesia with narcotics is not con-
Estimated fetal weight less than the 5th percentile for traindicated and may be used when necessary, attempting to manage
gestational age or prevent eclampsia with profound maternal sedation has been inef-
Oligohydramnios (i.e., amniotic fluid index below 5.0 cm or fective and even dangerous.
maximal vertical pocket of fluid less than 2.0 cm)
Persistent absent or reversed diastolic flow on umbilical artery Antepartum Management
Doppler velocimetry in a growth-restricted fetus When preeclampsia is suspected, a careful evaluation of mother and
fetus is essential. Maternal blood pressure, laboratory values, and fetal
Delivery should be considered for all women with severe preeclampsia well-being should be assessed. If the diagnosis of preeclampsia is con-
who have reached a favorable gestational age, which usually is defined firmed, maternal seizure prophylaxis should be considered, blood pres-
as more than 32 to 34 weeks’ gestation. sure should be controlled to a level that minimizes risk of maternal
stroke, and plans for delivery should be made according to the gesta-
DELIVERY AT OR NEAR TERM tional age.
The treatment of choice for preeclampsia at term is delivery. Expect-
ant management may be considered when preeclampsia is diagnosed ASSESSMENT AND MONITORING OF THE
at less than 32 to 34 weeks’ gestation, even if disease is severe. However, MOTHER AND FETUS
as gestational age approaches 34 weeks, short- and long-term neonatal Maternal Monitoring. There are two goals for antepartum moni-
outcomes are excellent, and the potential benefits of expectant man- toring of the mother:
agement become less compelling. At 34 to 37 weeks, decisions regard-
ing delivery are not guided by good evidence, and clinical judgment Recognizing the condition early, because infants of mothers
must consider the neonatal prognosis, severity of maternal disease, and with even mild preeclampsia are at increased risk for adverse
the wishes of the patient. outcomes.
Gauging the rate of progression of the condition to prevent
ROUTE OF DELIVERY severe morbidity by delivery and to determine whether fetal
Delivery is usually accomplished by the vaginal route, with cesarean well-being can be monitored safely by the usual intermittent
delivery reserved for obstetric indications. The decision to expedite observations
delivery in the setting of severe preeclampsia does not mandate imme-
diate cesarean birth.331 Cervical ripening agents may be used if the Ideally, identification of early changes allows intervention before
cervix is not favorable before induction332 and if the fetus can be satis- the advent of clinical symptoms. Although many hemodynamic,
factorily monitored; however, a prolonged induction is best avoided, volume, and metabolic changes antedate the diagnostic clinical signs
especially in the presence of IUGR or oligohydramnios. The rate of in women destined to develop preeclampsia, none is sensitive enough
vaginal delivery after labor induction decreases to about 33% at less to be clinically useful.7,33,112,167,235,336-338 The increased blood pressure
than 28 to 34 weeks’ gestation because of the high frequency of non- response to angiotensin II172,339,340 in women destined to have elevated
reassuring fetal heart rate tracings and failure of induction.333 Some blood pressure in late pregnancy was once the gold standard against
physicians recommend scheduled cesarean delivery for women with which other predictors were judged, but a large study failed to confirm
severe preeclampsia with a pregnancy of less than 30 weeks’ gestation the predictive value of the test,112,173 and it is neither simple nor safe
and with an unfavorable Bishop score.334 enough for extensive clinical use. Abnormal uterine artery Doppler
After the decision for delivery is made, induction should be carried velocimetry in the second trimester has a positive predictive value for
out aggressively and expeditiously. Cesarean delivery should be reserved preeclampsia of about 20%. Although useful for research identification
for obstetric indications. Because the probability of fetal compromise of subjects, the low sensitivity and positive predictive value limit its use
in preeclampsia is high, it is mandatory in all vaginal deliveries that in clinical care.341 The role of Doppler velocimetry in patient manage-
the fetus be monitored adequately. When feasible, internal monitoring ment remains uncertain. Other suggested markers include angio-
is preferable to allow determination of variability; however, external genic and antiangiogenic factors, but clinical use awaits additional
monitoring, if technically good, is adequate until internal monitoring evaluation.342

19. CHAPTER 35 Pregnancy-Related Hypertension 669
Clinical management is dictated by the overt clinical signs of pre- fetus with growth restriction. Fetal jeopardy, rather than lung maturity,
eclampsia. Proteinuria—the most valid clinical indicator of preeclamp- is the fetal criterion to determine delivery when preeclampsia occurs
sia—is often a late change, sometimes even preceded by seizures, and remote from term.
it is therefore not useful for early recognition of disease. Although
rapid weight gain and edema of the hands and face suggest fluid and Expectant Management of Severe
sodium retention characteristic of preeclampsia, they are not univer- Preeclampsia Remote from Term
sally present in or uniquely characteristic of preeclampsia. These signs Prolonged expectant antepartum management of women with severe
are at most a reason for close observation of blood pressure and preeclampsia is not practiced in most centers. With improvements in
urinary protein levels. Early recognition of preeclampsia is necessarily neonatal care, many clinicians regard delivery of women with severe
based primarily on diagnostic blood pressure increases in the late preeclampsia beyond 32 to 34 weeks’ gestation to be in the best inter-
second and early third trimesters compared with pressures in early ests of the mother and fetus. When gestational age is critical (<32
pregnancy. Blood pressure changes without proteinuria undoubtedly weeks), the physician may consider control of maternal blood pressure
occur in some normal women and in some with underlying renal or along with meticulous observation of maternal and fetal conditions.
vascular disease. Because the goal of early diagnosis is to identify This approach requires personnel and facilities for very close assess-
patients requiring more careful observation, overdiagnosis is prefera- ment of both patients.
ble to underdiagnosis. The initial evaluation and management of a woman suspected to
After blood pressure changes diagnostic of preeclampsia occur, evi- have severe preeclampsia between 24 and 32 to 34 weeks’ gestation
dence of multiorgan involvement should be sought through laboratory includes the following components:
assessment. A 24-hour or timed urine specimen should be collected,343
regardless of findings on urine dipstick evaluation.9 Because of the The pregnant woman is admitted to the hospital.
hectic protein excretion characteristic of the disorder,344 24-hour urine A course of antenatal corticosteroids is administered (see
collections may reveal excretion of more than 300 mg of protein, even Chapter 23). Barring rapid deterioration of the maternal or
with only trace proteinuria identified on the dipstick evaluation.9 fetal status, reasonable efforts should be made to delay delivery
Platelet count and liver enzyme tests should also be obtained.2 To rule for 48 hours to complete a full course of antenatal
out fulminant progression, repeated examination of pressure and corticosteroids. Neonates from preeclamptic pregnancies may
urinary protein is suggested within 24 hours. The frequency of subse- have a reduced incidence of respiratory distress syndrome, but
quent observations is determined by these initial observations and the this does not justify withholding antenatal corticosteroid
ensuing clinical progression. If the condition appears stable, once- or therapy.345,346
twice-weekly observations may be appropriate. Any evidence of pro- Seizure prophylaxis is undertaken with magnesium sulfate.
gression merits more frequent observations, perhaps in the hospital. Blood pressure is monitored at least every 1 to 2 hours.
The appearance of proteinuria is an especially important sign of pro- Fluid intake and urine output are strictly monitored.
gression and requires frequent observation. A 24-hour urine collection is used to determine protein
If deterioration in laboratory findings, symptoms, or clinical signs excretion and creatinine clearance.
occurs, the decision to continue the pregnancy is determined day by Laboratory studies include a complete blood cell count with a
day. Subjective evidence of central nervous system involvement (i.e., platelet count and smear and determinations of electrolytes,
headache, disorientation, and visual symptoms) and hepatic distention creatinine, ALT, AST, lactic acid dehydrogenase (LDH), uric
(i.e., abdominal pain and right upper quadrant or epigastric tender- acid, and albumin. A coagulopathy profile (i.e., prothrombin
ness) indicates worsening preeclampsia. Important clinical signs are time [PT], partial thromboplastin time [PTT], and fibrinogen)
blood pressure, urinary output, and fluid retention as evidenced by should be obtained if the ALT and AST values are more than
daily weight increase. twice normal or if the platelet count is less than 100,000 cells/μL.
Laboratory studies are performed at intervals of no less often than Assessment of fetal well-being includes a nonstress test,
every 48 hours. Tests should include a platelet count and fibrin split amniotic fluid volume determination, and estimation of fetal
products, urinary protein excretion and serum creatinine levels, and size. If growth restriction is recognized, umbilical artery
serum levels of transaminases. Doppler velocimetry is suggested.
