Preeklampsia

Chapter 31
Preeclampsia and
Hypertensive Disorders
BAHA M. SIBAI
Definitions 662 Diagnosis of Preeclampsia 667 Maternal and Perinatal Outcome 692
Gestational Hypertension 662 Prediction of Preeclampsia 668 Is Eclampsia Preventable? 692
Severe Hypertension 662 Prevention of Preeclampsia 669 Transport of the Eclamptic Patient 693
Proteinuria 662 Laboratory Abnormalities in Treatment of Eclamptic Convulsions 693
Edema 662 Preeclampsia 670 Intrapartum Management of
Preeclampsia and Eclampsia 662 Hemodynamic Monitoring in Eclampsia 694
Chronic Hypertension 663 Preeclampsia 680 Postpartum Management of
Gestational Hypertension 663 Expectant Management 683 Eclampsia 695
Preeclampsia 664 Recommended Management of Chronic Hypertension 696
Atypical Preeclampsia 664 Preeclampsia With Severe Definition and Diagnosis 696
Capillary Leak Syndrome: Facial Edema, Features 684 Etiology and Classification 696
Ascites and Pulmonary Edema, and Maternal and Perinatal Outcomes With Maternal and Perinatal Risks 697
Gestational Proteinuria 664 Preeclampsia 688 Goals of Antihypertensive Therapy in
Risk Factors for Preeclampsia 665 Counseling Women Who Have Had Pregnancy 697
Pathophysiology 666 Preeclampsia in Prior Pregnancies 688 Safety of Antihypertensive Drugs in
Uterine Vascular Changes 666 Remote Prognosis 689 Pregnancy 698
Vascular Endothelial Activation and Eclampsia 689 Recommended Management of Chronic
Inflammation 666 Pathophysiology 689 Hypertension in Pregnancy 699
Genetics and Genetic Imprinting 667 Diagnosis 689 Postpartum Management 701
Changes in Prostanoids 667 Time of Onset of Eclampsia 690 Hypertensive Emergencies in Chronic
Lipid Peroxide, Free Radicals, and Cerebral Pathology 690 Hypertension 701
Antioxidants 667 Differential Diagnosis 691 Hypertensive Encephalopathy 701
KEY ABBREVIATIONS
Acute fatty liver of pregnancy AFLP Glomerular filtration rate GFR
Acute respiratory distress syndrome ARDS Hemolysis, elevated liver enzymes, and HELLP
Alanine transaminase ALT low platelets syndrome
American College of Obstetricians and ACOG Hemolytic uremic syndrome HUS
Gynecologists Hypertensive disorders of pregnancy HDP
Angiotensin-converting enzyme ACE Immune thrombocytopenic purpura ITP
Aspartate transaminase AST Intrauterine growth restriction IUGR
Biophysical profile BPP Lactate dehydrogenase LDH
Blood pressure BP Low-dose aspirin LDA
Body mass index BMI Magnetic resonance imaging MRI
Central venous pressure CVP Mean arterial pressure MAP
Computed tomography CT Nonstress test NST
Confidence interval CI Placental-like growth factor PLGF
Disseminated intravascular coagulation DIC Posterior reversible encephalopathy PRES
Electrocardiogram ECG syndrome
Electroencephalography EEG Positive predictive value PPV
False-positive rate FPR Preeclampsia PE
Fetal growth restriction FGR Protein/creatinine ratio P/C ratio
Gestational hypertension GH Pulmonary capillary wedge pressure PCWP
661
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662 Section V Complicated Pregnancy
Relative risk RR Thrombotic thrombocytopenic purpura TTP

Respiratory distress syndrome RDS Thromboxane A2 TXA2
Small for gestational age SGA U. S. Preventive Services Task Force USPSTF
Soluble fms-like tyrosine kinase 1 sFlt-1 Vascular endothelial growth factor VEGF
Hypertensive disorders are among the most common medical oral antihypertensive agents or received intravenous (IV) anti-
complications of pregnancy; the reported incidence is between hypertensive medications prior to the 4-hour period.
5% and 10%,1,2 although incidence varies among different hos-
pitals, regions, and countries. These disorders are a major cause Proteinuria
of maternal and perinatal mortality and morbidity worldwide.3 Proteinuria may also be present before pregnancy, or it may be
The term hypertension in pregnancy is commonly used to describe newly diagnosed during pregnancy. The definition of proteinuria
a wide spectrum of patients who may have only mild elevations is the same no matter when it occurs:
in blood pressure (BP) or severe hypertension with dysfunc- • Greater than 0.3 g in a 24-hour urine collection or protein/
tion of various organ systems. The clinical manifestations in creatinine (P/C) ratio greater than 0.3. If it is not possible
these patients may be similar (e.g., hypertension, proteinuria); to measure 24-hour protein or P/C ratio, proteinuria can
however, they may result from different underlying causes such be defined as a dipstick measurement of at least 1+ on two
as chronic hypertension, renal disease, or pure preeclampsia (PE). occasions.
The three most common forms of hypertension that complicate • Protein excretion in the urine increases in normal pregnancy
pregnancy are (1) gestational hypertension, (2) preeclampsia, from approximately 5 mg/dL in the first and second trimes-
and (3) chronic essential hypertension. ters to 15 mg/dL in the third trimester. These low levels
are not detected by dipstick. The concentration of urinary
protein is influenced by contamination with vaginal secre-
DEFINITIONS tions, blood, bacteria, or amniotic fluid. It also varies with
Gestational Hypertension urine specific gravity and pH, exercise, and posture.
Hypertension may be present before pregnancy, or it may be • Proteinuria usually appears after hypertension in the course
diagnosed for the first time during pregnancy. In addition, in of the disease process, but in some women, it may appear
some women, hypertension may become evident only during before hypertension.
labor or during the postpartum period. For clinical purposes,
women with hypertension may be classified into one of the Edema
three categories listed above; these are described further in Table Edema is defined as excessive weight gain (>4 lb [1.8 kg] in 1
31-1.1,2 Recently, the diagnosis of PE and its subtypes have been week) in the second or third trimester, and it may be the first
expanded and revised by the members of the American College sign of the potential development of PE. However, 39% of
of Obstetricians and Gynecologists (ACOG) Task Force on patients with eclampsia do not have edema.
Hypertension in Pregnancy1:
• Systolic BP greater than 140 mm Hg but less than 160  Preeclampsia and Eclampsia
mm Hg or Preeclampsia is gestational hypertension (GH) plus protein-
• Diastolic BP greater than 90 mm Hg but less than uria. Box 31-1 lists criteria for diagnosis of GH and PE. The
110 mm Hg and ACOG Task Force on Hypertension in Pregnancy Group clas-
• These pressures must be observed on at least two occasions 4 sifies PE based on whether it is has severe features. The term
hours apart but no more than 7 days apart.4 mild preeclampsia has been removed from the ACOG classifica-
tion system and should not be used in clinical practice.
Severe Hypertension It is recognized that some women with GH may have
Severe hypertension refers to sustained elevations in systolic BP undiagnosed chronic hypertension, whereas others will sub-
to at least 160 mm Hg and/or in diastolic BP to at least sequently progress to develop the clinical syndrome of
110 mm Hg for at least 4 hours or once if the patient is receiving preeclampsia.5 In general, the likelihood of progression to PE
TABLE 31-1 HYPERTENSIVE DISORDERS OF PREGNANCY

CLINICAL FINDINGS CHRONIC HYPERTENSION GESTATIONAL HYPERTENSION* PREECLAMPSIA
Time of onset of hypertension <20 wk >20 wk Usually in third trimester
Degree of hypertension Mild or severe Mild Mild or severe
Proteinuria* Absent Absent Usually present
Cerebral symptoms May be present Absent Present in 30%
Hemoconcentration Absent Absent Severe disease
Thrombocytopenia Absent Absent Severe disease
Hepatic dysfunction Absent Absent Severe disease
*Defined as 1+ or more (or protein/creatinine ratio >0.30) by dipstick testing on two occasions or 300 mg or more in a 24-hour urine collection or protein.
Chapter 31 Preeclampsia and Hypertensive Disorders 663
BOX 31-1 CRITERIA FOR MILD GESTATIONAL TABLE 31-2 RECOMMENDED CRITERIA TO DIAGNOSE
HYPERTENSION IN HEALTHY PREGNANT WOMEN PREECLAMPSIA IN WOMEN WITH
• Systolic blood pressure >140 mm Hg but <160 mm Hg
PREEXISTING MEDICAL CONDITIONS
and diastolic blood pressure >90 mm Hg but CONDITION CRITERIA NEEDED
<110 mm Hg Hypertension only Proteinuria of ≥300 mg per 24 hr or
• Proteinuria of <300 mg per 24-hr collection thrombocytopenia
• Platelet count of >100,000/mm3 Hypertension plus proteinuria Worsening severe hypertension plus
• Normal liver enzymes (renal disease or class F proteinuria and either new onset
• Absent maternal symptoms diabetes) of symptoms, thrombocytopenia,
• Absent intrauterine growth restriction and or elevated liver enzymes
oligohydramnios by ultrasound
60 Eclampsia is defined as the occurrence of seizures after the

second half of pregnancy not attributable to other causes.9
50
40 Chronic Hypertension
Percent
Chronic hypertension is defined as hypertension present prior to

30
pregnancy or that is diagnosed before 20 weeks of gestation.
20 Hypertension that persists for more than 3 months postpartum
10
is also classified as chronic hypertension.2,3
0 Chronic Hypertension With Superimposed Preeclampsia

Saudan Barton Magee Valensise Women with chronic hypertension may develop superimposed
preeclampsia, which increases morbidity for both the mother
32-35 wk and fetus. The diagnosis of superimposed PE is based on one
<32 wk
or both of the following findings: development of new-onset
<34 wk
28-31 wk
proteinuria, defined as the urinary excretion of 0.3 g or more of
protein in a 24-hour specimen or a P/C ratio greater than 0.3
FIG 31-1 Rate of progression from gestational hypertension to pre- in women with hypertension and no proteinuria before 20
eclampsia by gestational age at diagnosis. (Data from references 5, weeks’ gestation; or, in women with hypertension and protein-
6, 7, and 8.)
uria before 20 weeks, severe exacerbation in hypertension plus
development of symptoms or thrombocytopenia and abnormal
depends on gestational age at time of diagnosis, with higher liver enzymes (Table 31-2).1,10,11
rates if the onset of hypertension is before 35 weeks’ gestation The ACOG Task Force report on hypertension in pregnancy
(Fig. 31-1).5-8 recommended that superimposed preeclampsia be stratified
into two groups to guide management: (1) superimposed pre-
Criteria for Preeclampsia or Gestational Hypertension eclampsia, defined as a sudden increase in blood pressure that
With Severe Features was previously well controlled or escalation of antihypertensive
Preeclampsia, or gestational hypertension with severe features, is medications to control BP, or (2) new-onset proteinuria (>300 mg/
defined when either disorder is present in association with any 24-hour collection or a P/C ratio >0.3), or a sudden and sus-
of the following abnormalities: tained increase in proteinuria in a woman with known protein-
• Systolic BP greater than 160 mm Hg or diastolic BP greater uria before conception or early in pregnancy.
than 110 mm Hg on two occasions at least 4 hours apart A diagnosis of superimposed preeclampsia with severe fea-
while the patient is on bed rest or once if the patient has tures should be made in the presence of any of the following:
received prior antihypertensive therapy. Prompt treatment is (1) severe-range BP (>160 mm Hg systolic or >110 mm Hg
recommended for severe BP values that are sustained for diastolic) despite escalation of antihypertensive therapy; (2) per-
longer than 30 minutes. sistent cerebral symptoms such as headaches or visual distur-
• New-onset persistent cerebral symptoms (headaches) or visual bances; (3) significant increase in liver enzymes (at least two
disturbances times the ULN concentration for a particular laboratory);
• Impaired liver function as indicated by abnormally elevated (4) thrombocytopenia (platelet count <100,000/µL); or
liver enzymes (at least twice the upper limit of normal [ULN]); (5) new-onset and/or worsening renal insufficiency.
severe, persistent right upper quadrant or epigastric pain that
is unresponsive to medications and not accounted for by an Gestational Hypertension
alternative diagnosis; or both Gestational hypertension is the most frequent cause of
• Pulmonary edema hypertension during pregnancy. The incidence ranges between
• Thrombocytopenia (platelet count <100,000/µL) 6% and 29% in nulliparous women2,4,12 and between 2% and
• Progressive renal insufficiency (serum creatinine >1.1 mg/dL) 4% in multiparous women.2 The incidence is markedly increased
It is important to note that the amount of proteinuria, pres- in patients with multiple gestations.13-15 In general, most cases
ence of oliguria, and presence of intrauterine growth restriction of GH develop at or beyond 37 weeks’ gestation, and thus
(IUGR) or fetal growth restriction (FGR) by ultrasound have the overall pregnancy outcome is usually similar to that seen
been removed as criteria for the diagnosis of severe disease. in women with normotensive pregnancies (Table 31-3).4,5,12
TABLE 31-3 PREGNANCY OUTCOME IN WOMEN WITH MILD GESTATIONAL HYPERTENSION

KNUIST ET AL12 HAUTH ET AL4 BARTON ET AL5 SIBAI2
(n = 396) (n = 715) (n = 405) (n = 186)
Gestation at delivery (week)* NR 39.7 37.4† 39.1
Before 37 weeks (%) 5.3 7.0 17.3 5.9
Before 34 weeks (%) 1.3 1.0 4.9 1.6
Birthweight (g)* NR 3303 3038 3217
SGA (%) 1.5‡ 6.9 13.8 7.0
<2500 g (%) 7.1 7.7 23.5 NR
Abruptio placentae (%) 0.5 0.3 0.5 0.5
Perinatal deaths (%) 0.8 0.5 0 0
Modified from Sibai BM. Diagnosis and management of gestational hypertension and preeclampsia. Obstet Gynecol. 2003;102:181.
*Mean values.
†
Women who developed hypertension at 24 to 35 weeks.
‡
Less than the third percentile.
NR, not reported; SGA, small for gestational age.
Proteinuria
Normal Facial
edema
Mild Vascular
Pulmonary stillbirth
Severe Blood edema Abnormal
pressure Preterm
Capillary leak Ascites Doppler Abruption
delivery
Oligohydramnios
Epigastric Pleural
pain effusions
Symptoms FGR
Fibrinolysis HELLP
CNS
Hemolysis
Bleeding Renal
failure
Nausea/ FIG 31-3 Fetal manifestations of preeclampsia. FGR, fetal growth
DIC
vomiting restriction.
Low platelets
↑Liver enzymes
FIG 31-2 Maternal manifestations in preeclampsia. CNS, central pathophysiology of early-onset PE may be different than that of
nervous system; DIC, disseminated intravascular coagulation; HELLP, PE that develops at term, during labor, or in the postpartum
hemolysis, elevated liver enzymes, and low platelets. period.17,20,21
The incidence of preeclampsia ranges between 2% and 7%
However, women with mild GH have higher rates of induction in healthy nulliparous women.2,4,12 In these women, PE is
of labor.4 generally mild, with the onset near term or during labor
Maternal and perinatal morbidities are substantially increased (75% of cases), and the condition conveys only a minimally
in women with severe GH.2,4 Indeed, these women have increased risk for adverse fetal outcome.2,4,12 In contrast, the
increased risk for morbidity compared with women with mild incidence and severity of PE are substantially higher in women
PE. The rates of abruptio placentae, preterm delivery (at <37 with multifetal gestation,10,13,15,22 chronic hypertension,10,11 pre-
and 35 weeks), and small-for-gestational-age (SGA) infants in vious PE,23-28 pregestational diabetes mellitus,10,29,30 or preexist-
these women are similar to those seen in women with PE and ing thrombophilias.31
severe features.2,16 It remains unclear whether this increase in
preterm delivery is secondary to scheduled early delivery accord- Atypical Preeclampsia
ing to physician preference or whether it occurs because of a The criteria for atypical preeclampsia include gestational pro-
disease process. teinuria or FGR plus one or more of the following symptoms
of preeclampsia: hemolysis, thrombocytopenia, elevated liver
enzymes, early signs and symptoms of preeclampsia-eclampsia
PREECLAMPSIA earlier than 20 weeks, and late postpartum preeclampsia-
Preeclampsia is a form of hypertension that is unique to eclampsia (>48 hours postpartum).
human pregnancy. The clinical findings of PE can manifest
as either a maternal syndrome (Fig. 31-2) or a fetal syndrome Capillary Leak Syndrome: Facial Edema,
(Fig. 31-3).17-19 In practice, the maternal syndrome of PE repre- Ascites and Pulmonary Edema, and
sents a clinical spectrum with major differences between near- Gestational Proteinuria
term PE without demonstrable fetal effects and PE that is Hypertension is considered to be the hallmark for the diag-
associated with low birthweight and preterm delivery.17,20 PE is nosis of preeclampsia. However, in some patients with PE,
clearly a heterogeneous condition for which the pathogenesis the disease may manifest as either a capillary leak (protein-
may be different in women with various risk factors.17,20,21 uria, facial and vulvar edema, ascites, pulmonary edema); exces-
The pathogenesis of PE in nulliparous women may be different sive weight gain, particularly during the second and early
than that in women with preexisting vascular disease, multifetal third trimester; or a spectrum of abnormal hemostasis with
gestations, diabetes mellitus, or previous PE. In addition, the multiple-organ dysfunction. These women usually present
BOX 31-2 RISK FACTORS FOR PREECLAMPSIA

• Nulliparity
• Age >40 years
• Pregnancy with assisted reproduction
• Interpregnancy interval >7 years
• Family history of preeclampsia
• Woman born small for gestational age
• Obesity/gestational diabetes mellitus
• Multifetal gestation
• Preeclampsia in previous pregnancy
• Poor outcome in previous pregnancy
• Fetal growth restriction, placental abruption, fetal death
• Preexisting medical-genetic conditions
• Chronic hypertension
• Renal disease
• Type 1 (insulin-dependent) diabetes mellitus
• Antiphospholipid antibody syndrome
• Factor V Leiden mutation
examination of the uterus to rule out molar pregnancy or

