chapter 45 - hypertensive disorders - vanderbilt … disorders in pregnancy. gestational...

Chapter 45

Hypertensive DisordersLinda S. Polley, M.D.

CLASSIFICATION OF HYPERTENSIVEDISORDERS

975

PREECLAMPSIA 976

Epidemiology 976

Pathogenesis 978

Prophylaxis 981

Clinical Manifestations 982

Obstetric Management 984

Complications of Preeclampsia 987

HELLP Syndrome 988

Anesthetic Management 990

Postpartum Management 997

Long-Term Outcomes 997

ECLAMPSIA 998

Epidemiology 998

Clinical Presentation and Diagnosis 998

Obstetric Management 999

Resuscitation and Seizure Control 999

Anesthetic Management 999

Long-Term Outcomes 1000

Hypertension is the most common medical disorder of preg-nancy in the United States, affecting 6% to 8% of pregnantwomen. It is also a leading cause of maternal and fetal mor-bidity and mortality worldwide1; approximately 63,000women die every year because of the maternal hypertensivesyndromes preeclampsia and eclampsia.2 Hypertensive dis-orders also result in fetal complications such as preterm birth,intrauterine growth restriction, and fetal/neonatal death.

CLASSIFICATION OF HYPERTENSIVEDISORDERS

The term hypertension in pregnancy encompasses arange of disorders—including preeclampsia and eclampsia,as well as gestational and chronic hypertension—that canbe difficult to diagnose, because they often appear similar inclinical presentation despite complex differences in theirunderlying causes and prognoses. Adding to the challengesfor clinicians and researchers alike, a long-standing absenceof consensus guidelines for categorizing hypertensive dis-orders resulted in the use of conflicting definitions thathave confounded attempts to compare and interpret datafrom all but the latest clinical studies. This problem waseventually resolved in 2000, when the National High BloodPressure Education Program (NHBPEP) Working Group onHigh Blood Pressure in Pregnancy published a classificationscheme establishing definitions that subsequently gainedwide international acceptance (Box 45-1). Unfortunately,the utility of much of the currently available data is com-promised by the disparities in previous definitions ofhypertensive disorders in pregnancy.

Gestational hypertension, the most common cause ofhypertension during pregnancy,3 has outcomes that aregenerally similar to those of normotensive pregnancies.4,5

In a woman with no preexisting hypertension or other signsor symptoms of preeclampsia, it manifests as elevated bloodpressure after 20 weeks’ gestation that resolves by 12 weekspostpartum.3,6 Most cases of gestational hypertensiondevelop after 37 weeks’ gestation. A diagnosis of gestationalhypertension is a retrospective diagnosis, because it can beestablished with certainty only after delivery.

Preeclampsia is defined as the new onset of hyperten-sion and proteinuria after 20 weeks’ gestation (Table 45-1).The NHBPEP has recommended that clinicians considerthe diagnosis of preeclampsia in the absence of proteinuriawhen any of the following findings are present: (1) persis-tent epigastric or right upper quadrant pain, (2) persistentcerebral symptoms, (3) fetal growth restriction, (4) throm-bocytopenia, and (5) elevated serum liver enzyme concen-trations.7 The term eclampsia is used when central nervoussystem (CNS) involvement results in the new onset of sei-zures in a woman with preeclampsia. The term HELLPsyndrome refers to the development of hemolysis, elevatedliver enzymes, and low platelets in a woman with pre-eclampsia. This condition is considered a variant of severepreeclampsia.

Chronic hypertension involves either (1) prepregnancyblood pressure levels � 140 mm Hg systolic or � 90 mm Hgdiastolic or (2) elevated blood pressure that fails to resolveafter delivery. The pathophysiology of chronic hypertensionis better understood than that of preeclampsia (see later),and much of what is known about chronic hypertension innonpregnant women is also relevant to pregnant women.

Chapter 45 Hypertensive Disorders 975

Table 45-2 compares the clinical findings in chronichypertension, gestational hypertension, and preeclampsia.

The term chronic hypertension with superimposedpreeclampsia is used when preeclampsia develops inwomen who had chronic hypertension before pregnancy.The diagnosis is made in the presence of a new onset ofproteinuria or a sudden increase in proteinuria and/orhypertension, or when other manifestations of severe pre-eclampsia appear. Morbidity with this condition isgreater for both mother and fetus than with preeclampsiaalone.8

PREECLAMPSIA

Preeclampsia is a multisystem disease unique to humanpregnancy. Although advances have been made in theunderstanding of the pathophysiology of the disease, the

specific proximal etiology remains unknown. Managementis supportive; delivery of the infant and placenta remainsthe only definitive cure.

The clinical syndrome of preeclampsia is defined asthe new onset of hypertension and proteinuria after20 weeks’ gestation. Previous definitions included edema,but edema is no longer part of the diagnostic criteriabecause it lacks specificity and occurs in many healthy preg-nant women.9 The severity of preeclampsia is categorizedas either mild or severe according to clinical criteria(see Table 45-1).

Epidemiology

Preeclampsia occurs in approximately 4% of pregnancies inthe United States.10,11 Delivery of the infant and placenta isthe only effective treatment; thus preeclampsia is a leadingcause of preterm delivery in developed countries.12 Thebirth of low-birth-weight and term neonates to preeclamp-tic mothers results in major medical, social, and economicburdens for families and societies.13 Preterm delivery is themost common indication for admission to the neonatalintensive care unit.14 Preeclampsia is also the leading indi-cation for maternal peripartum admission to an intensivecare unit.15

The clinical findings of preeclampsia manifest as amaternal syndrome (e.g., hypertension and proteinuriawith or without other systemic abnormalities) with or with-out a fetal syndrome (e.g., fetal growth restriction, oligo-hydramnios, abnormal oxygenation).7,16 In approximately75% of cases, preeclampsia is mild with an onset nearterm or during the intrapartum period.3,16 In contrast, dis-ease onset prior to 34 weeks’ gestation correlates withgreater disease severity and worsened outcomes for bothmother and fetus.1,16 The broad spectrum of disease sever-ity and clinical presentations lends support to the emerginghypothesis that preeclampsia encompasses multiple dis-eases that may differ in their pathogenic mechanisms.

Significant increases in the incidence of both preeclamp-sia and gestational hypertension between 1987 and 2004(Figure 45-1),17 including an alarming 47% increase in pre-eclampsia between 1990 and 2005,18,19 appear to haveresulted from major shifts in the demographics of pregnantwomen in the United States and other developed countries.Average maternal age is rising; older mothers are morelikely to have chronic hypertension, a recognized riskfactor for preeclampsia. Both the current epidemic of obes-ity and the greater prevalence of diabetes in the developedworld increase the risk of preeclampsia. The growing utili-zation of assisted reproductive technologies and the use ofdonated gametes increase risk of the disease by altering thematernal-fetal immune reaction20 and by increasing theincidence of multiple gestation, another risk factor for pre-eclampsia. Lastly, improvements in record-keeping and theuse of consistent disease definitions since 2000 have likelyincreased the number of reported cases.7

Multiple preconception and pregnancy-related risk fac-tors associated with the development of preeclampsia havebeen identified (Box 45-2). Preconception risk factors canbe divided into partner-related risk factors, which dependon a woman’s interaction with her sexual partner, andnon–partner-related risk factors, which depend only onthe woman’s personal health status.

BOX 45-1 Classification of Hypertensive Disorders inPregnancy

� Gestational hypertension� Preeclampsia:� Mild� Severe

� Chronic hypertension� Chronic hypertension with superimposed preeclampsia

From the Report of the National High Blood Pressure Education

Program Working Group on High Blood Pressure in Pregnancy.