Fetal Observation. Assessment of fetal well-being is required to
determine whether continuing the pregnancy is safe (see Chapter 21). After the complete assessment of the fetus and mother, the safety
With the diagnosis of gestational hypertension, fetal assessment for size and potential utility of expectant management should be reassessed
by sonography and for function by nonstress testing is indicated. After daily. Several factors mandate delivery regardless of gestational age.
the diagnosis of preeclampsia is made, it is mandatory to monitor the Under these circumstances, the initial dose of antenatal steroids should
fetal condition. Ultrasound evaluation of fetal weight and amniotic be administered, but pregnancy should not be unnecessarily prolonged
fluid volume and a nonstress test of the fetal heart rate should be per- to give the second dose.
formed. Alternatively, a complete biophysical profile may be performed.
Doppler velocimetry is not recommended unless fetal growth restric- CONTRAINDICATIONS TO
tion is identified. EXPECTANT MANAGEMENT
As long as the maternal condition is mild and stable, weekly moni- Immediate delivery should be considered if any of the following
toring of the fetus appears to be adequate. Unfortunately, no test of conditions are present:
fetal well-being is satisfactory when the mother’s condition is unstable,
and testing should be repeated whenever the maternal status changes. Maternal hemodynamic instability (e.g., shock)
Management of fetal growth restriction, a common complication of Non-reassuring fetal test results (e.g., persistently abnormal
preeclampsia, is discussed in Chapter 34. Amniotic fluid testing for fetal heart rate testing, estimated fetal weight less than the 5th
fetal lung maturity (see Chapter 23) may aid the decision to deliver the percentile for gestational age, oligohydramnios with amniotic

20. 670 CHAPTER 35 Pregnancy-Related Hypertension
fluid index <5.0 cm or maximal vertical pocket <2.0 cm, proteinuria. In the absence of other features of severe preeclampsia,
persistent absent or reversed diastolic flow on umbilical artery proteinuria greater than 5 g in 24 hours is not an indication for
Doppler velocimetry in a growth-restricted fetus) delivery. Several clinical studies have shown that neither the rate of
Persistent, severe hypertension unresponsive to medical therapy increase nor the amount of proteinuria affects maternal or perinatal
Persistent headache, visual aberrations, or epigastric or right outcome in the setting of preeclampsia.353,354 For this reason, after the
upper quadrant pain threshold of 300 mg in 24 hours for the diagnosis of preeclampsia has
Eclampsia been exceeded, 24-hour urinary protein estimations do not bear
Pulmonary edema repeating.
Renal failure with a marked rise in serum creatinine (i.e., The third reason is severe preeclampsia based solely on fetal growth
serum creatinine concentration increased by 1 mg/dL over restriction. Women with severe preeclampsia based only on the pres-
baseline) or urine output less than 0.5 mL/kg/hr for 2 hours ence of IUGR in the setting of preeclampsia may be managed expec-
that is unresponsive to hydration with two intravenous boluses tantly if they meet the following criteria355:
of 500 mL of fluid
Laboratory abnormalities (e.g., rapid increase in Mild IUGR, defined as an estimated fetal weight between the
aminotransferases that exceeds twice the upper limit of 5th and 10th percentile for gestational age (see Chapter 34)
normal, progressive decrease in the platelet count to less than Gestational age less than 32 weeks
100,000 cells/μL, coagulopathy in the absence of an alternative Reassuring fetal test results, defined as a reassuring nonstress
explanation) that worsen over a period of 6 to 12 hours test result, adequate amniotic fluid volume (AFI > 5.0 cm or
Abruptio placentae maximal vertical pocket >2.0 cm), and no persistent absent or
Gestational age more than 34 weeks reversed diastolic flow on umbilical artery Doppler velocimetry
HELLP syndrome (Some studies have reported that serious (see Chapter 21)
maternal complications in the setting of expectant management
of HELLP syndrome are uncommon with careful maternal These women should be admitted to the hospital for close maternal
monitoring.347,348 However, the aim of expectant management surveillance and daily fetal testing.356 The admission-to-delivery
is to improve neonatal morbidity and mortality, and it has not interval in such pregnancies averages only 3 days, and more
been shown that overall perinatal outcome is improved with than 85% of these women require delivery within 1 week of
expectant management compared with pregnancies delivered presentation.350,355
after a course of corticosteroids. Expectant management The fourth reason to consider expectant management is severe
remains an investigational approach.349,350) preeclampsia based solely on blood pressure criteria. Two studies have
Patient who does not want to undergo risks of expectant established a precedent for expectant management of patients with
management severe preeclampsia by blood pressure criteria alone in pregnancies less
than 32 weeks with reassuring fetal testing.351,352
If the fetus and mother have none of these signs or symptoms and the
informed woman agrees, expectant management may be considered. COMPONENTS OF EXPECTANT MANAGEMENT
Expectant management of severe preeclampsia is not associated
CANDIDATES FOR EXPECTANT MANAGEMENT with any direct maternal benefits. The mother is assuming a small but
In women with severe preeclampsia remote from term, the decision significant risk to her own health to delay delivery until a more favor-
to continue pregnancy beyond that required for corticosteroids able gestational age is reached for her child.
depends on the results of frequent maternal and fetal assessment and If the contraindications to expectant management described previ-
continual review of the ongoing risks of conservative management ously are absent, the following protocol may minimize the risk of
versus the benefit of further fetal maturation. These women should be maternal and fetal complications:
cared for in a hospital setting and cared for by or in consultation with
a maternal-fetal medicine specialist. In this environment, expectant Close supervision of the mother and fetus is crucial because it
management of severe preeclampsia remote from term may be consid- is impossible to predict the clinical course the disease will take
ered in four circumstances. after admission.349
The first is transient abnormal laboratory test results. Asymptom- The mother is hospitalized until delivery.
atic women before 34 weeks’ gestation with severe preeclampsia on the The patient is kept on bed rest with bathroom privileges.
basis of laboratory abnormalities that improve or resolve within 24 to Blood pressure is monitored every 2 to 4 hours while the
48 hours after hospitalization may be managed expectantly.351,352 If patient is awake.
initial laboratory abnormalities include elevated liver function test Maternal symptoms are assessed every 2 to 4 hours while she is
results (e.g., ALT, AST) less than twice the upper limit of normal, a awake.
platelet count of less than 100,000 cells/μL but greater than 75,000 Fluid intake and urine output are strictly recorded.
cells/μL, and coagulopathy in the absence of an alternative explanation, Complete blood cell count, electrolyte determinations, and
it is reasonable to delay delivery, administer antenatal corticosteroids, liver and renal function tests are performed at least twice
and repeat laboratory tests every 6 to 12 hours. If the laboratory values weekly, if not daily.
show a trend toward improvement, or if they resolve, expectant man- The mother is given antenatal corticosteroids, if not previously
agement may be continued until a more favorable gestational age. given.
Delivery is warranted if liver function test values or platelet counts Regular assessment of fetal well-being (at least daily nonstress
deteriorate or coagulopathy occurs. tests with a biophysical profile if nonreactive)3
The second reason to consider expectant management of severe Delivery occurs after 32 to 34 weeks’ gestation, depending on
preeclampsia remote from term is severe preeclampsia based solely on the clinical scenario.

21. CHAPTER 35 Pregnancy-Related Hypertension 671
If abnormal laboratory test results are obtained on admission, tests fluid challenge. The major problems to be managed are those of
should be repeated every 6 to 12 hours. Delivery should be considered high blood pressure, intravascular volume, and convulsions. Less
if there is no trend toward improvement within 12 hours of admission commonly, patients with DIC and myocardial dysfunction require
or if the condition worsens after an initial improvement. treatment.
There is no standardized protocol for fetal assessment in this setting.