hydropic/cystic degeneration of the placenta. Measurement
FIG 31-4 Vulvar edema in severe preeclampsia.
of uterine artery Doppler flow, which shows the classic “notch-
ing” characteristic of increased resistance in the placenta of
with clinical manifestations of atypical preeclampsia, such as patients with PE, is also recommended.32
proteinuria with or without facial edema, vulvar edema (Fig.
31-4), excessive weight gain (>4 lb/wk), ascites, or pulmonary Risk Factors for Preeclampsia
edema in association with abnormalities in laboratory values or Several factors have been identified with increased risk for pre-
presence of symptoms but without hypertension.32 Therefore we eclampsia (Box 31-2). Generally, PE is considered a disease
recommend that women with capillary leak syndrome with or of primigravid women. The risk increases in those who have
without hypertension be evaluated for platelet, liver enzyme, and limited sperm exposure with the same partner before concep-
renal abnormalities. Those with symptoms such as new onset of tion.17,20,36 The protective effects of long-term sperm exposure
unrelenting severe headache, severe visual disturbances, or with the same partner might provide an explanation for the high
abnormal blood tests should be considered to have PE.32 risk for PE in women younger than 20 years old. A previous
abortion (spontaneous or induced) or a previous normal preg-
Gestational Proteinuria nancy with the same partner is associated with a lower risk
It is generally agreed that urine dipstick protein measurements for PE. However, this protective effect is lost with a change of
should be performed at each prenatal visit after 20 weeks’ gesta- partner or with prolonged interval between pregnancies.37
tion. Gestational proteinuria is defined as urinary protein excre- Both Scandinavian and U.S. studies have confirmed the
tion of at least 300 mg per 24-hour timed collection, P/C ratio importance of paternal factors as a contributor to PE as well as
greater than 0.3, or persistent proteinuria (≥1+ on dipstick on an interpregnancy interval greater than 7 years.38,39 Using whole
at least two occasions at least 4 hr apart).1,3 In addition, new- population data, Lie and colleagues39 demonstrated that men
onset proteinuria greater than 2+ on one occasion is strongly who fathered one preeclamptic pregnancy were nearly twice
associated with proteinuria of greater than 300 mg in 24 hours. as likely to father a preeclamptic pregnancy with a different
The exact incidence of gestational proteinuria progressing to woman (odds ratio [OR], 1.8; 95% confidence interval [CI],
preeclampsia is unknown; however, isolated gestational protein- 1.2 to 2.6 after adjustment for parity), regardless of whether the
uria was identified in 4% of women enrolled in two multicenter new partner had a history of a preeclamptic pregnancy. Thus
trials.33,34 In addition, these studies reported that 4.3% to 7% mothers had a substantially increased risk in their second preg-
of patients had combined GH and gestational proteinuria. Thus nancy (2.9%) if their partner had fathered a preeclamptic first
it appears that at least one third of women with gestational pregnancy with another woman. This risk was nearly as high as
proteinuria may progress to PE.33,34 Indeed, some authors the average risk among primigravid women.39
have suggested that gestational proteinuria alone may herald the Recent advances in assisted reproductive technology (ART)
early manifestations of impending preeclampsia.33,35 In the have been associated with an increased risk for preeclamp-
absence of other pathology, the patient should be treated as sia.14,15,40 Among the factors cited are a greater proportion of
having potential PE and requires evaluation for the presence women older than 40 years, infertile women during their first
of symptoms; evaluation should include blood tests and fre- gestation, multifetal gestation, obese women with polycystic
quent monitoring of BP (at least twice per week or, alterna- ovary syndrome (PCOS), and women who become pregnant
tively, ambulatory home BP measurements), and the patient with donated gametes or embryos.40 The use of donated gametes
should be educated about the signs and symptoms of PE. In can influence the maternal-fetal immune interaction. In addi-
addition, women in whom convulsions develop in association, infertile women with recurrent miscarriage are also reported
tion with hypertension and proteinuria during the first half to be at increased risk for PE.41
of pregnancy should be considered to have eclampsia until Obesity reflected as increased body mass index (BMI) height-
proven otherwise. These women should undergo ultrasound ens the risk for preeclampsia.42 The worldwide increase in obesity
BOX 31-3 THEORIES ASSOCIATED WITH THE ETIOLOGY funnel-shaped vessels that communicate through multiple open-
OF PREECLAMPSIA ings into the intervillous space.
In contrast, pregnancies complicated by preeclampsia or by
• Abnormal trophoblast invasion or poor implantation FGR demonstrate inadequate maternal vascular response to
• Imbalance in angiogenesis
placentation. In these pregnancies, the previously mentioned
• Coagulation abnormalities
• Vascular endothelial damage
vascular changes are usually found only in the decidual segments
• Cardiovascular maladaptation of the uteroplacental arteries. Hence the myometrial segments
• Immunologic maladaptation of the spiral arterioles continue to exhibit their characteristic
• Genetic predisposition musculoelastic architecture, thereby leaving them responsive
• Exaggerated inflammatory response to hormonal influences.50,52 Additionally, the number of well-
• Increased oxidative stress developed arterioles is smaller than that found in normotensive
pregnancies.
It has been postulated that this defective vascular response
to placentation is due to inhibition of the second wave of
is thus likely to lead to a rise in the frequency of PE.43,44 Obesity endovascular trophoblast migration that normally occurs
has a strong link to insulin resistance, which is also a risk factor from about 16 weeks’ gestation onward. These pathologic
for PE. The exact mechanism by which obesity or insulin resis- changes may have the effect of curtailing the increased blood
tance is associated with PE is not well understood. supply required by the fetoplacental unit in the later stages
Earlier studies found an overall higher rate of thrombophilia of pregnancy and may correlate with the decreased utero
in women with PE compared with controls.31 Recently, a number placental blood flow seen in most cases of preeclampsia.50
of reports have failed to reproduce these findings.45-46 The dispar- Frusca and associates52 studied placental bed biopsy specimens
ity in results may reflect the heterogeneity of the women being obtained during cesarean delivery from normal pregnancies
studied. In the largest series of preeclamptic women with throm- (n = 14), preeclamptic pregnancies (n = 24), and chronic hyper-
bophilia, women had increasing risk for very early onset, severe tensive pregnancies only (n = 5). Biopsy specimens from the
disease (delivery before 28 weeks) compared with those who did preeclamptic group demonstrated abnormal vascular changes in
not have thrombophilia.31 every case, and 18 had acute atherosclerotic changes. In contrast,
13 of the 14 specimens from normotensive pregnancies had
Pathophysiology normal vascular physiologic changes. In addition, they found
The etiology of preeclampsia remains unknown. Many theories that the mean birthweight was significantly lower in the group
have been suggested, but most of them have not withstood the with atherosclerosis than it was in the other group without such
test of time. Some of the theories still under consideration are findings. It is important to note that these vascular changes may
listed in Box 31-3.17, 47-50 also be demonstrated in a significant proportion of normoten-
During normal pregnancy, impressive physiologic changes sive pregnancies complicated by FGR. Meekins and associates53
occur in the uteroplacental vasculature and in the cardiovascu- demonstrated that endovascular trophoblast invasion is not an
lar system. These changes are most likely induced by the interac- all-or-none phenomenon in normal and preeclamptic pregnan-
tion of the fetal (parental) allograft with maternal tissue. The cies. These authors observed that morphologic features found
development of mutual immunologic tolerance in the first tri- in one spiral artery may not be representative of all vessels in a
mester is thought to lead to important morphologic and bio- placental bed.
chemical changes in the systemic and uteroplacental maternal
circulation. Vascular Endothelial Activation
and Inflammation
Uterine Vascular Changes The mechanism by which placental ischemia leads to the clinical
The human placenta receives its blood supply from numer- syndrome of PE is thought to be related to the production of
ous uteroplacental arteries that are developed by the action placental factors that enter the maternal circulation and result
of migratory interstitial and endovascular trophoblasts into in endothelial cell dysfunction.47-49,54 Soluble fms-like tyrosine
the walls of the spiral arterioles. This transforms the utero- kinase 1 (sFlt-1) is a protein produced by the placenta. It acts
placental arterial bed into a low-resistance, low-pressure, by binding to the receptor-binding domains of vascular
high-flow system. The conversion of the spiral arterioles of the endothelial growth factor (VEGF), and it also binds to
nonpregnant uterus into the uteroplacental arteries has been placental-like growth factor (PLGF). Increased levels of this
termed physiologic changes.50,51 In a normal pregnancy, these protein in the maternal circulation results in reduced levels
trophoblast-induced vascular changes extend all the way from of free VEGF and free PLGF with resultant endothelial cell
the intervillous space to the origin of the spiral arterioles that dysfunction.54
represent the radial arteries in the inner one third of the myo- Maternal serum and placental levels of sFlt-1 are increased
metrium. It is suggested that these vascular changes are in pregnancies complicated by preeclampsia values above
effected in two stages, “the conversion of the decidual seg- seen during normal pregnancies. Maynard and coworkers55
ments of the spiral arterioles by a wave of endovascular tro- demonstrated that soluble placenta-derived VEGF receptor
phoblast migration in the first trimester and the myometrial (sFlt-1)—an antagonist of VEGF and PLGF—is unregulated in
segments by a subsequent wave in the second trimester.”52,53 PE, which leads to increased systemic levels of sFlt-1 that fall
This process is reportedly associated with extensive fibrinoid after delivery. Increased circulating sFlt-1 in PE is associated
formation and degeneration of the muscular layer in the arte- with decreased circulating levels of free VEGF and PLGF and
rial wall. These vascular changes result in the conversion of results in endothelial dysfunction. The magnitude of increase in
about 100 to 150 spiral arterioles into distended, tortuous, and sFlt levels correlates with disease severity,56 which lends further
support to VEGF–soluble Flt balance and represents one of the carried a major reproductive advantage. It is more likely that a
final common pathophysiologic pathways. rapidly growing number of susceptibility genes will be uncov-
First-trimester PLGF levels are decreased in future preeclamp- ered and that many of these will be found to interact with the
tic pregnancies and in pregnancies complicated by FGR, whereas maternal cardiovascular-hemostatic system or in the regulation
sFlt levels do not differ from controls.57 Again, these data are of maternal inflammatory responses.65 These loci segregate with
compatible with decidual angiogenic growth factors, in particu- different populations,66 and it should be noted that these loci
lar PLGF, as being essential for early placental development only explain a relatively small percentage of the overall cases of
(PLGF is low in both FGR and preeclampsia), with a later PE. In addition, although these linkage studies indicate maternal
involvement of sFlt as a fetal rescue signal steering the maternal susceptibility, they do not exclude the additional involvement of
response; that is, the degree of maternal systemic hypertension. fetal genes.66 Another important consideration regarding the
This hypothesis is supported by Levine and colleagues,56 who genetics of PE is the confounding effect of the so-called fetal
demonstrated that during the last 2 months of pregnancy in origins of adult disease hypothesis, which suggests that a
normotensive controls, the level of sFlt-1 increased and the level hostile intrauterine environment for a female fetus would
of PLGF decreased. form the basis for the insulin resistance syndrome with its
Levine and associates58 investigated urinary PLGF levels in associated endothelial dysfunction and, as such, that it would
pregnant women with and without PE and found that among lead to an increased risk for PE (see Chapter 5).20
normotensive pregnant women, urinary PLGF increased during Epigenetic features and imprinting are also involved in the
the first two trimesters, peaked at 29 to 32 weeks, and decreased pathogenesis of PE.66,67 Further evidence of the role of imprint-
thereafter. Among women who ultimately developed PE, the ing was recently suggested by Oudejans and van Dijk66 and
pattern of urinary PLGF was similar, but levels were significantly Nafee and associates.67
reduced beginning at 25 to 28 weeks. Particularly large differ-
ences were seen among those who subsequently developed early- Changes in Prostanoids
onset PE and in those who delivered SGA infants.58 A similar Several investigators have described levels of the various prosta-
study suggested that urinary angiogenic factors can identify glandins and their metabolites throughout pregnancy. They have
women with severe PE.59 measured the concentrations of these substances in plasma,
During the past decade, our understanding of the molecular serum, amniotic fluid, placental tissues, urine, and cord blood.
basis for the pathophysiologic abnormalities in preeclampsia has The data have been inconsistent, which reflects differences
reached an unprecedented level. Clear appreciation now exists in methodology.68,69 During pregnancy, prostanoid production
for the role of cell adhesion molecules (CAMs) and angiogenic increases in both maternal and fetoplacental tissues. Prostacyclin
proteins and for activation of the inflammatory system in the is produced by the vascular endothelium and in the renal cortex.
pathogenesis of microvascular dysfunction in women with It is a potent vasodilator and inhibitor of platelet aggregation.
PE.47,48,56 Evidence also suggests an exaggerated inflammatory Thromboxane A2 (TXA2) is produced by the platelets and tro-
response (abnormal cytokine production and neutrophil activa- phoblasts; it is a potent vasoconstrictor and platelet aggregator.
tion) in women with the clinical findings of PE.49 However, this Hence, these eicosanoids have opposite effects and play a major
enhanced inflammatory response is absent before the develop- role in regulating vascular tone and vascular blood flow. An
ment of PE.60 imbalance in prostanoid production or catabolism has been
Recent studies that have confirmed increased levels of asym- suggested as being responsible for the pathophysiologic
metric dimethylarginine at 23 to 25 weeks in pregnant women changes in preeclampsia. However, the precise role by which
who develop PE have emphasized the importance of the nitric prostaglandins are involved in the etiology of PE remains
oxide–cyclic guanosine monophosphate (cGMP) pathway.61,62 unclear.20
Endothelial dysfunction and inappropriate endothelial cell acti-
vation associated with alterations in nitric oxide levels in PE Lipid Peroxide, Free Radicals,
explains most typical clinical manifestations, including the and Antioxidants
increased endothelial cell permeability and increased platelet Evidence is accumulating that lipid peroxides and free radicals
aggregation.63 may be important in the pathogenesis of preeclampsia.40,50,70
Superoxide ions may be cytotoxic to the cell by changing the
Genetics and Genetic Imprinting characteristics of the cellular membrane and producing mem-
According to the genetic conflict theory, fetal genes are selected brane lipid peroxidation. Elevated plasma concentrations of
to increase the transfer of nutrients to the fetus, whereas mater- free radical oxidation products precede the development of PE.
nal genes are selected to limit transfer in excess of some optimal In addition, some studies reported lower serum antioxidant
level.17,20 The phenomenon of genomic imprinting means that activity in patients with PE than in those with normotensive
a similar conflict exists within fetal cells between genes that are pregnancies.17,20
maternally derived and those that are paternally derived. The Much of the controversy about oxidative stress is related to
conflict hypothesis suggests that placental factors (fetal genes) the nonspecificity of the markers. A recent study by Moretti and
act to increase maternal BP, whereas maternal factors act to reduce associates71 measured oxidative stress “on line” in exhaled breath
BP.20 Endothelial cell dysfunction may have evolved as a fetal (not subjective to in vitro artifacts) and confirmed greater oxida-
rescue strategy to increase nonplacental resistance when the tive stress in women with PE compared with nonpregnant con-
uteroplacental blood supply is inadequate. trols and those who had uncomplicated pregnancies.
Nilsson and associates64 published a model that suggests a
heritability estimate of 31% for PE and 20% for GH. It is Diagnosis of Preeclampsia
unlikely that one major PE gene will be found because such a Preeclampsia is a clinical syndrome that embraces a wide
gene would be selected against through evolution, unless it also spectrum of signs and symptoms that have been clinically
observed to develop alone or in combination. Elevated BP is these markers suffer from poor specificity and predictive values
the traditional hallmark for diagnosis of the disease. The that are too low for routine use in clinical practice.80-88
diagnosis of PE and the severity of the disease process are gener- During the past decade, several prospective and nested
ally based on maternal BP. Many factors may influence the case-control studies have found that certain maternal risk
measurement of BP, including the accuracy of the equipment factors, biophysical clinical factors, and serum biomarkers
used, the size of the sphygmomanometer cuff, duration of the obtained in the first trimester are associated with subsequent
rest period before recording, posture of the patient, and the development of hypertensive disorders of pregnancy (HDP),
Korotkoff phase used (phase IV or phase V for diastolic BP GH, or PE.79-83,89,90 These studies evaluated the use of these
measurement). It is recommended that all BP values be factors or markers alone or in combination, and they provided
recorded with the woman in a sitting position for ambula- detection rates for various subtypes of hypertension and PE with
tory patients or in a semireclining position for hospitalized a false-positive rate (FPR) of either 5% or 10%. Overall, neither
patients.2,3,18,19 The right arm should be used consistently, and the maternal factors nor the serum biomarkers, either alone or
the arm should be in a roughly horizontal position at heart level. combined, had an adequate detection rate for either all HDPs
For diastolic BP measurements, both phases—muffling sound or GH or PE developing at 37 weeks of gestation or later. In the
and disappearance sound—should be recorded. This is very same studies, using maternal factors and mean arterial pressure
important because the level measured at phase IV is about 5 to (MAP) in the first trimester, the detection rate for PE before 34
10 mm Hg higher than that measured at phase V. A rise in BP weeks was 73%, and for PE before 37 weeks, it was 60% with
has been used by several authors as a criterion for the diagnosis an FPR of 10%. Using data from the Maternal-Fetal Medicine
of hypertension in pregnancy. This definition is usually unreli- Foundation, the use of combined maternal factors and biophysi-
able because a gradual increase in BP from the second to third cal and biochemical markers increased the detection rate to 95%
trimester is seen in most normotensive pregnancies. Villar and for PE that required delivery before 34 weeks of gestation and
Sibai72 prospectively studied BP changes during the course of 77% for PE that required delivery at before 37 weeks of gesta-
pregnancy in 700 young primigravidas and found that 137 tion with an FPR of 10%.90 However, the positive predictive
patients (19.6%) had PE. The sensitivity and positive predictive value (PPV) for such a screen remained less than 10%. In addi-
values for PE of a threshold increase in diastolic BP of at least tion, these studies were conducted in a heterogeneous group of
15 mm Hg on two occasions were 39% and 32%, respectively. women at various risks for HDP and PE. A recent study by
The respective values for a threshold increase in systolic pressures Giguère and colleagues91 evaluated combined maternal factors
were 22% and 33%. and serum markers measured in the first trimester in 7929
Three recent studies from New Zealand,73 the United States,74 women who were at very low risk for GH (2.7%) and PE
and Turkey75 investigated pregnancy outcomes in women with (1.8%). In those with PE, the incidence was 0.2% at less than
a rise in diastolic BP of more than 15 mm Hg but an absolute 34 weeks and 1.2% at less than 37 weeks of gestation. They
diastolic level below 90 mm Hg compared with gravidas found that a clinical model that included maternal risk factors,
who remained normotensive. The New Zealand report73 and a BMI, and MAP had a detection rate of 54% and a PPV of 3%
Turkish study75 included women with elevated BPs without with an FPR of 10% for preeclampsia at less than 37 weeks of
proteinuria, whereas the American investigation74 included gestation, whereas a full model that also included serum bio-
women with an increased diastolic pressure by 15 mm Hg or markers had a detection rate of 39% and a PPV of 2% for PE
more plus proteinuria (≥300 mg/24 hours). Overall, pregnancy at less than 37 weeks of gestation.
outcomes were similar among women who remained normoten- Based on the results of this study and other reports in
sive and those who demonstrated a rise in diastolic pressure of recent years, it is clear that evaluation of maternal clinical
15 mm Hg or higher but did not reach 90 mm Hg. The use of factors and other biophysical and biomarkers measured in
a specific rise in BP over baseline as a diagnostic criterion is the first trimester is useful only for the prediction of those
principally influenced by two factors: gestational age at time of who will ultimately progress to PE that will require delivery
first observation and frequency of BP measurements. Thus a prior to 34 weeks of gestation. However, given the poor PPV
15 mm Hg rise in diastolic BP is unreliable to diagnose PE. for PE before 34 weeks and the poor detection rates for all cases
of GH and PE, the clinical indications for a PE screening test
Prediction of Preeclampsia in the first trimester remain unclear. Currently, no prospective
A review of the world literature reveals that more than 100 clini- studies or randomized trials have evaluated the benefits
cal, biophysical, and biochemical tests have been recommended and risks of first-trimester screening for prediction of PE.
to predict or identify the patient at risk for future development Until then, the use of such tests for screening should remain
of preeclampsia.76-84 The results of the pooled data for the investigational.92
various tests and the lack of agreement among serial tests Doppler ultrasound is a useful method to assess uterine artery
suggest that none of these clinical tests is sufficiently reliable blood flow velocity in the second trimester. An abnormal uterine
for use as a screening test in clinical practice.28 artery velocity waveform is characterized by a high resistance
Numerous biochemical markers have been proposed to index or by the presence of an early diastolic notch (unilateral
predict which women are destined to develop PE. These bio- or bilateral).77,78,81 Pregnancies complicated by abnormal
chemical markers were generally chosen on the basis of specific uterine artery Doppler findings in the second trimester are
pathophysiologic abnormalities that have been reported in asso- associated with more than a sixfold increase in the rate of
ciation with PE. Thus these markers have included markers of PE.77 However, the sensitivity of an abnormal uterine artery
placental dysfunction, endothelial and coagulation activation, Doppler for predicting PE ranges from 20% to 60% with a PPV
angiogenesis, and markers of systemic inflammation. However, of 6% to 40%.77,81 Current data do not support Doppler
the results of various studies to evaluate the reliability of these studies for routine screening of pregnant women for PE, but
markers in predicting PE have been inconsistent, and many of uterine artery Doppler could be beneficial as a screening test
BOX 31-4 INTERVENTIONS USED TO effects of calcium supplementation have been recorded in the
PREVENT PREECLAMPSIA trials reviewed. In contrast, a recent evidence-based review by
the U.S. Food and Drug Administration (FDA) concluded
• High-protein and low-salt diet that “the relationship between calcium and risk of hyperten-
• Nutritional supplementation (protein)
sion in pregnancy is inconsistent and inconclusive, and the
• Calcium
• Magnesium
relationship between calcium and the risk of pregnancy-
• Zinc induced hypertension and preeclampsia is highly unlikely.”
• Fish and evening primrose oil At present, the benefit of calcium supplementation for
• Antihypertensive drugs, including diuretics PE prevention in women with low dietary calcium intake
• Antithrombotic agents remains unclear.28 It is also important to note that none of the
• Low-dose aspirin published randomized trials included women with high-risk
• Dipyridamole factors such as previous PE, chronic hypertension, twins, or
• Heparin pregestational diabetes mellitus.28 Based on available data, the
• Vitamins E and C author does not recommend using calcium supplementation
• Sildenafil
for the prevention of PE.
Antiplatelet Agents Including Low-Dose Aspirin

in women at very high risk for PE if an effective preventive Preeclampsia is associated with vasospasm and activation of the
treatment should become available. coagulation-hemostasis systems. Enhanced platelet activation
The ACOG task force report on hypertension in pregnancy plays a central role in the previously mentioned process and
recommends only using risk factors for identifying women reflects abnormalities in the thromboxane-prostacyclin balance.
considered at increased risk for PE.1,3 Hence, several authors have used pharmacologic manipulation
to alter the previously mentioned ratio in an attempt to prevent
Prevention of Preeclampsia or ameliorate the course of PE.
Numerous clinical trials describe the use of various methods to Aspirin inhibits the synthesis of prostaglandins by irreversibly
prevent or reduce the incidence of preeclampsia.28,92 Because the acetylating and inactivating cyclooxygenase (COX). In vitro,
etiology of the disease is unknown, these interventions have been platelet COX is more sensitive to inhibition by low doses of
used in an attempt to correct theoretic abnormalities in PE. A aspirin (<80 mg) than vascular endothelial COX. This bio-
detailed review of these trials is beyond the scope of this chapter; chemical selectivity of low-dose aspirin appears to be related to
however, the results of these studies have been the subject of its unusual kinetics, which result in presystemic acetylation of
several recent systemic reviews.92 In short, randomized trials platelets exposed to higher concentrations of aspirin in the portal
have evaluated protein or salt restriction; zinc, magnesium, circulation.
fish oil, or vitamin C or E supplementation; the use of diuret- Most randomized trials for the prevention of PE have used
ics and other antihypertensive agents; and the use of heparin low-dose aspirin (LDA; 50 to 150 mg/dL). The rationale
to prevent PE in women with various risk factors. These trials for recommending LDA prophylaxis is the theory that the
have had limited sample sizes, and results have revealed vasospasm and coagulation abnormalities in preeclampsia
minimal to no benefit. Some of the methods studied are sum- are caused partly by an imbalance in the TXA2/prostacyclin
marized in Box 31-4. ratio.20,28
Recently, the Perinatal Antiplatelet Review of International
Calcium Supplementation Studies (PARIS) collaborative group performed a meta-analysis
The relationship between dietary calcium intake and hyperten- of the effectiveness and safety of antiplatelet agents, predomi-
sion has been the subject of several experimental and obser- nantly aspirin, for the prevention of PE. Thirty-one trials that
vational studies. Epidemiologic studies have documented an involved 32,217 women are included in this review, and a 10%
inverse association between calcium intake and maternal BP and reduction was seen in the risk for PE associated with the use
the incidences of PE and eclampsia. The BP-lowering effect of of antiplatelet agents (RR, 0.90; 95% CI, 0.84 to 0.96). For
calcium is thought to be mediated by alterations in plasma renin women with a previous history of hypertension or PE (n = 6107)
activity and parathyroid hormone. who were assigned to antiplatelet agents, the relative risk for
Thirteen clinical studies (15,730 women) have compared the developing PE was 0.86 (95% CI, 0.77 to 0.97). No significant
use of calcium with no treatment or with a placebo in pregnancy. differences were found between treatment and control groups in
These trials differ in the populations studied (low risk or high any other measures of outcome. The reviewers concluded that
risk for hypertensive disorders of pregnancy), study design (ran- antiplatelet agents, largely LDA, have small to moderate ben-
domization, double-blind, or use of a placebo), gestational age efits when used for prevention of PE. LDA was also found to
at enrollment (20 to 32 weeks’ gestation), sample size in each be safe. However, more information is clearly required to assess
group (range, 22 to 588), dose of elemental calcium used (156 which women are most likely to benefit from this therapy, when
to 2000 mg/day), and the definition of hypertensive disorders treatment is optimally started, and what dose to use.28
of pregnancy used. Several studies have evaluated the efficacy of aspirin in the
In the Cochrane review, calcium supplementation was associ- prevention of PE in high-risk pregnancies as determined by
ated with reduced hypertension (relative risk [RR], 0.65; 95% Doppler ultrasound or other risk factors when aspirin was used
CI, 0.53 to 0.81) and reduced PE (RR, 0.45; 95% CI, 0.31 early in pregnancy. A meta-analysis suggested that LDA improves
to 0.65), particularly for those at high risk and with low base- pregnancy outcome in these women when aspirin is started
line dietary calcium intake; for those with adequate calcium before 16 weeks’ gestation. However, this review has numerous
intake, the difference was not statistically significant. No side flaws in design and data analysis. A large multicenter study
TABLE 31-4 LOW-DOSE ASPIRIN IN HIGH-RISK complications was dependent on baseline risk for PE in the
WOMEN: NATIONAL INSTITUTE study population. Contrary to the results of other systematic
OF CHILD HEALTH AND HUMAN reviews, they found that the beneficial effects of LDA were not
DEVELOPMENT TRIAL dependent on the dose of LDA, and they were evident when
LDA was used between 12 and 28 weeks’ gestation. Moreover,
PREECLAMPSIA (%)
they found that LDA did not increase the risk of bleeding
ENTRY CRITERIA N ASPIRIN* PLACEBO* complications (abruptio placentae, postpartum hemorrhage,
Normotensive and no 1613 14.5 17.7 neonatal intracerebral hemorrhage) or perinatal death. Based on
proteinuria results of this review, the Task Force members recommended
Proteinuria and 119 31.7 22.0 that women considered at increased risk for PE—that is,
hypertension
Proteinuria only 48 25.0 33.3 those with a history of PE, preexisting chronic hypertension
Hypertension only 723 24.8 25.0 or renal disease, pregestational diabetes, autoimmune disease,
Insulin-dependent 462 18.3 21.6 or multifetal gestation—should receive LDA (81 mg/day)
diabetes starting at 12 to 28 weeks until delivery to reduce the likeli-
Chronic hypertension 763 26.0 24.6
Multifetal gestation 678 11.5 15.9
hood of developing subsequent PE, preterm birth, or FGR.
Previous preeclampsia 600 16.7 19.0 However, such recommendation is in contrast to that of the
ACOG Task Force on Hypertension in Pregnancy, which rec-
Data from Caritis SN, Sibai BM, Hauth J, et al, for the National Institute of Child
Health and Human Development. Low-dose aspirin therapy to prevent preeclampsia in
ommended LDA only to women with prior PE that resulted
women at high risk. N Engl J Med. 1998;338:701. in delivery at less than 34 weeks or to those with prior recur-
*No difference was reported for any of the groups regarding the rate of preeclampsia. rent PE.
sponsored by the National Institute of Child Health and Heparin or Low-Molecular-Weight Heparin
Human Development (NICHD) included 2539 women with Several observational studies and randomized trials have
pregestational insulin-treated diabetes mellitus, chronic hyper- evaluated the prophylactic use of low-molecular-weight heparin
tension, multifetal gestation, or PE in a previous pregnancy and (LMWH) for the prevention of PE and other adverse pregnancy
showed no beneficial effect from LDA in such high-risk women outcomes. The results of these studies were the subject of several
(Table 31-4). recent reviews. Two recent large randomized trials conducted
During the past three decades, several randomized controlled in Italy95 and in Canada96 revealed that prophylactic LMWH
trials (RCTs) and systematic reviews evaluated the benefits and does not reduce the rate of PE in women at high risk for this
risks of using LDA in pregnancy for the prevention of PE and complication. In addition, a meta-analysis of published trials
its complications in women with one or more of the risk factors demonstrated no benefit from LMWH.97 Therefore it is the
listed above. The results of the RCTs were conflicting, and the authors’ opinion that LMWH should not be used for PE
systematic reviews were inconclusive.93 This is not surprising prevention.
given that the published trials and those included in various
reviews differed in regard to the enrolled study populations Vitamins C and E
(minimal risk to extremely high risk for PE, preterm birth, FGR, Reduced antioxidant capacity, increased oxidative stress, or both
and perinatal death), gestational age at enrollment (12 to 32 in the maternal circulation and in the placenta have been pro-
weeks), dose of aspirin utilized (50 to 150 mg/day), number of posed to play a major role in the pathogenesis of PE. Conse-
study subjects and number of centers in each trial, definition of quently, several trials were designed using vitamins C and E for
PE and adverse perinatal outcomes, and whether the systemic the prevention of PE. The first trial suggested a beneficial effect
review included unplanned subgroup analysis.93 from pharmacologic doses of vitamins E and C in women identi-
The U.S. Preventive Services Task Force (USPSTF) recently fied as being at risk for PE by means of abnormal uterine
published a report on LDA for the prevention of morbidity and Doppler flow velocimetry. However, the study had limited
mortality from preeclampsia.94 The report contained an exhaus- sample size and must be confirmed in other populations. In
tive review of published trials regarding the efficacy and safety contrast, several randomized trials with large sample sizes in
of LDA in pregnancy for the prevention of PE and other adverse women at low risk and very high risk for PE found no reduc-
perinatal outcomes in women considered at high risk for PE. tion in the rate of PE with vitamin C and E supplementation
The review considered 15 randomized trials (8 quality) in (Table 31-5).29,98-103
women at increased risk for PE to evaluate maternal and peri-
natal benefits and 13 randomized trials (8 quality) to evaluate Laboratory Abnormalities in Preeclampsia
the incidence of PE. Preeclampsia incidence in women consid- Women with preeclampsia may exhibit a symptom complex that
ered at increased risk ranged from 8% to 30%. In addition, two ranges from minimal BP elevation to derangements of multiple-
large observational studies were included to evaluate the safety organ systems. The renal, hematologic, and hepatic systems are
of LDA use in pregnancy. most likely to be involved.
In women considered at increased risk for preeclampsia,
the USPSTF members found that LDA administered after 12 Renal Function
weeks’ gestation reduced the risk of PE by an average of 24% Renal plasma flow and glomerular filtration rate (GFR) increase
(pooled relative risk [PRR], 0.76; 95% CI, 0.62 to 0.95), during normal pregnancy. These changes are responsible for a
reduced the average risk of preterm birth by 14% (PRR, 0.86; fall in serum creatinine, urea, and uric acid concentrations.98 In
95% CI, 0.76 to 0.98), and reduced the risk of FGR by 20% PE, vasospasm and glomerular capillary endothelial swelling
(PRR, 0.80; 95% CI, 0.65 to 0.99). In addition, they found (glomerular endotheliosis) lead to an average reduction in GFR
that the magnitude of risk reduction with LDA for the above of 25% below the rate for normal pregnancy. Serum creatinine
TABLE 31-5 MULTICENTER TRIALS OF VITAMINS C AND E FOR THE PREVENTION OF PREECLAMPSIA
PREECLAMPSIA
STUDY GROUP WOMEN ENROLLMENT GESTATIONAL AGE (WEEKS) VITAMINS C AND E (%) PLACEBO (%)
ACTS98 Nulliparas 14 to 22 56/935 (6) 47/942 (5)
VIP99 High risk 14 to 22 181/1196 (15) 187/1199 (16)
Global Network100 High risk 12 to 20 49/355 (14) 55/352 (16)
WHO101 High risk 14 to 22 164/681 (24) 157/674 (23)
NICHD102 Nulliparas 9 to 16 358/4993 (7.2) 332/4976 (6.7)
INTAPP103 High risk 12 to 18 69/1167 (6) 68/1196 (5.7)
DAPIT29 Pregestational diabetes 8 to 22 57/375 (15) 70/3784 (19)
DAPIT, Diabetes and Preeclampsia Intervention Trial; INTAPP, International Trial of Antioxidants in the Prevention of Preeclampsia; NICHD, National Institute of Child Health and
Development; VIP, Vitamins in Pregnancy; WHO, World Health Organization.
is rarely elevated in PE, but uric acid can be increased. In a study hypertension during pregnancy, Burrows and Kelton found a
of 95 women with severe PE, Sibai and associates reported a platelet count of less than 150,000/mm3 in 15% of cases.
mean serum creatinine of 0.91 mg/dL, a mean uric acid of Leduc and associates studied the coagulation profile—the
6.6 mg/dL, and a mean creatinine clearance of 100 mL/min. platelet count, fibrinogen, prothrombin time (PT), and partial
The clinical significance of elevated uric acid levels in thromboplastin time (PTT)—in 100 consecutive women with
preeclampsia-eclampsia has been confusing. Hyperuricemia is severe PE. A platelet count lower than 150,000/mm3 was found
associated with renal dysfunction, especially decreased renal in 50% of the women, and a count lower than 100,000/mm3
tubular secretion, and has been consistently associated with glo- was found in 36%. Thirteen women had a fibrinogen level of
merular endotheliosis. In addition, it has been linked with less than 300 mg/dL, and two had prolonged PT and PTT as
increased oxidative stress in PE. Despite the fact that uric acid well as thrombocytopenia on admission. These researchers found
levels are elevated in women with PE, this test is not sensitive the admission platelet count to be an excellent predictor of
or specific for the diagnosis of PE or for predicting adverse subsequent thrombocytopenia and concluded that fibrino-
perinatal outcome. gen levels, PT, and PTT should be obtained only in women
Elevated uric acid levels above 6 mg/dL are often found in with a platelet count of less than 100,000/mm3. A recent
women with normotensive multifetal pregnancies. As a result, study by Barron confirmed these observations in more than 800
some authors have suggested that to secure a diagnosis of PE women with hypertension in pregnancy.
based on elevated uric acid values, the upper limit should be
adjusted for those with multiple gestation. Elevated uric acid Hemolysis, Elevated Liver Enzymes, and Low Platelets
values are also found in women with acute fatty liver of preg- (HELLP) Syndrome
nancy and underlying renal disease; therefore it is suggested Considerable debate surrounds the definition, diagnosis,
that uric acid values not be used for the diagnosis of PE or incidence, etiology, and management of HELLP syndrome.104
as an indication for delivery in women with PE. Patients with such findings were previously described by many
investigators. Weinstein considered it a unique variant of PE
Hepatic Function and coined the term HELLP syndrome for this entity. Barton
The liver is not primarily involved in preeclampsia, and hepatic and associates performed liver biopsies in patients with PE and
involvement is observed in only 10% of women with severe PE. HELLP syndrome, and periportal necrosis and hemorrhage were
Fibrin deposition has been found along the walls of hepatic the most common histopathologic findings. In addition, they
sinusoids in preeclamptic patients with no laboratory or histo- found that the extent of the laboratory abnormalities in HELLP
logic evidence of liver involvement. When liver dysfunction does syndrome, including the platelet count and liver enzymes, did
occur in PE, mild elevation of serum transaminases is most not correlate with hepatic histopathologic findings.
common. Bilirubin is rarely increased in PE, but when elevated,
the indirect fraction predominates. Elevated liver enzymes are a LABORATORY CRITERIA FOR DIAGNOSIS
feature of the hemolysis, elevated liver enzymes, and low plate- Various diagnostic criteria have been used for HELLP. Hemo-
lets (HELLP) syndrome, a variant of severe PE. lysis, defined as the presence of microangiopathic hemolytic
anemia, is the hallmark of the triad of HELLP syndrome.104
Hematologic Changes The classic findings of microangiopathic hemolysis include
Many studies have evaluated the hematologic abnormalities in an abnormal peripheral smear (schistocytes, burr cells, echino-
women with preeclampsia. Plasma fibrinopeptide A, D-dimer cytes), elevated serum bilirubin (indirect form), low serum hap-
levels, and circulating thrombin-antithrombin complexes are toglobin levels, elevated lactate dehydrogenase (LDH) levels,
higher in women with PE than in normotensive gravidas. In and a significant drop in hemoglobin levels. A significant per-
contrast, plasma antithrombin III activity is decreased. These centage of published reports included patients who had no evi-
findings indicate enhanced thrombin generation. dence of hemolysis; hence, these patients will not fit the criteria
Plasma fibrinogen rises progressively during normal preg- for HELLP syndrome.104 In some studies in which hemolysis is
nancy. In general, plasma fibrinogen levels are rarely reduced in described, the diagnosis is suspect because it has been based on
women with PE in the absence of placental abruption. the presence of an abnormal peripheral smear (no description of
Thrombocytopenia is the most common hematologic type or degree of abnormalities) or elevated LDH levels (thresh-
abnormality in women with severe PE. It is correlated with old of 180 to 600 U/L).
the severity of the disease process and the presence or absence No consensus exists in the literature regarding the liver func-
of placental abruption. In a study of 1414 women with tion test to be used or the degree of elevation in these tests to
diagnose elevated liver enzymes. In his original report, Weinstein also found that most cases occurred in women who had anteced-
mentioned abnormal serum levels of aspartate transaminase ent placental abruption or peripartum hemorrhage, and it
(AST), abnormal alanine transaminase (ALT), and abnormal occurred in all four women in their study who had subcapsular
bilirubin values; however, specific levels were not suggested. liver hematomas. In the absence of these complications, the
In subsequent studies in which elevated liver enzymes were frequency of DIC was only 5%.
described, either AST or ALT, the values considered to be abnor- In view of the previously mentioned diagnostic problems,
mal ranged from 17 to 72 U/L.104 In clinical practice, many of we recommended that uniform and standardized laboratory
these values are considered normal or slightly elevated. values be used to diagnose HELLP syndrome.104 Plasma hap-
Low platelet count is the third abnormality required to estab- toglobin and bilirubin values should be included in the diagnosis
lish the diagnosis of HELLP syndrome; no consensus has been of hemolysis. In addition, the degree of abnormality of liver
reached among various published reports regarding the diagnosis enzymes should be defined as a certain number of standard
of thrombocytopenia. The reported cut-off values have ranged deviations (SDs) from the normal value for each hospital popu-
from 75,000/mm3 to 279,000/mm3, and a level of less than lation. Our laboratory criteria to establish the diagnosis are
100,000/mm3 is most often cited.104 presented in Box 31-5.
Many authors have used elevated total LDH (usually
>600 U/L) as a diagnostic criteria for hemolysis. Of the five CLINICAL FINDINGS
isoforms of LDH, only two of them—LDH1 and LDH2—are The reported incidence of HELLP syndrome in preeclampsia
released from ruptured red blood cells. In most women with has been variable, which reflects the differences in diagnostic
severe preeclampsia-eclampsia, the elevation in total LDH is criteria. The syndrome appears to be more common in white
probably caused mostly by liver ischemia. Therefore many women and is also more common in preeclamptic women
authors advocate that elevated bilirubin values (indirect form), who have been managed conservatively.104
abnormal peripheral smear, or a low serum haptoglobin level Early detection of HELLP syndrome can be a challenge in
should be part of the diagnostic criteria for hemolysis. that many women present with nonspecific symptoms or subtle
Based on a retrospective review of 302 cases of HELLP syn- signs of PE. The various signs and symptoms reported are not
drome, Martin and colleagues devised the following classifica- diagnostic of PE and may also be found in women with severe
tion based on the nadir of the platelet count. Class 1 HELLP preeclampsia-eclampsia without HELLP syndrome.104 Right
syndrome was defined as a platelet nadir below 50,000/mm3, upper quadrant or epigastric pain and nausea or vomiting have
class 2 as a platelet nadir between 50,000 and 100,000/mm3, been reported with a frequency ranging from 30% to 90%
and class 3 as a platelet nadir between 100,000 and 150,000/ (Table 31-6). Most women gave a history of malaise typical of
mm3. These classes have been used to predict the rapidity of a nonspecific viral-like syndrome for several days before presen-
recovery postpartum, maternal-perinatal outcome, and the need tation, which led one investigator to suggest performing labora-
for plasmapheresis. tory investigations (complete blood count [CBC] and liver
Hemolysis, defined as the presence of microangiopathic hemo- enzymes) in all pregnant women with suspected PE who have
lytic anemia, is the hallmark of HELLP syndrome. The role of
disseminated intravascular coagulation (DIC) in preeclampsia is
controversial. Most authors do not regard HELLP syndrome BOX 31-5 CRITERIA TO ESTABLISH THE DIAGNOSIS OF
to be a variant of DIC because coagulation parameters such HELLP SYNDROME
as PT, PTT, and serum fibrinogen are normal.85 However, the
diagnosis of DIC can be difficult to establish in clinical practice. Hemolysis (as least two of these):
• Peripheral smear (schistocytes, burr cells)
When sensitive determinants of this condition are used—such
• Serum bilirubin (≥1.2 mg/dL)
as antithrombin III, fibrinopeptide A, fibrin monomer, D-dimer, • Low serum haptoglobin
α2-antiplasmin, plasminogen, prekallikrein, and fibronectin— Severe anemia unrelated to blood loss
many patients have laboratory values consistent with DIC. Elevated liver enzymes
Unfortunately, these tests are time consuming and are not • Aspartate transaminase or alanine transaminase at
suitable for routine monitoring. Consequently, less sensitive least twice the ULN
parameters are often used. Sibai and associates defined DIC • Lactate dehydrogenase twice or more of the ULN
as the presence of thrombocytopenia, low fibrinogen levels Low platelets (<100,000/mm3)
(plasma fibrinogen <300 mg/dL), and fibrin split products
above 40 mg/mL. These authors noted the presence of coagu- HELLP, hemolysis, elevated liver enzymes, and low platelets; ULN, upper
limit of normal.
lopathy in 21% of 442 patients with HELLP syndrome. They
TABLE 31-6 SIGNS AND SYMPTOMS IN WOMEN WITH HELLP SYNDROME