Am J Obstet Gynecol 2000; 183:S1-22.

TABLE 45-1 Diagnostic Criteria for Mild and SeverePreeclampsia

Mild Preeclampsia Severe PreeclampsiaBP � 140/90 mm Hg

after 20 weeks’gestation

BP � 160/110 mm HgProteinuria > 5 g/24 hrElevated serum creatininePulmonary edemaOliguriaIntrauterine growth restrictionHeadacheVisual disturbancesEpigastric or right upper

quadrant painSigns of HELLP syndrome

Proteinuria (300 mg/24 hr or 1+ result ondipstick specimen)

BP, blood pressure, shown as systolic/diastolic; HELLP, hemolysis,

elevated liver enzymes, and low platelets.

Adapted from the American College of Obstetricians and

Gynecologists. Diagnosis and management of preeclampsia and

eclampsia. ACOG Practice Bulletin No. 33. Washington DC,

ACOG, January 2002. (Obstet Gynecol 2002; 99:159-67.)

976 Part X The Parturient with Systemic Disease

PARTNER-RELATED RISK FACTORSThe unifying theme among partner-related risk factors islimited maternal exposure to paternal sperm antigens priorto conception, suggesting an immunologic role in the patho-physiology of preeclampsia. The leading risk factor for pre-eclampsia is nulliparity. Long considered a disease ofprimigravid women, preeclampsia is also more commonin (1) teenagers, (2) parous women who have conceivedwith a new partner, (3) women who have used barriermethods of contraception prior to conception, and (4)women who have conceived with donated sperm.21,22

Long-term sperm exposure with the same partner appearsto be protective; this protective effect is lost in a pregnancyconceived with a new sexual partner.

In a study of 1.7 million births in the Medical BirthRegistry of Norway, men who fathered one preeclampticpregnancy were found to be nearly twice as likely tofather a preeclamptic pregnancy in a different woman, irre-spective of her previous obstetric history.23 Therefore,paternal genes (in the fetus) contribute significantly to apregnant woman’s risk of preeclampsia. It is of note thatthe accuracy of epidemiologic studies is compromised by

use of birth certification data, which do not always reflecttrue paternity.

NON–PARTNER-RELATED RISK FACTORSWomen with a history of preeclampsia in a previous preg-nancy are at increased risk for preeclampsia in a subsequentpregnancy.24 Women of advanced maternal age (older than35 years) are also at higher risk.1 A maternal or paternalfamily history of preeclampsia increases a woman’s risk.23

In addition, women with a history of previous placentalabruption, intrauterine growth restriction, or fetal death areat greater risk for preeclampsia in a subsequent pregnancy.25

Non-Hispanic blacks constitute a high-risk group, withhigher rates of chronic hypertension,26-28 obesity,29-33 andpreeclampsia.1,34-38 Black women with severe preeclampsiademonstrate more extreme hypertension, require moreantihypertensive therapy,39 and are more likely to die fromthe condition than women of other racial backgrounds.40

MATERNAL COMORBIDITIES AND LIFESTYLE FACTORSObesity is a primary risk factor for preeclampsia, and riskescalates with increasing body mass index (BMI).41,42

TABLE 45-2 Hypertensive Disorders of Pregnancy

Clinical Feature Chronic Hypertension Gestational Hypertension Preeclampsia

Time of onset ofhypertension

< 20 weeks’ gestation Typically in third trimester � 20 weeks’ gestation

Severity of hypertension Mild or severe Mild Mild or severeProteinuria* Absent Absent Typically presentSerum urate > 5.5 mg/dL

(0.33 mmol/L)Rare Absent Present in almost all cases

Hemoconcentration Absent Absent Present in severe diseaseThrombocytopenia Absent Absent Present in severe diseaseHepatic dysfunction Absent Absent Present in severe disease

*Defined as � 1+ result on dipstick testing on two occasions or � 300 mg in a 24-hour urine collection.

From Sibai BM. Treatment of hypertension in pregnant women. N Engl J Med 1996; 335:257-65.

Gestational hypertensionPreeclampsia

35.0

30.0

25.0

20.0

15.0

10.0

5.0

0.0

Inci

denc

e pe

r 10

00

1987– 88

1989– 90

1991– 92

1993– 94

1995– 96

1997– 98

1999–2000

2001– 02

2003– 04

FIGURE 45-1 Age-adjusted incidence per 1000 deliveriesfor women with gestational hypertension or preeclampsiafor 2-year periods, 1987-2004. (Adapted from Wallis AB,Saftlas AF, Hsia J, Atrash HK. Secular trends in the rates ofpreeclampsia, eclampsia, and gestational hypertension,United States, 1987-2004. Am J Hypertens 2008;21:521-6.)


A systematic review found that an increase in body massindex of 5 to 7 kg/m2 was associated with a twofold higherrisk of preeclampsia.41 Obesity is strongly associated withinsulin resistance, another risk factor for preeclampsia. Asthe prevalence of obesity continues to increase worldwide,the incidence of preeclamptic pregnancies is anticipated toincrease as well.

Women with chronic hypertension are also atincreased risk of preeclampsia. A large case-control studyfound that preexisting hypertension increased the odds ofdevelopment of preeclampsia threefold.43 As women indeveloped countries delay childbirth, the impact of chronichypertension will be greater because of the increased prev-alence of hypertension with advancing age.44

Diabetes mellitus is also associated with the develop-ment of preeclampsia. In a study of 334 diabetic pregnan-cies, the incidence of preeclampsia was 9.9%, comparedwith 4.3% in nondiabetic controls. The incidence of pre-eclampsia also increased with the severity of diabetes asdetermined by the White classification.45

The metabolic syndrome, which occurs in 7% ofwomen of childbearing age in the United States, is charac-terized by the presence of obesity, hyperglycemia, insulinresistance, and hypertension.46 Because the metabolic syn-drome increases the risk for both preeclampsia43 and car-diovascular disease, women with a history of preeclampsiaencounter greater risk of premature cardiovascular diseaselater in life.47-52 Insulin resistance has been implicated as acommon factor in both preeclampsia and cardiovascular

disease; microvascular dysfunction may be a predisposingfactor for both coronary artery disease and preeclampsia.53

Paradoxically, cigarette smoking during pregnancy hasbeen associated with a decreased risk of preeclampsia,54-56

an effect consistently observed in studies in various coun-tries. Women who smoke during pregnancy have a 30%to 40% lower risk for development of preeclampsia thanwomen who do not smoke. In a large systematic review,the relative risk was 0.68 (95% confidence interval, 0.67 to0.69). The protective effect is also dose-related54,55,57;heavier smokers have a lower incidence of preeclampsiathan those who smoke fewer cigarettes.

The duration of this protective effect after smoking ces-sation has been studied, with conflicting results; the biolog-ic mechanism remains unknown but is thought to involvenicotine inhibition of thromboxane A2 synthesis, stimula-tion of nitric oxide release, or a combination of these pro-cesses.55 Further research on the mechanism of this effectmay help elucidate the pathogenesis of preeclampsia.

Pathogenesis

The exact pathogenic mechanisms responsible for the ini-tiation and progression of preeclampsia are not known. Theplacenta is the pathogenetic focus of the disease.

ABNORMAL PLACENTATION AND THEMATERNAL SYNDROMEPreeclampsia is known to be a two-stage disorder.58 Theasymptomatic first stage occurs early in pregnancy with afailure of trophoblastic invasion. In normal pregnancy, tro-phoblasts invade the decidual and myometrial segments ofthe spiral arteries, causing loss of vascular smooth muscleand the inner elastic lamina (Figure 45-2). The luminaldiameter of the spiral arteries increases fourfold, resultingin the creation of flaccid tubes that provide a low-resistancevascular pathway to the intervillous space. Further, theremodeled arteries are unresponsive to vasoactive stim-uli.59,60 These alterations in maternal vasculature ensureadequate blood flow to nourish the growing fetus andplacenta.