We perform fetal kick counts and nonstress tests at least daily, ultra- SEIZURE PROPHYLAXIS AND TREATMENT
sound assessment of amniotic fluid volume once or twice per week, Most seizures occur during the intrapartum and postpartum
ultrasound estimation of fetal growth every 10 to 14 days, and weekly periods, when the preeclamptic process is most likely to accelerate. In
Doppler velocimetry of the umbilical artery if the fetus is growth the Magpie study, 10,000 preeclamptic women were randomized to
restricted. receive magnesium sulfate or placebo. Magnesium sulfate clearly
Several management strategies with no proven benefit in the setting reduced the risk of eclampsia in this trial,369 and it was shown in sepa-
of severe preeclampsia are often recommended, but they are best rate trials to be superior for this purpose to other prophylactic medica-
avoided. They include the routine use of continuous fetal heart rate tions, including phenytoin370,371 and diazepam.372,373
monitoring, routine initiation of antihypertensive therapy (antihyper- Despite the demonstrated efficacy of magnesium sulfate, it is diffi-
tensive therapy should be avoided, with the exception of women with cult to select preeclamptic women for whom the risks of seizure exceed
chronic hypertension and those being managed according to standard the risk of prophylaxis. In the Magpie study, treatment was effective
protocols for severe preeclampsia by blood pressure criteria only and safe even in developing countries, but most of these women had
remote from term),352 prolonged (>48 hours) antepartum administra- significant disease. Twenty-five percent were defined as having severe
tion of magnesium sulfate for seizure prophylaxis, serial 24-hour urine preeclampsia, and 75% required antihypertensive therapy. Although
collections for protein quantitation, and routine assessment of fetal the use of magnesium prophylaxis in so-called mild preeclampsia is
lung maturity. However, the latter may be useful between 30 and 34 controversial, the incidence of eclampsia increased by 50% in a large
weeks when there is contradictory or equivocal evidence of maternal obstetric service when magnesium prophylaxis was limited to women
or fetal deterioration. with severe disease.374 A review of eclamptic patients from another
Postpartum administration of intravenous dexamethasone does large U.S. center indicates the difficulty in selecting preeclamptic
not reduce the severity or duration of disease. The serendipitous obser- women with disease severe enough to warrant therapy. None of the
vation that women who had received antepartum steroids appeared to clinical signs and symptoms considered to be prognostic of seizures
evidence improvement in the HELLP syndrome357 stimulated several was absolutely reliable. Seventeen percent of women who had seizures
retrospective and observational studies.358-363 These studies and a small, did not have headache, 80% did not have epigastric pain, and 20% had
randomized, controlled trial364 suggest improvement in laboratory normal deep tendon reflexes (Table 35-6). The lack of absolute correla-
findings and prolongation of pregnancy. The determination of appro- tion with proteinuria is consistent with the observations by Chesley
priate dosing and whether the benefit of therapy exceeds risks await and Chesley276 more than 50 years ago that 24% of patients do not have
larger, randomized, controlled trials. Its benefit for patients with proteinuria before seizures.
HELLP syndrome remains controversial.365 Most U.S. investigators recommend prophylactic anticonvulsant
therapy for all women with a blood pressure elevation diagnostic of
OUTCOMES OF EXPECTANT MANAGEMENT preeclampsia, regardless of whether other signs and symptoms, includ-
Several studies have shown that with close monitoring, pregnancies ing proteinuria, are present. This approach includes women for whom
complicated by severe preeclampsia could be managed expectantly and the risks of treatment may exceed the risks from seizures. The first
extended by 5 to 19 days, on average, with good maternal and neonatal requirement for anticonvulsant prophylaxis is that the agent and
outcomes. However, pregnancies with a growth-restricted fetus typi- dosage schedule must be extremely safe for the mother. Safety for the
cally deliver in 3 to 5 days.351,352,366,367 fetus and neonate is the next criterion.
Magnesium Sulfate. Magnesium sulfate offers considerable
Intrapartum Management advantages for prophylaxis in women with preeclampsia. Its pharma-
The intrapartum management of women with preeclampsia tests the cokinetic processes during pregnancy are well established, as are its
obstetric and medical skills of the health care team. The patient with efficacy and safety for the mother and fetus.
severe preeclampsia or eclampsia is acutely ill, with functional derange-
ments of many organ systems.368 Improved appreciation of the gravity
of this situation and enhanced methods of maternal monitoring have TABLE 35-6 FREQUENCY OF SYMPTOMS
reduced mortality rates. One study from the United Kingdom demon- PRECEDING ECLAMPSIA
strated a significant reduction in maternal death due to eclampsia from
15.1% in the 1940s to less than 3.9% after 1950.368 Failure to recognize Symptom Frequency (%)
and appropriately manage this grave condition probably accounts
Headache 83
for most deaths. Even mildly preeclamptic women can experience an Hyperreflexia 80
acceleration of disease during labor. Proteinuria 80
Baseline information should be obtained to determine renal func- Edema 60
tion, coagulation status, and liver function. Determination of the Clonus 46
serum protein concentration informs the choice of appropriate fluid Visual signs 45
administration. Some investigators advocate the use of intensive car- Epigastric pain 20
diovascular monitoring, with Swan-Ganz catheters or with central
Adapted from Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr:
venous pressure catheters in all women with severe preeclampsia or Reassessment of intravenous MgSO4 therapy in preeclampsia-
eclampsia (see Chapter 57). Such a practice is probably indicated in eclampsia. Obstet Gynecol 57:199-202, 1981; with permission from the
oliguric patients whose urinary output does not improve with a modest American College of Obstetricians and Gynecologists.

22. 672 CHAPTER 35 Pregnancy-Related Hypertension
TABLE 35-7 EFFECTS ASSOCIATED WITH TABLE 35-8 SAFETY AND EFFICACY OF
VARIOUS SERUM MAGNESIUM INTRAVENOUS MAGNESIUM
LEVELS SULFATE THERAPY
Effect Serum Level (mEq/L) Factor Number (%)
Anticonvulsant prophylaxis 4-6 Number of women treated 1870
Electrocardiographic changes 5-10 Number of women with seizures 11 (0.6)
Loss of deep tendon reflexes 10 Number with seizure morbidity 1 (0.05)
Respiratory paralysis 15 Number with morbidity from treatment 0 (0)
Cardiac arrest >25
Adapted from Sibai BM, Lipshitz J, Anderson GD, Dilts PV Jr:
Reassessment of intravenous MgSO4 therapy in preeclampsia-
eclampsia. Obstet Gynecol 57:199-202, 1981; with permission from the
American College of Obstetricians and Gynecologists.
The volume of distribution of magnesium is greater than that of
sucrose, indicating that the distribution of this ion goes beyond extra-
cellular fluid and enters bones and cells.375 Magnesium circulates dosages found to be usually effective and safe (Table 35-8). No study
largely unbound to protein and is almost exclusively excreted in urine. has compared magnesium concentrations in patients successfully or
It is reabsorbed in the proximal tubule by a process limited by trans- unsuccessfully treated with MgSO4 · 7 H2O. We do not recommend
port maximum (Tmax), and its excretion increases as the filtered load titrating levels to any specific therapeutic range, and there is no evi-
increases above the Tmax.376 In women with normal renal function, the dence that levels greater than 6 mEq/L increase efficacy. Magnesium is
half-time for excretion is about 4 hours.375 Because excretion depends not a perfect anticonvulsant, and some women have convulsions even
on delivery of a filtered load of magnesium that exceeds the Tmax, the with high serum concentrations.377
half-time of excretion is prolonged in women with a decreased GFR. Based on extensive experience, intravenous administration of mag-
The clinically relevant effects of elevated serum magnesium nesium at doses up to 2 g/hr appears to be safe if renal function is
concentrations are related primarily to the membrane effects. normal. In the Magpie study, doses of 1 g/hr given intravenously were
Magnesium slows or blocks neuromuscular and cardiac conducting effective without serious complications in 5000 treated women; some
system transmission, decreases smooth muscle contractility, and were treated in underdeveloped nations.
depresses central nervous system irritability. These actions produce Magnesium sulfate therapy at effective anticonvulsant doses is safe
the desired anticonvulsant effect and cause decreased uterine and for the fetus and neonate. Neonatal serum magnesium concentrations
myocardial contractility, depressed respirations, and interference are almost identical to those of the mother.378 Although amniotic fluid
with cardiac conduction. These effects occur at different serum mag- magnesium concentrations increase with prolonged infusion because
nesium concentrations (Table 35-7). Doses of magnesium sulfate of fetal renal excretion, fetal serum magnesium levels do not increase,
sufficient for anticonvulsant therapy cause little change in blood and there is no evidence of cumulative effects on the neonate of pro-
pressure. longed magnesium administration for seizure prophylaxis.
Depression of deep tendon reflexes occurs at serum concentrations In a study of 118 infants of mothers treated with magnesium
lower than those associated with adverse cardiac and respiratory effects. sulfate, the average serum magnesium concentration was 3.7 mEq/L.