WEINSTEIN108 SIBAI ET AL107 MARTIN ET AL106 RATH ET AL109
(n = 57) (%) (n = 509) (%) (n = 501) (%) (n = 50) (%)
Right upper quadrant epigastric pain 86 63 40 90
Nausea, vomiting 84 36 29 52
Headache NR 33 61 NR
Hypertension NR 85 82 88
Proteinuria 96 87 86 100
Modified from Sibai BM. Diagnosis, controversies, and management of HELLP syndrome. Obstet Gynecol. 2004;103:981.
HELLP, hemolysis, elevated liver enzymes, and low platelets; NR, not reported.
BOX 31-6 MEDICAL AND SURGICAL DISORDERS OFTEN Occasionally, the presence of this syndrome is associated with
CONFUSED WITH HELLP SYNDROME hypoglycemia that leads to coma, severe hyponatremia, and
cortical blindness. A rare but interesting complication of HELLP
• Acute fatty liver of pregnancy syndrome is transient nephrogenic diabetes insipidus. Unlike
• Appendicitis
central diabetes insipidus, which results from the diminished or
• Gallbladder disease
• Glomerulonephritis
absent secretion of arginine vasopressin by the hypothalamus,
• Hemolytic uremic syndrome transient nephrogenic diabetes insipidus is characterized by a resis-
• Hepatic encephalopathy tance to arginine vasopressin mediated by excessive vasopressi-
• Hyperemesis gravidarum nase. It is postulated that elevated circulating vasopressinase may
• Idiopathic thrombocytopenia result from impaired hepatic metabolism of the enzyme.
• Pyelonephritis
• Systemic lupus erythematosus MANAGEMENT OF HELLP SYNDROME
• Antiphospholipid antibody syndrome Management of preeclamptic women who present with HELLP
• Thrombotic thrombocytopenic purpura syndrome is highly controversial.104 Consequently, several thera-
• Viral hepatitis
peutic modalities have been described in the literature to treat
HELLP, hemolysis, elevated liver enzymes, and low platelets.
or reverse HELLP syndrome. Most of these modalities are
similar to those used in the management of severe PE remote
from term (Box 31-7).
The clinical course of women with true HELLP syndrome is
these symptoms during the third trimester.104 Headaches are usually characterized by progressive and sometimes sudden dete-
reported by 33% to 61% of the patients, whereas visual changes rioration in the maternal condition.104 Because the presence of
are reported in about 17%. A small subset of patients with this syndrome has been associated with increased rates of mater-
HELLP syndrome may present with symptoms related to nal morbidity and mortality, many authors consider its presence
thrombocytopenia, such as bleeding from mucosal surfaces, to be an indication for immediate delivery. There is also a con-
hematuria, petechial hemorrhages, or ecchymosis. sensus of opinion that prompt delivery is indicated if the
Although most patients have hypertension (82% to 88%; see syndrome develops beyond 34 weeks’ gestation or earlier if
Table 31-6), it may be only mild in 15% to 50% of the cases obvious multiorgan dysfunction, DIC, liver infarction or
and absent in 12% to 18%. Most of the patients (86% to 100%) hemorrhage, renal failure, suspected abruption, or nonreas-
have proteinuria by dipstick examination, although it has been suring fetal status are apparent. Delivery is also indicated if
reported to be absent in 13% of cases. the syndrome develops before 23 weeks’ gestation.1,104
On the other hand, considerable disagreement exists about
DIFFERENTIAL DIAGNOSIS the management of women with HELLP syndrome at or
The presenting symptoms, clinical findings, and many of the before 34 weeks of gestation when the maternal condition is
laboratory findings in women with HELLP syndrome overlap stable, except for mild to moderate abnormalities in blood
with a number of medical syndromes, surgical conditions, tests, and fetal condition is reassuring. In such patients, some
and obstetric complications; therefore the differential diagno- authors recommend the administration of corticosteroids to
sis of HELLP syndrome should include any of the conditions accelerate fetal lung maturity followed by delivery after 24
listed in Box 31-6. Because some women with HELLP syn- hours,104 whereas others recommend prolonging pregnancy
drome may present with gastrointestinal, respiratory, or hema- until the development of maternal or fetal indications for
tologic symptoms in association with elevated liver enzymes or delivery or until achievement of fetal lung maturity. Some
low platelets in the absence of hypertension or proteinuria, many of the measures used in these latter cases have included one
initially are misdiagnosed as having other conditions such as or more of the following: bed rest, antihypertensive agents,
upper respiratory infection, hepatitis, cholecystitis, pancreatitis, antithrombotic agents (LDA, dipyridamole), plasma volume
acute fatty liver of pregnancy (AFLP), or immune thrombocy- expanders (crystalloids, albumin, fresh frozen plasma [FFP]),
topenic purpura (ITP).104 Conversely, some women with other and corticosteroids (prednisone, prednisolone, dexamethasone,
conditions—such as thrombotic thrombocytopenic purpura or betamethasone).104
(TTP), hemolytic uremic syndrome (HUS), systemic lupus ery-
thematosus (SLE), sepsis, or catastrophic antiphospholipid anti- EXPECTANT MANAGEMENT OF HELLP SYNDROME
body syndrome—may be erroneously diagnosed as having Few large case series describe expectant management of
HELLP syndrome. In addition, PE may occasionally be super- women with true HELLP, partial HELLP, or severe PE with
imposed on one of these disorders, which further contributes to isolated liver enzyme elevation. In general, these reports
the diagnostic difficulty. Because of the remarkably similar clini- suggest that transient improvement in laboratory values or
cal and laboratory findings of these disease processes, even the pregnancy prolongation from a few days to a few weeks is
most experienced clinician can face a difficult diagnostic chal- possible in a select group of women with HELLP syndrome.
lenge. Therefore efforts should be made to attempt to identify It is important to note that most of the patients included in
an accurate diagnosis, given that management strategies may be these studies were ultimately delivered within 1 week of
different among these conditions. It is important to emphasize expectant management.104
that affected women may have a variety of unusual signs and Investigators from the Netherlands have reported their experi-
symptoms, none of which are diagnostic of severe PE. Pregnant ence with expectant management in women with HELLP syn-
women with probable PE who present with atypical symp- drome before 34 weeks’ gestation. Visser and Wallenburg
toms should have a CBC, a platelet count, and liver enzyme reported the use of plasma volume expansion using invasive
determinations irrespective of maternal BP findings. hemodynamic monitoring and vasodilators in 128 women with
BOX 31-7 THERAPEUTIC MODALITIES USED TO TREAT The results of these studies suggest that expectant man
OR REVERSE HELLP SYNDROME agement is possible in a very select group of women with
suspected HELLP syndrome before 34 weeks’ gestation.
Plasma volume expansion However, despite pregnancy prolongation in some of these
• Bed rest cases, the overall perinatal outcome was not improved com-
• Crystalloids
• Albumin 5% to 25%
pared with fetuses at a similar gestational age who were
Antithrombotic agents delivered within 48 hours after the diagnosis of HELLP
• Low-dose aspirin syndrome.
• Dipyridamole Confounding variables make it difficult to evaluate any treat-
• Heparin ment modality proposed for this syndrome. Occasionally, some
• Antithrombin III patients without true HELLP syndrome may demonstrate ante-
Immunosuppressive agents partum reversal of hematologic abnormalities following bed rest,
• Steroids use of corticosteroids, or plasma volume expansion. However,
Miscellaneous most of these patients experienced deterioration in either mater-
• Fresh-frozen plasma infusions nal or fetal condition within 1 to 10 days after conservative
• Exchange plasmapheresis
• Dialysis
management. It is doubtful that such limited pregnancy prolon-
gation will result in improved perinatal outcome, and maternal
Modified from Sibai BM. The HELLP syndrome (hemolysis, elevated liver and fetal risks are substantial.104
enzymes, and low platelets): much ado about nothing? Am J Obstet In summary, the results of these studies suggest that
Gynecol. 1990;162:311. expectant treatment is possible in a select group of women
HELLP, hemolysis, elevated liver enzymes, and low platelets.
with HELLP syndrome before 34 weeks’ gestation. However,
the number of women who were studied in these reports is
inadequate to evaluate maternal safety; therefore such treat-
HELLP syndrome before 34 weeks’ gestation. Magnesium ment should be considered experimental. In addition, most
sulfate and steroids were not used in such women. Twenty-two experts—including members of the ACOG Task Force—
of the 128 patients were delivered within 48 hours; the remain- recommend delivery of such patients after completion of a
ing 102 patients had pregnancy prolongation for a median of course of corticosteroids for fetal lung maturity or if the
15 days (range, 3 to 62 days). Fifty-five of these 102 women had gestational age is less than 24 weeks.1,3
antepartum resolution of HELLP syndrome, with a median
pregnancy prolongation in these women of 21 days (range, 7 to CORTICOSTEROIDS TO IMPROVE PREGNANCY
62 days). No maternal deaths or serious maternal morbidity was OUTCOME IN WOMEN WITH HELLP SYNDROME
reported. However, 11 of the 128 pregnancies (8.6%) resulted It is well established that antenatal glucocorticoid therapy reduces
in fetal death at 25 to 34.4 weeks, and 7 neonatal deaths (5.5%) neonatal complications and neonatal mortality in women with
at 27 to 32 weeks’ gestation were reported. severe PE at 34 weeks’ gestation or less (see Chapter 29). The rec-
Van Pampus and coworkers reported the use of bed rest, ommended regimens of corticosteroids for the enhancement of
antihypertensive medication, and salt restriction in 41 women fetal maturity are betamethasone (12 mg intramuscularly every
with HELLP syndrome before 35 weeks’ gestation. Fourteen 24 hours, two doses) or dexamethasone (6 mg intramuscularly
women (34%) were delivered within 24 hours; in the remaining every 12 hours, four doses). These regimens have been identified
27 women, pregnancy was prolonged a median of 3 days (range, as the most appropriate for this purpose because they readily
0 to 59 days). Fifteen of these 27 women showed complete cross the placenta and have minimal mineralocorticoid activity.
normalization of the laboratory values. No serious maternal However, it is unclear whether the same or different regimens
morbidities were noted, but 10 fetal deaths were reported at 27 are beneficial in women with HELLP syndrome.
to 35.7 weeks’ gestation. Corticosteroids have been suggested as safe and effective drugs
The study by Ganzevoort and colleagues included 54 women for improving maternal and neonatal outcome in women with
with HELLP syndrome at the time of enrollment. In a subse- HELLP or partial HELLP syndrome. A review of the literature
quent publication, the same authors compared maternal and reveals substantial differences in methodology, time of adminis-
perinatal complications in these women to the respective out- tration, and drug selection among investigators who advocate
comes in women without HELLP. They found that the median the use of corticosteroids in women with HELLP syndrome.
number of days of pregnancy prolongation and maternal and Different regimens of steroids have been suggested for prevent-
perinatal complications were similar between the two groups. ing respiratory distress syndrome (RDS) as well as to accelerate
One randomized, double-blind trial compared prednisolone maternal recovery in the postpartum period.104 The regimens
(n = 15) to placebo (n = 16) in patients with HELLP syndrome of steroids used included intramuscular betamethasone (12
before 30 weeks’ gestation. Prednisolone was given intravenously mg/12 hr or 24 hours apart on two occasions) or IV dexametha-
twice a day. The primary outcome measures were the entry-to- sone (various doses at various time intervals) or a combination
delivery interval and the number of “recurrent HELLP” exacer- of the two. Some studies used steroids only in the antepartum
bations in the antepartum period. The mean entry-to-delivery period (for 24 hours, 48 hours, repeat regimens, or chronically
interval was similar between the two groups (6.9 days for pred- for weeks until delivery). In other studies, steroids were given
nisolone and 8 days for placebo). Three cases of liver hematoma for 48 hours before delivery and then were continued for 24 to
or rupture were reported, along with one maternal death in the 48 hours postpartum, whereas others recommend their admin-
placebo group. The perinatal mortality rate was similar between istration only in the postpartum period.104
the two groups (20% in the prednisolone group and 25% in the Some randomized trials have compared the use of high-dose
placebo group). dexamethasone to either no treatment or betamethasone in
TABLE 31-7 MATERNAL COMPLICATIONS WITH DEXAMETHASONE VERSUS PLACEBO IN HELLP SYNDROME
NO. WITH PLACEBO (%) NO. WITH DEXAMETHASONE (%) CRUDE RELATIVE RISK (95% CI)
Acute renal failure* 8 (13) 6 (10) 0.8 (0.3-2.1)
Oliguria 4 (6) 5 (7.6) 1.3 (0.4-4.5)
Pulmonary edema* 1 (2) 3 (4.6) 3.1 (0.3-28)
Eclampsia 10 (15) 8 (14) 0.8 (0.3-1.9)
Infections 10 (15) 5(8) 0.5 (0.2-1.4)
Death 1 (2) 3 (5) 3.0 (0.3-28)
Platelet transfusion 10 (15) 12 (18) 1.2 (0.6-2.6)
Plasma transfusion 6 (9) 5 (8) 0.8 (0.3-2.6)
Modified from Fonseca JE, Mendez F, Catano C, Arias F. Dexamethasone treatment does not improve the outcome of women with HELLP syndrome: a double-blind, placebo-
controlled, randomized clinical trial. Am J Obstet Gynecol. 2005;193:1591-1598.
*Only included patients without the event before randomization.
CI, confidence interval.
TABLE 31-8 MATERNAL COMPLICATIONS COMPARING TABLE 31-9 MATERNAL COMPLICATIONS IN 316
DEXAMETHASONE VERSUS PLACEBO PREGNANCIES WITH HELLP SYNDROME,
FOR POSTPARTUM HELLP SYNDROME PARTIAL HELLP SYNDROME, OR SEVERE
DEXAMETHASONE PLACEBO PREECLAMPSIA WITH NORMAL
COMPLICATION* (n = 56) (n = 49) LABORATORY VALUES
n % n % PARTIAL SEVERE
HELLP HELLP HELLP
Pulmonary edema 2 3.6 5 10.2 (n = 67) (n = 71) (n = 178)
Hemorrhagic manifestation 20 35.7 16 32.7
Acute renal failure 9 16.1 12 24.5 Blood products transfusion 25* 4 3
Oliguria 27 48.2 22 44.9 (%)
Blood transfusion 16 28.6 19 38.6 Disseminated intravascular 15* 0 0
Any complication 37 66.1 25 51 coagulation (%)
Death 2 3.6 2 4.1 Wound hematoma, infection 14‡ 11§ 2§
(%)†
Modified from Katz L, de Amorim MM, Figueiroa JN, Pinto e Silva JL. Postpartum Pleural effusion (%) 6‡ 0 1
dexamethasone for women with hemolysis, elevated liver enzymes, and low platelets Acute renal failure (%) 3‡ 0 0
(HELLP) syndrome: a double-blind, placebo-controlled, randomized clinical trial. Am J
Eclampsia (%) 9 7 9
Obstet Gynecol. 2008;198:283.
*Each patient may have more than one complication. Abruptio placentae (%) 9 4 5
Pulmonary edema (%) 8 4 3
Subcapsular liver hematoma 1.5 0 0
women with presumed HELLP syndrome. These studies were (%)
Intracerebral hemorrhage (%) 1.5 0 0
summarized in a review by Sibai.104 The results of these studies Death (%) 1.5 0 0
demonstrated improved laboratory values and urine output
From Audibert F, Friedman SA, Frangieh AY, Sibai BM. Clinical utility of strict
in patients receiving dexamethasone but found no differ- diagnostic criteria for the HELLP (hemolysis, elevated liver enzymes, and low platelets)
ences in serious maternal morbidity. In addition, the number syndrome. Am J Obstet Gynecol. 1996;175:460.
of patients studied was limited, and neither of these small studies *P < .001, HELLP vs. partial and severe HELLP.
†
Percentages of women who had cesarean delivery.
used a placebo. ‡
P < .05, HELLP vs. severe HELLP.
More recently, three randomized, double-blind placebo trials §
P < .05, partial vs. severe HELLP.
were conducted to evaluate dexamethasone versus placebo in HELLP, hemolysis, elevated liver enzymes, and low platelets.
women with antepartum and postpartum HELLP syndrome.
Two of the trials were multicenter, and one was a single-center
trial. The results of the two large, multicenter trials are sum- increased rates of wound hematomas and the need for transfu-
marized in Tables 31-7 and 31-8. Overall, these trials revealed sion of blood and blood products.104 The rate of these complica-
no maternal benefit of using dexamethasone in women with tions depends on the population studied, the laboratory criteria
HELLP syndrome.105 It is my opinion that corticosteroids used to establish the diagnosis, and the presence of associated
should only be used for 48 hours to accelerate fetal lung preexisting medical conditions (chronic hypertension, lupus) or
maturity in women who have reached 24 to 34 weeks’ gesta- obstetric complications (abruptio placentae, peripartum hemor-
tion. In addition, it is recommended that dexamethasone not rhage, fetal demise, eclampsia).104 The development of HELLP
be used to treat maternal symptoms of HELLP syndrome syndrome in the postpartum period also increases the risk for
either beyond 34 weeks or in the postpartum period.1,3 renal failure and pulmonary edema. The presence of placental
abruption increases the risk for DIC, pulmonary edema, and
MATERNAL AND PERINATAL OUTCOME renal failure and also increases the need for blood transfusions.
The presence of HELLP syndrome is associated with an Patients who have a large volume of ascites appear to have a high
increased risk for maternal death (1%) and increased rates of rate of cardiopulmonary complications. Finally, women who
maternal morbidities such as pulmonary edema (8%), acute meet all the criteria suggested for diagnosis will have higher rates
renal failure (3%), DIC (15%), abruptio placentae (9%), of maternal complications than those who have partial HELLP
liver hemorrhage or failure (1%), acute respiratory distress or elevated liver enzymes only (Table 31-9).
syndrome (ARDS), sepsis, and stroke (<1%).104 Pregnancies It is generally agreed that perinatal mortality and morbid-
complicated by HELLP syndrome are also associated with ity are substantially increased in pregnancies complicated by
the HELLP syndrome. The reported perinatal death rate in the development of pulmonary edema and acute renal failure
recent series ranged from 7.4% to 34%, and this high peri- (Table 31-11). The differential diagnosis should include exacer-
natal death rate is mainly experienced at a very early gesta- bation of SLE, TTP, and HUS.
tional age (<28 weeks) in association with severe FGR or
placental abruption.104 It is important to emphasize that neo- RECOMMENDED MANAGEMENT
natal morbidities in these pregnancies are dependent on gesta- The clinical course of women with HELLP syndrome is usually
tional age at time of delivery, and they are similar when corrected characterized by progressive and sometimes sudden deteriora-
for gestational age to those in preeclamptic pregnancies without tion in maternal and fetal condition. Therefore patients with a
the HELLP syndrome. The rate of preterm delivery is about suspected diagnosis of HELLP syndrome should be hospital-
70%, and 15% occur before 28 weeks’ gestation. As a result, ized immediately and observed in a labor and delivery unit
these infants have a high rate of acute neonatal complications. (Fig. 31-5). Such patients should be managed as if they have
The HELLP syndrome may develop antepartum or post- PE with severe features and should initially receive IV mag-
partum. Analysis of 442 cases studied by Sibai and associates nesium sulfate as prophylaxis against convulsions and anti-
revealed that 309 (70%) had evidence of the syndrome antepar- hypertensive medications to maintain systolic BP below
tum, whereas 133 (30%) developed the condition postpartum. 160 mm Hg or diastolic BP below 105 mm Hg.104 This can
Four maternal deaths were reported, and morbidity was frequent be achieved with a 5-mg bolus dose of hydralazine repeated
(Table 31-10). as needed every 20 minutes for a maximal dose of 25 mg/
In the postpartum period, the time of onset of the manifesta- hour. BP is recorded every 20 minutes during therapy and
tions can range from a few hours to 7 days, but most develop every hour once the desired values are achieved. If hydralazine
within 48 hours postpartum. Thus laboratory assessment for does not lower BP adequately, or if maternal side effects such as
potential HELLP syndrome should be considered during tachycardia or headaches develop, another agent such as labetalol
the first 48 hours postpartum in women with significant or nifedipine can be used.
hypertension or symptoms of severe PE. Eighty percent of The recommended dose of labetalol is 20 to 40 mg given
the women who develop HELLP syndrome postpartum had intravenously every 10 minutes for a maximum of 300 mg,
PE before delivery, whereas 20% had no evidence of PE during and the dose of nifedipine is 10 to 20 mg orally every 20
either the antepartum or intrapartum periods. It is my experi- minutes for a maximum dose of 50 mg within an hour.
ence that patients in this group are at increased risk for During the observation period, maternal and fetal condi-
tions should be followed carefully.
The recommended regimen of magnesium sulfate is a
TABLE 31-10 SERIOUS MATERNAL COMPLICATIONS loading dose of 6 g given over 20 minutes, followed by a
IN 442 PATIENTS WITH maintenance dose of 2 g/hr as a continuous IV solution.
HELLP SYNDROME Magnesium sulfate is initiated at the beginning of the observa-
COMPLICATION N (%) tion period and is then continued during labor and for at
least 24 hours postpartum. In those with abnormal renal
Disseminated intravascular coagulation 92 (21)
Abruptio placentae 69 (16) function (oliguria or serum creatinine ≥1.2 mg/dL), the dose
Acute renal failure 33 (8) of magnesium sulfate should be reduced and perhaps even
Severe ascites 32 (8) discontinued.
Pulmonary edema 26 (6) Once the diagnosis of HELLP syndrome is confirmed, a deci-
Pleural effusions 26 (6)
Cerebral edema 4 (1) sion must be made regarding the need for delivery (see Fig.
Retinal detachment 4 (1) 31-5). Women with HELLP syndrome at less than 35 weeks’
Laryngeal edema 4 (1) gestation should be referred to a tertiary care facility if their
Subcapsular liver hematoma 4 (1) condition is stable. The first priority is to assess and stabilize the
Adult respiratory distress syndrome 3 (1) maternal condition, particularly BP and coagulation abnormali-
Death, maternal 4 (1)
ties. The next step is to evaluate fetal status with the use of fetal
From Sibai BM, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442 heart rate (FHR) monitoring, biophysical profile (BPP), or
pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome).
Am J Obstet Gynecol. 1993;169:1000. Doppler assessment of fetal vessels. Finally, a decision must be
HELLP, hemolysis, elevated liver enzymes, and low platelets. made as to whether delivery should be initiated or delayed for
TABLE 31-11 OUTCOME AND COMPLICATIONS OF HELLP SYNDROME IN RELATION TO TIME OF ONSET
ANTEPARTUM ONSET (n = 309) (%) POSTPARTUM ONSET (n = 133) (%) RELATIVE RISK 95% CI
Delivery at <27 wk* 15 3 4.84 2.0-11.6
Delivery at 37-42 wk† 15 25 0.61 0.41-0.91
Pulmonary edema 5 9 0.50 0.24-1.05
Acute renal failure† 5 12 0.46 0.24-0.87
Eclampsia 7 10 0.73 0.38-1.40
Abruptio placentae 16 15 1.05 0.65-1.70
DIC 21 20 1.09 0.73-1.64
From Sibai BM, Ramadan MK, Usta I, et al. Maternal morbidity and mortality in 442 pregnancies with hemolysis, elevated liver enzymes, and low platelets (HELLP syndrome). Am J
*P < .0007.
†
P < .002.
CI, confidence interval; DIC, disseminated intravascular coagulation; HELLP, hemolysis, elevated liver enzymes, and low platelets.
• Refer to tertiary care facility (<35 weeks)