In contrast, in the preeclamptic woman only the decidualsegments undergo change, and the myometrial portionsremain small, constricted, and hyperresponsive to vasomo-tor stimuli. This failure of normal angiogenesis results insuperficial placentation. The abnormal maternal responseto placentation leads to decreased placental perfusion andplacental infarcts, predisposing the fetus to intrauterinegrowth restriction (Figure 45-3). Placental ischemia wor-sens throughout pregnancy as narrowed vessels are increas-ingly unable to meet the needs of the growing fetoplacentalunit.

In some women, the reduced perfusion of the intervillousspace in the first stage leads to the symptomatic secondstage, which is characterized by widespread maternalendothelial dysfunction and an accentuated systemicinflammatory response, and may or may not be accompa-nied by the occurrence of intrauterine fetal growth restric-tion. In the absence of preeclampsia, healthy endotheliumprevents platelet activation, activates circulating anticoagu-lants, buffers the response to pressors, and keeps fluid inthe intravascular compartment. These normal functions aredisrupted in preeclampsia. In the symptomatic second

BOX 45-2 Risk Factors for Preeclampsia

Preconception� Partner-related� Nulliparity� Limited preconceptional exposure to paternal sperm

(teenage mother, primipaternity, assisted reproductivetechnology)

� Partner who fathered a preeclamptic pregnancy inanother woman

� Non–partner-related� History of preeclampsia in previous pregnancy� Advanced maternal age (> 35 years)� Family history of preeclampsia� History of placental abruption, intrauterine growth

restriction, or fetal death� Non-Hispanic black racial background

� Maternal disease–related� Obesity� Chronic hypertension� Diabetes mellitus� Thrombotic vascular disease

� Behavioral� Cigarette smoking (risk reduction)

Pregnancy-Associated� Multiple gestation� Hydatidiform mole

From Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk

factors for preeclampsia. JAMA 1991;266:237-41.


stage, the pregnant woman develops hypertension and pro-teinuria, and is at risk for other manifestations of severedisease (e.g., HELLP syndrome, eclampsia, end-organdamage). Clinical manifestations usually appear after 20weeks’ gestation.

Not all women with impaired placental perfusiondevelop preeclampsia. The same failure of uterine vascularremodeling occurs in women with isolated intrauterinegrowth restriction61 and in approximately one third ofcases of spontaneous preterm birth without maternal clin-ical manifestations of preeclampsia.62

Numerous theories about the pathogenesis of pre-eclampsia have been examined and rejected over theyears. Currently the most widely accepted explanation isthat the placenta fails to embed adequately and, in responseto hypoxia caused by poor placental perfusion, releases fac-tors into the circulation that damage the maternal endothe-lium and give rise to the multisystem manifestations of thematernal syndrome.11 The placenta but not the fetus isrequired for the development of preeclampsia; womenwith molar pregnancy, in which the placenta grows withouta fetus, can have severe preeclampsia. The disease syn-drome likely occurs in women with specific genetic andimmunologic susceptibility.

GENETIC FACTORSThe genetic inheritance of preeclampsia is complex, but agenetic component is likely because the incidence of pre-eclampsia is higher among family members; a number ofsusceptibility loci have been reported.63 Genetic studies ofpreeclampsia are challenging because the syndrome occursonly in women (i.e., half of the total population) and man-ifests only during the reproductive years in women whobecome pregnant. In a summary of inheritance studies,Arngrimsson et al.64 concluded that, considering these lim-itations, data support a major dominant gene with variablepenetrance or multifactorial inheritance.

Preeclampsia has been classified into the early form(type I), with symptom onset before 34 weeks’ gestation,and the late form (type II), with symptom onset after34 weeks’ gestation (Table 45-3). Early-onset preeclampsiabegins with abnormal placentation, has a high rate of recur-rence, and has a clear genetic component.65-67 In contrast,late-onset preeclampsia likely results from the interactionbetween a normal placenta and a woman genetically ormetabolically predisposed to the disease. These women,who often have long-standing hypertension, obesity,diabetes, or other forms of microvascular disease, are chal-lenged to meet the demands of the growing fetoplacentalunit and decompensate near term. Decompensationmanifests as late-onset or, less frequently, postpartumpreeclampsia.68

According to genetic conflict theory,69 fetal genes areselected to maximize nutrient transfer to the fetus, andmaternal genes are selected to restrict this transferbeyond a specific optimal level. The genetic conflicttheory predicts that placental factors (fetal genes) act toincrease maternal blood pressure, whereas maternal factorsact to reduce blood pressure. In this model, endothelial celldysfunction may have evolved as a fetal rescue strategy toincrease nonplacental vascular resistance when the utero-placental blood supply is inadequate.70

IMMUNOLOGIC FACTORSThe immune system appears to play a major role in thedevelopment of preeclampsia. Epidemiologic evidence sug-gests that long-term exposure to paternal antigens in spermis protective (as discussed earlier).71

A

B

FIGURE 45-2 Sections through spiral arteries (A) at the myometrial-endometrial junction of the nonpregnant uterus and (B) at themyometrial-decidual junction in late normal pregnancy. (�150) (FromSheppard BL, Bonnar J. Uteroplacental arteries and hypertensivepregnancy. In Bonnar J, MacGillivray I, Symonds G, editors. PregnancyHypertension. Baltimore, University Park Press, 1980:205.)

LF

FIGURE 45-3 This figure shows lipid-laden cells (L) and fibrindeposition (F) in this occluded decidual vessel characteristic of bothsevere preeclampsia and severe intrauterine growth restriction. (�150)(From Sheppard BL, Bonnar J. Uteroplacental arteries and hypertensivepregnancy. In Bonnar J, MacGillivray I, Symonds G, editors. PregnancyHypertension. Baltimore, University Park Press, 1980:205.)


The immune cells that predominate in the decidua—theendometrium in the nonpregnant state becomes the decid-ua in pregnancy—are a specific group of uterine naturalkiller cells that interact with fetal trophoblast cell markersvia killer immunoglobulin receptors to influence tropho-blastic invasion. Specific genotypic combinations of mater-nal killer immunoglobulin receptors and trophoblastichuman leukocyte antigen C (HLA-C) increase the risk ofpreeclampsia. Normal placentation requires a balance ofinhibition and activation of uterine natural killer cells thatis mediated by maternal and fetal factors.72

Activated autoantibodies to the angiotensin receptor-1(AT1) are present in many preeclamptic women in associ-ation with defective remodeling of the uteroplacental vas-culature.73,74 These autoantibodies activate AT1 receptorson cardiac myocytes, trophoblast cells, endothelial cells, andvascular smooth muscle cells.75-77 Introduction of theseautoantibodies into pregnant mice results in hypertension,proteinuria, and greater production of soluble fms-liketyrosine kinase-1 characteristic of the syndrome of pre-eclampsia in humans (see later). Zhou et al.78 demonstratedthat agonistic autoantibodies (AAs) against the angiotensinreceptor-1 (AT1-AAs), which are recovered from the circu-lation of women with preeclampsia, can induce pre-eclampsia-like signs and symptoms in pregnant mice.Although this issue was not addressed specifically, it is pos-sible that AT1-AAs contribute to the greater sensitivity toangiotensin II that Gant et al.79 observed several decadesago. AT1 receptor-activating autoantibodies may induce theproduction of reactive oxygen species and block tropho-blastic invasion76,77 and thus may play a significant role inthe pathophysiology of preeclampsia (see Figure 45-5).