The presence of deep tendon reflexes indicates that the serum magne- There was no correlation of magnesium levels with Apgar scores.379
sium concentration is not dangerously high. If deep tendon reflexes are Administration of magnesium to the mother may have additional ben-
lost, the serum magnesium concentration may be greater than 10 mEq/ eficial effects for the fetus, which are being tested in controlled trials
L, but brisk deep tendon reflexes do not signify inadequate magnesium (see Chapter 29).
dosage. Any attempt to titrate magnesium therapy until deep tendon Phenytoin. Phenytoin is an effective anticonvulsant with pharma-
reflexes are eliminated is irrational and dangerous. cologic effects that would not be predicted to produce adverse effects
In the United States, magnesium sulfate is routinely given intrave- on the fetus or neonate. In several small studies, there were no obvious
nously, rather than by more painful intramuscular injections. A typical adverse fetal or maternal effects.380,381 Although phenytoin is not as
loading dose is 4 to 6 g given intravenously over about 15 to 30 minutes, effective as magnesium for prophylaxis or treatment of eclampsia,372,382
followed by 1 to 2 g/hr as a continuous infusion. Magnesium is admin- it can be used safely when magnesium is inappropriate, such as in
istered by continuous infusion because intermittent bolus infusions women with myasthenia gravis or markedly compromised renal func-
result in only transient elevations of magnesium level. To ensure con- tion. Phenytoin nonetheless does have potential severe adverse effects
sistent infusion and to avoid inadvertent administration of large doses that may be magnified by unfamiliarity of obstetric personnel with its
of magnesium, mechanically controlled infusion is mandatory. In all use.
patients, deep tendon reflexes should be checked regularly (at least Anticonvulsant Therapy. Magnesium is more effective than
every 2 hours) to make sure they remain present, and the respiratory phenytoin or benzodiazepam to treat eclamptic seizures.372 An initial
rate must be monitored. infusion of 4 g can be administered safely intravenously over as little
The rate of infusion is modified for patients with compromised as 5 minutes, and intravenous MgSO4 can be administered at 1 to 2 g/hr
renal function. If the maternal creatinine level is greater than 1.0 mg/ to maintain therapeutic serum magnesium levels. If a patient already
dL, serum magnesium levels should be obtained and the infusion rate receiving magnesium has an eclamptic seizure, it is safer to terminate
limited to no more than 1 g/hr if there is further evidence of renal seizures with another agent, such as 5 to 10 mg of diazepam (Valium),
impairment. If overdosage occurs, especially with apnea, calcium glu- 4 mg of lorazepam (over 2 to 5 minutes),383 or a short-acting barbitu-
conate (10 mL of a 10% solution injected intravenously over 3 minutes) rate, such as pentobarbital (125 mg given intravenously). If these
is an effective antidote. The “therapeutic concentrations” of magne- measures fail, general anesthesia may be necessary to terminate the
sium have been empirically determined and are the levels attained with seizures.

23. CHAPTER 35 Pregnancy-Related Hypertension 673
TABLE 35-9 DRUGS FOR TREATMENT OF HYPERTENSIVE EMERGENCIES
Time Course of Action
Intramuscular Interval
Drug Onset Maximum Duration Dosage Intravenous Dosage between Doses Mechanism
Hydralazine 10-20 min 20-40 min 3-8 hr 10-50 mg 5-25 mg 3-6 hr Direct dilatation of
arterioles
Sodium 0.52-2 min 1-2 min 3-5 min — IV solution: 0.01 g/L; Direct dilatation of
nitroprusside IV infusion rate: arterioles and veins
3-4 μg/kg/min
Labetalol 1-2 min 10 min 6-16 hr — 20-50 mg 3-6 hr α- and β-Adrenergic
blocker
Nifedipine 5-10 min 10-20 min 4-8 hr — 10 mg orally 4-8 hr Calcium channel blocker
Most seizures terminate spontaneously within 1 to 2 minutes. The necessary. A test dose of 1 mg is given over 1 minute, and blood pres-
most important measures for any seizure before pharmacologic therapy sure is determined to avoid idiosyncratic hypotensive effects; 4 mg is
is initiated are prevention of injury and protection of the airway to then infused over 2 to 4 minutes. After 20 minutes, the blood pressure
prevent aspiration. is determined, and the following criteria for action are taken into
account:
ANTIHYPERTENSIVE THERAPY
Antihypertensive agents are not administered routinely to women If there was no effect from the first dose of hydralazine, the
with preeclampsia. There is no evidence that administration of these dose is repeated.
agents has beneficial fetal effects. The suggestion that lowering blood If a suboptimal effect was obtained, a second, smaller dose is
pressure reduces the risk of seizures has not been tested. The goal of given.
antihypertensive treatment is prevention of intracranial bleeding and If diastolic blood pressure is between 90 and 100 mm Hg,
stroke. therapy is not repeated until diastolic blood pressure increases
Therapy is reserved for women in whom blood pressure is elevated to 105 mm Hg.
to more than 160 mm Hg systolic or more than 105 to 110 mm Hg
diastolic, which are the levels associated with intracranial bleeding or Other Drugs. In rare instances, hydralazine may not effectively
stroke.384,385 The goal of blood pressure control is not to attain normal lower blood pressure to the desired level. If blood pressure control is
blood pressure but merely to reduce blood pressure to a level that can not adequate after the administration of 20 mg of hydralazine, other
provide a margin of maternal safety (i.e., 135 to 145 mm Hg systolic hypotensive agents must be used.
and 95 to 100 mm Hg diastolic) without compromising adequate The calcium entry blocker nifedipine has been taken orally in doses
uterine perfusion. These patients have elevated blood pressure with of 10 mg, which may be repeated after 30 minutes if needed to lower
reduced plasma volume. Overly aggressive treatment lowers maternal blood pressure rapidly. For maintenance dosing, 10 to 20 mg can then
cardiac output and uterine perfusion and may result in iatrogenic fetal be given every 3 to 6 hours as needed. It is quite effective and well toler-
distress. ated; headache is the most common side effect.386
Several agents available for reducing blood pressure rapidly Labetalol, a mixed α-adrenergic and β-adrenergic antagonist, also
are described in Table 35-9. Not listed in this table are potent is useful for reducing blood pressure acutely. It is given intravenously
diuretic agents that lower blood pressure rapidly by depleting as a bolus infusion, beginning with 10 mg and followed by repeated
plasma volume, because the use of these agents in the plasma volume– doses that may be increased up to twofold (e.g., 20 mg, 40 mg, 80 mg),
depleted patient may reduce maternal cardiac output and uterine with doubling every 10 minutes as needed (up to 300 mg) for blood
perfusion. pressure control.387 The major reservation about the use of labetalol is
Hydralazine. The agent most widely used to reduce blood pres- that, unlike the vasodilators hydralazine and nifedipine, it does not
sure in women with severe preeclampsia is hydralazine. As a direct reduce afterload. There are theoretical disadvantages with using labet-
vasodilator, it offers two major advantages. First, vasodilation with alol for managing cardiac failure associated with the hypertension of
hydralazine results in a reflex increase in cardiac output and increased preeclampsia.
uterine blood flow as blood pressure decreases. Second, the increase in Methyldopa (formerly designated α-methyldopa) is a safe and well-
cardiac output blunts the hypotensive effect and makes it difficult to tested drug. However, its delayed onset of action (4 to 6 hours), even
overdose the patient. The important side effects of hydralazine are when administered intravenously, limits its usefulness for hypertensive
headache and epigastric pain, which may be confused with worsening emergencies. On the basis of side effects and experience, nifedipine or
preeclampsia. labetalol are preferred when hydralazine is ineffective.
The pharmacokinetic profile of hydralazine is outlined in Table
35-9. The onset of action occurs in 10 to 20 minutes, and peak action MANAGEMENT OF OLIGURIA
occurs 20 minutes after administration, even when the agent is given In preeclamptic women, oliguria can have a prerenal or renal origin
intravenously. The duration of action is 3 to 8 hours. The use of con- (see Chapters 44 and 57). Even though plasma volume is decreased in
tinuous intravenous infusions of hydralazine is not sensible because preeclamptic patients, the use of fluids is controversial. Excessive fluid
minute-to-minute control cannot be attained. An alternative approach infusion can lead to congestive heart failure and perhaps cerebral
is to administer the drug as a bolus infusion, repeated at 20-minute edema388; nevertheless, oliguria can be corrected in many patients by
intervals until the desired control is attained and then repeated as fluid infusion.