• Admit to labor and delivery area
• IV magnesium sulfate
• Antihypertensives if systolic blood pressure is at
least 160 mm Hg and diastolic blood pressure is
at least 105 mm Hg
• <24 weeks or limits of viability

• ≥34 weeks
• Fetal distress
• Maternal distress
Eclampsia Yes
Delivery
Disseminated intravascular coagulopathy
Renal failure
Abruptio placentae
Respiratory distress
Suspect liver hematoma
No
• Complete steroid course
24-34 weeks
• 24-48 hours latency
FIG 31-5 An algorithm for the management of hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome. IV, intravenous.
48 hours to allow the full benefit of corticosteroids. Thus in BOX 31-8 INDICATIONS AND MANAGEMENT DURING
practice, prompt delivery is undertaken in all patients with CESAREAN DELIVERY IN HELLP SYNDROME
true HELLP syndrome except in those with a gestational age
between 24 to 34 weeks with stable maternal and fetal condi- Indications for Cesarean Delivery
tions. These latter patients are given betamethasone and are
• Nonreassuring fetal status
generally then delivered within 24 hours after the last dose
• Abnormal fetal presentation
of corticosteroids. Maternal and fetal conditions are assessed • Gestation <30 weeks and Bishop score <5
continuously during this time. In some of these women, • Gestation <32 weeks with IUGR or oligohydramnios and
transient improvement in maternal laboratory values may be Bishop score <5
seen; however, delivery is still recommended despite such • Known subcapsular liver hematoma
improvement.104 • Suspected abruptio placentae
Management During Cesarean Delivery

INTRAPARTUM MANAGEMENT
The presence of HELLP syndrome is not an indication for • General anesthesia for platelet count <75,000/mm3
immediate cesarean delivery, and such an approach might • Transfuse 6 U of platelets if count <40,000/mm3
• Insert subfascial drain
prove detrimental for both mother and fetus. The decision
• Secondary skin closure or leave subcutaneous drain
to perform a cesarean delivery should be based on gestational • Observe for bleeding from upper abdomen before
age, fetal condition, the presence of labor, and the cervical closure
Bishop score. Elective cesarean delivery is recommended for
all women with HELLP syndrome before 30 weeks’ gestation HELLP, hemolysis, elevated liver enzymes, and low platelets; IUGR, intra-
who are not in labor and have a Bishop score of less than 5. uterine growth restriction.
Elective cesarean delivery is also undertaken for those with
HELLP syndrome complicated by FGR or oligohydramnios,
particularly if the gestational age is less than 32 weeks in the Epidural anesthesia is also contraindicated, particularly if the
presence of an unfavorable cervical Bishop score (Box 31-8). platelet count is less than 75,000/mm3. Therefore general anes-
Women in labor and those whose membranes have ruptured thesia is the method of choice for cesarean delivery in most
are allowed to deliver vaginally in the absence of obstetric com- thrombocytopenic women. O’Brien and coworkers assessed
plications. When induction is indicated, labor is initiated with the impact of glucocorticoid administration on the use of epi-
either oxytocin infusion or prostaglandins in patients with a dural anesthesia in 37 women with partial HELLP syndrome
gestational age of more than 30 weeks, irrespective of the amount who had a platelet count of less than 90,000/mm3 before steroid
of cervical dilation or effacement. A similar approach is used for administration. They found that administration of corticoste-
those at 30 weeks’ gestation or less if the cervical Bishop score roids in these patients increased the use of epidural anesthesia,
is at least 5. particularly in those who achieved a latency period of 24 hours
Maternal pain relief during labor and delivery can be provided before delivery (8 of 14 in the steroid group vs. 0 of 10 in the
by intermittent use of small doses of systemic opioids. Local group that did not receive steroids; P = .006).
infiltration anesthesia can be used for all vaginal deliveries if an Platelet transfusions are indicated either before or after
episiotomy or repair of a laceration is necessary. The use of a delivery in all patients with HELLP syndrome in the pres-
pudendal block is contraindicated in these patients because of ence of significant bleeding—such as subcapsular hematoma
the risk for bleeding and hematoma formation into this area. of the liver, ecchymosis, bleeding from gums, oozing from
FIG 31-6 Subfascial drains used at the time of cesarean section.
puncture sites and wounds, or intraperitoneal bleeding—

and in all those with a platelet count less than 20,000/mm3.
However, repeated platelet transfusions are generally not neces-
sary because of the short half-life of the transfused platelets in FIG 31-7 Computed tomographic scan of the liver demonstrates
hepatic infarct.
such patients. Correction of thrombocytopenia is also important
before any surgery. Administration of 6 units of platelets is
recommended in all patients with a platelet count less than
40,000 to 50,000/mm3 before intubation if cesarean delivery is The clinical and laboratory findings of HELLP syndrome may
needed. Generalized oozing from the incision site can occur first appear during the postpartum period.104 In these women,
during surgery or in the immediate postpartum period because the time of onset of the manifestations ranges from a few hours
of the continued drop in platelet count in some patients. The to 7 days, although most develop within 48 hours postpar-
risk for hematoma formation at these sites is about 20%, and tum.104 Hence, all postpartum women and their health care
some prefer to use a vertical skin incision for this reason, whereas providers should be educated to be aware of the signs and symp-
others use a subfascial drain and keep the skin incision open toms of HELLP syndrome. Management of patients with post-
for at least 48 hours in women who require cesarean delivery partum HELLP syndrome should be similar to that in the
(Fig. 31-6).104 antepartum period, including the use of magnesium sulfate.
POSTPARTUM MANAGEMENT Hepatic Complications in HELLP Syndrome

After delivery, patients with HELLP syndrome should receive Marked elevations in serum aminotransferases (>1000 to
close monitoring of vital signs, fluid intake and output, labora- 2000 IU/L) are not typical of uncomplicated HELLP syn-
tory values, and pulse oximetry for at least 48 hours. IV mag- drome; however, when they do occur, the possibility of
nesium sulfate prophylaxis is generally continued for 48 hours, hepatic infarction and subcapsular hematoma of the liver
and antihypertensive drugs are used if the systolic BP is at least must be considered. The differential diagnosis should also
155 mm Hg or if the diastolic BP is at least 105 mm Hg. In include AFLP, abruptio placentae with DIC, acute cholecystitis
general, most women will show evidence of resolution of with sepsis, viral hepatitis, and TTP. In addition to the signs and
the disease process within 48 hours after delivery. However, symptoms of PE, physical examination findings consistent with
some patients—especially those with placental abruption peritoneal irritation and hepatomegaly may be present.
complicated by DIC, severe thrombocytopenia (platelet
count <20,000/mm3), or severe ascites or those with signifi- HEPATIC INFARCTION
cant renal dysfunction—may show delayed resolution or Marked elevation in serum aminotransferases (usually 1000 to
even deterioration in their clinical condition. Such patients 2000 IU/L or higher) and LDH (usually 10,000 to 20,000 IU/L)
are at risk for the development of pulmonary edema from trans- associated with right upper quadrant pain and fever is charac-
fusion of blood and blood products, fluid mobilization, and teristic of hepatic infarction; this diagnosis can be confirmed by
compromised renal function. These patients are also at risk for hepatic imaging (Fig. 31-7). Follow-up imaging after delivery
acute tubular necrosis and may require dialysis and intensive typically demonstrates resolution of the infarcts. These women
monitoring for several days. Some authors have suggested that may have underlying antiphospholipid antibody syndrome.104
such patients might benefit from plasmapheresis or plasma
transfusions. In practice, most of these women will recover with HEPATIC HEMATOMA AND RUPTURE
supportive therapy only. If the patient continues to deteriorate HELLP syndrome may be complicated by hepatic rupture
for more than 72 hours after delivery, however, or shows with the development of a hematoma beneath the Glisson
improvement in laboratory values and then starts to show capsule (Fig. 31-8). Histology of the liver adjacent to the rupture
thrombocytopenia and abnormal liver enzymes again, a diag- shows periportal hemorrhage and fibrin deposition along with
nosis of TTP/HUS should be considered. In such cases, plas- a neutrophilic infiltrate suggestive of hepatic PE. The hematoma
mapheresis is indicated. may remain contained or it may rupture, with resulting
Liver hematoma at 40 weeks

Pleural effusions, intubation
3.2 cm
13.8 cm
8/27/2013 9/10/2013
FIG 31-8 Computed tomographic scan of liver demonstrates subcapsular hematoma at presentation and 2 weeks postpartum.
hemorrhage into the peritoneal cavity. Women who develop a

hepatic hematoma typically have abdominal pain, and many
have severe thrombocytopenia, shoulder pain, nausea, and vom-
iting. The aminotransferases are usually modestly elevated, but
values of 4000 to 5000 IU/L can occasionally be seen. If hepatic
rupture occurs, swelling of the abdomen from hemoperitoneum
and shock rapidly ensue.
The management of a contained hematoma is to support
the patient with volume replacement and blood transfusion,
as needed, with consideration for percutaneous embolization
of the hepatic arteries. If the size of the hematoma remains
stable and the laboratory abnormalities are resolving, the patient
may be discharged home with outpatient follow-up. It may take
months for the hematoma to resolve completely.
Surgical repair has been recommended for hepatic hemor-
rhage without liver rupture. This complication, however, can be FIG 31-9 Subcapsular hematoma in a patient with hemolysis, elevated
liver enzymes, and low platelets (HELLP) syndrome.
managed conservatively in patients who remain hemodynami-
cally stable. Management should include close monitoring of
hemodynamics and coagulation status. Serial assessment of the A team experienced in liver trauma surgery should be con-
subcapsular hematoma with ultrasound or computed tomogra- sulted. If hepatic rupture is suspected, an incision in the upper
phy (CT) is necessary, as is immediate intervention for rupture abdomen is necessary for adequate surgical exposure. A lower
or worsening of maternal status. It is important with conserva- abdominal midline incision can be extended superiorly. If a
tive management to avoid exogenous sources of trauma to the Pfannenstiel incision was used for operative delivery, a separate
liver—such as abdominal palpation, convulsions, or emesis— upper abdominal midline incision should be made to maximize
and to use care in transportation of the patient. Indeed, any visualization of the upper abdomen and liver. Options at lapa-
sudden increase in intraabdominal pressure could potentially rotomy include packing and drainage, surgical ligation of the
lead to rupture of the subcapsular hematoma (Fig. 31-9). hemorrhaging hepatic segments, embolization of the hepatic
Rupture of a subcapsular hematoma of the liver is a life- artery to the involved liver segment, and loose suturing of the
threatening complication of HELLP syndrome. Profound omentum or surgical mesh to the liver to improve integrity.
hypovolemic shock in a previously hypertensive patient is the Shrivastava and associates in a case report described the success-
hallmark of hematoma rupture. In most instances, rupture ful use of an argon-beam coagulator to obtain hemostasis from
involves the right lobe and is preceded by the development of a a ruptured liver hematoma in a patient with HELLP syndrome,
parenchymal hematoma. Patients frequently present with shoul- although previous experience with this modality was unsuccess-
der pain, shock, evidence of massive ascites, respiratory diffi- ful. Even with appropriate treatment, maternal and fetal
culty, pleural effusions, and often with a dead fetus. Ultrasound mortality is almost 50%. Mortality is most commonly associ-
or CT of the liver should be performed to rule out the presence ated with exsanguination with coagulopathy and sepsis.
of subcapsular hematoma of the liver and to assess for the pres- Initial survivors are at increased risk for developing ARDS,
ence of intraperitoneal bleeding. Paracentesis can confirm intra- pulmonary edema, liver failure, and acute renal failure in the
peritoneal bleeding. postoperative period.
The presence of ruptured subcapsular liver hematoma that Reck and colleagues reviewed cases with HELLP syndrome–
results in shock is a surgical emergency that requires acute associated liver rupture (4 patients from their center in
multidisciplinary treatment (Box 31-9). Resuscitation should Germany and 49 identified from a MedLine literature search
consist of massive transfusions of blood, correction of coagu- covering 1990 to 1999). Despite surgical interventions, HELLP
lopathy with FFP and platelets, and immediate laparotomy. syndrome–associated liver rupture carried a mortality rate of
BOX 31-9 MANAGEMENT OF PATIENTS WITH and review of the literature, we have developed a manage-
DOCUMENTED SUBCAPSULAR HEMATOMA OF THE LIVER ment plan of hepatic hematoma associated with HELLP syn-
drome. This plan emphasizes the potential for transfusion of
General Considerations large amounts of blood and blood products and the need for
1. Inform the blood bank about the potential need for aggressive intervention if rupture of the hematoma is sus-
large amounts of packed red blood cells, fresh-frozen pected (see Box 31-9). We recommend that 30 units of packed
plasma, and platelet concentrate. red blood cells, 20 U of FFP, 30 to 50 U of platelets, and 20 to
2. Ensure consultation with a general or vascular surgeon. 30 U of cryoprecipitate be available if rupture of a subcapsular
3. Avoid direct and indirect manipulation of the liver.
4. Arrange for close monitoring of hemodynamic status.
hematoma is suspected.
5. Administer intravenous magnesium sulfate to prevent We agree with the observations of others that a stable
seizures. patient with an unruptured subcapsular hematoma should
be conservatively managed. Constant monitoring must con-
Unruptured Hematoma tinue during this management, however, because patients can
• Conservative management rapidly become unstable after rupture of the hematoma. Survival
• Correct coagulopathy clearly is associated with rapid diagnosis and immediate medical
• Serial computed tomography scans or ultrasound or surgical stabilization, so these patients should be managed in
Expanding or Ruptured Hematoma an intensive care unit (ICU) with close monitoring of hemody-
namic parameters and fluid status to avoid the potential for
• Massive transfusions
• Immediate laparotomy
pulmonary edema or respiratory compromise.
Postpartum follow-up for patients with subcapsular hema-
Minimal Bleeding toma of the liver should include serial CT, magnetic resonance
• Observation imaging (MRI), or ultrasonography until the defect resolves.
• Draining area with closed suction Although the data on subsequent pregnancy outcome after a
subcapsular hematoma of the liver in pregnancy are limited, we
Severe Bleeding have managed three such patients who have had subsequent
• Application of laparotomy sponges as packs for pressure normal maternal and fetal outcomes, and Wust and coworkers
• Embolization of the hepatic artery to the involved liver reported the successful outcome of four subsequent pregnancies
segment
in three women with a history of hepatic rupture and PE or
• Surgical ligation of hemorrhaging hepatic segment
• Loosely sutured omentum or surgical mesh to the liver
HELLP syndrome.
to improve integrity
• Argon beam coagulator to liver surface Hemodynamic Monitoring in Preeclampsia
• Hepatic lobectomy The cardiovascular hemodynamics of preeclampsia have been
• Hepatectomy and temporary portocaval shunt followed investigated over the years by many authors who have used
by liver transplantation various techniques for measurement of BP, cardiac output, pul-
monary capillary wedge pressure (PCWP), and central venous
pressure (CVP).
39% (19 of 49) in their review. The main causes of death were Hemodynamic findings in women with PE are variable. A
hemorrhagic shock (n = 11) and multiorgan failure (n = 7). review of the English literature demonstrates considerable dis-
Based on their review, these authors suggested an interdisciplin- agreement regarding one or more of the hemodynamic param-
ary approach for patients with ruptured liver or hepatic failure eters studied. This lack of agreement has been attributed to
that includes the use of temporary packing of the liver to control differences in the definition of PE, variable severity and duration
bleeding. In those patients with hepatic failure or uncontrollable of the disease process, presence of underlying cardiac or renal
hepatic hemorrhage, they noted that a liver transplantation as a disease, techniques used to measure cardiac output and BP, and
last-resort measure must be considered. therapeutic interventions applied before obtaining the various
measurements. In addition, the dynamic minute-to-minute fluc-
LIVER TRANSPLANTATION FOR INTRACTABLE HEMORRHAGE tuation of the cardiovascular parameters studied makes it diffi-
For women with intractable hemorrhage despite the previously cult to standardize the conditions under which these observations
described interventions, and for those with necrosis with subse- are made, which limits the value of a single measurement.
quent liver failure, liver transplantation has been successful in Invasive techniques have been used by many authors to study
case reports and case series. Shames and colleagues queried the the hemodynamic findings in untreated women with severe PE.
Organ Procurement and Transplantation Network database The reported cardiac index ranged from a low of 2.8 to a high
regarding liver transplantations performed for complications of 4.8 L/m2 per minute, and the reported PCWP ranged from
from HELLP syndrome. Eight deceased donor liver transplanta- a low of 3.3 to a high of 12 mm Hg. The findings suggest that
tions were identified in the United States with this indication cardiac index and PCWP are either low or normal in severe PE.
between October 1987 and November 2003. At the time of The reported CVP values also ranged from 2 to 6 mm Hg. The
their review, six of the eight patients were alive, whereas two findings demonstrate that treated patients with PE have
maternal deaths occurred within 1 month of transplantation. In normal to high cardiac index, normal to high systemic vas-
addition, two patients required retransplantation. Based on the cular resistance index, and normal to high PCWP.
results of their review, these authors presented an algorithm in In summary, variable hemodynamic findings accompany
which liver transplantation is considered for patients with com- PE. Moreover, the clinical utility of invasive hemodynamic
plicated HELLP syndrome, including ongoing, uncontrolled monitoring in PE is debatable. Most of the invasive monitor-
hemorrhage or liver necrosis and failure. From our experience ing data indicate that both cardiac output and systemic vascular
resistance appear to be elevated in women with severe PE. This TABLE 31-12 MATERNAL OUTCOME IN RANDOMIZED
finding suggests that the problem in PE is a systemic vascular TRIAL COMPARING INDUCTION
resistance that is inappropriately high for the level of cardiac AND EXPECTANT MONITORING
output. Both the PCWP and the CVP appear to be in the low IN MILD GESTATIONAL
to normal range; however, no correlation is found between the HYPERTENSION–PREECLAMPSIA
two values.
RELATIVE
INDUCTION EXPECTANT RISK
Antepartum Management of Gestational (n = 377) (%) (n = 379) (%) (95% CI)
Hypertension–Preeclampsia Composite adverse 117 (31) 166 (44) 0.71 (0.59-0.86)
GESTATIONAL HYPERTENSION outcome
Women with gestational hypertension–preeclampsia (GH- HELLP syndrome 4 (1) 11 (3) 0
PE) are at risk for progression to severe hypertension, PE Pulmonary edema 0 2 (1) 0
with severe features, HELLP syndrome, or eclampsia.1-8 The Abruptio placentae 0 0 0
Eclampsia 0 0 0
risks are increased with a lower gestational age at the time of Maternal ICU 6 (2) 14 (4) 0
diagnosis,5-8 and therefore these patients require close obser- admission
vation of maternal and fetal conditions. Maternal evaluations Cesarean delivery 54 (14) 72 (19) 0.75 (0.55-1.04)
require weekly prenatal visits; education about reporting pre- Modified from Koopmans CM, Bijlenga D, Groen H, et al. Induction of labour versus
eclamptic symptoms; and evaluation of CBC, platelet count, expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’
liver enzymes, and serum creatinine.1-3 Fetal evaluation includes gestation (HYPITAT): a multicentre, open-label randomize controlled trial. Lancet.
2009;374:979-988.
ultrasound examination of fluid and estimated fetal weight at CI, confidence interval; HELLP, hemolysis, elevated liver enzymes, and low platelets;
the time of diagnosis and weekly or twice weekly nonstress tests ICU, intensive care unit.
(NSTs) and evaluation of amniotic fluid volume (AFV).1,3
Restriction of dietary salt and physical activity has not proved TABLE 31-13 NEONATAL OUTCOME IN RANDOMIZED
beneficial in the management of these patients.1-3 Additionally, TRIAL COMPARING INDUCTION VERSUS
the results of several randomized trials reveal that control of EXPECTANT MANAGEMENT IN MILD
maternal BP with antihypertensive drugs does not improve HYPERTENSION-PREECLAMPSIA
pregnancy outcome in these women.
In the absence of progression to severe disease, women NO. WITH NO. WITH
INDUCTION EXPECTANT
with GH-PE can continue pregnancy until 37 weeks’ gesta- NEONATAL OUTCOME (%) MONITORING (%)
tion. During labor and immediately postpartum, they do not
Composite adverse outcome 24 (6) 32 (8)
require seizure prophylaxis because the rate of eclampsia in these Perinatal deaths 0 0
women is less than 1 in 500.1,2 Apgar <7 at 5 min 7 (2) 9 (2)
The Hypertension and Preeclapmsia Intervention Trial At Cord pH <7.05 9 (3) 19 (6)
Term (HYPITAT) was a multicenter, open-label RCT con- Neonatal intensive care unit 10 (3) 8 (2)
admission
ducted at 6 academic and 32 nonacademic hospitals in the Respiratory distress 1 (0.25) 1 (0.25)
Netherlands. It included 756 women with a singleton pregnancy syndrome
at a gestational age between 360/7 weeks and 410/7 weeks who
Modified from Koopmans CM, Bijlenga D, Groen H, et al. Induction of labour versus
had mild GH (n = 496) or nonsevere GH (n = 246); 377 were expectant monitoring for gestational hypertension or mild pre-eclampsia after 36 weeks’
randomized to induction, 379 to expectant monitoring. The gestation (HYPITAT): a multicentre, open-label randomized controlled trial. Lancet.
primary outcome was a composite of adverse maternal out- 2009;374:979-988.
comes: progression to severe disease or HELLP syndrome,
eclampsia, pulmonary edema, placental abruption, postpar- HOSPITALIZATION
tum hemorrhage, thromboembolic disease, or death. Second- In the past, management of these women has involved hospital
ary outcomes were a composite of adverse neonatal outcomes bed rest for the duration of pregnancy with the belief that such
and rate of cesarean delivery. No cases of maternal, fetal, or management diminishes the frequency of progression to severe
neonatal death and no cases of eclampsia or abruption were disease and allows rapid intervention in the event of sudden
reported in either group. However, women randomized to the disease progression, including the development of placental
induction group had a significant reduction in the primary abruption, eclampsia, or hypertensive crisis. However, these
outcome (31% vs. 44%; RR, 0.71; 95% CI, 0.59 to 0.86) complications are extremely rare among compliant women with
mainly because of differences in the rates of severe hyperten- mild hypertension or nonsevere hypertension and absent symp-
sion. No differences were found in the overall secondary out- toms. In addition, the results of two randomized trials in women
comes; however, subgroup analysis revealed significant differences with GH and several observational studies in women with mild
in the primary outcomes in the group enrolled with mild PE hypertension and nonsevere PE suggest that most of these
(33% vs. 54%; RR, 0.61; 95% CI, 0.45 to 0.8) but not in those women can be safely managed at home or in a day care facil-
with mild GH (31% vs. 38%; RR, 0.81; 95% CI, 0.63 to 1.03). ity provided they undergo frequent maternal and fetal
Unfortunately, the sample size was inadequate to answer the evaluation.1-3
question in those with nonsevere GH only. Moreover, in the
induction group, the rate of cesarean delivery was lower in nul- BED REST
liparous women and in those with a cervical Bishop score of less Complete or partial bed rest for the duration of pregnancy is
than 2, which refutes the belief that induction of labor in these often recommended for women with nonsevere hypertension–
women increases the rate of cesarean delivery. Results of this trial PE. No evidence to date suggests that this practice improves
are summarized in Tables 31-12 and 31-13. pregnancy outcome. In addition, no published randomized
trials have compared complete bed rest and restricted activity symptoms of organ dysfunction such as severe headaches, visual
in the management of women with PE. On the other hand, changes, altered mentation, right upper quadrant or epigastric
prolonged bed rest for the duration of pregnancy increases the pain, nausea or vomiting, and shortness of breath.1-3 In addition,
risk for thromboembolism. The ACOG Task Force report rec- they should undergo laboratory testing for serum creatinine,
ommends that bed rest not be used in management of GH-PE.1 platelet count, and liver enzymes. Coagulation function tests
are not necessary in the presence of a normal platelet count
BLOOD PRESSURE MEDICATIONS and liver enzymes. The frequency of laboratory testing will
Several randomized trials have described the use of antihy- depend on the initial findings, the severity of the maternal
pertensive drugs compared with no treatment or a placebo condition, and the ensuing clinical progression.
in the management of women with nonsevere hypertension
or PE remote from term. Overall, these trials revealed lower RECOMMENDED MANAGEMENT
rates of progression to severe disease with no improvement The primary objective of management in women with GH-PE
in perinatal outcome.1-3 Of note, the sample size of these trials must always be safety of the mother and then delivery of a
is inadequate to evaluate differences in FGR, abruptio placentae, mature newborn that will not require intensive and prolonged
perinatal death, or maternal outcome. It is recommended that neonatal care. This objective can be achieved by formulating a
antihypertensive medications not be used routinely to control management plan that takes into consideration the severity of
mild levels of hypertension. the disease process, gestational age, maternal and fetal status at
the initial evaluation, presence of labor, and the wishes of the
FETAL AND MATERNAL SURVEILLANCE mother.
It is universally agreed that fetal testing is indicated during
expectant management of women with GH or PE.1-3 Most HYPERTENSION OR PREECLAMPSIA WITHOUT
authorities in the United States recommend daily fetal move- SEVERE FEATURES
ment counting (FMC) in association with either an NST or Once the diagnosis of GH or PE is made, subsequent manage-
BPP to be performed at the time of diagnosis and serially ment will depend on the results of maternal and fetal evaluation
thereafter until delivery (1 to 2 times per week).1-3 Because (Fig. 31-10). In general, women with disease that develops
uteroplacental blood flow may be reduced in some of these at 37 weeks’ gestation or later should undergo induction of
women, ultrasound estimation of fetal weight and amniotic fluid labor.
status is also recommended at the time of diagnosis and serially In women who remain undelivered, close maternal and fetal
thereafter, with the frequency depending on findings. Doppler evaluation are essential. These women are instructed to eat a
flow velocimetry is recommended in the presence of suspected regular diet with no salt restriction and to restrict their activity,
IUGR.1,3 The frequency of these tests is usually dependent on but complete bed rest is not advised. Diuretics and antihyper-
the severity of hypertension or PE, gestational age at the time tensive medications are not used because of the potential to
of diagnosis, and fetal growth findings. Most clinical series mask the diagnosis of severe disease.1 At the time of initial and
suggest testing once weekly in women with GH or PE, twice subsequent visits, women are educated and instructed about
weekly if fetal growth delay is suspected, and daily during reporting symptoms of severe PE. Those who are managed as
expectant management of women with PE without severe fea- outpatients are also advised to come to the hospital or out-
tures at less than 32 weeks’ gestation. However, no large prospec- patient facility immediately if they develop abdominal pain,
tive studies have assessed outcomes of these monitoring significant headache, uterine contractions, vaginal spotting,
techniques in women with GH or PE. or decreased fetal movement.
Maternal surveillance is indicated in all women with GH In women with nonsevere GH, fetal evaluation should include
and PE. The goal of monitoring in women with GH is to an NST and an ultrasound examination of estimated fetal
observe progression of the condition to severe hypertension weight (EFW) and AFV using the amniotic fluid index (AFI).
or to PE.1-3 In women with PE, the goal is early detection of If the results are normal, repeat testing is performed every week
progression to PE with severe features. In those with severe as previously described.
features, the goal is to detect the development of organ dys Maternal evaluation includes weekly measurements of hema-
function; therefore all such women should be evaluated for tocrit, platelet count, serum creatinine, and liver function tests.
Maternal and fetal evaluation
>37 weeks gestation

>34 weeks gestation
Labor or rupture of membranes Yes
Delivery
Suspected abruption
Abnormal maternal-fetal testing
Pregnancy prolongation Estimated fetal weight less than fifth percentile
for fetal benefit
Definite risks to mother No
Potential risks to fetus
Inpatient/outpatient
maternal-fetal testing
FIG 31-10 Management plan for patients with gestational hypertension–preeclampsia.
• Admit to labor and delivery, observe for 24-48 hours

• Corticosteroids, magnesium sulfate prophylaxis
• Antihypertensives for severe blood pressure
• Ultrasound, fetal heart rate monitoring
• Monitor symptoms and laboratory tests
Contraindications to continued expectant management?