ANTIANGIOGENIC PROTEINSTwo endogenous antiangiogenic proteins of placentalorigin have now been identified that, on the basis ofrodent models, likely play an important role in the patho-genesis of preeclampsia.80,81 Soluble fms-like tyrosinekinase-1 (sFlt-1) is upregulated in the placentas ofwomen with preeclampsia; it antagonizes the angiogenicgrowth factors, vascular endothelial growth factor (VEGF)and placental growth factor (PlGF).

Maynard et al.80 demonstrated that sFlt-1 levels riseduring gestation and fall after delivery, and that highercirculating sFlt-1 levels reduce circulating levels of freeVEGF and PlGF, causing endothelial dysfunction thatcan be rescued by exogenous VEGF and PlGF.Furthermore, these investigators found that the adminis-tration of sFlt-1 to pregnant rats induced hypertension,proteinuria, and glomerular endotheliosis, the last beingthe classic renal lesion of preeclampsia. VEGF and PlGFcause rat renal arteriolar relaxation in vitro, which isblocked by sFlt-1. In response to higher circulating levelsof sFlt-1, VEGF and PlGF levels are reduced, resulting inendothelial dysfunction in maternal vessels (Figure 45-4).58

Levine et al.82,83 demonstrated that increased sFlt-1 levelsand reduced levels of PlGF predicted the subsequentdevelopment of preeclampsia prior to the developmentof any maternal symptoms. Another antiangiogenicprotein, soluble endoglin (sEng), is elevated in cases ofHELLP syndrome.81 Of interest, one study has reportedthat cigarette smoking, known to be protective againstpreeclampsia, is associated with lower maternal sFlt-1concentrations during pregnancy than are seen innonsmokers.84 The study of antiangiogenic proteins is a

TABLE 45-3 Differences between Early- and Late-Onset Preeclampsia

Early-Onset Late-Onset

Onset of clinical symptoms < 34 weeks’ gestation > 34 weeks’ gestationRelative frequency (% of cases) 20 80Risk for adverse outcome High NegligibleAssociation with intrauterine fetal

growth restrictionYes No

Clear familial component* Yes NoPlacental morphology Abnormaly Normaly

Etiology Placentalz Maternal§

Risk factors (relative risk) Family history (2.9) Diabetes (3.56)Multiple pregnancy (2.93)Increased blood pressure at registration (1.38)Increased body mass index (2.47)Maternal age � 40 yr (1.96)Cardiovascular disorders (3.84)

*Defined as recurrence across generations and occurrence within families.

yFrom Egbor M, Ansari T, Morris N, et al. Morphometric placental villous and vascular abnormalities in early- and late-onset preeclampsia with

and without fetal growth restriction. Br J Obstet Gynaecol 2006; 113:580-9.

zReduced extravillous trophoblast invasion.

§Predisposed maternal constitution reflecting microvascular disease or predisposed genetic constitution with cis- or trans-acting genomic

variations subject to interaction.

From Oudejans CB, van Dijk M, Oosterkamp M, et al. Genetics of preeclampsia: Paradigm shifts. Hum Genet 2007; 120:607-12.


very active area of current research, and rapid progressis being made in understanding the role of theseproteins in the pathogenesis of preeclampsia. However,the importance of recent findings is tempered by theknowledge that preeclampsia does not develop in allwomen with high sFlt-1 and low PlGF levels, and doesoccur in some women with low sFlt-1 and high PlGFlevels.83,85

Kanasaki et al.86 hypothesized that a molecular defectupstream from the soluble factors (released in responseto placental hypoxia) contributes to preeclampsia.The investigators have demonstrated that pregnant micedeficient in catechol-O-methyltransferase (COMT)demonstrate a preeclampsia-like phenotype in responseto the absence of 2-methoxyestradiol (2-ME), a naturalmetabolite of estradiol that is elevated during the thirdtrimester of normal pregnancy. Administration of 2-MEto COMT-deficient mice suppresses placental hypoxiaand sFlt-1 elevation. In addition, women with severe pre-eclampsia have significantly lower levels of COMT and2-ME than women with normal pregnancies. The resultsof this study suggest that 2-ME may have utility both as adiagnostic marker for preeclampsia and as a treatment forthe disease.

Current understanding of the pathogenesis of pre-eclampsia is illustrated in Figure 45-5.87 In summary,despite exciting new advances, the pathogenesis of pre-eclampsia is complex and not completely understood. Thefindings and proposed etiologies might be distinctly differ-ent or might be related to one another in ways not yetknown. It is likely that preeclampsia is more than onedisease.88

Prophylaxis

Administration of low-dose aspirin has been proposedfor the prevention of preeclampsia, on the basis of theobservation that thromboxane levels are increased rela-tive to prostacyclin levels in preeclamptic pregnancies.Aspirin inhibits the synthesis of prostaglandins by the irre-versible acetylation and inactivation of cyclooxygenase.Thromboxane and prostacyclin are arachidonic acid me-tabolites and physiologic antagonists important in vaso-regulation. Thromboxane is a potent vasoconstrictor, andprostacyclin is a strong vasodilator. Aspirin inhibits the bio-synthesis of platelet thromboxane A2, and it has beenhypothesized that preeclampsia could be prevented byavoiding the imbalance in the thromboxane-to-prostacyclinratio. Although several small early trials suggested a benefitto aspirin,89,90 data from subsequent large, randomized, pla-cebo-controlled trials did not confirm these results.91,92

Despite these findings, some investigators believe thatlow-dose aspirin may be of benefit in selected women athigher risk for severe early-onset preeclampsia.93,94 Nearlyall existing studies on aspirin prophylaxis have been limitedby inconsistent definitions of preeclampsia and a narrowfocus on disease prevention.95 Future research may targetpharmacologic intervention as a component of treatment.

Calcium supplementation has been studied for pre-eclampsia prophylaxis on the basis of observations thatdietary calcium intake and the incidence of preeclampsiahave an inverse relationship.96 A meta-analysis of earlytrials suggested that prenatal administration of calciumsupplementation reduced the incidence of preeclampsia.97

However, these results were not confirmed in the mostdefinitive trial to date.98 In a multicenter, randomized,

Maintenance levels offree VEGF and PIGF

Normal endothelialfunction

Maternal vessel

Free VEGF and PIGF

Endothelial dysfunction

Maternal vessel

Multiorgan disease

• Hypertension

• Glomerular dysfunction

• Proteinuria

• Brain edema

• Liver edema

• Coagulation abnormalities

• No hypertension

• Normal glomerular function

• No proteinuria

• No brain edema

• No liver edema

• No coagulation abnormalities

Normal organ functionVessel

remodeling Blood flowincreases

Normoxia

sFlt-1

No vesselremodeling Blood flow

decreases

Hypoxia

sFlt-1

sFlt-1

?