24. 674 CHAPTER 35 Pregnancy-Related Hypertension
To avoid complications, the physician should not prescribe hypo- partum, or postpartum period. Delayed onset of pulmonary edema
tonic fluids. They worsen the dilutional decreases in serum osmolality requires special awareness because the edema usually occurs during
that may occur with any of the following: oliguria from renal causes, postpartum diuresis, when most concerns about the complications of
elevated antidiuretic hormone (ADH) level in response to stress, and preeclampsia are diminishing.
oxytocin treatment. Management of pulmonary edema requires intensive monitoring,
Fluids must be administered with the understanding that oliguria with the capability to assess pulmonary and cardiac function accu-
may have a renal origin and that the patient is at risk for fluid overload- rately and to perform mechanical ventilation as needed (see Chapter
ing. Because acute renal failure resulting in permanent renal damage 57). With accurate assessment of cardiopulmonary function and
is rare in pregnancy (whereas pulmonary edema is a common event aggressive treatment, the mortality resulting from pulmonary edema
on some obstetric services), oliguria should be defined conservatively in preeclampsia has been greatly reduced.390
as less than 20 to 30 mL/hr for 2 hours.
If there are no clinical signs or history suggesting congestive heart Postpartum Management in Preeclampsia
failure, 1000 mL of isotonic crystalloid can safely be infused in 1 hour. Delivery does not immediately reverse the pathophysiologic changes
If urine output increases, fluid infusion is maintained at 100 mL of of preeclampsia, and it is necessary to continue palliative therapy
isotonic crystalloid per hour. If the oliguria does not resolve, further for various periods. Some of the constraints on therapy, however,
fluid infusion should be guided by central venous or, preferably, pul- are eliminated by delivery of the fetus. Approximately one third
monary wedge pressures (see Chapter 57). of convulsions occur in the postpartum period, most within 24 hours
Relatively small amounts of intrapartum and postpartum blood and virtually all within 48 hours, although there are rare exceptions.
loss can result in profound hypovolemia and shock in patients who Most physicians advocate continuing anticonvulsant therapy for 24
already have compromised blood volumes. A large peripheral line hours after delivery. For simplicity, magnesium sulfate therapy
should be in place at all times in case rapid replacement of blood is usually continued, but because there is no need to consider
volume becomes necessary. fetal effects, any safe anticonvulsant regimen is reasonable at this
time.
MANAGEMENT OF LESS COMMON PROBLEMS Anticonvulsant efficacy rather than sedation is the goal, and barbi-
Disseminated Intravascular Coagulation. Evidence of DIC is turate anticonvulsants in usual therapeutic doses require days to
an important indicator of severity and progression of preeclampsia. achieve effective levels. Similarly, phenytoin must be administered
DIC is measurable by the usual clinical tests in 20% of severely pre- intravenously in large doses to achieve therapeutic levels within hours,
eclamptic and eclamptic women and is sufficient to cause coagulation with the attendant dangers of cardiac arrhythmia. Serum magnesium
problems in less than 10%. concentrations decrease with increased urinary output, and with puer-
Definitive therapy for DIC is removal of the inciting factor. In pre- peral diuresis, it is extremely unlikely that the serum magnesium
eclampsia, whether the cause of the coagulation disorder is endothelial concentration is therapeutic at usual doses. Despite this drawback,
cell damage, release of thromboplastic materials, vasospasm with convulsions rarely occur in the postpartum period, suggesting that
attendant microangiopathic changes, or local consumption of pro- rapid diuresis indicates resolution of the preeclamptic process and that
coagulants in the choriodecidual space, the inciting factor is pregnancy therapy may no longer be required.
related, and definitive therapy is termination of the pregnancy. The On the basis of these considerations, it appears reasonable to dis-
long-range follow-up of women with preeclampsia indicates that all continue magnesium sulfate therapy when diuresis occurs before 24
organ system functions return to normal. It is unlikely that occlusion hours after delivery. Some investigators recommend continuing mag-
of the microvasculature by thrombi in mild forms of DIC causes per- nesium sulfate administration for longer than 24 hours in selected
manent damage. patients, but it is difficult to determine the basis on which this selection
Evidence of early DIC is not by itself an absolute indication for can be made. In one randomized trial limited to women with mild
immediate delivery. With rapidly deteriorating renal or hepatic func- preeclampsia, there was no difference in seizure risk when magnesium
tion or DIC complicated by spontaneous hemorrhage, however, deliv- was discontinued after only 12 hours.391 Unfortunately, this study was
ery should be expeditious. limited by a relatively small sample, and it is likely that any future
The experience with heparin anticoagulation, which has been used studies will be similarly underpowered because of the rarity of the
to maintain pregnancies in women with symptomatic DIC or as a outcome.
prophylactic measure to prevent DIC, indicates that these approaches Hypertension may take considerably longer than 24 to 48 hours to
are not effective.389 The use of heparin during labor in women in whom resolve. Women who are hypertensive 6 weeks after delivery may be
DIC necessitates delivery has not been studied extensively. The experi- normotensive at long-term follow-up.74 The indications for therapy are
ences already cited, however, indicate that the approach may be similar to those for the antepartum period. The patient with blood
dangerous. pressure greater than 160 mm Hg systolic or 105 mm Hg diastolic after
If procoagulants decrease to a level associated with spontaneous delivery should be treated; the fetus no longer influences therapeutic
hemorrhage, appropriate procoagulant therapy should be given before choices. If rapid blood pressure control is necessary, sodium nitroprus-
delivery. This should be done whether the anticipated mode of delivery side is more effective and better tolerated than hydralazine. Diuretics
is vaginal or cesarean (see Chapter 40). and conventional oral antihypertensive agents can be started to achieve
Pulmonary Edema. Pulmonary edema occurs in a small number smooth control. The woman who remains hypertensive (>100 mm Hg
of women with preeclampsia. In the past, this complication was associ- diastolic pressure) should be sent home with continued antihyperten-
ated with high rates of maternal mortality. The pathogenesis of pul- sive therapy.
monary edema often is iatrogenic fluid overload, but it can be Patients with lesser elevations require no therapy. The choice of
cardiogenic or involve transudation of fluid into alveoli. The noncar- drugs is based on the usual step method of antihypertensive therapy.
diogenic variety results from decreased colloid oncotic pressure or a The patient sent home with a therapeutic regimen must be warned
pulmonary vascular leakage, and it can occur in the antepartum, intra- about symptoms of hypotension, and she must be seen at weekly

25. CHAPTER 35 Pregnancy-Related Hypertension 675
intervals, because the need for therapy diminishes rapidly in some Aspirin trials to prevent preeclampsia are a prototype. More than
cases. 35,000 women have been included in randomized, controlled trials of
various sizes and quality to determine the benefit of aspirin.399 Small,
Therapies No Longer Recommended single-center studies suggested benefit,400-402 but larger, multicenter
Strict sodium restriction and diuretic therapy have no role in the pre- trials showed no effect.36,403 One potential explanation is publication
vention or treatment of preeclampsia. In women with marked sodium bias in favor of positive results. Results also might have varied because
retention as manifested by significant edema, modest sodium restric- of the heterogeneity of preeclampsia, with benefit of therapy evident
tion may not alter the course of the disease but can reduce discomfort. in only a subset.
Diuretics should not be given because plasma volume is already A meta-analysis of trials that enrolled a large number of pregnant
decreased, and further volume depletion can affect the fetus adversely. women found benefit for antiplatelet treatment (i.e., aspirin) to reduce
Attempts to modify the progression of the disease by volume expan- the frequency of the diagnosis of preeclampsia, preterm delivery, and
sion have not been conclusively shown to be helpful and require growth-restricted infants.399,404 There was a modest reduction of the
more thorough evaluation before being used in routine management incidence of preeclampsia (17%), with 72 women needing treatment
of preeclampsia.392 to prevent one case of preeclampsia. There was a 14% reduction in the
Sodium nitroprusside is a potent, short-acting, direct vasodilator rate of fetal and neonatal deaths, with a number needed to treat of 243
that allows excellent moment-to-moment blood pressure control. to prevent one death. The investigators concluded that antiplatelet
However, because elevated fetal concentrations of serum cyanide, agents such as aspirin have moderate benefits when used for preven-
sometimes to toxic levels, have been reported in animal studies,393 this tion of preeclampsia and its consequences.