• Eclampsia
Yes • <230/7 weeks
Delivery • Pulmonary edema
• Abnormal fetal testing
• Acute renal failure, disseminated intravascular coagulopathy
• Abruptio placentae
No
Offer continued expectant management

• Inpatient only, discontinue magnesium sulfate after 12-24 hours
• Daily maternal-fetal testing, symptoms, blood pressure, lab tests
Are there additional complications?

• Persistent symptoms
• HELLP/partial HELLP syndrome
• Fetal weight less than fifth percentile + oligohydramnios or umbilical artery REDF
• Labor/rupture of membrane 330/7-335/7 weeks
Yes No
24-32 weeks
Deliver
expectant management
after 48 hr
Deliver at 340/7 weeks
FIG 31-11 Management plan for patients with preeclampsia with severe features before 34 weeks’ gestation. HELLP, hemolysis, elevated liver
enzymes, and low platelets; REDF, reversed end-diastolic flow.
The women are usually seen twice a week for evaluation of PREECLAMPSIA WITH SEVERE FEATURES
maternal BP, urine protein by dipstick or P/C ratio (GH only), The incidence of preeclampsia with severe features ranges from
and symptoms of impending eclampsia. This evaluation is 0.6% to 1%.105 Pregnancies complicated by PE with severe
extremely important for early detection of progression to severe features are associated with serious maternal and perinatal com-
disease. The onset of maternal symptoms and/or a sudden plications, particularly preterm delivery, FGR, placental abrup-
increase in BP to severe values requires prompt hospitalization tion, and perinatal death (Table 31-14). As a result, knowledge
for close evaluation. of the anticipated maternal, fetal, and neonatal risks is essential
In women with PE at less than 37 weeks’ gestation but at for appropriate counseling and management.
more than 32 weeks, outpatient management can be consid-
ered for reliable patients with a systolic BP of 155 mm Hg Expectant Management
or less or diastolic BP of 105 mm Hg or less and no symp- The clinical course of PE with severe features may be charac-
toms. Women who do not satisfy these criteria are hospital- terized by progressive deterioration in both maternal and fetal
ized, particularly those with PE before 32 weeks. During conditions. Because these pregnancies have been associated
ambulatory management, women are instructed to have limited with increased rates of maternal morbidity and mortality and
activity at home and are given instructions about prompt report- with significant risks for the fetus (growth restriction, hypox-
ing of symptoms of severe disease; these women are then seen emia, and death), it is generally agreed that all such patients
twice weekly. Fetal evaluation includes daily FMC, twice-weekly should be delivered if the disease develops after 34 weeks’
NST, and serial ultrasound evaluation of fetal growth and AFV. gestation. Prompt delivery is also indicated when eclampsia is
If disease progression is evident—that is, if a significant increase imminent—when persistent, severe symptoms do not respond
in BP to levels above the threshold mentioned previously, new to treatment—or in the presence of multiorgan dysfunction or
onset of symptoms, evidence of abnormal blood tests, or abnor- severe IUGR (<5th percentile) in association with abnormal
mal fetal growth are apparent—these women are hospitalized for umbilical artery Doppler studies, such as reversed end-diastolic
the duration of pregnancy. Women managed in the hospital flow (REDF) or severe oligohydramnios (largest vertical pocket
receive similar maternal and fetal evaluations. Obstetric manage- <2 cm), suspected placental abruption, nonreassuring fetal
ment is summarized in Figure 31-11. testing, gestational age less than 24 weeks, or fetal demise.1-3,105
TABLE 31-14 PREGNANCY OUTCOME IN WOMEN WITH MILD AND SEVERE PREECLAMPSIA
HAUTH ET AL4 BUCHBINDER ET AL*16 HNAT ET AL23
MILD SEVERE MILD SEVERE MILD SEVERE
OUTCOME (n = 217) (%) (n = 109) (%) (n = 62) (%) (n = 45) (%) (n = 86) (%) (n = 70) (%)
Delivery at <37 wk NR NR 25.8 66.7 14.0 33.0
Delivery at <35 wk 1.9† 18.5† 9.7 35.6 2.3 18.6
SGA infant* 10.2 18.5 4.8 11.4 NR NR
Abruptio placentae 0.5 3.7 3.2 6.7 0 1.4
Perinatal death 1.0 1.8 0 8.9 0 1.4
*Included women with previous preeclampsia. The other studies included only nulliparous women.
†
Rates for delivery at <34 wk.
Although delivery is beneficial to the mother, it must be in maternal complications between the two groups. Thus the
weighed against the risks associated with prematurity. In the data support the use of steroids to reduce neonatal complica-
past, it was believed that infants born prematurely to severely tions in women with severe PE at 34 weeks’ gestation or less.
preeclamptic women had lower rates of neonatal mortality and
morbidity compared with infants of similar gestational age born Recommended Management of Preeclampsia
to nonpreeclamptic women. This belief was based on the clinical With Severe Features
impression that fetuses of preeclamptic women have accelerated The presence of severe disease mandates immediate hospital-
lung and neurologic maturation as a result of stress in utero. ization in labor and delivery. IV magnesium sulfate is begun
Reduced risk for prematurity-associated neonatal morbidity has to prevent convulsions, and antihypertensive medications are
never been documented in case-control studies. In contrast, administered to lower severe levels of hypertension (systolic
several recent case-control investigations have demonstrated pressure ≥160 mm Hg and/or diastolic pressure ≥110 mm Hg).
that premature infants born after PE with severe features The aim of antihypertensive therapy is to keep the systolic pres-
have similar neonatal complications and mortality and have sure between 140 and 155 mm Hg and the diastolic pressure
higher rates of admission to neonatal ICUs compared with between 90 and 105 mm Hg. During the observation period,
other premature infants of similar gestational age. In addi- maternal and fetal conditions are assessed, and a decision is made
tion, the results of case-controlled studies reveal that fetuses regarding the need for delivery (see Fig. 31-11). Those with a
of preeclamptic women do not exhibit accelerated lung or gestational age of 24 to 34 weeks are given corticosteroids to
neurologic maturation.104 accelerate fetal lung maturity. Maternal evaluation includes
During expectant management, women should be aware monitoring of BP, intake and urine output, cerebral status, and
that the decision to continue such management will be made the presence of persistent severe epigastric pain, tenderness,
on a daily basis and that the median time of pregnancy pro- labor, or vaginal bleeding. Laboratory evaluation includes a
longation is 7 days with a range of 2 to 35 days. Only three platelet count, liver enzymes, and serum creatinine. Fetal evalu-
randomized trials have compared a policy of early elective deliv- ation includes continuous fetal heart monitoring, a BPP, and
ery after corticosteroids with a policy of delayed delivery.105 One ultrasound assessment of fetal growth and AFV. Patients with
trial was conducted in South Africa and included patients at a resistant severe hypertension despite maximal doses of IV
gestational age of 26 to 34 weeks, one United States trial included labetalol (300 mg within an hour) plus maximum doses of
women at 28 to 32 weeks, and a recent trial from Latin Ameri- hydralazine (25 mg) or oral rapid-acting nifedipine (50 mg)
can countries included patients with a gestational age of 28 to or persistent cerebral symptoms while on magnesium sulfate
34 weeks. The first two studies totaled 133 women and revealed are delivered irrespective of gestational age.
improved neonatal outcome in those who had delivery delayed, After the initial evaluation, the need for immediate delivery
whereas the multicenter Latin American study revealed no peri- versus the potential neonatal benefit and the relative maternal
natal benefits and increased maternal morbidity. Nevertheless, and fetal risks of expectant management should be determined.33
the results of retrospective and observational studies of more Women who develop eclampsia, pulmonary edema, or docu-
than 2000 women suggest that expectant management is mented or suspected placental abruption; those with DIC
associated with reduced short-term neonatal morbidity in a or moderate to severe renal dysfunction (serum creatinine
select group of women with a gestational age between 24 and ≥1.5 mg/dL); and those with gestational age less than 230/7
32 weeks.1,3,104 weeks’ gestation should be delivered after maternal stabiliza-
In the past, uncertainty surrounded the efficacy and safety tion. In addition, those with a nonreassuring FHR tracing
of corticosteroids administered to women with PE with severe (repetitive decelerations) and those with a persistent BPP of
features before 34 weeks’ gestation. A prospective double-blind 4 or less should be delivered promptly.33 Women with a fetus
randomized trial of 218 women with severe PE with a gesta- between 230/7 and 236/7 weeks should receive extensive counsel-
tional age between 26 and 34 weeks receiving either betametha- ing about the minimal neonatal benefit and high maternal com-
sone (n = 110) or placebo (n = 108) reported a significant plications from expectant management, and treatment should
reduction in the rate of RDS (RR, 0.53; 95% CI, 0.35 to 0.82) be individualized.
in the steroid-treated group. Corticosteroid use also was associ- For pregnancies at 240/7 weeks or greater without any indi-
ated with a reduction in the risks for neonatal intraventricular cation for prompt delivery, corticosteroids are administered
hemorrhage (RR, 0.35; 95% CI, 0.15 to 0.86), neonatal infec- to accelerate fetal lung maturity.33 With a gestational age
tion (RR, 0.39; 95% CI, 0.39 to 0.97), and neonatal death (RR, between 330/7 to 336/7 weeks, severe FGR with absent or
0.5; 95% CI, 0.28 to 0.89). However, no differences were noted reversed umbilical artery diastolic flow, largest amniotic fluid
vertical pocket less than 2 cm, preterm labor or premature is nonreactive, and twice-weekly amniotic fluid assessment (see
rupture of the membranes (PROM), HELLP syndrome or Chapter 11).33 Ultrasound assessment of fetal growth is per-
partial HELLP syndrome, or persistent symptoms—such as formed every 2 weeks.33 Severe oligohydramnios (largest ver
headaches, visual changes, epigastric or right upper quadrant tical pocket <2 cm) is considered an indication for delivery in
pain, nausea, or vomiting—the fetus should be delivered no women with a gestational age of more than 30 weeks irrespective
later than 24 hours after the last dose of corticosteroids. of other fetal testing results. In those at 30 weeks or less of gesta-
These gravidas should remain on magnesium sulfate with tion, pregnancy may be continued with a reassuring NST, BPP,
continuous monitoring of uterine contractions and FHR and umbilical artery Doppler studies. Umbilical artery Doppler
until delivery. studies are performed weekly, and they should be done more
Women with a pregnancy between 240/7 and 326/7 weeks’ often when FGR is suspected or when testing reveals abnormal
gestation with stable maternal and fetal conditions during the diastolic flow or severe oligohydramnios. If umbilical artery dia-
initial 24-hour observation period are considered candidates for stolic flow is absent, Doppler studies should be performed daily.
expectant management (see Fig. 31-11). In these women, mag- In general, most patients with preeclampsia without severe
nesium sulfate is generally discontinued after 24 hours with features managed expectantly will require delivery within 2
transfer to a high-risk antepartum floor for close observation. weeks, but some patients may continue their pregnancies for
Because of the potential for rapid deterioration in maternal several weeks. It is important to emphasize that this therapy
and fetal conditions during expectant management, these is appropriate only in a select group of patients and should
women should generally be managed in a tertiary care hos- be undertaken in a facility with adequate maternal and neo-
pital with adequate maternal and neonatal intensive care natal intensive care facilities. Once the decision is made for
facilities. They should be cared for in consultation with a delivery, magnesium sulfate should be administered in labor and
maternal-fetal medicine specialist, and the mother should for at least 24 hours postpartum.33
receive counseling from a neonatologist.33
Oral antihypertensive medications are used as needed to keep Intrapartum Management
systolic BP between 140 and 155 mm Hg and diastolic BP The goals of management of women with gestational
between 90 and 105 mm Hg.33 Oral labetalol and oral calcium hypertension-preeclampsia are early detection of FHR abnor-
channel blockers (nifedipine or nicardipine) have been com- malities and progression from mild to severe disease and preven-
monly used in reported studies. My regimen consists of an tion of maternal complications. Pregnancies complicated by PE,
initial dose of labetalol of 200 mg every 8 hours to be particularly those with severe disease or FGR, are at risk for
increased up to 800 mg every 8 hours (600 to 2400 mg/day) reduced fetal reserve and placental abruption.2 Therefore women
as needed. If the maximal dose is inadequate to achieve the with PE should receive continuous monitoring of FHR and
desired BP goal, short-acting oral nifedipine is added with uterine activity. The presence of uterine tachysystole or recurrent
an initial dose of 10 mg every 6 hours and is subsequently FHR decelerations may be the first sign of placental abruption
increased up to 20 mg every 4 hours (40 to 120 mg/day). An in these women.
alternative regimen may include the long-acting (XL) version of Some women with GH-PE progress to severe disease as a
nifedipine (30 to 60 mg) every 8 hours. During titration of oral result of changes in cardiac output and stress hormones
antihypertensive agents, if the patient has persistent severe during labor. Therefore women with GH-PE should have BP
hypertensive episodes (systolic BP ≥160 mm Hg and/or dia- recordings every hour and should be assessed for symptoms sug-
stolic BP ≥105 mm Hg), BP should be assessed every 15 gestive of severe disease. Those who develop severe hypertension
minutes. If the BP remains in the severe range after 60 minutes, or symptoms should be managed as patients with PE with severe
the patient should be transferred to the labor and delivery unit features.
for more intensive monitoring and treatment with IV medica- Maternal pain relief during labor and delivery can be provided
tions such as hydralazine or labetalol. Patients with resistant by either systemic opioids or segmental epidural anesthesia.
severe hypertension after maximal doses of IV hydralazine Epidural analgesia is considered to be the preferred method
(25 mg) or labetalol (300 mg) should receive magnesium of pain relief in women whose GH and PE are nonsevere.
sulfate and be delivered. In addition, patients who develop Although no unanimity of opinion exists regarding the use of
persistent severe hypertension despite combined maximal epidural anesthesia in women with PE with severe features,
doses of oral labetalol (2400 mg/day) plus short-acting nife- evidence suggests that epidural anesthesia is also safe in these
dipine (120 mg/day) or nifedipine XL (180 mg/day) should women. A randomized trial of 116 women with severe PE who
also be considered for delivery. received either epidural analgesia or patient-controlled analgesia
Maternal assessment includes frequent evaluation of symp- (PCA) reported no differences in cesarean delivery rates, and the
toms such as new onset of severe headaches that do not respond group who received epidural had significantly better pain relief
to repeated doses of analgesics, blurred or double vision or during labor.
inability to see, confusion, persistent nausea, vomiting, epigas- The use of either epidural, spinal, or combined techniques
tric or right upper quadrant pain, shortness of breath, uterine of regional anesthesia is considered by most obstetric anesthesi-
activity, and vaginal bleeding. In addition, intake and output ologists to be the method of choice during cesarean delivery.
should be closely monitored.33 In women with PE with severe features, general anesthesia
Laboratory assessment includes daily testing of the CBC carries the risk for aspiration and failed intubation owing to
with platelet count, transaminases, LDH, and serum creatinine airway edema, and it is associated with marked increases in
levels.32 Coagulation studies are obtained only if thrombocyto- systemic and cerebral pressures during intubation and extu-
penia or suspicion of abruption is present. bation.1 Women with airway or laryngeal edema may require
Fetal assessment includes daily fetal kick counts, at least daily awake intubation under fiberoptic observation with the
NST with uterine activity monitoring with a BPP if the NST availability of immediate tracheostomy. Changes in systemic
A B
FIG 31-12 Retinal ischemia and injury in severe preeclampsia. A, Scattered, yellowish opaque lesions of the retinal pigment epithelium. B, Fluo-
roscein angiograms showing patchy delayed filling of the choriocapillaris.
and cerebral pressures may be attenuated by pretreatment with and cardiovascular complications such as encephalopathy, hem-
labetalol or nitroglycerine injections. It is important to recognize orrhage, and congestive heart failure (CHF) and to prevent
that regional anesthesia is contraindicated in the presence retinal injury (Fig. 31-12).1,2 For ethical reasons, no randomized
of coagulopathy or severe thrombocytopenia (platelet count trials have been done to determine the level of hypertension to
<50,000/mm3). treat in order to prevent these complications. Antihypertensive
therapy is recommended by some for sustained systolic BP
Prevention of Eclamptic Seizures values of 160 mm Hg or more and for sustained diastolic values
Magnesium sulfate is the drug of choice to prevent convul- of 110 mm Hg or more. Some experts recommend treating
sions in women with preeclampsia. The results of recent ran- diastolic levels of 105 mm Hg, and still others use a mean arte-
domized trials revealed that magnesium sulfate is superior rial BP of 130 mm Hg or more.1,2 The definition of sustained
to placebo or no treatment for prevention of convulsions hypertension is not clear and ranges from 30 minutes to 2 hours.
in women with PE with severe features. The overall results I recommend that antihypertensive medications are
of these four trials demonstrate that magnesium sulfate pro- indicated with sustained elevations in systolic BP to levels
phylaxis, compared with placebo (two trials, 10,795 women), of 160 mm Hg or greater and/or when diastolic BP is
nimodipine (one trial, 1750 women), and no treatment (one 105 mm Hg or higher for at least 60 minutes.33 If the desired
trial, 228 women) in severe PE is associated with a significantly target of BP level is not achieved after maximum doses of IV
lower rate of eclampsia (RR, 0.39; 95% CI, 0.28 to 0.55). medications are used, I recommend the insertion of an arte-
Results from one of the largest randomized trials to date, that rial line with the initiation of a continuous IV administration
of 10,141 women with PE in 33 nations (largely in the Third of medications such as nicardipine, nitroprusside, labetalol or
World), has been recently reported. Almost all the enrolled nitroglycerine. This may require admitting the patient to an
patients had severe disease by U.S. standards: 50% received intensive care facility. Several antihypertensive medications can
antihypertensives before randomization, 75% received antihy- be used to treat severe hypertension in PE. The most commonly
pertensives after randomization, and the remainder had severe recommended medications include IV bolus doses of hydrala-
PE or imminent eclampsia. Among all enrolled women, the zine, bolus doses of labetalol, or oral nifedipine (rapid-acting
rate of eclampsia was significantly lower in those assigned to tablets or long-acting capsules). Other antihypertensive medica-
magnesium sulfate (0.8% vs. 1.9%; RR, 0.42; 95% CI, 0.29 to tions recommended for treatment of severe hypertension have
0.60). However, among the 1560 women enrolled in the western included IV nicardipine and mini boluses of diazoxide.
world, the rates of eclampsia were 0.5% in the magnesium group Despite the extensive literature on the subject, it remains
versus 0.8% with placebo, a difference that was not significant unclear which is the ideal antihypertensive medication to use in
(RR, 0.67; 95% CI, 1.19 to 2.37). the acute control of hypertension in women with severe PE. The
Two randomized placebo-controlled trials evaluated the effi- results of a recent meta-analysis of relevant randomized trials
cacy and safety of magnesium sulfate in women with mild PE. found that parenteral hydralazine was associated with more
One of these trials included 135 women, and the other included adverse effects compared with other antihypertensives; however,
only 222 women. No instances of eclampsia were reported in such a finding was not confirmed in a recent large randomized
either group in both of these trials. In addition, the findings of trial. Based on the available evidence, hydralazine, labetalol,
both studies revealed that magnesium sulfate does not affect or nifedipine can be used to treat severe hypertension in
either the duration of labor or the rate of cesarean delivery. PE.2,3,33 The provider should be familiar with the dosage to
However, neither of these studies had an adequate sample size be used, the expected response, and potential side effects of
to address the efficacy of magnesium sulfate to prevent convul- each of these drugs. Both hydralazine and nifedipine are associ-
sions. Therefore whether magnesium sulfate treatment bene- ated with tachycardia and headaches and thus are not the first
fits women with mild PE remains unclear. drugs of choice in patients with a heart rate above 100 beats/
min. In such case, labetalol is preferred. Labetalol, however,
Control of Severe Hypertension should be avoided in patients with moderate to severe asthma,
The objective of treating acute and sustained severe hypertension bradycardia (heart rate <60 beats/min), and in those with CHF.
that lasts more than 60 minutes is to prevent cerebrovascular Compared with other antihypertensive medications, nifedipine
has the advantage of increased renal blood flow with an associ- contraindication for induction. However, most of the women
ated increase in urine output.33 Thus it may be the drug of choice included in these studies had a gestational age beyond 32 weeks
in those with decreased urine output and for treatment of severe at the time of induction, and only two of these studies included
hypertension in the postpartum period.33 In the past, there has data on patients earlier than 28 weeks undergoing induction of
been a theoretic concern that the combined use of magnesium labor.33 Both of these studies reported a cesarean delivery rate
sulfate and nifedipine in patients with severe PE can result in above 95% and thus recommended elective cesarean delivery in
excessive hypotension and neuromuscular blockade. However, a such patients.
recent review on this subject found that therapy with both In general, the decision to perform a cesarean delivery
magnesium sulfate and nifedipine does not increase the risk for versus a trial of labor in such patients should be individ
the previously described complications in women with PE. Nev- ualized and based on one or more of the following
ertheless, if neuromuscular blockade develops in these patients, factors: fetal gestational age, fetal presentation, presence
this can be easily reversed by the administration of 1 g of IV or absence of severe FGR, oligohydramnios, results of
calcium gluconate. umbilical artery Doppler, BPP, FHR monitoring, presence
For the treatment of severe hypertension in pregnancy, the of labor, and cervical Bishop score. On the basis of the avail-
recommended dosage is IV hydralazine given as bolus injec- able data, we recommend cesarean delivery for all women
tions of 5 to 10 mg every 20 minutes for a maximal dose of with a gestation of less than 28 weeks and for those with
25 mg in 60 minutes. The recommended dose of labetalol is severe FGR, severe oligohydramnios, BPP of 4 or less, or
20 to 80 mg intravenously every 10 minutes for a maximal reverse umbilical artery Doppler flow at less than 32 weeks
dose of 300 mg; and the dosage of nifedipine is 10 to 20 mg of gestation.
orally every 20 minutes for a maximal dose of 50 mg within
60 minutes.33 Sustained BP values of 160 mm Hg systolic or Postpartum Management
more or 105 to 110 mm Hg diastolic or more for at least During the immediate postpartum period, women with PE
60 minutes require therapy intrapartum. It is important to should receive close monitoring of BP and of symptoms consis-
emphasize that BP recordings during labor that utilize electronic tent with severe disease, and accurate measurements of fluid
equipment may not be reliable for lack of a standardized cuff intake and urinary output should be obtained.
position and for the effects of labor and pain. Therefore BP These women often receive large amounts of IV fluids during
recordings should be accurately measured and then confirmed labor as a result of prehydration before the administration of
with a sphygmomanometer prior to the use of acute IV medica- epidural analgesia, and IV fluids are given during the administra-
tions to treat severe sustained systolic hypertension. For women tion of oxytocin and magnesium sulfate in labor and postpar-
with severe thrombocytopenia and sustained systolic values tum. In addition, during the postpartum period, mobilization
greater than 150 mm Hg or diastolic readings greater than of extracellular fluid leads to increased intravascular volume.
100 mm Hg are the recommended thresholds for therapy.33 For As a result, women with severe PE—particularly those
this author, the first-line agent is IV labetalol, and if maximal with abnormal renal function, capillary leak, or early-onset
doses are ineffective, hydralazine can be added. Oral nifedip- disease—are at increased risk for pulmonary edema and
ine is my first choice in the postpartum period. exacerbation of severe hypertension postpartum. Careful
evaluation of the volume of IV fluids, oral intake, blood
Mode of Delivery products, and urine output are advised in addition to moni-
No randomized trials have compared the optimal method of toring by pulse oximetry and chest auscultation.2,33
delivery in women with GH-PE. A plan for vaginal delivery In general, most women with GH become normotensive
should be attempted in all women with disease without other during the first week postpartum.1,2 In contrast, in women
indications for cesarean delivery and in most women with with PE, hypertension often takes longer to resolve. In addi-
severe disease, particularly those beyond 30 weeks’ gestation, in some women with PE, an initial decrease in BP is
tion.1,2,17 The decision to perform a cesarean delivery should be seen immediately postpartum, followed by development of
based on gestational age, fetal condition, presence of labor, and hypertension again between days 3 and 6. Moreover, a recent
cervical Bishop score. In general, the presence of PE with severe study found that resolution of hypertension and proteinuria
features is not an indication for cesarean delivery per se. may take up to 1 year postpartum. Oral antihypertensive drug
No randomized trials have compared the optimal methods treatment is recommended if the systolic BP is at least
of delivery in patients with severe hypertension or severe 150 mm Hg or if the diastolic BP is at least 100 mm Hg.
PE. The method for delivery will depend on gestational age, Various agents may be used. A common regimen is to prescribe
cervical Bishop score, and fetal condition. The cesarean delivery oral nifedipine, 10 mg every 6 hours, or long-acting nifedipine.33
rate among reported studies33 in patients as less than 34 weeks’ If the BP is well controlled and maternal symptoms are absent,
gestation ranged from 66% to 96% with the higher rates for the woman is discharged home with instructions for daily BP
patients with onset prior to 28 weeks’ gestation. This high cesar- measurements by a home-visiting nurse for the first week post-
ean delivery rate is expected considering that a deterioration in partum or longer if necessary. Antihypertensive medications are
either fetal or maternal condition is the indication for delivery discontinued if the BP remains below the hypertensive levels for
during expectant management (high rates of severe FGR, oligo- at least 24 hours. Recently, some authors have suggested that 5
hydramnios, nonreassuring fetal status, abnormal presentation, days of oral furosemide therapy (20 mg/dL) enhances recovery
and maternal complications).33 Thus, a very small percentage of and reduces the need for antihypertensive therapy in women
these patients will be considered candidates for medical induc- with severe disease.
tion of labor. Severe hypertension or PE with severe features may de-
Several retrospective studies have evaluated induction of labor velop for the first time during the postpartum period. Hence,
in patients with PE before 34 weeks’ gestation and absent any postpartum women should be educated about the signs and
symptoms of severe hypertension or PE. These women are In a later report, subsequent pregnancy outcome and long-
at increased risk for eclampsia, pulmonary edema, stroke, term prognosis were studied in 108 women who had severe PE
and thromboembolism. Therefore medical providers and in the second trimester. These women were followed for a
personnel who respond to patient phone calls should be edu- minimum of 2 years (range, 2 to 12 years) and had a total of
cated and instructed about symptoms of severe postpartum 169 subsequent pregnancies. Fifty-nine subsequent pregnancies
hypertension. Women who have persistent new-onset severe (35%) were normotensive, and 110 (65%) were complicated by
headaches that do not respond to maximum doses of analgesics PE. Overall, 21% of all subsequent pregnancies were compli-
or who have persistent severe visual changes or new-onset epi- cated by severe PE in the second trimester. In addition, these
gastric pain with nausea or vomiting and those with sustained women had a higher risk for developing chronic hypertension;
severe hypertension require evaluation and potential hospitaliza- the highest incidence was in those who had recurrent severe PE
tion. Some women may require magnesium sulfate for at least in the second trimester (55%).
24 hours and antihypertensive therapy. If neurologic symptoms Hnat and associates23 reported subsequent pregnancy outcome
exist or the symptoms do not respond to magnesium sulfate and in women with previous PE enrolled in a multicenter trial. The
lowering of maternal BP, brain imaging is undertaken to rule rate of recurrent PE was 17%. The authors also noted that these
out the presence of cerebral pathology. women had a high rate of severe PE and poor perinatal outcome.
In addition, even in those who remained normotensive in their
Maternal and Perinatal Outcomes subsequent pregnancy, the likelihood of adverse pregnancy
With Preeclampsia outcome (preterm delivery, SGA infants, and perinatal death)
Maternal and perinatal morbidity is substantially increased in was greater.
women with severe GH. Indeed, these women have higher mor- Some women with PE remote from term may have placental
bidity rates than women with mild preeclampsia.19 In addition, abruption. The risk for this complication is increased signifi-
the rates of placental abruption, preterm delivery (at less than cantly in those with PE before 34 weeks’ gestation and particu-
37 and 35 weeks), and rates of SGA infants in these pregnancies larly in those who have PE in the second trimester. For women
are similar to those observed in women with PE with severe with PE complicated by placental abruption, the risk for
features. However, whether this increase in rate of preterm deliv- abruption in subsequent pregnancies ranges from 5% to
ery is a result of early delivery chosen by the physician or because 20%.
of the disease process itself remains unknown. Therefore these Pregnancy outcome and long-term prognosis were studied in
women should be managed as if they had severe PE.33 37 women with PE complicated by pulmonary edema, and 18
Maternal and perinatal outcomes in PE are usually depen- of these women had subsequent pregnancies. Ten of the 18 were
dent on one or more of the following four factors: (1) gesta- normotensive, 4 were complicated by chronic hypertension, and
tional age at onset of PE and at the time of delivery, (2) the 4 were had PE; 1 of the latter women also had pulmonary
severity of the disease process, (3) the presence of multifetal edema.
gestation, and (4) the presence of preexisting medical con Pregnancy outcome and remote prognosis were also studied
ditions such as pregestational diabetes, renal disease, or in 18 women with severe PE complicated by acute renal failure.
thrombophilias. All 18 had acute tubular necrosis, 9 of whom required dialysis,
PE with severe features is also associated with an increased and 2 died within 8 weeks after birth. All women had serial
risk for maternal mortality (0.2%) and increased rates of mater- evaluation of renal function, urine microscopic testing, and elec-
nal morbidity (5%), such as convulsions, pulmonary edema, trolyte studies at the onset of acute renal failure and during
retinal ischemia and injury (see Fig. 31-12), acute renal or liver follow-up. All 16 surviving patients had normal renal function
failure, liver hemorrhage, DIC, and stroke. These complications on long-term follow-up (average, 4 years). Four of the 16 women
are usually seen in women who develop PE before 32 weeks’ had seven subsequent pregnancies: one ended in miscarriage,
gestation and in those with preexisting medical conditions. one was complicated by PE at 35 weeks, and five were term
pregnancies without complications.
Counseling Women Who Have Had Women with a history of HELLP syndrome are at increased
Preeclampsia in Prior Pregnancies risk for all forms of PE in subsequent pregnancies (Table
We examined the pregnancy outcomes and incidences of PE in 31-15). In general, the rate of PE in subsequent pregnancies
subsequent pregnancies and the frequency of chronic hyperten- is about 20%, with significantly higher rates if the onset of
sion and diabetes mellitus in women who had severe PE (287 HELLP syndrome is during the second trimester. The rate of
women) or eclampsia (119 women) in their first pregnancies recurrent HELLP syndrome ranges from 2% to 19%, and the
(aged 11 to 25 yr) compared with 409 women (aged 12 to most reliable data suggest a recurrence risk of less than 5%.
25 yr) who remained normotensive during their first pregnan- This lower rate of 5% has been recently confirmed by the results
cies. Each woman had at least one subsequent pregnancy (range, of a systemic review. Because of the previously mentioned risks,
1 to 11) and was followed for a minimum of 2 years (range, 2 these women are informed that they are at increased risk for
to 24). No significant difference was reported in the inci- adverse pregnancy outcomes (preterm delivery, FGR, placental
dences of diabetes mellitus in the two groups (1.3% vs. 1.5%), abruption, and fetal death) in subsequent pregnancies and there-
but the incidence of chronic hypertension was significantly fore require close monitoring during subsequent gestations.
higher in the PE patients (14.8% vs. 5.6%; P < .001). This At present, no preventive therapy is available for recurrent
difference became even greater for women followed more HELLP syndrome. Case series describe subsequent pregnancy
than 10 years (51% vs. 14%; P < .001). The incidence of severe outcomes in women with previous ruptured liver hematomas.
PE was also significantly higher in the second pregnancies We have followed three such women through four subsequent
(25.9% to 4.6%) and in the subsequent pregnancies (12.2% pregnancies without complications. Other authors have reviewed
to 5.0%) of women with PE. the literature and have reported on several such women, who
TABLE 31-15 PREGNANCY OUTCOME AFTER HELLP SYNDROME