Pla

cent

aU

teru

sP

lace

nta

Ute

rus

Preeclampsia

Normal pregnancyA

B

FIGURE 45-4 Hypothesis on the role ofsoluble fms-like tyrosine kinase-1 (sFlt-1) inpreeclampsia. A, During normal pregnancy,the uterine spiral arteries are infiltrated andremodeled by endovascular invasivetrophoblasts, thereby increasing blood flowsignificantly in order to meet the oxygenand nutrient demands of the fetus. B, Inthe placenta of preeclamptic women,trophoblast invasion does not occur andblood flow is reduced, resulting inplacental hypoxia. In addition, increasedamounts of sFlt-1 are produced by theplacenta and scavenge vascular endothelialgrowth factor (VEGF) and placentalgrowth factor (PlGF), thereby loweringcirculating levels of unbound VEGF andPlGF. This altered balance causesgeneralized endothelial dysfunction,resulting in multiorgan disease. It remainsunknown whether hypoxia is the triggerfor stimulating sFlt-1 secretion in theplacenta of preeclamptic mothers andwhether the higher sFlt-1 levels interferewith trophoblast invasion and spiral arteryremodeling. (From Luttun A, Carmeliet P.Soluble VEGF receptor Flt1: The elusivepreeclampsia factor discovered? J ClinInvest 2003; 111:600-2.)


placebo-controlled trial involving 2589 healthy nulliparouswomen, ingestion of 2 g of elemental calcium daily did notreduce the occurrence of preeclampsia or gestational hyper-tension either overall or in a subset of women with lowbaseline calcium intake.98

Antioxidant supplementation has also been investi-gated as prophylaxis because of the oxidative stress observedin preeclampsia. Numerous studies have been conducted toinvestigate a possible prophylactic or therapeutic role forantioxidant supplementation in the hypertensive disordersof pregnancy. However, in randomized trials, supplementa-tion with 1000 mg of vitamin C and 400 IU of vitamin E didnot reduce the incidence of preeclampsia in healthy nullip-arous women99 or in women at increased risk for preeclamp-sia.100,101 In a multicenter, randomized, placebo-controlledtrial of 2410 women with risk factors for preeclampsia, therewas a greater incidence of low birth weight, unexplained fetaldeath after 24 weeks’ gestation, and umbilical cord bloodacidosis in patients randomly assigned to the antioxidantgroup.101 Conversely, a different multicenter randomizedtrial did not find a higher risk of death or other adverse out-comes in the neonates born to antioxidant-supplementedmothers, although the results concurred about the lack ofbenefit from vitamin C and E supplementation in healthynulliparous women.99 Systematic reviews published in2005 caution that although vitamin C and E supplementationis not contraindicated in pregnancy, only limited data areavailable regarding the safety of high doses of these vitaminsin pregnant women.102,103

Clinical Manifestations

Preeclampsia occurs more frequently in nulliparous womenand most commonly manifests during the third trimester,often near term. Women with early-onset disease (prior to34 weeks’ gestation) have worse outcomes than womenwith late-onset disease. The disease typically regresses rap-idly after delivery, with resolution of symptoms within48 hours. However, preeclampsia can also manifest post-partum with hypertension, proteinuria, or the occurrence ofseizures. Postpartum preeclampsia usually manifests within7 days of delivery.104

Disease manifestations of severe preeclampsia occur inall body systems as the result of widespread endothelialdysfunction.

CENTRAL NERVOUS SYSTEMAlthough the term preeclampsia suggests that eclampsiais the end-stage of preeclampsia, it is more accurate toregard eclampsia as the outward manifestation of diseaseprogression in the brain, similar to other organ involve-ment. The etiology of eclamptic seizures remains unclear(see later). CNS manifestations include severe headache,visual disturbances, hyperexcitability, hyperreflexia, andcoma.7,105-107

Noninvasive measurements of cerebral blood flow andresistance suggest that the loss of cerebral vascular autoreg-ulation and vascular barotrauma are the main determinantsof the cerebral vascular changes seen in preeclampsia andeclampsia.108

Geneticfactors Oxidative

stress

Other factors

Growth restriction

Othermediators

Hypertension

sEng

sFlt-1

NK cells

AT1-AAs

Proteinuria

Other complications

Cerebraledema

Liverdysfunction

Placental dysfunction

O2-

O2-

O2-

O2-

O2-

O2-

FIGURE 45-5 Angiotensin receptor autoantibodies(AT1-AAs) in preeclampsia. AT1-AAs and otherfactors (such as oxidative stress and genetic factors)may cause placental dysfunction, which in turn leadsto the release of antiangiogenic factors (such assoluble fms-like tyrosine kinase-1 [sFlt-1] and solubleendoglin [sEng]) and other inflammatory mediators toinduce preeclampsia. AT1-AAs may also act directlyon the maternal vasculature to enhance angiotensin IIsensitivity and hypertension. NK, natural killer; O2

–,superoxide. (From Parikh SM, Karumanchi SA.Putting pressure on preeclampsia. Nat Med 2008;14:810-2.)


AIRWAYIn pregnant women, the internal diameter of the trachea isreduced because of mucosal capillary engorgement.In women with preeclampsia, these changes can be exag-gerated along with upper airway narrowing as a result ofpharyngolaryngeal edema, which may compromise visu-alization of airway landmarks during direct laryngoscopy.Subglottic edema can cause airway obstruction. Signs ofairway obstruction include hoarseness, snoring, stridor, andhypoxemia.109

PULMONARYPulmonary edema is a severe complication that occurs inapproximately 3% of women with preeclampsia.110 It is rel-atively uncommon in healthy younger women; the risk risesin older multigravid women and in women with preeclamp-sia superimposed on chronic hypertension or renal disease.

Plasma colloid osmotic pressure is diminished in normalpregnancy because of decreased plasma albumin concentra-tion, and it is reduced even further in preeclampticwomen.111 Women with normal pregnancies have meanosmotic pressures of approximately 22 mm Hg in thethird trimester and approximately 17 mm Hg during theearly postpartum period. In contrast, a study of women withpreeclampsia demonstrated mean colloid osmotic pressuresof approximately 18 mm Hg before delivery and 14 mm Hgafter delivery.112 Decreased colloid osmotic pressure, incombination with greater vascular permeability and theloss of intravascular fluid and protein into the interstitium,increases the risk of pulmonary edema and can result in theacute respiratory distress syndrome.113

CARDIOVASCULARWomen with preeclampsia have increased vascular toneand greater sensitivity to vasoconstrictor influences, lead-ing to the clinical manifestations of hypertension,vasospasm, and end-organ ischemia.114 Preeclampsia ischaracterized by severe vasospasm as well as exaggera-ted hemodynamic responses to circulating catechola-mines.79,115-117 Characteristically, blood pressure andsystemic vascular resistance are elevated. In mild disease,plasma volume may be normal; however, it may be reducedas much as 40% in women with severe disease.118

Severe preeclampsia is usually a hyperdynamic state.Many studies have attempted to characterize the hemody-namic characteristics of preeclampsia with the use of inva-sive monitoring techniques.119-124 Interpretation andcomparison of the results of these studies have been diffi-cult because of variation in patient populations, definitionsof preeclampsia, disease severity, prior treatment, and thepresence or absence of concomitant comorbid disease.Hemodynamic characteristics in preeclamptic women aremore complex than originally thought, in part becausehemodynamic measurements change with treatment anddisease progression. Overall, studies have found that themajority (approximately 80%) of affected women exhibithyperdynamic left ventricular function,122 mild to moder-ately increased systemic vascular resistance,122 and normalleft and right cardiac filling pressures.122,123 A smaller groupof women constituting a high-risk group present withdecreased left ventricular function, markedly reduced sys-temic vascular resistance, and severely decreased intravas-cular volume.122,125

HEMATOLOGICThrombocytopenia is the most common hematologicabnormality in women with preeclampsia, occurring in15% to 20% of affected women. Platelet counts less than100,000/mm3 occur most commonly in women withsevere disease or HELLP syndrome and correlate withboth the severity of the disease process and the incidenceof placental abruption.95

Studies using thromboelastrography have found thatwomen with mild preeclampsia are relatively hypercoagula-ble in comparison with women without preeclampsia, andthose with severe disease are relatively hypocoagulable.126

The syndrome of disseminated intravascular coagula-tion (DIC) occurs in some women with preeclampsia.Activation of the coagulation system is marked by theintravascular disappearance of procoagulants, the intravas-cular appearance of fibrin degradation products, and end-organ damage secondary to microthrombi formation.127 Inadvanced DIC, procoagulants (e.g., fibrinogen, platelets)decrease to a level that permits spontaneous hemorrhage.