agent is rarely used in humans. Using another analytical strategy, meta-analysis of individual
Diazoxide is a thiazide analogue that has no diuretic effect, but it patient data, the Perinatal Antiplatelet Review of International Studies
is an extremely potent antihypertensive agent, acting as a direct vaso- (PARIS) Collaborative Group attempted to differentiate the success of
dilator. It is rarely used because of effects on maternal and fetal carbo- aspirin in subsets according to maternal diagnosis, dosage of aspirin,
hydrate metabolism and its profound and slowly reversible effect on and time when therapy was initiated. Although the group did confirm
blood pressure. a reduction in preterm birth and the incidence of preeclampsia by 10%
There is little evidence that therapeutic efforts alter the underlying with aspirin, they did not identify any particular subgroups for whom
pathophysiology of preeclampsia. Therapeutic intervention for clini- aspirin was more effective. There was no difference in perinatal death
cally evident preeclampsia is palliative. At best, it may slow the progres- for women treated with prophylactic aspirin.405
sion of the condition, but it is more likely to allow continuation of the The estimated number of women to treat to prevent one case of
pregnancy. Bed rest is a usual and reasonable recommendation for the preterm birth in this study was 500 for low-risk pregnancies (incidence
woman with mild preeclampsia, although its efficacy is not clearly of 2%) and 50 for high-risk pregnancies when the estimated incidence
established.394 Prophylactic hospitalization with increased bed rest may of preeclampsia was 20%. Decisions about the choice of aspirin with
reduce the incidence of preeclampsia for women at high risk identified this degree of efficacy must consider the short-term adverse effects on
by increased angiotensin sensitivity.395 It is unclear, however, which of the mother and infant, which have not been evident in the large
the several behavioral modifications involved in hospital residence is number of women treated, and the long-term outcome, which is
important. Anecdotal reports of clinical improvement with bed rest largely unknown.406
must be tempered by the recognition of the unpredictable course of Calcium supplementation to prevent preeclampsia was initiated
preeclampsia. with similar enthusiasm. Calcium was tested in a large, randomized,
controlled trial in the United States396 based on initial studies and
Follow-up Assessment for Preeclampsia meta-analyses.407 The conclusion of this study was unequivocal, finding
Because the early recognition and treatment of significant blood pres- no evidence that 2 g of supplemental calcium administered to preg-
sure elevation reduce morbidity, all women with a clinical diagnosis of nant women from early gestation onward reduced the incidence of
preeclampsia deserve long-range follow-up. Decisions for evaluation preeclampsia, altered blood pressure, or affected fetal weight. A review
and treatment should be deferred until 12 weeks after delivery because of published studies concluded that any benefit of calcium was related
some women who are hypertensive at 6 weeks are normotensive years to low calcium intake before pregnancy in some women.408 Based on
later. The woman who is normotensive 12 weeks after delivery should this rationale, the World Health Organization conducted a trial of
be advised of her increased risk for hypertension in later life77 and calcium supplementation in populations with low calcium intake.
should be counseled to have her blood pressure checked at least yearly. Treatment did not reduce the diagnosis of preeclampsia but did reduce
Because of the association between preeclampsia and later cardiovas- adverse outcomes.409 Calcium administration has therefore been pro-
cular disease,78 formal assessment of cardiovascular risk factors in such posed as useful in low calcium consuming populations.410
patients is prudent. Oxidative stress has been suggested as important in preeclampsia.
The results of antioxidant therapy are similar to those with calcium
and aspirin; an initial small trial of antioxidant vitamins C and E sug-
Prevention of Preeclampsia gested benefit,411 but a subsequent, larger trial did not.397 There was
Since the preeclamptic syndrome was first recognized, prevention concern about the safety of this therapy for the fetus because an excess
has been attempted. Sodium restriction and nutrient supplements of low-birth-weight infants (but not IUGR or premature infants)
have been unsuccessful.18 Randomized, controlled trials based on occurred in the antioxidant-treated group. The largest trial of low-risk
several hypotheses for preventing preeclampsia have been performed. women is ongoing, with results expected in 2008. This study initiated
The sequence of studies for each intervention has been similar, antioxidant treatment far earlier in pregnancy than the other studies
with initial small, single-center studies suggesting benefit and (start date at 9 to 16 weeks), with 40% of women enrolled before 12
subsequent larger, well-powered studies finding no significant weeks, whereas the other studies began at an average of 18 weeks. This
benefit.36,396-398 may be relevant because oxidative stress is known to accompany the

26. 676 CHAPTER 35 Pregnancy-Related Hypertension
establishment of the intervillous circulation at 8 to 10 weeks’ gesta- cies other than the first pregnancy, in which underlying hypertension
tion.412 The primary outcome in this study is a composite outcome of is a more common predisposing factor.414
maternal and fetal morbidity. Final decisions about efficacy and safety One review of 28 women with preeclampsia and stroke examined
await the conclusion of this trial.408 blood pressures before the event. The range of systolic values ranged
The results of these studies of prophylaxis raise several important from 159 to 198 mm Hg, and the range for diastolic values was much
points: greater, from 81 to 133 mm Hg (mean, 98 mm Hg). Only five women
had diastolic values greater than 105 mm Hg.385 Morbidity is difficult
Randomized clinical trials of appropriate population and size to predict by blood pressure, although it seems to be significantly
to achieve sufficient power must guide clinical management. increased when systolic pressures exceed 160 mm Hg and may be
Nonetheless, the success in small trials and the failure in large, increased when diastolic pressures exceed 100 mm Hg.385 The National
multicenter trials may be related to the heterogeneity of High Blood Pressure Education Program Working Group on High
patients with preeclampsia.174 Prophylaxis may be effective in a Blood Pressure in Pregnancy has recommended initiating therapy
specific subset of women (e.g., calcium supplementation in when systolic pressures exceed 150 to 160 mm Hg and diastolic pres-
women with low average calcium intake). sures exceed 100 to 110 mm Hg.
Because the diagnosis of preeclampsia is based on signs that
usually have minimal causal significance, prophylactic therapy Effects of Chronic Hypertension on the Fetus
should be aimed at the pathophysiology and judged by effects The perinatal mortality rate for infants born to hypertensive mothers
on perinatal outcome. increases as maternal blood pressure rises.101 Without antihypertensive
The aspirin and calcium data suggest that initiation of therapy therapy, a woman with a systolic pressure of 200 mm Hg or a diastolic
before disease is clinically evident may be successful if specific pressure of 120 mm Hg had only a 50% chance of bearing a living
interventions can be applied to appropriately selected subjects. infant. The perinatal mortality rate is strikingly higher in hypertensive
women with proteinuria, indicating the impact of superimposed pre-
eclampsia on the fetus.
Chronic Hypertension The perinatal mortality rate for infants of women with superim-
posed preeclampsia is greater than for infants of women in whom the
Differentiation of chronic hypertension from preeclampsia is complex condition arises de novo.415 There are two explanations for this difference.
but essential. Even more important is the difficult discrimination First, the decidual vessels of women with even mild preexisting
between exacerbation of preexisting hypertension and the onset of hypertension demonstrate vascular changes similar to the changes in
superimposed preeclampsia. The rate of progression and the effect on renal arterioles seen in women with long-standing hypertension.416
the mother and fetus of these conditions are different in the two dis- Decreased uteroplacental perfusion resulting from this change may be
eases. Management of hypertension in early pregnancy requires early additive and perhaps synergistic with the decidual vascular changes of
recognition of blood pressure elevation, baseline testing to aid in the preeclampsia. The decidual vascular changes likely explain the higher
later diagnosis of superimposed preeclampsia, and meticulous mater- incidence of abruptio placentae among women with superimposed
nal and fetal observation. If a decision is made to use antihypertensive preeclampsia.
therapy, antihypertensive drugs must be chosen on the basis of con- Second, preeclampsia appears earlier in pregnancies of hypertensive
siderations specific to pregnancy. women than in those of normotensive women. Fetal growth restriction
is common in infants of hypertensive women, and it increases in fre-
quency and severity with increasing maternal blood pressure.101
Epidemiology Some investigators suggest that hypertension without preeclampsia
The prevalence of chronic hypertension increases with advancing age. has no adverse effect on the fetus,286,417 but this observation ignores the
In whites, the risk increases from 0.6% (18 to 29 years old) to 4.6% effects of growth restriction. In a study of almost 300 pregnancies of
(30 to 39 years old). In African-American women, the risks increased women with chronic hypertension, perinatal death occurred only in
to 2% and 22.3%, respectively.413 Preeclampsia occurs in 25% of hyper- growth-restricted infants.418
tensive women, compared with 4% in previously normotensive
women.