NO. OF WOMEN NO. OF PREGNANCIES HELLP (%) PREECLAMPSIA (%)
Sibai et al110 139 192 3 19
Sullivan et al111 122 161 19 23
Van Pampus et al112 77 92 2 16
Chames et al113* 40 42 6 52
Modified from Sibai BM. Diagnosis, controversies, and management of HELLP syndrome. Obstet Gynecol. 2004;103:981.
*HELLP (hemolysis, elevated liver enzymes, and low platelets) at 28 weeks’ or less in a previous pregnancy.
had subsequent uneventful pregnancies under close maternal

and fetal observation. ECLAMPSIA
Liver function tests were studied in 54 women at a median Eclampsia is the occurrence of convulsions or coma unre-
of 31 months (range, 3 to 101 months) after pregnancies com- lated to other cerebral conditions with signs and symptoms
plicated by the HELLP syndrome. Serum levels of AST, LDH, of preeclampsia. Early writings of both the Egyptians and
and conjugated bilirubin were found to be normal. However, Chinese warned of the dangers of convulsions encountered
total bilirubin levels were elevated in 11 (20%) of the studied during pregnancy. Hippocrates noted that headaches, convul-
women. The authors of this report suggested the possibility that sions, and drowsiness were ominous signs associated with preg-
a dysfunction of the bilirubin-conjugating mechanism repre- nancy. The term eclampsia appeared in a treatise on gynecology
sents a risk factor for the development of this syndrome. written by Varandaeus in 1619. Clonic spasms in association
Two reports describe long-term renal function after HELLP with pregnancy were described by Pew in 1694. In 1772, De la
syndrome. One of the reports included 23 patients whose preg- Motte recognized that prompt delivery of pregnant women with
nancies were complicated by HELLP syndrome and acute renal convulsions favored their recovery.
failure: 8 of these women had 11 subsequent pregnancies, 9 of Eclampsia is defined as the development of convulsions or
which resulted in term gestation. All 23 women also had normal unexplained coma during pregnancy or postpartum in
BP and renal function at an average follow-up of 4.6 years patients with signs and symptoms of PE. In the western world,
(range, 0.5 to 11 years). The other study compared renal func- the reported incidence of eclampsia ranges from 1 in 2000 to 1
tion after at least 5 years after HELLP syndrome in 10 patients in 3448 pregnancies. The reported incidence is usually higher in
with the respective findings in 22 patients with previous normo- tertiary referral centers, with multifetal gestation, and in those
tensive gestation. No differences were reported in renal function without prenatal care.12
tests between the two groups. These findings suggest that the
development of HELLP syndrome with or without renal failure Pathophysiology
does not affect long-term renal function. The pathogenesis of eclamptic convulsions continues to be the
subject of extensive investigation and speculation. Several theo-
Remote Prognosis ries and pathologic mechanisms have been implicated as possible
Women with PE should also be counseled regarding future etiologic factors, but none of these has been proved conclusively.
cardiovascular risks and risks for underlying renal disease. Evi- It is not clear whether the pathologic features in eclampsia are
dence suggests that women with PE remote from term are at a cause or an effect of the convulsions.86
particular increased risk for chronic hypertension later in
life. In addition, these patients—particularly those with recur- Diagnosis
rent PE—are more likely to have underlying renal disease. In a The diagnosis of eclampsia is secure in the presence of gen-
recent report, 86 Japanese women who had severe hypertension, eralized edema, hypertension, proteinuria, and convulsions.
severe proteinuria, or both during pregnancy had a postpartum However, women in whom eclampsia develops exhibit a
renal biopsy. The authors found that women who had gesta- wide spectrum of signs that range from severe hyperten-
tional proteinuria or PE before 30 weeks’ gestation were more sion, severe proteinuria, and generalized edema to absent
likely to have had underlying renal disease. or minimal hypertension, no proteinuria, and no edema.86
Several recent studies suggested that women who develop Hypertension is considered the hallmark for the diagnosis of
PE may be at increased risk for coronary artery disease later eclampsia. The hypertension can be severe (≥160 mm Hg sys-
in life. Indeed, many of the risk factors and pathophysiologic tolic or ≥110 mm Hg diastolic), as in 20% to 54% of cases,16,86
abnormalities of PE are similar to those of coronary artery dis- or it can be mild (systolic BP between 140 and 160 mm Hg or
ease. Ramsey and associates demonstrated for the first time, diastolic BP between 90 and 110 mm Hg), as in 30% to 60%
using laser Doppler imaging in vivo, impaired microvascular of cases.12,86 However, in 16% of cases, hypertension may be
function in women 15 to 25 years of age following a preg- absent.16 In addition, severe hypertension is more common in
nancy complicated by PE. Thus microvascular dysfunction, patients who develop antepartum eclampsia (58%) and in those
which is associated with insulin resistance, may be a predis who develop eclampsia at 32 weeks’ gestation or later (71%).16
posing vascular mechanism for both coronary heart disease Moreover, hypertension is absent in only 10% of women who
and PE. In addition, pregnancies complicated by PE are at in- develop eclampsia at or before 32 weeks’ gestation.16
creased risk for stroke later in life. Therefore pregnancies com- The diagnosis of eclampsia is usually associated with pro-
plicated by PE may identify women at risk for vascular teinuria (at least 1+ on a dipstick).16,86 In a series of 399 women
disease in later life and may provide the opportunity for with eclampsia, substantial proteinuria (≥3+ on a dipstick) was
lifestyle and risk-factor modification to alter their risk for present in only 48% of the cases, whereas proteinuria was absent
complications. in 14% of the cases.16 Abnormal weight gain in excess of 2 lb/
wk (with or without clinical edema) during the third trimester considered to have eclampsia until proved otherwise.32 These
might be the first sign before the onset of eclampsia. However, women should have an ultrasound examination to rule out
edema was absent in 26% of 399 eclamptic women studied.16 molar pregnancy or hydropic degeneration of the placenta, and
Several clinical symptoms are potentially helpful in estab- they also should have an extensive neurologic and medical evalu-
lishing the diagnosis of eclampsia. These include persistent ation to rule out another pathologic process.
occipital or frontal headaches, blurred vision, photophobia, Late postpartum eclampsia is defined as eclampsia that
epigastric or right upper quadrant pain, and altered mental occurs more than 48 hours but less than 4 weeks after deliv-
status. Women had at least one of these symptoms in 59% to ery. Historically, eclampsia was believed not to occur more
75% of the cases (Table 31-16). Headaches are reported by 50% than 48 hours after delivery. However, several recent reports
to 75% of patients, whereas visual changes are reported in 19% have confirmed the existence of late postpartum eclampsia.86
to 32% of patients.86 These symptoms may occur before or after These women have signs and symptoms consistent with PE in
the onset of convulsions.86 association with convulsions.32,86 Some women demonstrate a
clinical picture of PE during labor or immediately postpartum
Time of Onset of Eclampsia (56%), whereas others demonstrate these clinical findings for
The onset of eclamptic convulsions can be during the antepar- the first time more than 48 hours after delivery (44%). Of inter-
tum, intrapartum, or postpartum period. The reported fre- est is the fact that late-postpartum eclampsia developed despite
quency of antepartum convulsions among recent series has the use of prophylactic magnesium sulfate during labor and for
ranged from 38% to 53% (Table 31-17),16 whereas the fre- at least 24 hours postpartum in previously diagnosed preeclamp-
quency of postpartum eclampsia has ranged from 11% to 44%.16 tic women.86 Therefore women in whom convulsions develop in
Although most cases of postpartum eclampsia occur within association with hypertension or proteinuria or with headaches
the first 48 hours, some cases can develop beyond 48 hours or blurred vision after 48 hours of delivery should be considered
postpartum and have been reported as late as 23 days post- to have eclampsia and initially treated as such.32
partum.16 In the latter cases, an extensive neurologic evalua-
tion may be required to rule out the presence of other cerebral Cerebral Pathology
pathology.86 Autoregulation of the cerebral circulation is a mechanism for
Almost all cases of eclampsia (91%) develop in the third tri- the maintenance of constant cerebral blood flow during
mester (≥28 weeks).16 The remaining cases occur between 21 changes in BP, and it may be altered in eclampsia. Through
and 27 weeks’ gestation (7.5%) or at or before 20 weeks’ gesta- active changes in cerebrovascular resistance at the arteriolar level,
tion (1.5%).16 Eclampsia that occurs before the twentieth cerebral blood flow normally remains relatively constant when
week of gestation is generally associated with molar or cerebral perfusion pressure ranges between 60 and 120 mm Hg.
hydropic degeneration of the placenta with or without a In this normal range, vasoconstriction of cerebral vessels occurs
coexistent fetus.32,86 Although rare, eclampsia can occur during in response to elevations in BP, whereas vasodilation occurs as
the first half of pregnancy without molar degeneration of the BP is lowered. Once cerebral perfusion pressure exceeds 130 to
placenta.32,86 These women may be misdiagnosed as having 150 mm Hg, however, the autoregulatory mechanism fails. In
hypertensive encephalopathy, a seizure disorder, or TTP. Women extreme hypertension, the normal compensatory vasoconstric-
in whom convulsions develop in association with hypertension tion may become defective, and cerebral blood flow increases.
and proteinuria during the first half of pregnancy should be As a result, segments of the vessels become dilated, ischemic,
and increasingly permeable. Thus exudation of plasma occurs
and gives rise to focal cerebral edema and compression of the
TABLE 31-16 SYMPTOMS IN WOMEN WITH ECLAMPSIA vessels, which results in a decreased cerebral blood flow.86 Hyper-
DOUGLAS & KATZ CHAMES tensive encephalopathy, a possible model for eclampsia, is an
REDMAN114 ET AL115 ET AL116 acute clinical condition that results from abrupt severe hyperten-
(n = 325) (%) (n = 53) (%) (n = 89) (%) sion and subsequent significant increases in intracranial pressure.
Headache 50 64 70 Because this is an acute disturbance in the hemodynamics of
Visual changes 19 32 30 cerebral arterioles, morphologic changes in anatomy may not be
Right upper 19 Not reported 12 uniformly evident in pathologic material. Several autopsy find-
quadrant
epigastric ings that are relatively constant include cerebral swelling and
pain fibrinoid necrosis of vessel walls.
At least one 59 Not reported 75 The cause of eclampsia is unknown, and many questions
From Sibai BM. Diagnosis, differential diagnosis and management of eclampsia. Obstet regarding the pathogenesis of its cerebral manifestations remain
Gynecol. 2005;105:402. unanswered. Cerebral pathology in cortical and subcortical
TABLE 31-17 TIME OF ONSET OF ECLAMPSIA IN RELATION TO DELIVERY

DOUGLAS & REDMAN114 KNIGHT118 KATZ115 TUFFNELL117 MATTAR & SIBAI15 CHAMES ET AL116
(n = 383) (%) (n = 214) (%) (n = 53) (%) (n = 82) (%) (n = 399) (%) (n = 89) (%)
Antepartum 38 96 53 45 53 67*
Intrapartum 18 41 36 12 19 —
Postpartum 44 75 11 26 28 33
<48 hr 39 5 24 11 7
>48 hr 5 6 2 17 26
*Includes antepartum and intrapartum cases.
white matter in the form of edema, infarction, and hemorrhage reduced apparent diffusion coefficient (restricted diffusion) were
(microhemorrhage and intracerebral parenchymal hemorrhage) present in 6 of 27 eclamptic women studied by Zeeman and
is a common autopsy finding in patients who die of eclampsia. colleagues and in 3 of 17 eclamptic and preeclamptic women
However, although autopsy series provide information regarding studied by Loureiro and associates. In addition, 5 of the 6
the central nervous system (CNS) abnormality in patients who women reported by Zeeman and colleagues had persistent
die of eclampsia, this information is not necessarily indicative abnormalities on repeat MRI testing 6 to 8 weeks later, which
of the CNS abnormality present in most patients who survive suggests these lesions might not be reversible. Moreover, 4 of the
this condition.86 The diagnosis of eclampsia is not dependent on 17 women reported by Loureiro and associates had persistent
any single clinical or diagnostic neurologic findings. Focal neu- MRI abnormalities at a median of 8 weeks of follow-up.
rologic signs such as hemiparesis or an unconscious state are rare In summary, cerebral imaging findings in eclampsia are
in cases of eclampsia reported from countries in the developed similar to those found in patients with hypertensive encepha-
world.86 Although eclamptic patients may initially manifest lopathy. The classic findings are referred to as posterior reversible
a variety of neurologic abnormalities—including cortical encephalopathy syndrome (PRES); Figure 31-13 demonstrates
blindness, focal motor deficits, and coma—fortunately, most such a lesion. This syndrome is also seen in patients with revers-
have no permanent neurologic deficits.16,86 These neurologic ible cerebral vasoconstriction syndrome and is usually seen in
abnormalities are probably due to a transient insult, such as patients who present in the postpartum period with signs and
hypoxia, ischemia, or edema. symptoms similar to eclampsia. The diagnosis is confirmed by
Several neurodiagnostic tests—such as electroencephalog- angiogram (Fig. 31-14). Cerebral imaging is not necessary for
raphy (EEG), CT, cerebral Doppler velocimetry, MRI, and the diagnosis and management of most women with eclamp-
cerebral angiography (both traditional and MRI angiography)— sia; however, it is indicated for patients with focal neurologic
have been studied in women with eclampsia. In general, the deficits or prolonged coma. In these patients, hemorrhage
EEG is acutely abnormal in most eclamptic patients; however, and other serious abnormalities that require specific pharma-
these abnormalities are not pathognomonic of eclampsia. In cologic therapy or surgery must be excluded. Cerebral
addition, the abnormal EEG findings are not affected by the imaging may also be helpful in patients who have an atypical
use of magnesium sulfate. Moreover, lumbar puncture is not presentation for eclampsia (onset before 20 weeks’ gestation or
helpful in the diagnosis and management of eclamptic women. more than 48 hours after delivery and eclampsia refractory to
The results of CT and MRI studies reveal the presence of edema adequate magnesium sulfate therapy). Advances in MRI and
and infarction within the subcortical white matter and adjacent magnetic resonance angiography (MRA), as well as in cerebral
gray matter mostly in the parietooccipital lobes (Box 31-10). vascular Doppler velocimetry, may aid our understanding
Cerebral angiography and Doppler velocimetry suggest the pres- regarding the pathogenesis and may improve long-term outcome
ence of vasospasm. of this condition.86
On the basis of cerebral imaging findings, attention has been
directed to hypertensive encephalopathy as a model for the CNS Differential Diagnosis
abnormalities in eclampsia. The two conditions share many The presenting symptoms, clinical findings, and many of the
clinical, radiologic, and pathologic features. Normal cerebral laboratory findings overlap with a number of medical and
blood flow autoregulation fails in patients with hypertensive
encephalopathy and in some patients with eclampsia.86 Two
theories have been proposed to explain these cerebral abnor-
malities, forced dilation and vasospasm,86 and the forced
dilation theory suggests that the lesions in eclampsia are
caused by loss of cerebrovascular autoregulation.
Recently, MRI and apparent diffusion coefficient mapping
were used to characterize the relative frequency of vasogenic and
cytotoxic edema in two small series of eclamptic women; cere-
bral edema (mostly vasogenic) was present in up to 93% to
100%. However, concurrent foci of infarction evidenced by
BOX 31-10 REPORTED COMPUTED TOMOGRAPHY SCAN

AND MAGNETIC RESONANCE IMAGING FINDINGS IN
COMPLICATED ECLAMPSIA
Diffuse white matter low-density areas
Patchy areas of low density
Occipital white matter edema
Loss of normal cortical sulci
Reduced ventricular size
Acute hydrocephalus
Cerebral hemorrhage
• Intraventricular hemorrhage
• Parenchymal hemorrhage (high density)
Cerebral infarction
• Low-attenuation areas FIG 31-13 Magnetic resonance imaging of the brain reveals posterior
• Basal ganglia infarctions reversible encephalopathy syndrome in a patient with eclampsia.
Arrows point at vasogenic edema that is considered reversible.
the maternal mortality rate may be as high as 14% in devel-