HEPATICHepatic manifestations of preeclampsia include periportalhemorrhage and fibrin deposition in hepatic sinusoids.Damage ranges from mild hepatocellular necrosis to themore ominous HELLP syndrome and can be associatedwith potential subcapsular bleeding and risk of hepatic rup-ture. Spontaneous hepatic rupture is rare but is associatedwith a 32% maternal mortality rate.128

RENALRenal manifestations of preeclampsia include persistentproteinuria, changes in the glomerular filtration rate, andhyperuricemia. The presence of proteinuria is a definingelement of preeclampsia. The characteristic renal histologiclesion of preeclampsia is glomerular capillary endotheliosis,which manifests as glomerular enlargement and endothelialand mesangial cell swelling. Increasing urinary excretion ofprotein likely results from changes in the pore size orcharge selectivity of the glomerular filter and impairedproximal tubular reabsorption.129

During normal pregnancy, the glomerular filtrationrate (GFR) increases by 40% to 60% during the first tri-mester,130,131 with a resulting decrease in levels of theserum markers of renal clearance, including blood ureanitrogen (BUN), creatinine, and uric acid. In preeclampsia,the GFR is 34% lower than in normal pregnancy.129

Notably, women with preeclampsia may have BUN andcreatinine measurements in the normal range for nonpreg-nant women despite significantly decreased GFR relative tonormal pregnant women.

The association between preeclampsia and hyperurice-mia was recognized as early as 1917.132 Most evidence sug-gests that decreased renal clearance is the primarymechanism of elevated uric acid concentrations.133

Because levels of serum uric acid begin to increase asearly as 25 weeks’ gestation,134 this process has been inves-tigated as a possible early predictor of preeclampsia.However, a systematic review found that hyperuricemia isa poor predictor of maternal and fetal complications.135

Oliguria, a possible late manifestation of severe pre-eclampsia, parallels the severity of disease. Persistent oligu-ria (less than 400 mL urine output in 24 hours) requires


immediate assessment of intravascular volume status.Progression to renal failure is rare and is typically precededby hypovolemia, placental abruption, and/or DIC.

UTEROPLACENTAL BLOOD FLOWUteroplacental blood flow can be impaired in pregnanciescomplicated by preeclampsia. In contrast to normal preg-nancy, downstream resistance in the uteroplacental bedincreases, diastolic flow velocity decreases, and the systol-ic-to-diastolic flow velocity ratio increases in the womanwith preeclampsia.136 The systolic-to-diastolic blood pres-sure ratio, calculated from Doppler ultrasonographic deter-mination of blood flow velocities, reflects intrinsic arterialresistance. Pathophysiologic changes can lead to intrauter-ine fetal growth restriction (the fetal syndrome) in somepregnancies complicated by severe preeclampsia.

Obstetric Management

Optimal management of the woman with preeclampsiarequires a team approach. There is considerable overlapin areas of concern to the obstetrician and the anesthesiaprovider.

Obstetric management of preeclampsia centers on thefollowing: (1) fetal and maternal surveillance, (2) treatmentof hypertension, (3) seizure prophylaxis, (4) decisionsregarding the timing and route of delivery, and (5) admin-istration of corticosteroids to women with severe pre-eclampsia or HELLP syndrome. Delivery remains the onlycure. Obstetric care of the woman with mild preeclampsiadiffers little from routine management of healthy pregnantwomen, with the exception of careful monitoring so as todetect the progression of disease to severe preeclampsia.Pregnancy outcomes for women with mild disease at orbeyond 37 weeks’ gestation are similar to those forwomen with uncomplicated pregnancies.3

MATERNAL AND FETAL SURVEILLANCEMaternal surveillance is indicated for all preeclampticwomen. In women with mild disease, the goal is early detec-tion of severe disease. In women with severe disease, thegoal is detection of the development of organ dysfunction.All women should be evaluated for (1) severe headache,(2) visual disturbances, (3) altered mentation, (4) dyspnea,(5) right upper quadrant or epigastric pain, (6) nauseaand vomiting, (7) decreased urine output, and (8) CNShyperexcitability.7

Initial laboratory investigations for the pregnant womanin whom hypertension develops after 20 weeks’ gestationare listed in Table 45-4. The admission platelet count is anexcellent predictor of subsequent thrombocytopenia.137

For mildly preeclamptic women with a platelet countexceeding 100,000/mm3,137 further coagulation testing isnot required because coagulopathy is rarely present inseverely preeclamptic women who have a normal plateletcount.137 With a platelet count less than 100,000/mm3,other hemostatic abnormalities (e.g., prolongation of pro-thrombin time [PT] and partial thromboplastin time[PTT], and reduced fibrinogen concentration) may bepresent.137 Further coagulation studies may be useful, par-ticularly if risk factors for DIC are present (e.g., placentalabruption, HELLP syndrome). Liver function testsare obtained in all women with preeclampsia because

abnormal levels may prompt delivery. Approximately20% of preeclamptic women have elevated serum transam-inase measurements.138

Although there is widespread consensus that fetal sur-veillance is indicated as part of the expectant managementof women with severe preeclampsia, there is no universallyaccepted regimen of tests. Most obstetricians recommenddaily fetal movement counts with either nonstress testing orbiophysical profile testing at the time of diagnosis and atregular intervals thereafter.16 Ultrasonography is used toestimate fetal weight and amniotic fluid volume. Dopplerultrasonography is sometimes used to measure fetal bloodflow velocimetry if intrauterine growth restriction issuspected.139,140

TREATMENT OF ACUTE HYPERTENSIONAntihypertensive medications are used to treat severehypertension with the goal of preventing adverse maternalsequelae such as hypertensive encephalopathy, cerebrovas-cular hemorrhage, myocardial ischemia, and congestiveheart failure.16 There is no evidence to suggest that antihy-pertensive therapy delays progression of the disease orimproves perinatal outcome.141 The obstetrician usuallyinitiates antihypertensive therapy, although the anesthesiaprovider may also be involved in acute events.

Although the acute control of maternal blood pressure iscritical, rapid changes in maternal perfusion pressure may

TABLE 45-4 Initial Laboratory Investigations for PregnantWomen in Whom Hypertension Develops after 20 Weeks’Gestation

Test Rationale

Hemoglobin andhematocrit

Hemoconcentration supportsdiagnosis of preeclampsia and is anindicator of severity.

Measurements are decreased ifhemolysis is present.

Platelet count Thrombocytopenia suggests severepreeclampsia.

Quantificationof proteinexcretion

Pregnancy-associated hypertensionwith proteinuria should beconsidered preeclampsia (pure orsuperimposed) until provenotherwise.

Serum creatinine Abnormal or rising creatinine levelsuggests severe preeclampsia,especially in presence of oliguria.

Serumtransaminase

Rising serum transaminasemeasurements suggest severepreeclampsia with hepaticinvolvement.

Serum uric acid Increased serum uric acid levelssuggest the diagnosis ofpreeclampsia.