Diagnosis
Chronic hypertension is defined as hypertension that is observable
Pathogenesis before pregnancy or that is diagnosed before the 20th week of gesta-
tion. Hypertension is defined as a blood pressure greater than
Effects of Chronic Hypertension on the Mother 140/90 mm Hg. If the diagnosis of hypertension is confirmed for the
Blood pressure elevation during pregnancy without the superimposi- first time during pregnancy and it persists beyond the 84th day after
tion of preeclampsia has the same impact as blood pressure increases delivery, it is classified as chronic hypertension.
in any other 10-month period. Systolic and diastolic blood pressures
that exceed 160 and 105 mm Hg, respectively, increase the risk of mor-
bidity even over this short period.
Pharmacologic Management
Maternal morbidity and mortality rates are greater among women of Hypertension
with superimposed preeclampsia than among those with preeclampsia
arising de novo. Blood pressure elevation with superimposed pre- Antihypertensive Therapy in the Reduction of
eclampsia is also greater, increasing the possibility of intracranial Maternal and Fetal Morbidity and Mortality
bleeding. Two thirds of cases of eclampsia occur in first pregnancies, Antihypertensive therapy reduces maternal mortality as effectively
but two thirds of maternal deaths due to eclampsia occur in pregnan- during pregnancy as at any other time. Lowering of markedly elevated

27. CHAPTER 35 Pregnancy-Related Hypertension 677
blood pressure (>100 mm Hg diastolic pressure) can reduce the risk of dosage for the mother may be excessive for the fetus.426 Drug effects of
morbid events even over 10 months, whereas the impact of such reduc- minimal importance to the mother and fetus may be of great impor-
tion on the minimal morbidity associated with less elevated pressures tance to the infant.
is unlikely. Antihypertensive therapy for women with mild to moderate
hypertension can reduce the risk for severe hypertension in later EFFECT ON UTERINE BLOOD FLOW
pregnancy.419 Maternal medication may affect fetal well-being by altering uterine
It has been postulated that antihypertensive therapy for the mother blood flow. Antihypertensive drugs act by reducing cardiac output or
and fetus might reduce the incidence of superimposed preeclampsia, systemic vascular resistance, which may affect blood flow to the uterus.
but there has been no evidence of that effect in large trials of antihy- Optimal drug choice in pregnancy avoids agents that reduce uterine
pertensive therapy administered during pregnancy. A Cochrane review and therefore uteroplacental blood flow. Agents that reduce cardiac
indicates no effect of antihypertensive therapy on the perinatal mortal- output are best avoided because they almost inevitably reduce uterine
ity rate, but antihypertensive therapy was begun in the first trimester blood flow. Antihypertensive drugs that act on total peripheral resis-
in only 2 of 46 studies included in the review.419 Because pathologic tance may increase, decrease, or have no effect on uterine perfusion,
and pathophysiologic changes are present as early as 14 weeks’ gesta- depending on the pattern of blood flow redistribution.
tion, it is possible that therapy was begun too late to have any effect Reliable information on the effects of antihypertensive drugs on
on preeclampsia or fetal outcomes. There is no evidence that antihy- human uterine blood flow is scant. Data on the potential effects of
pertensive therapy increased perinatal mortality rates in any of these these drugs are based on studies in pregnant animals in which it was
studies.420,421 If therapy is indicated for maternal considerations (dia- assumed that humans and sheep respond identically or in which blood
stolic pressure >100 mm Hg), it is safe for the fetus if the choice of flow to the kidney—an exquisitely autoregulated organ that usually
drug is appropriate.422 receives 10% of cardiac output—was compared with blood flow to the
There is some suggestion that antihypertensive therapy may be uterus, an organ whose perfusion increases 500-fold over several
associated with an increased risk of small infants. This increase is small months. With these limitations, Table 35-10 outlines the available
and driven largely by therapy with β-blockers, specifically atenolol.423 information about antihypertensive agents used in pregnancy.
Overview of Therapy for Hypertension USE OF DRUGS
in Pregnancy Two common classes of antihypertensive medications—diuretics
Antihypertensive therapy can be used safely in pregnancy when indi- and β-adrenergic blockers—warrant comment.
cated by the maternal condition. Therapy reduces the maternal risks Diuretics. The indiscriminate use of diuretic agents during preg-
of markedly elevated pressures, and in women with mild to moderate nancy has appropriately been condemned and is no longer common.
hypertension, it prevents severe hypertension later in pregnancy. In an epidemiologic assessment of 8000 pregnancies, a small but sig-
The decision to use antihypertensive therapy is based on maternal nificant increase in perinatal mortality rate was demonstrated in
considerations. women receiving continued or intermittent diuretic therapy, especially
Antihypertensive medication is reserved for women with diastolic when the drug was begun late in pregnancy.427 Lack of expansion of
pressures above 90 mm Hg. Women using hypertensive therapy when intravascular volume during pregnancy also has adverse prognostic
they become pregnant, regardless of pretreatment blood pressure, are significance.337,428 In women taking diuretics from early pregnancy
best served by continuation of therapy. There is no evidence that anti- onward, plasma volume does not expand as much as in normal preg-
hypertensive therapy presents a substantial risk to the fetus, and dis- nancy.429,430 Because of this, some physicians have recommended that
continuation of therapy may adversely affect long-range compliance diuretics be avoided entirely during pregnancy.286,431 However, diuretics
with drug therapy, increasing the risk to the mother. are used frequently in nonpregnant patients for antihypertensive
Perhaps in no other area of medicine is therapy with the potential therapy, and their efficacy, safety, and infrequency of side effects are
for benefit or danger to two individuals so poorly evaluated. There is extensively documented.432 The combination of diuretics with other
virtually no information from large, randomized, controlled trials antihypertensive drugs allows the use of lower doses of the other agents
about the fetal and maternal benefits and risks of antihypertensive by preventing sodium retention.
therapy for mild to moderate chronic hypertension in pregnancy. Despite these theoretical concerns, when continuous diuretic
therapy is begun before 24 to 30 weeks’ gestation, there is no evidence
Choice of Antihypertensive Agents of an increased perinatal mortality rate or decreased neonatal
EFFECT ON THE FETUS weights.277,279 However, diuretic therapy should never be instituted if
Fetal considerations, particularly teratogenic concerns, influence there is any evidence of reduced uteroplacental perfusion, such as fetal
the choice of antihypertensive agents (see Chapter 20). Few of the growth restriction or preeclampsia. Diuretic therapy increases the
available antihypertensive agents have been associated with morpho- serum concentration of uric acid and thereby renders uric acid deter-
logic teratogenic effects; exceptions are the angiotensin-converting minations invalid for evaluating superimposed preeclampsia.
enzyme (ACE) inhibitors (discussed later). Because development does b-Adrenergic Antagonists. β-Adrenergic antagonists are the
not end with gross organ development, long-term follow-up of infants initial antihypertensive agents for nonpregnant patients in many set-
and children treated in utero is needed. Such information is available tings. These agents lower blood pressure by reducing cardiac output
only for methyldopa. Children of mothers treated with this agent and perhaps by interfering with renin release.
during pregnancy showed no signs of neurologic or somatic abnor- Infants born to women treated with β-blockers in pregnancy are
malities when examined at age 7 years.424 more often growth restricted compared with infants born to women
Maternal drug therapy can have pharmacologic effects on the fetus. treated with placebo or other antihypertensive drugs.433,434 Most
For example, maternal treatment with propranolol reduced fetal and growth-restricted infants were born to women who received ateno-
maternal cardiac output in animal studies.425 Because of the potential lol.423 β-Adrenergic antagonists vary according to their β1-adrenergic
pharmacokinetic differences between mother and fetus, appropriate subtype-specific (e.g., metoprolol, atenolol) and lipid solubility. For

28. 678 CHAPTER 35 Pregnancy-Related Hypertension
TABLE 35-10 ANTIHYPERTENSIVE AGENTS USED IN PREGNANCY
Side Effects
Agent Mechanism Cardiac Output Renal Blood Flow Maternal Neonatal
Thiazide Initial: decreased plasma Decreased Decreased Electrolyte depletion, serum Thrombocytopenia
volume and cardiac output uric acid increase,
thrombocytopenia,
hemorrhagic pancreatitis
Later: decreased total Unchanged Unchanged or
peripheral resistance increased
Methyldopa False neurotransmission, Unchanged Unchanged Lethargy, fever, hepatitis,
central nervous system hemolytic anemia, positive
effect Coombs test result
Hydralazine Direct peripheral vasodilation Increased Unchanged or Flushing, headache,
increased tachycardia, palpitations,
lupus syndrome
Prazosin Direct vasodilator and Increased or Unchanged Hypotension with first dose;
cardiac effects unchanged little information on use in
pregnancy
Clonidine Central nervous system Unchanged or Unchanged Rebound hypertension; little
effects increased information on use in
pregnancy
Propranolol β-Adrenergic blockade Decreased Decreased Increased uterine tone with Depressed respiration
possible decrease in
placental perfusion
Labetalol α- and β-Adrenergic Unchanged Unchanged Tremulousness, flushing, See propranolol
blockade headache
Reserpine Depletion of norepinephrine Unchanged Unchanged Nasal stuffiness, depression, Nasal congestion,
from sympathetic nerve increased sensitivity to increased respiratory
endings seizures tract secretions,
cyanosis, anorexia
Enalapril Angiotensin-converting Unchanged Unchanged Hyperkalemia, dry cough Neonatal anuria
enzyme inhibitor
Nifedipine Calcium channel blocker Unchanged Unchanged Orthostatic hypotension, None demonstrated in
headache, tachycardia humans
example, atenolol more readily crosses the placenta compared with infants whose mothers received methyldopa, there was a small but
metoprolol. Some of the β-adrenergic antagonists, such as oxprenolol, statistically significant decrease in head circumference, although this
also have β-agonist effects. The decision, both theoretical and empiric, effect was not found in follow-up studies.424
about the safety and efficacy of these drugs requires evaluation of the Other Drugs. Several other antihypertensive drugs are available
pharmacologic characteristics of each drug rather than consideration that may offer theoretical advantages for use in pregnancy. More data
of them as a class. are required about the efficacy and the immediate and long-range
Labetalol. Unlike atenolol, labetalol possesses both α-adrenergic safety of these drugs in pregnancy.