oping countries. The high maternal mortality reported from
developing countries occurs primarily among patients who have
had multiple seizures outside the hospital and those without
prenatal care. In addition, this high mortality rate could be
attributed to the lack of resources and intensive care facilities
needed to manage maternal complications from eclampsia. Of
4024 pregnancy-related deaths reported from 1979 to 1992, a
total of 790 (19.6%) were considered to have been caused by
PE-eclampsia, and 49% of these 790 were considered to have
been related to eclampsia. In this series, the risk for death from
PE or eclampsia was higher for women older than 30 years, those
without prenatal care, and black women; the greatest risk for
death was found among women with pregnancies at or before
28 weeks’ gestation.
Pregnancies complicated by eclampsia are also associated
with increased rates of maternal morbidities such as placental
abruption (7% to 10%),86 DIC (7% to 11%),86 pulmonary
edema (3% to 5%), acute renal failure (5% to 9%), aspiration
pneumonia (2% to 3%), and cardiopulmonary arrest (2%
to 5%).86 ARDS and intracerebral hemorrhage are rare com
plications in series of eclamptic patients reported from the
developed world. It is important to note that maternal complica-
FIG 31-14 Cerebral arteriogram demonstrates cerebral vasoconstric- tions are greatest among women who develop antepartum
tion. Arrows show diffused vasoconstriction in small blood vessels.
eclampsia, particularly among those who develop eclampsia
remote from term.86
BOX 31-11 DIFFERENTIAL DIAGNOSIS OF ECLAMPSIA Perinatal mortality and morbidity remain high in eclamptic
pregnancies. The reported perinatal death rate in recent series
• Hypertensive encephalopathy
ranged from 5.6% to 11.8%.86 This high perinatal death rate is
• Seizure disorder
• Hypoglycemia, hyponatremia
related to prematurity, placental abruption, and severe FGR.86
• Posterior reversible encephalopathy syndrome (PRES; The rate of preterm delivery is about 50%, and about 25% of
see Fig. 31-13) cases occur before 32 weeks’ gestation.86
• Thrombotic thrombocytopenic purpura
• Postdural puncture syndrome Is Eclampsia Preventable?
• Vasculitis, angiopathy Prevention of eclampsia requires knowledge of its etiology and
• Amniotic fluid embolism pathophysiology and of methods to predict patients at high risk
• Cerebrovascular accident for development of convulsions. However, as discussed earlier,
• Hemorrhage the pathogenesis of eclampsia is largely unknown. Prevention
• Ruptured aneurysm or malformation
of eclampsia can be primary, by preventing the development
• Arterial embolism, thrombosis
• Cerebral venous thrombosis
and/or progression of PE, or it can be secondary, by using
• Hypoxic ischemic encephalopathy pharmacologic agents that prevent convulsions in women with
• Angiomas established PE. Prevention can also be tertiary, by preventing
subsequent convulsions in women with established eclampsia.
Current management schemes designed to prevent eclampsia
surgical conditions.32 For convulsions that develop in association are based on early detection of GH or PE and subsequent use
with hypertension or proteinuria during pregnancy or immedi- of preventive therapy in such women. Some of the recom-
ately postpartum, the most common cause is eclampsia. Rarely, mended preventive therapies have included close monitoring
other etiologies that produce convulsions in pregnancy or post- (in-hospital or outpatient), use of antihypertensive therapy to
partum may mimic eclampsia.86 keep maternal BP below a certain level (less than severe range
These diagnoses are particularly important in the presence or to normal values), timely delivery, and prophylactic use
of focal neurologic deficits, prolonged coma, or atypical eclamp- of magnesium sulfate during labor and immediately post
sia. In addition, in some patients, GH or PE may develop in partum in those considered to have PE. These management
association with disorders such as connective tissue disease, schemes assume that the clinical course in the development of
thrombophilias, seizure disorder, or hypertensive encephalopa- eclampsia is characterized by a gradual process that begins with
thy, which further contributes to the diagnostic difficulty. There- progressive weight gain, followed by hypertension (mild to
fore an effort should be made to identify an accurate diagnosis severe) and proteinuria, with the subsequent onset of premoni-
given that management strategies may differ among these condi- tory symptoms, and ending with the onset of generalized con-
tions (Box 31-11). vulsions or coma.86 This clinical course may be present in some
women who develop eclampsia in developed countries. However,
Maternal and Perinatal Outcome recent data from large series of eclamptic women from the
Eclampsia is associated with a slightly increased risk for United States and Europe indicate that about 20% to 40% of
maternal death in developed countries (0% to 1.8%),86 but eclamptic women do not have any premonitory signs or
symptoms before the onset of convulsions.16 In many of these with adequate facilities and with consultants from other spe-
cases, the onset of convulsions is abrupt and does not follow an cialties. For those eclamptic patients who are remote from term,
indolent progression from mild to severe disease before the onset referral should be made to a tertiary care center. The following
of eclampsia.86 steps should be taken before transfer of these critically ill patients:
It is also assumed that appropriate and timely standard pre- 1. The referring physician or nurse should consult with
ventive therapy will prevent eclampsia in virtually all patients the physician at the perinatal center regarding the referral
with GH-PE.86 The efficacy of in-hospital management of and appropriate treatment. All maternal records, includ-
patients with GH or PE for the prevention of eclampsia has not ing prenatal data and a detailed summary of the patient’s
been evaluated in randomized trials. Moreover, data from retro- condition, should be transmitted.
spective studies from developed countries indicate that about 2. BP should be stabilized, and convulsions should be
50% of eclamptic women develop their first convulsion while controlled.
in the hospital under “close medical supervision.”86 Thus early 3. Adequate prophylactic anticonvulsive medications should
and prolonged hospitalization of women with mild hyperten- be given. An accepted regimen is 4 or 6 g IV magnesium
sion or PE may not prevent most cases of eclampsia. sulfate as a loading dose over 20 minutes.
Several randomized trials have described the use of antihyper- 4. Maternal laboratory assessment (CBC with platelet
tensive drugs versus no treatment or a placebo in the treatment count, liver enzymes) and fetal monitoring should be
of women with mild hypertension or PE. Overall, these trials undertaken.
revealed lower rates of progression to severe disease. How Patients should be sent in an ambulance with medical person-
ever, the study design and the sample size of these trials is nel in attendance for proper management in cases of subsequent
inadequate to evaluate potential benefits regarding prevention convulsions.
of eclampsia.
Prophylactic magnesium sulfate is recommended only for Treatment of Eclamptic Convulsions
women who are hospitalized with the established diagnosis of Eclamptic convulsions are a life-threatening emergency and
PE.1-3 Its use is recommended only during labor and for 12 to require proper care to minimize morbidity and mortality. The
24 hours’ postpartum1-3; therefore it can be expected to have a development of an eclamptic convulsion is frightening to
potential effect in preventing eclampsia that develops only observe. Initially, the patient’s face becomes distorted with pro-
during this time (40% of total). trusion of her eyes. This is followed by a congested facial expres-
Several randomized trials have compared the efficacy of mag- sion. Foam often exudes from the mouth, and the woman
nesium sulfate with other anticonvulsive agents for the preven- usually bites her tongue unless it is protected. Respirations are
tion of recurrent seizures in women with eclampsia. In these absent throughout the seizure. The convulsion, which can be
trials, magnesium sulfate was compared with diazepam, phe- divided into two phases, typically continues for 60 to 75 seconds.
nytoin, and a lytic cocktail. Overall, these trials revealed that The first phase, which lasts 15 to 20 seconds, begins with facial
magnesium sulfate was associated with a significantly lower twitching and proceeds to the body becoming rigid with gener-
rate of recurrent seizures (9.4% vs. 23.1%; RR, 0.41; 95% CI, alized muscular contractions. The second phase lasts about 60
0.32 to 0.51) and a lower rate of maternal death (3% vs. 4.8%; seconds and consists of the muscles of the body alternately
RR, 0.62; 95% CI, 0.39 to 0.99) than that observed with other contracting and relaxing in rapid succession. This phase begins
agents. with the muscles of the jaw and rapidly involves the eyelids,
The low incidence of eclampsia in developed countries is other facial muscles, and then all the muscles of the body. Coma
probably related to prevention of cases of eclampsia in women follows the convulsion, and the woman usually remembers
with a classic presentation and with a classic progression from nothing of the recent events. If she has repeated convulsions,
mild to severe PE.86 As a result, most eclamptic cases described some degree of consciousness returns after each convulsion. She
in reported series from the United States and Europe have an may enter a combative state and may be agitated and difficult
atypical presentation (abrupt onset, development of convulsions to control. Rapid and deep respirations usually begin as soon as
while receiving prophylactic magnesium sulfate, or onset of con- the convulsions end. Maintenance of oxygenation is usually not
vulsions beyond 48 hours after delivery).86 Indeed, most eclamp- a problem after a single convulsion; the risk for aspiration is low
tic convulsions in these series developed in hospitalized women, in the well-managed patient.
and in some of these women, the onset of convulsions was not Because eclampsia is so frightening, the natural tendency
preceded by warning signs or symptoms.86 Overall, the percent- is to attempt to abolish the convulsion. However, drugs such
age of eclampsia considered unpreventable in these series ranged as diazepam should not be given in an attempt to stop or
from 31% to 87%.86 shorten the convulsion, especially if the patient does not have
an IV line in place and someone skilled in intubation is not
Transport of the Eclamptic Patient immediately available. If diazepam is used, no more than 5 mg
During the past 20 years, a marked reduction has been seen in should be given over 60 seconds. Rapid administration of diaz-
the incidence of eclampsia. Consequently, most obstetricians epam may lead to apnea, cardiac arrest, or both.
have little or no experience in the management of eclampsia. A
recent survey of a random sample of obstetricians from all 50 Prevention of Maternal Injury During the Convulsions
states indicated that about 50% of obstetricians in private prac- The first priority in the management of eclampsia is to
tice had not seen an eclamptic patient during the past year. prevent maternal injury and to support cardiovascular
Because management of the eclamptic patient requires the function. During or immediately after the acute convulsive
availability of neonatal and obstetric ICUs and personnel episode, supportive care should be given to prevent serious
with special expertise, it is recommended that eclamptic maternal injury and aspiration, assess and establish airway
women at term be cared for only at level II or III hospitals patency, and ensure maternal oxygenation. During this time,
the bed’s side rails should be elevated and padded; a padded 40

tongue blade is inserted between the teeth (avoid inducing a gag 18-year-old G1
reflex), and physical restraints may also be needed. To minimize mild preeclampsia
the risk for aspiration, the patient should lie in the lateral decu-
bitus position, and vomitus and oral secretions are suctioned
Delivery
as needed.86 Aspiration may be caused by forcing the padded
tongue blade to the back of the throat, stimulating the gag reflex
with resultant vomiting. 30
Serum Mg (mg/dL)
Adequate oxygenation should be maintained during the con-
vulsive episode because hypoventilation and respiratory acidosis
often occur. Although the initial seizure lasts only a few minutes, 16
it is important to maintain oxygenation by supplemental oxygen
14
administration through a face mask with or without an oxygen
reservoir at 8 to 10 L/min.86 After the convulsion has ceased, 12
the patient begins to breathe again, and oxygenation is rarely 10
a problem. However, maternal hypoxemia and acidosis may
develop in women who have had repetitive convulsions, in those 8
with aspiration pneumonia or pulmonary edema, or as a result 6
of a combination of these factors. It is my policy to use trans-
cutaneous pulse oximetry to monitor oxygenation in all 4
eclamptic patients. Arterial blood gas analysis is required if the 2 Cord blood
pulse oximetry results are abnormal (oxygen saturation ≤92%).
Sodium bicarbonate is not given unless the pH is below 7.10.
2 4 6 8 10 14 20 24 30 34 40 50
Prevention of Recurrent Convulsions Time (hours)

The next step in the management of eclampsia is to prevent (since initiation of loading dose)
recurrent convulsions. Magnesium sulfate is the drug of choice FIG 31-15 Magnesium levels over time in a patient with magnesium
to treat and prevent subsequent convulsions in women with toxicity. (From McCubbin JH, Sibai BM, Abdella TN, et al. Cardiopul-
eclampsia.86 A loading dose of 6 g over 15 to 20 minutes is monary arrest due to acute maternal hypermagnesemia [letter].
recommended, followed by a maintenance dose of 2 g per Lancet. 1981;1:1058.)
hour as a continuous IV solution. About 10% of eclamptic
women have a second convulsion after receiving magnesium breech presentation. The 3160-g male infant had Apgar scores
sulfate.86 In these women, another bolus of 2 g magnesium of 8 and 9 at 1 and 5 minutes, respectively. Maternal and cord
sulfate can be given intravenously over 3 to 5 minutes. An occa- blood magnesium levels at delivery were 5.8 mg/dL. Both
sional patient will have recurrent convulsions while receiving mother and baby were discharged from the hospital with no
adequate and therapeutic doses of magnesium sulfate. In this apparent sequelae. Of interest, the patient reported she could
patient, recurrent seizures can be treated with Ativan 2 mg intra- hear and see what was occurring around her, but she could not
venously over 3 to 5 minutes.86 make any movements while she was intubated. Figure 31-15
Rarely, a woman may experience an eclamptic seizure, lapse presents the maternal magnesium levels in this case.
into a coma, and die. Magnesium toxicity should be considered
in those women who do not regain consciousness. A case report Control of Severe Hypertension
of magnesium sulfate toxicity details the features of this serious The next step in the management of eclampsia is to reduce the
complication. Within a few minutes of starting what was sup- BP to a safe range. The objectives of treating severe hypertension
posed to be a magnesium loading dose, 4 g magnesium sulfate are to avoid loss of cerebral autoregulation and to prevent CHF
in 250 mL saline, the patient went into cardiorespiratory arrest. without compromising cerebral perfusion or jeopardizing utero-
Immediate resuscitation was performed, including intubation; placental blood flow, which is already reduced in many women
about half of the loading dose had been given. A coma ensued with eclampsia.86 Thus maintaining systolic BP between 140
that was believed to have been caused by an intracerebral acci- and 160 mm Hg and diastolic BP between 90 and 105 mm Hg
dent or eclampsia; the loading dose was continued, and main- is a reasonable goal. This can be achieved with bolus 5 to
tenance therapy was started. Initial blood gases were normal, 10 mg doses of hydralazine every 20 minutes or labetalol (20
and the electrocardiogram (ECG) was normal 15 minutes after to 40 mg intravenously) every 10 minutes as needed.86 Other
the arrest. The patient’s vital signs were stable; however, mechan- potent antihypertensive medications, such as sodium nitroprus-
ical ventilatory support was required, and her pupils were non- side or nitroglycerine, are rarely needed in eclampsia. Diuretics
reactive. Serum electrolytes, glucose, blood urea nitrogen, and are not used except in the presence of pulmonary edema.
creatinine were normal; CT scan of the head and cerebral angio-
grams were also normal. A magnesium level of 35 mg/dL was Intrapartum Management of Eclampsia
reported 3.5 hours later from a blood sample taken through Maternal hypoxemia and hypercarbia cause FHR and uterine
femoral venipuncture at the time of arrest; the magnesium activity changes during and immediately after a convulsion.
sulfate infusion was stopped immediately. During the first 5 The FHR tracing may reveal bradycardia, transient late
hours after the cardiorespiratory arrest, 1344 mg of magnesium decelerations, decreased beat-to-beat variability, and com-
was excreted in the urine. Twelve hours after the arrest, an pensatory tachycardia. Uterine contractions can increase
uncomplicated low vertical cesarean delivery was done for a in frequency and tone.86 These changes usually resolve
spontaneously within 3 to 10 minutes after the termination systemic and cerebral pressures during intubation and extuba-
of convulsions and correction of maternal hypoxemia. The tion.86 Women with airway or laryngeal edema may require
patient should not be rushed to emergency cesarean delivery awake intubation under fiberoptic observation with the avail-
based on these findings, especially if the maternal condition ability of immediate tracheostomy. Changes in systemic or cere-
remains stable. bral pressures may be attenuated by pretreatment with labetalol
In a review of 10 women who had undergone electronic or nitroglycerine injections.86
internal fetal monitoring during an eclamptic convulsion, 6 had
fetal bradycardia (FHR <120 beats/min) that varied in duration Postpartum Management of Eclampsia
from 30 seconds to 9 minutes. The interval from onset of the After delivery, women with eclampsia should receive close moni-
seizure to the fall in FHR was 5 minutes. Transitory fetal tachy- toring of vital signs, fluid intake and output, and symptoms for
cardia occurred frequently after the prolonged bradycardia. In at least 48 hours. These women usually receive large amounts of
addition, loss of beat-to-beat variability with transitory late IV fluids during labor, delivery, and postpartum. In addition,
decelerations occurred during the recovery phase. Uterine hyper- during the postpartum period, mobilization of extracellular fluid
activity demonstrated by both increased uterine tone and leads to increased intravascular volume. As a result, women with
increased frequency of uterine contractions occurs during an eclampsia, particularly those with abnormal renal function;
eclamptic seizure. The duration of the increased uterine activity those with abruptio placentae; and those with preexisting
varies from 2 to 14 minutes. chronic hypertension are at increased risk for pulmonary edema
Fetal outcome is generally good after an eclamptic convul- and exacerbation of severe hypertension postpartum.86 Careful
sion. The mechanism for the transitory fetal bradycardia may attention to fluid status is essential.
be a decrease in uterine blood flow caused by intense vaso- Parenteral magnesium sulfate should be continued for at
spasm and uterine hyperactivity. The absence of maternal least 24 hours after delivery or for at least 24 hours after the
respiration during the convulsion may also result in fetal last convulsion. If oliguria is present (<100 mL/4 hr), both
hypoxia and heart rate changes. Because the FHR pattern the rate of fluid administration and the dose of magnesium
usually returns to normal after a convulsion, other condi- sulfate should be reduced. Once delivery has occurred, other
tions should be considered if an abnormal pattern persists. oral antihypertensive agents such as labetalol or nifedipine can
It may take longer for the heart rate pattern to return to baseline be used to keep systolic BP below 155 mm Hg and diastolic BP
in an eclamptic woman whose fetus is preterm with growth below 105 mm Hg. Nifedipine offers the benefit of improved
restriction. Placental abruption may occur after the convulsion diuresis in the postpartum period.
and should be considered if uterine hyperactivity remains or the
bradycardia persists.86 Subsequent Pregnancy Outcomes and Remote Prognosis
The presence of eclampsia is not an indication for cesarean Women with a history of eclampsia are at increased risk for
delivery. The decision to perform a cesarean delivery should all forms of PE in subsequent pregnancies (Table 31-18). In
be based on gestational age, fetal condition, presence of general, the rate of PE in subsequent pregnancies is about
labor, and cervical Bishop score.86 Cesarean delivery is recom- 25%, with substantially higher rates if the onset of eclampsia
mended for those with eclampsia before 30 weeks’ gestation who was in the second trimester. The rate of recurrent eclampsia
are not in labor with an unfavorable cervix (Bishop score <5). is about 2%. Because of these risks, these women should be
Patients in labor or whose membranes have ruptured are allowed informed that they are at increased risk for adverse pregnancy
to deliver vaginally in the absence of obstetric complications. outcome in subsequent pregnancies. At present, no preventive
When labor is indicated, it is initiated with either oxytocin infu- therapy exists for recurrent antepartum eclampsia.
sions or prostaglandins in all patients with a gestational age at The long-term effects of eclampsia on maternal BP and
or above 30 weeks, irrespective of the Bishop score. A similar neurologic outcome have been the subject of few reports. The
approach is used for those before 30 weeks’ gestation if the cervi- findings of these studies revealed that eclampsia did not cause
cal Bishop score is at least 5. hypertension in women who were normotensive before the
Maternal pain relief during labor and delivery can be provided eclamptic pregnancy. Two of these studies found that the rate of
by either systemic opioids or epidural anesthesia as recom- chronic hypertension on follow-up was significantly higher in
mended for women with severe PE.2 Either epidural, spinal, or those who had eclampsia remote from term compared with
combined techniques of regional anesthesia can be used for those who had eclampsia at or beyond 37 weeks of gestation. In
cesarean delivery. Regional anesthesia is contraindicated in the addition, one of these reports revealed that women who had
presence of coagulopathy or severe thrombocytopenia (platelet eclampsia as multiparas were at increased risk for death from
count <50,000/mm3). In women with eclampsia, general anes- cardiovascular renal disease. Moreover, these investigations
thesia increases the risk for aspiration and failed intubation due revealed no evidence of neurologic deficit during the follow-up
to airway edema and is associated with marked increases in period.
TABLE 31-18 RECURRENT PREECLAMPSIA-ECLAMPSIA IN WOMEN WITH ECLAMPSIA

CHESLEY119 LOPEZ-LLERA & HORTA120 ADELUSI & OJENGBEDE121 SIBAI ET AL122
No. of women 171 110 64 182
No. of pregnancies 398 110 64 366
Eclampsia (%) 1.0 — 15.6 1.9
Preeclampsia (%) 23 35 27 22
From Sibai BM. Diagnosis, differential diagnosis and management of eclampsia. Obstet Gynecol. 2005;105:402.
third trimester. These women are more likely to be erroneously

CHRONIC HYPERTENSION diagnosed as having GH.
The frequency of chronic hypertension in pregnancy is esti- Women with chronic hypertension are at increased risk for
mated at 1% to 5%. It is more common in older obese women superimposed PE. The development of superimposed PE is
and in black women. Because of the current trend of childbear- associated with high rates of adverse maternal and perinatal
ing at an older age and the obesity epidemic, it is expected that outcomes.14 The diagnosis of superimposed PE should be made
the incidence of chronic hypertension in pregnancy will con- as described previously based on changes in BP, development of
tinue to rise. During the new millennium, and estimating a new-onset proteinuria, new-onset symptoms, or changes in
prevalence of chronic hypertension during pregnancy of 3%, at laboratory tests.
least 120,000 pregnant women (3% of 4 million pregnancies)
with chronic hypertension will be seen annually in the United Etiology and Classification
States. The etiology and severity of chronic hypertension are important
considerations in the management of pregnancy. Chronic hyper-
Definition and Diagnosis tension is subdivided into primary (essential) and secondary
In pregnancy, chronic hypertension is defined as elevated BP that hypertension. Primary hypertension is by far the most common
is present and documented before conception. In women whose type of chronic hypertension seen during pregnancy (90%). In
prepregnancy BP is unknown, the diagnosis is based on the 10% of cases, chronic hypertension is secondary to one or more
presence of sustained hypertension before 20 weeks of gesta- underlying disorders such as renal disease (glomerulonephritis,
tion, defined as either systolic BP of at least 140 mm Hg or interstitial nephritis, polycystic kidneys, renal artery stenosis),
diastolic BP of at least 90 mm Hg on at least two occasions collagen vascular disease (lupus, scleroderma), endocrine disor-
measured at least 4 hours apart. ders (diabetes mellitus with vascular involvement, pheochromo-
The diagnosis may be difficult to establish in women with cytoma, thyrotoxicosis, Cushing disease, hyperaldosteronism),
previously undiagnosed chronic hypertension who begin prena- or coarctation of the aorta.
tal care after 16 weeks’ gestation because physiologic decline in Chronic hypertension during pregnancy can be subclassified
BP occurs at that time. An analysis of pregnancy outcome in as either mild or severe, depending on the systolic and diastolic
211 patients with mild chronic hypertension suggests that the BP readings. Systolic and diastolic (Korotkoff phase V) BPs
use of antihypertensive drugs is not necessary to achieve a good of at least 160 mm Hg or 110 mm Hg, respectively, constitute
pregnancy outcome (Table 31-19). The changes in average MAP severe hypertension.
throughout the course of pregnancy are summarized in Figure For management and counseling purposes, chronic hyperten-
31-16. This decrease may result in normal BP findings in the sion in pregnancy is also categorized as either low risk or high
second trimester that will eventually increase again during the risk, as described in Figure 31-17. The patient is considered to
TABLE 31-19 RATES OF ADVERSE PREGNANCY OUTCOME IN OBSERVATIONAL STUDIES DESCRIBING MILD
CHRONIC HYPERTENSION IN PREGNANCY
PREECLAMPSIA (%) ABRUPTIO PLACENTAE (%) DELIVERY <37 WK (%) SGA (%)
Rey & Couturier (n = 337)
124
21 0.7 34.4 15.5
McCowan et al123 (n = 142) 14 NR 16 11.0
Sibai et al14 (n = 763) 25 1.5 33.3 11.1
Giannubilo et al126 (n = 233) 28 0.5 NR 16.5
Chappell et al125 (n = 822) 22 NR 22.7 27.2
Sibai et al127 (n = 369) 17 2.4 29.3 15.0
215 pregnancies
8-19 wk with mild chronic
gestation hypertension
(MAP 108 8.3 mm Hg)
104 (49%) 71 (34%) 40 (17%)
20-26 wk
MAP MAP MAP
gestation
decreased unchanged unchanged
4 (4%) 11 (16%) 13 (32%)
27-41 wk Severe
gestation exacerbation
of hypertension
FIG 31-16 Mean arterial blood pressure (MAP) during pregnancy. (Modified from Sibai BM, Abdella TN, Anderson GD. Pregnancy outcome in
211 patients with mild chronic hypertension. Obstet Gynecol. 1983;61:571.)
Evaluation preconception
or before 20 weeks
• Assess etiology and severity

• Assess presence of other medical
• conditions or target organ damage
• Assess prior obstetric history
• Uncomplicated essential hypertension • Secondary hypertension

• No previous perinatal loss • Target organ damage*
• Systolic pressure 160 mm Hg and • Previous perinatal loss
• diastolic 110 mm Hg • Systolic pressure 160 mm Hg
• or diastolic 110 mm Hg
• Systolic 160
Low risk • or diastolic 110 High risk
• Preeclampsia
FIG 31-17 Initial evaluation of women with chronic hypertension. *Left ventricular dysfunction, retinopathy, dyslipidemia, maternal age >40 years,
microvascular disease, stroke. (From Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol. 2002;100:369.)
be at low risk when she has mild essential hypertension (OR, 2.1; 95% CI, 1.1 to 3.9) compared with normotensive
without any organ involvement. The BP criteria are based on patients.
measurements at the initial visit irrespective of treatment In addition to PE and abruption, women with high-risk
with antihypertensive medications. For example, if the patient chronic hypertension are at increased risk for life-threatening
has a BP of 140/80 mm Hg on antihypertensive drugs, she is maternal complications such as pulmonary edema, hypertensive
still classified as low risk. It is important to note that a patient encephalopathy, retinopathy, cerebral hemorrhage, and acute
initially classified as low risk early in pregnancy may become renal failure. These risks are particularly increased in women
high risk if she later develops severe hypertension or PE. with uncontrolled severe hypertension, significant renal disease
early in pregnancy, or left ventricular dysfunction before
Maternal and Perinatal Risks conception.
Pregnancies complicated by chronic hypertension are at Fetal and neonatal complications are also increased in
increased risk for the development of superimposed PE, pla- women with chronic hypertension. The risk for perinatal
cental abruption, and fetal growth restriction. The reported mortality is three to four times greater compared with that
rates of PE in the literature in mild hypertension range from of the general obstetric population (OR, 3.4; 95% CI, 3.0 to
14% to 28% (see Table 31-19).14 The rate of PE in women with 3.7). The likelihood of premature delivery and a growth-
severe chronic hypertension ranges from 50% to 79%. Sibai and restricted infant is also increased in women with chronic
associates14 studied the rate of superimposed PE among 763 hypertension. In women with severe chronic hypertension in
women with chronic hypertension followed prospectively at the first trimester, the reported rates of preterm delivery were
several tertiary medical centers in the United States. The overall 62% to 70%, and the rates of an SGA infant were 31% to 40%.
rate of superimposed PE was 25%. The rate was not affected Recently, Sibai and associates15 reported risk factors for adverse
by maternal age, race, or presence of proteinuria early in preg- perinatal outcome in a secondary analysis of 763 women with
nancy; however, it was significantly greater in women who had mild chronic hypertension who were enrolled in a multicenter
hypertension for at least 4 years (31% vs. 22%), in those trial that compared low-dose aspirin with a placebo for the
who had PE during a previous pregnancy (32% vs. 23%), and prevention of PE. They found that the development of super-
in those whose diastolic BP was 100 mm Hg or higher (42% imposed PE was associated with higher rates of preterm delivery
vs. 24%).14 (OR, 3.9; 95% CI, 2.7 to 5.4), neonatal intraventricular hemor-
The reported rate of placental abruption in women with rhage (OR, 4.5; 95% CI, 1.5 to 14.2), and perinatal death (OR,
mild chronic hypertension has ranged from 0.7% to 2.7% 2.3; 95% CI, 1.4 to 4.8). In addition, the presence of protein-
(see Table 31-19). The rate in those with severe or high-risk uria early in pregnancy was an independent risk factor associated
hypertension may be 5% to 10%. In a recent multicenter study with higher rates of preterm delivery (OR, 3.1; 95% CI, 1.8 to
that included 763 women with chronic hypertension, the overall 5.3), an SGA infant (OR, 2.8; 95% CI, 1.6 to 5.0), and neonatal
rate of abruption was reported at 1.5%, and the rate was signifi- intraventricular hemorrhage (OR, 3.9; 95% CI, 1.3 to 11.6).14
cantly higher in those who developed superimposed PE than
in those without this complication (3% vs. 1%, P = .04).14 Goals of Antihypertensive Therapy
However, the rate was not influenced by maternal age, race, or in Pregnancy
duration of hypertension.14 In addition, the results of a system- In nonpregnant individuals, long-term BP control can lead
atic review of nine observational studies revealed that in women to significant reductions in the rates of stroke and cardiovas-
with chronic hypertension, the rate of abruption is doubled cular morbidity and mortality. In contrast to hypertension
in pregnancy, the duration of therapy is shorter, the benefits interpretation of these reports is difficult because it is impossible
to the mother may not be obvious during the short time to ascertain the exact number of women exposed to antihyper-
of treatment, and the exposure to medication will include tensive drugs during pregnancy. Also, it is likely that the number
both mother and fetus. In this respect, the clinician must of published case reports is an underestimate of the actual
balance the potential short-term maternal benefits against number of women who experience the reported adverse reaction.
possible short-term and long-term benefits and risks to the This limitation is amplified by the fact that information related
fetus and infant. to previous exposure during pregnancy is nonexistent. Further-
Most women with chronic hypertension during pregnancy more, the condition for which pregnant women are treated
have mild, essential, uncomplicated hypertension and are at with antihypertensive drugs can be partially responsible for the
minimal risk for cardiovascular complications within the short adverse fetal and neonatal outcomes.
time frame of pregnancy. Several retrospective and prospective In general, available information about teratogenicity, except
studies have been conducted to determine whether antihyper- in laboratory animals, is limited and selective. All available data
tensive therapy in these women improves pregnancy outcome. have been obtained from registries such as state Medicaid regis-
An overall summary of these studies revealed that regardless try data. Because of absent multicenter randomized trials in
of the antihypertensive therapy used, maternal cardiovascular women with chronic hypertension, no placebo-controlled evalu-
and renal complications were minimal or absent. No available ations have been done regarding the safety of these drugs when
data suggest that short-term antihypertensive therapy is ben- used at the time of conception and throughout pregnancy. At
eficial for the mother or the fetus in the setting of low-risk the present time, only minimal data are available to help the
hypertension except for a reduction in the rate of exacerba- clinician evaluate the benefits or risks of most antihypertensive
tion of hypertension. However, only three trials have had a drugs when used in pregnancy. Nevertheless, the limited data
sufficient sample size to evaluate the risks for superimposed in the literature suggest potential adverse fetal effects, such
PE and placental abruption. as oligohydramnios and fetal-neonatal renal failure, when
Recently, the benefits of tight blood pressure control versus angiotensin-converting enzyme (ACE) inhibitors are used in
less blood pressure control in women with chronic hypertension the second or third trimester. Similar effects are to be expected
in pregnancy were studied in a large multicenter study, the with the use of angiotensin II receptor blockers. Therefore these
Control of Hypertension in Pregnancy Study (CHIPS). The trial agents should be avoided once pregnancy is established (see
included 736 women with chronic hypertension; 361 were Chapter 8).
assigned to tight control and 371 were assigned to less tight The use of atenolol during the first and second trimesters
control. The investigators found no difference between groups has been associated with significantly reduced fetal growth
in primary outcome (pregnancy loss or high-level neonatal care) along with decreased placental growth and weight. On the
or in serious maternal complications. However, women in the other hand, no such effects on fetal or placental growth have
less-tight control group had a higher rate of progression to severe been reported with other β-blockers—such as metoprolol,
hypertension. In contrast, the tight control group had a signifi- pindolol, and oxprenolol—but data on the use of these
cantly higher rate of SGA infants (19.7% vs. 13.9%). agents in early pregnancy are very limited.
No placebo-controlled trials have examined the benefits of Prospective trials that have examined the effect of either meth-
antihypertensive therapy in women with severe hypertension in yldopa or labetalol in women with mild chronic hypertension
pregnancy, and none are likely to be performed. Antihyperten- revealed no adverse maternal or fetal outcomes with the use of
sive therapy is necessary in women with severe hypertension these medications. In a large and unique trial in which methyl-
to reduce the acute risks for stroke, CHF, and renal failure. dopa or labetalol was started between 6 and 13 weeks’ gestation
In addition, control of severe hypertension can permit preg- in patients with chronic hypertension, none of the exposed
nancy prolongation and thereby improve perinatal outcome. newborns had major congenital anomalies.
However, no evidence suggests that control of severe hyper- Clinical experience is extensive with the use of thiazide diuret-
tension reduces the rate of either superimposed PE or pla- ics during pregnancy. The available data suggest that treatment
cental abruption. with diuretics in the first trimester and throughout gestation is
No trials have examined the treatment of women with chronic not associated with an increased risk for major fetal anomalies
hypertension and other risk factors such as preexisting renal or adverse fetal-neonatal events. Information is sparse regarding
disease, diabetes mellitus, or cardiac disease. On the other hand, the use of calcium channel blockers in women with mild chronic
evidence from retrospective and observational studies suggests hypertension; however, the available evidence suggests that
that uncontrolled mild to moderate hypertension may exacer- the use of calcium channel blockers, particularly nifedipine,
bate target-organ damage during pregnancy in women with in the first trimester was not associated with increased rates
renal disease, diabetes mellitus with vascular disease, or left of major birth defects. The effects of nifedipine on fetal-
ventricular dysfunction. Therefore some authors recommend neonatal outcome were evaluated in a prospective randomized
aggressive treatment of mild hypertension in these women trial of 283 women with mild to moderate hypertension in
because of the belief that such management may reduce both pregnancy in which 47% of the participants had chronic hyper-
short- and long-term cardiovascular complications. tension. Sixty-six of these women were enrolled between 12
and 20 weeks’ gestation. In this study, the use of slow-release
Safety of Antihypertensive Drugs nifedipine was not associated with adverse fetal-neonatal
in Pregnancy outcomes.
The potential adverse effects of most commonly prescribed anti- The long-term effects on children of mothers exposed to
hypertensive agents are either poorly established or unclearly antihypertensive drugs during pregnancy are lacking except for
quantified. Most of the evidence on harm associated with anti- limited information concerning the use of methyldopa and nife-
hypertensives in pregnancy is limited to case reports. The dipine. A follow-up study of infants after 7.5 years showed no
long-term adverse effects on development among those exposed obstetric history should include maternal and neonatal out-
to methyldopa in utero compared with infants not exposed to comes of previous pregnancies and should stress any history of
such treatment. A similar study that examined the effects of the development of placental abruption, superimposed PE,
slow-release nifedipine after 1.5 years of follow-up demonstrated preterm delivery, FGR, intrauterine fetal death, and neonatal
no adverse effects on development. morbidity and mortality.
Laboratory evaluation is obtained to assess the function of
Recommended Management of Chronic different organ systems likely to be affected by chronic hyperten-
Hypertension in Pregnancy sion and as a baseline for future assessments. For all patients,
The primary objective in the management of pregnancies com- these should include urinalysis, urine culture and sensitivity,
plicated by chronic hypertension is to reduce maternal risks and 24-hour urine evaluations for protein, electrolytes, CBC, and
achieve optimal perinatal survival. This objective can be achieved screening for diabetes.
by formulating a rational approach that includes preconception Women with long-standing hypertension for several years,
evaluation and counseling, early antenatal care, frequent ante- particularly those with a history of poor compliance or poor
partum visits to monitor both maternal and fetal well-being, BP control, should be evaluated for target-organ damage that
timely delivery with intensive intrapartum monitoring, and includes left ventricular hypertrophy, retinopathy, and renal
proper postpartum management. injury. These women should undergo an ECG examination
and echocardiography if the ECG is abnormal, ophthalmo-
Evaluation and Classification logic evaluation, and creatinine clearance.
Women with chronic hypertension should ideally be coun- Selectively, certain tests should be obtained to identify sec-
seled before pregnancy, when extensive evaluation and com- ondary causes of hypertension such as pheochromocytoma,
plete workup can be undertaken. Assessment of the etiology primary hyperaldosteronism, or renal artery stenosis. These con-
and severity of the hypertension, as well as the coexistence ditions require selective biochemical testing and are amenable to
of other medical illnesses, and ruling out the presence of diagnosis with either CT or MRI. Pheochromocytoma should
target-organ damage resulting from long-standing hyperten- be suspected in women with paroxysmal severe hypertension,
sion can be accomplished. An in-depth history should delin- hyperglycemia, and sweating (see Chapter 43). Primary aldoste-
eate in particular the duration of hypertension, the use of ronism is extremely rare in pregnancy and should be considered
antihypertensive medications, their type, and the response to in women with severe hypertension and marked hypokalemia
these medications. Also, attention should be given to the pres- (see Chapter 43). Based on this evaluation, the patient is then
ence of cardiac or renal disease, diabetes mellitus, thyroid disease, classified as having low-risk or high-risk chronic hypertension
and a history of cerebrovascular accident or CHF. A detailed and is managed accordingly (Fig. 31-18).
Pregnant women with chronic