Adapted from the Report of the National High Blood Pressure

Education Program Working Group on High Blood Pressure in

Pregnancy. Am J Obstet Gynecol 2000; 183:S1-22.


adversely affect uteroplacental perfusion and oxygen deliv-ery to the fetus. Antihypertensive medications should becarefully titrated to avoid abrupt changes in maternalblood pressure. The aim of therapy is to lower the meanarterial blood pressure by no more than 15% to 25%, with atarget diastolic blood pressure of 100 to 105 mm Hg.142

Commonly used drugs are hydralazine, labetalol, esmolol,and sodium nitroprusside (Table 45-5); in usual clinicaldoses, all are considered safe for the fetus.

Hydralazine

Hydralazine has been used safely in pregnant women fordecades and has been considered the drug of choice fortreating severe hypertension in preeclampsia. Hydralazineexerts a potent and direct vasodilating effect. Plasmavolume expansion prior to its administration decreasesthe risk of maternal hypotension. Other side effectsinclude tachycardia, palpitations, headache, and neonatalthrombocytopenia.143,144

Labetalol

Labetalol, formerly considered second-line therapy forsevere hypertension, is now also advocated as first-linetherapy.145 It is a combined alpha- and beta-adrenergicreceptor antagonist with a 1:7 ratio of alpha- to beta-adrenergic receptor antagonism when administered intra-venously. Labetalol should be avoided in women withsevere asthma or congestive heart failure.146

A systematic review147 and a meta-analysis148 of existingsmall, randomized controlled trials concluded that the effi-cacy of intravenous labetalol is similar to that of intrave-nous hydralazine but with fewer maternal side effects.In the largest randomized trial to date, hydralazine was as-sociated with more maternal tachycardia and palpitations

but less neonatal bradycardia and hypotension than labet-alol.149 Both antihypertensive drugs are considered safe andeffective for the treatment of severe hypertension in preg-nant women.

Esmolol

Concerns about the use of esmolol during pregnancy arosein 1989, following reports of dose-dependent prolongedfetal bradycardia in a study of gravid ewes receiving esmo-lol by stepped infusion.150 Subsequent human case reportshave reported variable responses,151-153 but in most casesfetal bradycardia was transient and the fetal heart rate(FHR) returned to baseline after discontinuation of thedrug. Placental transfer is rapid, and the anesthesia pro-vider should expect to observe the clinical effects of beta-adrenergic receptor blockade in the fetus. Eisenach andCastro150 demonstrated that maternal administration ofesmolol produced similar levels of beta-adrenergic recep-tor blockade in both gravid ewes and fetal lambs, in con-trast to the lesser extent of beta-adrenergic blockadeobserved in fetal lambs after maternal labetaloladministration.154

Sodium Nitroprusside

Sodium nitroprusside is a powerful smooth musclevasodilator that interacts with sulfhydryl groups on endo-thelial cells and results in the release of nitric oxide.155,156

Occasionally administered to preeclamptic women whoshow no response to hydralazine or labetalol therapy,sodium nitroprusside relaxes arterial vessels and reducesboth afterload and venous return, with an almost instan-taneous onset of action.

Sodium nitroprusside is a potent drug that requires care-ful titration; continuous intra-arterial blood pressure mon-itoring is mandatory. Because sodium nitroprussidemetabolism produces cyanide, which undergoes placentaltransfer, there is a potential risk of fetal cyanide toxicity.However, fetal harm is unlikely to result from short-termuse of sodium nitroprusside in clinical doses of 2 mg/kg/minor less. The drug is typically used for a limited period oftime as a bridge to delivery.

Nifedipine

Nifedipine, a calcium entry–blocking drug, lowers bloodpressure by relaxing arterial and arteriolar smooth muscle.Although it has been used in pregnant women for the treat-ment of acute severe hypertension, its sublingual adminis-tration has been associated with cerebral ischemia andinfarction, myocardial infarction, complete heartblock, and death.157 Sublingual nifedipine has not beenendorsed by the American College of Obstetricians andGynecologists (ACOG) for treatment of acute severe hyper-tension in pregnancy, and the U.S. Food and DrugAdministration (FDA) has not approved sublingual nifedi-pine for the treatment of a hypertensive emergency in anypatient group.158

Nifedipine interactions with magnesium sulfate mayhave adverse effects in both mother and fetus. Severe hy-potension159,160 and neuromuscular blockade161,162 havebeen reported with concurrent use of the two drugs.Nonreassuring FHR patterns have also been reported withconcurrent administration of nifedipine and magnesiumsulfate.159,160

TABLE 45-5 Treatment of Acute Severe Hypertension*In Preeclampsia/Eclampsia

MedicationOnset ofActiony Dose

Hydralazine 10-20 min 5 mg IV every 20 min upto maximum dose of20 mg IV

Labetalol 5-10 min 20 mg IV, then additionaldoses every 10 min, asneeded, up tomaximum dose of220 mg IV

Sodiumnitroprussidez

0.5-1 min 0.25-5 mg/kg/min IVinfusion

IV, intravenously.

*Blood pressure � 160 mm Hg systolic, � 105 mm Hg diastolic,

or both, if sustained.

yFrom Stoelting R, Hillier S. Pharmacology & Physiology in

Anesthetic Practice. Philadelphia, Lippincott Williams & Wilkins,

2006.

zRisk of fetal cyanide poisoning with treatment >4 hours.

Adapted from the Report of the National High Blood Pressure




SEIZURE PROPHYLAXISThe routine use of magnesium sulfate for seizure prophy-laxis in women with severe preeclampsia is an establishedobstetric practice in the United States and has gained pop-ularity throughout the world. There is clear evidence thatmagnesium sulfate is the best available agent for preventionof recurrent seizures in women with eclampsia163,164; thusits use has been extended to seizure prophylaxis in womenwith preeclampsia.

What is the evidence for the efficacy of magnesium sul-fate in the prevention of seizures for women with pre-eclampsia? Randomized trials have compared theadministration of magnesium sulfate to prevent seizuresin women with severe preeclampsia with that of pla-cebo165,166 and with use of the cerebral vasodilator nimodi-pine.167 Sibai168 reviewed available randomized trials andconcluded that administration of magnesium sulfate isassociated with significantly lower rates of eclampsia.Although this agent is effective at preventing seizures,there is no evidence that administration of magnesium sul-fate improves overall outcomes. Specifically, there is no evi-dence that use of magnesium sulfate lowers the incidence ofmaternal mortality or placental abruption. In addition,magnesium sulfate was associated with a significantincrease in the rate of respiratory depression in all trials.168

Similarly, there is no evidence for improved perinataloutcomes with prophylactic magnesium sulfate administra-tion. Prophylactic magnesium sulfate did not reduce therate of perinatal death in randomized trials,165,167,169 nordid it increase perinatal morbidity (i.e., respiratory distress,Apgar scores less than 7 at 5 minutes, need for intubation,or days in the neonatal intensive care unit).166,167 In thepast, higher rates of fetal, neonatal, and pediatric deathshave been described with maternally administered magne-sium sulfate at higher doses for tocolysis.170 In contempo-rary obstetric practice, magnesium is no longerrecommended for this indication, and doses used for sei-zure prophylaxis do not exceed 2 g/hr.