and β-adrenergic antagonist activity. It is commonly used during preg- One agent that is widely used in nonpregnant patients is enalapril,
nancy for acute treatment of preeclampsia and as therapy for chronic an ACE inhibitor. Unexplained fetal death in pregnant ewes and rabbit
hypertension. Although some reports have suggested potential growth does treated with another ACE inhibitor, captopril, have been borne
restriction,433 other studies have not.435,436 Experience has not identified out by clinical experience. Although there are no reports of fetal death,
it as a teratogen (see Pharmacologic Recommendations, later). renal agenesis and neonatal renal dysfunction have been reported.438
Hydralazine. Although hydralazine seems to be an ideal antihy- This class of drugs is now considered pregnancy category X. There is
pertensive drug for pregnant women, side effects, including headache less experience with angiotensin II receptor blockers (ARBs) such as
and palpitations caused by reflex increase in cardiac output, usually losartan and telmisartan, although case reports suggest problems
prevent its use in effective dosages for chronic hypertension. Tachy- similar to those with ACE inhibitors.439-441 ACE inhibitors and ARBs
phylaxis has been described with hydralazine, making its use limited should be discontinued before pregnancy or as soon as pregnancy is
to short-term blood pressure control. detected.442
Methyldopa. Methyldopa, the drug used in the largest study and
the only drug whose safety for infants has been demonstrated in long- Pharmacologic Recommendations
range follow-up assessments, is the benchmark of antihypertensive ACE inhibitors and ARBs should be discontinued during pregnancy.
therapy in pregnancy. It frequently causes drowsiness, however, espe- No other drugs are absolutely contraindicated.
cially when used in the large doses necessary when diuretics are not The drug regimens suggested in the following paragraphs are
used concomitantly, and occasionally to a degree that is incapacitating, preferred because of the available information regarding efficacy,
particularly for ambulatory patients.437 In the original examination of side effects, and long-term follow-up. If a woman has established

29. CHAPTER 35 Pregnancy-Related Hypertension 679
excellent blood pressure control, however, especially after unsuccessful of these forms by physiologic changes of pregnancy and because of the
trials of other agents, she should continue the successful regimen on risks of diagnostic procedures to the mother and fetus.
becoming pregnant. Women receiving atenolol should switch to Pheochromocytoma is a potentially lethal complication, especially
another β-adrenergic antagonist of equivalent efficacy, such as during the intrapartum period. This condition can be simply, accu-
metoprolol. rately, and inexpensively diagnosed in many individuals with fixed
The use of diuretic therapy is associated with few acute adverse hypertension by determination of the serum or urinary catecholamine
effects and potentiates other drug effects. Although the use of diuretics concentration. Hypertensive women in whom this analyte has not
from early pregnancy onward appears safe,277-279 theoretical concerns been measured in the past should undergo this determination in early
raised by the effects of these agents on plasma volume militate against pregnancy.
their use as initial therapy. Diuretics are also contraindicated for Coarctation of the aorta is a rare cause of hypertension in women
women with evidence of decreased uterine perfusion manifested as of reproductive age. It can be detected readily by determination of a
IUGR or preeclampsia. If the pregnancy is less than 30 weeks’ gestation, lag between radial and femoral pulses, which should be measured as
these drugs appear safe despite theoretical concerns. The initial dose part of the physical examination of hypertensive patients.
should be 25 mg of hydrochlorothiazide equivalent, increasing at 2- to Extensive antenatal fetal surveillance should be employed for preg-
4-day intervals to 50 mg/day. Sodium restriction should be avoided, nancies with preeclampsia or growth-restricted infants.3 Because of the
and dietary potassium should be supplemented when diuretics are controversy surrounding uncomplicated hypertension and perinatal
used. mortality and because the origin of the increased mortality is placental
Because of its established efficacy and fetal safety, methyldopa has insufficiency, many clinicians employ some form of antenatal surveil-
for many years been chosen to initiate antihypertensive therapy in lance for uncomplicated cases in the third trimester.
pregnancy. The initial dosage is 250 mg taken at night and then 250 mg
twice daily, increasing to a maximum of 1 g twice daily. If the maximal
dose is not tolerated or does not control blood pressure, another agent
should be added (not substituted). The addition of a diuretic usually References
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Labetalol or nifedipine is commonly added to methyldopa therapy logia 167:478, 1969.
2. Gifford R, August P, Cunningham G, et al: The National High Blood Pres-
when a second agent is required, and they are increasingly used as
sure Education Program Working Group on High Blood Pressure in Preg-
first-line therapy. If three drugs appear to be necessary to control blood nancy. Bethesda, National Institutes of Health and National Heart, Lung,
pressure, consultation with a cardiologist or nephrologist is prudent. and Blood Institute, 2000.
Used as a primary or secondary agent, labetalol is begun at 100 mg 3. Report of the National High Blood Pressure Education Program Working
taken twice each day; it is given up to 2.4 g per day in divided doses, Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol 183:
but the typical maximal dosage is 400 to 600 mg twice each day. Nife- S1-S22, 2000.
dipine may be given 10 to 30 mg three times each day or as 30 to 60 mg 4. North RA, Taylor RS, Schellenberg JC: Evaluation of a definition of pre-
once each day in sustained-release form. eclampsia. BJOG 106:767-773, 1999.
5. Zhang J, Klebanoff MA, Roberts JM: Prediction of adverse outcomes
by common definitions of hypertension in pregnancy. Obstet Gynecol
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changes in normal pregnancy and pre-eclampsia. Br J Haematol 50:461-
Obstetric management of the woman with chronic hypertension com- 465, 1982.
prises the following measures: 7. Abuelo JG: Validity of dipstick analysis as a method of screening for pro-
teinuria in pregnancy. Am J Obstet Gynecol 169:1654, 1993.
Recognizing superimposed preeclampsia early in the pregnancy 8. Kuo VS, Koumantakis G, Gallery ED: Proteinuria and its assessment in
Monitoring fetal well-being normal and hypertensive pregnancy. Am J Obstet Gynecol 167:723-728,
Excluding pheochromocytoma 1992.
9. Meyer NL, Mercer BM, Friedman SA, Sibai BM: Urinary dipstick protein:
Early in pregnancy, studies of renal function (i.e., creatinine clear- A poor predictor of absent or severe proteinuria. Am J Obstet Gynecol
170(Pt 1):137-141, 1994.
ance and 24-hour protein excretion), a serum urate determination, and
10. American College of Obstetricians and Gynecologists (ACOG): Diagnosis
a platelet count should be performed. These baseline studies may aid and management of preeclampsia and eclampsia. ACOG practice bulletin
in differentiating exaggeration of the usual blood pressure changes no. 33, January 2002. Obstet Gynecol 99:159-167, 2002.
of pregnancy from superimposed preeclampsia later in pregnancy. 11. Brown MA, Lindheimer MD, de Swiet M, et al: The classification and
Because preeclampsia occurs at earlier gestational ages in hypertensive diagnosis of the hypertensive disorders of pregnancy: Statement from the
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