hypertension
Low risk* High risk†
• Ultrasound examination at 16-20 • Hospitalization at initial visit if

• weeks, repeat at 30-32 weeks and • uncontrolled hypertension
• monthly after that until term • Antihypertensive drugs are needed
• Nonstress test and/or biophysical • to keep systolic pressure <140 and
• profile at 32 weeks and then weekly • diastolic pressure <90 mm Hg for
• women with target organ damage
• Ultrasound examination at 16-20
1. Antihypertensive drugs if develops • weeks, repeat at 28 weeks and then
severe hypertension • every 3 weeks until delivery
• Nonstress test and/or biophysical
2. If preeclampsia develops, if • profile at 28-32 weeks and then
antihypertensive drugs are used, or • weekly
if there is abnormal fetal growth,
begin immediate fetal testing with
nonstress test or biophysical 1. Hospitalization if exacerbation
profile. Continue serial testing to severe hypertension, if
until delivery. preeclampsia, or evidence of
abnormal fetal growth
2. Frequent evaluation of maternal

and fetal well-being
3. Consider delivery at 36-37 weeks
FIG 31-18 Antepartum management of chronic hypertension. Low risk (*) includes those with controlled hypertension on medication and those
not receiving antihypertensive drugs; high risk (†) includes those with uncontrolled hypertension, left ventricular dysfunction, and/or coexisting
medical diseases (renal, diabetes mellitus, systemic lupus erythematosus). (From Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol.
2002;100:369.)
LOW-RISK HYPERTENSION TABLE 31-20 DRUGS USED TO TREAT HYPERTENSION

Women with low-risk chronic hypertension without super- IN PREGNANCY
imposed PE usually have a pregnancy outcome similar to
STARTING MAXIMUM
that of the general obstetric population. In addition, discon- DRUG DOSE DOSE COMMENTS
tinuation of antihypertensive therapy early in pregnancy does
Acute Treatment of Severe Hypertension
not affect the rate of PE, abruptio placentae, or preterm delivery Hydralazine 5-10 mg IV 20 mg* Avoid in cases of
in these women. Many clinicians choose to discontinue antihy- q20 min tachycardia and
pertensive treatment at the first prenatal visit because most of persistent
these women will experience a good pregnancy outcome without headaches
such therapy. Although many of these women will not require Labetalol 20-40 mg IV 220 mg* Avoid in women
q10-15 min with asthma or
subsequent pharmacologic therapy, careful management is still congestive
essential (see Fig. 31-16). At the time of initial and subsequent heart failure
visits, women are educated about nutritional requirements, Nifedipine 10-20 mg oral 50 mg* Avoid in case of
weight gain, and sodium intake (maximum of 2.4 g/day). They q30 min tachycardia and
palpitations
are also counseled that consumption of alcohol and smoking Long-Term Treatment of Hypertension
during pregnancy can aggravate maternal hypertension and are Methyldopa 250 mg bid 4 g/day
associated with adverse effects on the fetus such as FGR and Labetalol 100 mg bid 2400 mg/day
abruptio placentae. During each subsequent visit, they are Nifedipine 10 mg bid 120 mg/day
observed closely for early signs of PE and FGR. Thiazide 12.5 mg bid 50 mg/day
diuretic
Fetal evaluation should include an ultrasound examination at
16 to 20 weeks’ gestation, to be repeated at 30 to 32 weeks and *If desired blood pressure levels are not achieved, switch to another drug.
monthly thereafter until term. Antihypertensive treatment
with either nifedipine or labetalol is initiated if the patient
develops severe hypertension before term. The development BP of 160 mm Hg or more or diastolic BP of 110 mm Hg
of severe hypertension, PE, or abnormal fetal growth requires or more. In women without target-organ damage, the aim
immediate fetal testing with NST or BPP. Women who of antihypertensive therapy is to keep systolic BP between
develop severe hypertension require hospitalization, and 140 and 150 mm Hg and diastolic BP between 90 and
those with documented FGR by ultrasound examination 100 mm Hg. In addition, antihypertensive therapy is indi-
require intensive surveillance and often delivery. If superim- cated in women with mild hypertension plus target-organ
posed PE is diagnosed at or beyond 37 weeks, delivery is under- damage because of the short-term maternal benefits from
taken as well. In the absence of these complications, the lowering BP in such women. In these women, maintaining
pregnancy may be continued until 40 weeks’ gestation. systolic BP below 140 mm Hg and diastolic BP below
90 mm Hg is advised. In some women, BP may be difficult to
HIGH-RISK HYPERTENSION control initially, which demands the use of IV therapy with
Women with high-risk chronic hypertension are at increased risk hydralazine or labetalol or oral short-acting nifedipine with
for adverse maternal and perinatal complications. The likelihood doses as described in Table 31-20. For maintenance therapy, the
and impact of these complications will depend on the etiology choices are either oral methyldopa, labetalol, slow-release nife-
of the hypertension as well as the degree of target-organ damage. dipine, or a diuretic. Methyldopa remains the drug most com-
Women with significant renal insufficiency (serum creatinine monly recommended to treat hypertension during pregnancy;
>1.4 mg/dL), diabetes mellitus with vascular involvement (class however, it is rarely used in nonpregnant hypertensive women.
R/F), severe collagen vascular disease, cardiomyopathy, or coarc- The recommended drug of choice for control of hypertension
tation of the aorta should receive thorough counseling regarding in pregnancy is labetalol, starting at 100 mg twice daily to
the adverse effects of pregnancy before conception. These women be increased to a maximum of 2400 mg/day. If maternal BP
should be advised that pregnancy may exacerbate their condi- is not controlled with maximal doses of labetalol, a second
tion, with the potential for CHF, acute renal failure requiring drug such as a thiazide diuretic or nifedipine may be added.
dialysis, and even death. In addition, perinatal loss and neonatal For women with diabetes mellitus and vascular disease, oral
complications are markedly increased in these women. All such nifedipine is recommended. Oral nifedipine or a thiazide
women should be managed by, or in consultation with, a sub- diuretic is the drug of choice for young black women with
specialist in maternal-fetal medicine in association with other hypertension because these women often manifest a low-renin-
medical specialists as needed. In addition, these women must be type hypertension or salt-sensitive hypertension. If maternal BP
observed and delivered at a tertiary care center with the appro- is adequately controlled with these medications, the patient can
priate resources for maternal and neonatal care. continue with the same drug after delivery.
Hospitalization of women with high-risk uncontrolled Diuretics are commonly prescribed in women with essential
hypertension at the time of the first prenatal visit is recom- hypertension before conception, although the use of diuretics
mended. This facilitates evaluation of cardiovascular and renal throughout pregnancy is controversial. Of concern, women who
status and also facilitates regulation of antihypertensive medica- use diuretics from early in pregnancy do not have an increase in
tions and other prescribed treatments (e.g., insulin, cardiac plasma volume to the degree expected in normal pregnancy.
drugs, thyroid medications) if needed. Women who receive ACE However, this reduction in plasma volume has not been shown
inhibitors or angiotensin II receptor antagonists should have to be associated with an adverse effect on fetal outcome. There-
these medications discontinued under close observation. Anti- fore it is appropriate to start diuretics as a single agent during
hypertensive therapy with one or more of the drugs listed in pregnancy or to use them in combination with other agents,
Table 31-20 is subsequently used in all women with systolic particularly in women with excessive salt retention. However,
diuretics should be discontinued immediately if superimposed

PE develops or with evidence of suspected FGR because of the HYPERTENSIVE EMERGENCIES
potential for reduced uteroplacental blood flow secondary to IN CHRONIC HYPERTENSION
reduced plasma volume in women with these complications. On rare occasions, pregnant women may present with life-
Early and frequent prenatal visits are the key for successful threatening clinical conditions that require immediate control
pregnancy outcome in women with high-risk chronic hyperten- of BP, such as hypertensive encephalopathy, acute left ventricular
sion. These women need close observation throughout preg- failure, acute aortic dissection, or increased circulating catechol-
nancy and may require serial evaluation of 24-hour urine protein amines (pheochromocytoma, clonidine withdrawal, cocaine
excretion and a CBC with a metabolic profile at least once every ingestion). Patients at highest risk for these complications
trimester. Further laboratory testing can be performed depend- include those using multiple drugs to control their hypertension
ing on the clinical progress of the pregnancy. During each visit, and also women with underlying cardiac or chronic glomerular
the woman should be advised about the adverse effects of renal disease, superimposed PE in the second trimester, and
smoking and alcohol abuse, and she should receive nutritional placental abruption complicated by DIC. Although a diastolic
advice regarding diet and salt intake. BP of 115 mm Hg or greater is usually considered a hyperten-
Fetal evaluation should include an ultrasound examination at sive emergency, this level is actually arbitrary, and the rate of
16 to 20 weeks’ gestation, to be repeated at 28 weeks and sub- change of BP may be more important than its absolute level.
sequently every 3 weeks until delivery. NST or BPP testing The association of elevated BP with evidence of new or progres-
is usually started at 28 to 32 weeks and then repeated weekly. sive end-organ damage determines the seriousness of the clinical
The development of uncontrolled severe hypertension or PE situation.
requires maternal hospitalization for more frequent evalua-
tion of maternal and fetal well-being. The development of Hypertensive Encephalopathy
FGR also requires intensive surveillance, and the develop- Untreated essential hypertension progresses to a hypertensive
ment of these complications at or beyond 34 weeks’ gestation crisis in up to 1% to 2% of cases for unknown reasons. Hyper-
should be considered an indication for delivery. In all other tensive encephalopathy is usually seen in patients with
women, delivery should be considered at 36 to 37 weeks’ gesta- a systolic BP above 220 mm Hg or a diastolic BP above
tion after documentation of fetal lung maturity. 130 mm Hg. Patients with an acute onset of hypertension may
develop encephalopathy at pressure levels that are generally tol-
Postpartum Management erated by those with chronic hypertension. Normally, cerebral
Women with high-risk chronic hypertension are at risk for post- blood flow is about 50 mL/min per 100 g tissue. When the BP
partum complications such as pulmonary edema, hypertensive falls, cerebral arterioles normally dilate, whereas when BP
encephalopathy, and renal failure. These risks are particularly increases, they constrict to maintain constant cerebral blood
increased in women with target-organ involvement, superim- flow. This mechanism usually remains operative between 60 and
posed PE, or placental abruption. In these patients, BP must 120 mm Hg diastolic BP. Hypertensive encephalopathy is
be closely controlled for at least 24 hours after delivery. IV currently considered to be a derangement of the autoregula-
labetalol or hydralazine can be used as needed, and diuretics may tion of cerebral arterioles, which occurs when the upper limit
be appropriate in women with circulatory congestion and pul- of autoregulation is exceeded. With severe hypertension (130
monary edema. This therapy is usually required in those who to 150 mm Hg cerebral perfusion pressure), cerebral blood
develop exaggerated and sustained severe hypertension in the vessels constrict as much as possible and then reflex cerebral
first week postpartum. vasodilation occurs. This results in overperfusion, damage to
Oral therapy may be needed to control BP after delivery. In small blood vessels, cerebral edema, and increased intracranial
some women, it is often necessary to switch to a new agent such pressure (breakthrough theory). Others believe that hypertensive
as an ACE inhibitor, particularly in those with pregestational encephalopathy results from an exaggerated vasoconstrictive
diabetes mellitus and those with cardiomyopathy. Some patients response of the arterioles that results in cerebral ischemia (over-
may wish to breastfeed their infant, and all antihypertensive regulation theory). Patients who have impaired autoregulation
drugs are found in the breast milk, although the milk-to-plasma that involves the cerebral arterioles may experience necrotizing
ratio of these drugs varies. Additionally, the long-term effect of arteriolitis, microinfarcts, petechial hemorrhages, multiple small
maternal antihypertensive drugs on breastfeeding infants has not thrombi, or cerebral edema. Typically, hypertensive encepha-
been specifically studied. Milk concentrations of methyldopa lopathy has a subacute onset over 24 to 72 hours.
appear to be low and are considered to be safe. The β-blocking During a hypertensive crisis, other evidence for end-organ
agents (atenolol and metoprolol) are concentrated in breast damage may be present: cardiac, renal, or retinal dysfunction
milk, whereas labetalol and propranolol have low concentra- secondary to impaired organ perfusion and loss of autoregula-
tions. Concentrations of diuretic agents in breast milk are low; tion of blood flow. Ischemia of the retina with flame-shaped
however, they may induce a decrease in milk production. retinal hemorrhages, retinal infarcts, or papilledema may occur
Little information is available about the transfer of calcium and can cause decreased visual acuity. Impaired regulation of
channel blockers to breast milk, but no side effects are apparent. coronary blood flow and a marked increase in ventricular wall
ACE inhibitors and angiotensin II receptor antagonists should stress may result in angina, myocardial infarction (MI), CHF,
be avoided because of their effects on neonatal renal function, malignant ventricular arrhythmia, pulmonary edema, or dissect-
even though their concentrations appear to be low in breast milk ing aortic aneurysm. Necrosis of the afferent arterioles of the
(see Chapter 24). glomerulus results in hemorrhages of the cortex and medulla,
Finally, in breastfeeding women, the use of methyldopa as fibrinoid necrosis, and proliferative endarteritis that results in
a first-line oral therapy is a reasonable choice. If methyldopa elevated serum creatinine (>3 mg/dL), proteinuria, oliguria,
is contraindicated, labetalol may be used. hematuria, hyaline or red blood cell casts, and progressive
azotemia. Severe hypertension may result in placental abruption acute renal failure, MI, fetal distress, or death. Hypertension that
with resultant DIC. In addition, high levels of angiotensin II, proves increasingly difficult to control is an indication to termi-
norepinephrine, and vasopressin accompany ongoing vascular nate the pregnancy. If the patient’s outcome appears to be grave,
damage. These circulating hormones increase relative efferent consideration of perimortem cesarean delivery should be made.
arteriolar tone, which results in sodium diuresis and hypovole- The drug of choice in a hypertensive crisis is sodium nitro-
mia. Because levels of renin and angiotensin II are increased, prusside. Other agents such as nitroglycerin, nifedipine,
the aldosterone level is also elevated. The impact of these trimetaphan, labetalol, and hydralazine can also be used.
endocrine changes may be important in maintaining the hyper-
tensive crisis. SODIUM NITROPRUSSIDE
Sodium nitroprusside causes arterial and venous relaxation by
Treatment of Hypertensive Encephalopathy interfering with both influx and the intracellular activation of
The ultimate goal of therapy is to prevent the occurrence of a calcium. It is given as an IV infusion of 0.25 to 3 µg/kg/min.
hypertensive emergency. Patients at risk for a hypertensive crisis The onset of action is immediate, and its effect may last 3 to 5
should receive intensive management during labor and for a minutes after discontinuing the infusion. Hypotension caused
minimum of 48 hours after delivery. Although pregnancy may by nitroprusside should resolve within a few minutes of stopping
complicate the diagnosis, once the life-threatening conditions the infusion because the drug’s half-life is so short. If it does not
are recognized, pregnancy should not in any way slow or alter resolve, other causes for hypotension should be suspected.
the mode of therapy. The only reliable clinical criterion to The effect of nitroprusside on uterine blood flow is contro-
confirm the diagnosis of hypertensive encephalopathy is versial. Nitroprusside is metabolized into thiocyanate, which is
prompt response of the patient to antihypertensive therapy. excreted in the urine. Cyanide can accumulate if production is
The headache and sensorium often clear dramatically, some- increased as a result of large doses (>10 µg/kg/min) or pro-
times within 1 to 2 hours after the treatment. The overall longed administration (>48 hours), or if there is renal insuffi-
recovery may be somewhat slower in patients with uremia and ciency or decreased metabolism in the liver. Signs of toxicity
when symptoms have been present for a prolonged period before include anorexia, disorientation, headache, fatigue, restlessness,
the therapy is given. Sustained cerebrovascular deficits should tinnitus, delirium, hallucinations, nausea, vomiting, and meta-
suggest other diagnoses. bolic acidosis. When it is infused at less than 2 µg/kg/min,
Patients with hypertensive encephalopathy or other hyperten- cyanide toxicity is unlikely. At a maximal dose rate of 10 µg/kg/
sive crisis should be hospitalized for bed rest. IV lines should be min, infusion should never last more than 10 minutes. Animal
inserted for fluids and medications. Although the tendency is to experiments and the few reported cases of nitroprusside use in
restrict sodium intake in patients with a hypertensive emergency, pregnancy have revealed that thiocyanate toxicity to mother
volume contraction from sodium diuresis may be present. A and fetus rarely occur if it is used in a regular pharmacologic
marked drop in diastolic BP with a rise in heart rate on standing dose. Tachyphylaxis to nitroprusside usually develops before
from the supine position is evidence of volume contraction. toxicity occurs. Whenever toxicity is suspected, therapy should
Infusion of normal saline solution during the first 24 to 48 hours be initiated with 3% sodium nitrite at a rate not to exceed 5 mL/
to achieve volume expansion should be considered. Saline infu- min up to a total dose of 15 mL. Then, infusion of 12.5 g of
sion can help decrease the activity of the renin-angiotensin- sodium thiosulfate in 50 mL of 5% dextrose in water over a 10
aldosterone axis and can result in better BP control. Simultaneous minute period should be started.
repletion of potassium losses and continuous monitoring of BP,
volume status, urinary output, ECG readings, and mental status NITROGLYCERIN
are mandatory. An intraarterial line provides the most accurate Nitroglycerin is an arterial but mostly venous dilator. It is given
BP information. Laboratory studies include a CBC with dif- as an IV infusion of 5 µg/min that is gradually increased every
ferential, reticulocyte count, platelets, and blood chemistries. A 3 to 5 minutes to titrate BP up to a maximal dose of 100 mg/
urinalysis should be obtained for protein, glucose, blood, cells, min. It is the drug of choice in PE associated with pulmonary
casts, and bacteria. Assessment for end-organ damage in the edema and for control of hypertension associated with tra-
CNS, retina, kidneys, and cardiovascular system should be done cheal manipulation. Side effects such as headache, tachycardia,
periodically. Antepartum patients should have continuous fetal and methemoglobinemia may develop. It is contraindicated in
monitoring. hypertensive encephalopathy because it increases cerebral blood
flow and intracranial pressure.
LOWERING BLOOD PRESSURE IN
HYPERTENSIVE ENCEPHALOPATHY
Certain risks are associated with an overly rapid or excessive KEY POINTS
reduction of elevated BP. The aim of therapy is to lower mean
BP by no more than 15% to 25%. Small reductions in BP in ◆ Hypertension is the most common medical complica-
the first 60 minutes, working toward a diastolic level of 100 tion during pregnancy.
to 110 mm Hg, have been recommended. Although cerebral ◆ Preeclampsia is a leading cause of maternal mortality
blood flow is maintained constantly over a wide range of BPs, and morbidity worldwide.
autoregulation has a lower and upper limit. In chronically hyper- ◆ The pathophysiologic abnormalities of preeclampsia are
tensive women who have a rightward shift of the cerebral auto- numerous, but the etiology is unknown.
regulation curve secondary to medial hypertrophy of the cerebral ◆ At present, there is no proven method to prevent pre-
vasculature, lowering BP too rapidly may produce cerebral isch- eclampsia. However, low-dose aspirin may have a role
emia, stroke, or coma. Coronary blood flow, renal perfusion, in certain women.
and uteroplacental blood flow also may deteriorate, resulting in
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Chapter 31

Relative risk RR Thrombotic thrombocytopenic purpura TTP

TABLE 31-1 HYPERTENSIVE DISORDERS OF PREGNANCY

60 Eclampsia is defined as the occurrence of seizures after the

Chronic hypertension is defined as hypertension present prior to

0 Chronic Hypertension With Superimposed Preeclampsia

TABLE 31-3 PREGNANCY OUTCOME IN WOMEN WITH MILD GESTATIONAL HYPERTENSION

BOX 31-2 RISK FACTORS FOR PREECLAMPSIA

examination of the uterus to rule out molar pregnancy or

Antiplatelet Agents Including Low-Dose Aspirin

TABLE 31-6 SIGNS AND SYMPTOMS IN WOMEN WITH HELLP SYNDROME

• Refer to tertiary care facility (<35 weeks)

• <24 weeks or limits of viability

Management During Cesarean Delivery

FIG 31-6 Subfascial drains used at the time of cesarean section.

puncture sites and wounds, or intraperitoneal bleeding—

POSTPARTUM MANAGEMENT Hepatic Complications in HELLP Syndrome

Liver hematoma at 40 weeks

hemorrhage into the peritoneal cavity. Women who develop a

Maternal and fetal evaluation

>37 weeks gestation

FIG 31-10 Management plan for patients with gestational hypertension–preeclampsia.

• Admit to labor and delivery, observe for 24-48 hours

Contraindications to continued expectant management?

Offer continued expectant management

Are there additional complications?

TABLE 31-15 PREGNANCY OUTCOME AFTER HELLP SYNDROME

had subsequent uneventful pregnancies under close maternal

TABLE 31-17 TIME OF ONSET OF ECLAMPSIA IN RELATION TO DELIVERY

BOX 31-10 REPORTED COMPUTED TOMOGRAPHY SCAN

the maternal mortality rate may be as high as 14% in devel-

the bed’s side rails should be elevated and padded; a padded 40

Prevention of Recurrent Convulsions Time (hours)

TABLE 31-18 RECURRENT PREECLAMPSIA-ECLAMPSIA IN WOMEN WITH ECLAMPSIA

third trimester. These women are more likely to be erroneously

104 (49%) 71 (34%) 40 (17%)

4 (4%) 11 (16%) 13 (32%)

• Assess etiology and severity

• Uncomplicated essential hypertension • Secondary hypertension

Pregnant women with chronic

Low risk* High risk†

• Ultrasound examination at 16-20 • Hospitalization at initial visit if

2. Frequent evaluation of maternal

3. Consider delivery at 36-37 weeks

LOW-RISK HYPERTENSION TABLE 31-20 DRUGS USED TO TREAT HYPERTENSION

diuretics should be discontinued immediately if superimposed

Barton JR, Sibai BM. Gastrointestinal complications of preeclampsia. Semin

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