Only two well-controlled trials have evaluated the use ofmagnesium sulfate for seizure prevention in mild pre-eclampsia. In both studies, there was no difference in thenumber of women who progressed to severe preeclamp-sia.171,172 The risk-to-benefit ratio of magnesium sulfateprophylaxis in mild preeclampsia is unclear and does notjustify its routine use for prevention of seizures.168

The mechanism of the anticonvulsant effect of magne-sium is not well understood. Eclamptic seizures were pre-viously thought to result from cerebral vasospasm, and itwas also believed that the cerebrovasodilating properties ofmagnesium reduced the rate of eclamptic seizures byrelieving vasospasm.173 However, more recent evidencesuggests that abrupt, sustained blood pressure elevationoverwhelms myogenic vasoconstriction and causes forceddilation of the cerebral vessels, hyperperfusion, and cere-bral edema.108,173-175 This raises the question of howmagnesium sulfate—a vasodilator—could be effective inseizure prophylaxis; magnesium would be expected toworsen cerebral hyperperfusion and edema. Using a ratmodel, Euser and Cipolla173 demonstrated that the mesen-teric vessels are more sensitive to magnesium-inducedvasodilation than cerebral vessels. Their observations sug-gest that the effectiveness of magnesium sulfate seizureprophylaxis is more closely related to lowering of the

systemic blood pressure than to direct effects on cerebralblood flow.

No consensus exists regarding the following issues: (1)the ideal time to initiate treatment with magnesium sulfate,(2) the best loading and maintenance doses, and (3) theoptimal duration of therapy. Many obstetricians administera loading dose of 4 to 6 g over 20 to 30 minutes, followed bya maintenance infusion of 1 to 2 g/hr. The infusion is com-monly initiated with the onset of labor and continued for 24hours postpartum. Sibai168 has recommended that severelypreeclamptic women undergoing cesarean delivery shouldreceive magnesium sulfate at least 2 hours before the pro-cedure, during surgery, and for 12 hours postpartum.

Magnesium sulfate is eliminated almost entirely by renalexcretion, and serum levels of this agent may become dan-gerously high in the presence of renal insufficiency. Sideeffects include chest pain and tightness, palpitations,nausea, blurred vision, sedation, transient hypotension,and rarely pulmonary edema.166,176-178 In untreatedpatients, the normal range for serum magnesium concen-trations is 1.7 to 2.4 mg/dL. The therapeutic range liesbetween 5 and 9 mg/dL.172 Reflex testing is used as a clin-ical screen for hypermagnesemia; when deep tendonreflexes are preserved, the more serious side effects areusually avoided. Patellar reflexes are lost at serum magne-sium levels of approximately 12 mg/dL. Respiratory arrestoccurs at 15 to 20 mg/dL, and asystole occurs when thelevel exceeds 25 mg/dL.179 Preeclamptic women withrenal impairment should be monitored closely becausemagnesium toxicity can occur with usual dosing regimens.Serial measurement of serum magnesium levels may behelpful in the management of women with renaldysfunction.

Treatment of suspected magnesium toxicity involvesimmediate discontinuation of the infusion and the intrave-nous administration of calcium gluconate (1 g) over 10minutes.180 In the rare event of respiratory compromise,the patient may require endotracheal intubation andmechanical ventilation until spontaneous ventilationreturns.

In the developing world, a lack of infrastructure, equip-ment, and expertise precludes the timely administration ofintravenous magnesium sulfate in most women with severepreeclampsia. A lack of resources for the treatment of sys-temic magnesium toxicity is also an obstacle to the use ofmagnesium sulfate. Labetalol has been proposed as a prac-tical, inexpensive, orally administered alternative forwomen in developing countries.181

In summary, published evidence supports the adminis-tration of magnesium sulfate for the prevention of eclamp-tic seizures, but there is no evidence of better maternal orneonatal outcomes as a result of its use.

ROUTE AND TIMING OF DELIVERYVaginal delivery should be attempted in all women withmild disease, assuming no other indications for cesareandelivery exist. Vaginal delivery should also be attemptedin most women with severe disease, especially thosebeyond 34 weeks’ gestation.7,182 The Report of theNHBPEP Working Group on High Blood Pressure inPregnancy7 states, ‘‘Vaginal delivery is preferable to cesar-ean delivery for women with preeclampsia, because itavoids addition of the stress of surgery to the multiple


physiologic aberrations [of the disease]. Acute palliation forseveral hours does not increase maternal risk if performedappropriately. Labor induction should be carried outaggressively once the decision for delivery has been made.In gestation remote from term in which delivery is indi-cated, and with fetal and maternal conditions stableenough to permit pregnancy to be prolonged 48 hours,glucocorticoids can be safely administered to acceleratefetal pulmonary maturity.’’ Cesarean delivery is appropriatewhen the maternal or fetal condition mandates immediatedelivery or when other indications for cesarean deliveryexist (Table 45-6).

The timing of delivery can be difficult and requires theobstetrician to weigh the risks and benefits for boththe mother and fetus. The primary objective of obstetricmanagement of preeclampsia is the safety of the mother.Delivery is always an appropriate therapeutic option for themother but may not be in the best interests of the verypreterm fetus. Immediate delivery increases neonatalmorbidity and mortality and can lead to prolonged neonatalintensive care unit stays for the treatment of the complica-tions of prematurity. Conversely, attempts to prolongpregnancy increase the risk of maternal morbidity and mor-tality and can also lead to intrauterine fetal asphyxia ordeath. The obstetric management plan should considermaternal and fetal status at the time of initial assessment,fetal gestational age, the presence or absence of labor, andstatus of the fetal membranes (i.e., intact versus ruptured).182

The clinical course of severe preeclampsia is marked byprogressive deterioration of both the maternal and fetalconditions.183 Because these pregnancies are associatedwith high rates of maternal morbidity and mortality, thereis widespread agreement that delivery is indicated if severedisease develops after 34 weeks’ gestation. Women withrefractory severe hypertension despite maximum doses ofantihypertensive agents or women who have persistentcerebral symptoms while receiving magnesium sulfate aredelivered within 24 to 48 hours, regardless of gestationalage. Other clear indications for delivery include severe intra-uterine growth restriction, multiple-organ failure, suspectedplacental abruption, and nonreassuring fetal testing before34 weeks’ gestation.183,184 In contrast, the management of

severe preeclampsia remote from term—with evidence ofboth maternal and fetal stability—remains controversial.

Expectant management, an alternative to immediateintervention, refers to the prolongation of pregnancy withclose monitoring until (1) the development of maternal orfetal indications for delivery, (2) the attainment of fetal lungmaturity, or (3) 34 weeks’ gestation. The goal is the safeprolongation of gestation in order to optimize perinataloutcome. Two randomized trials185,186 have compared therisks and benefits of aggressive and conservative (expectant)management of severe preeclampsia. Aggressive manage-ment was defined as corticosteroid therapy followed bydelivery within 48 hours, and expectant management con-sisted of corticosteroid therapy followed by delivery only forspecific maternal or fetal indications. Both trials demon-strated that conservative management was associated withbetter perinatal outcome, with reasonable maternal safety.In the largest trial of expectant management, Sibai et al.186

studied 95 women with severe preeclampsia at 28 to 32weeks’ gestation, managed either expectantly or aggres-sively, and found a significant prolongation of pregnancy,shorter stays in the neonatal intensive care unit, and a lowerincidence of neonatal respiratory distress syndrome in theexpectant management group, without any increase in theincidence of maternal complications.

CORTICOSTEROID ADMINISTRATION FOR SEVEREPREECLAMPSIA OR HELLP SYNDROMETo accelerate fetal lung maturity, all women in whomsevere preeclampsia or HELLP syndrome develops between24 and 34 weeks’ gestation should receive a course of cor-ticosteroid therapy. A randomized double-blind trial of 218women with severe preeclampsia at 26 to 34 weeks’ gesta-tion found that those receiving betamethasone, comparedwith those receiving placebo, had a significantly lower rateof neonatal respiratory distress syndrome as well as reducedrates of neonatal intraventricular hemorrhage, infection,and death.187

Complications of Preeclampsia

Severe preeclampsia is associated with an increased risk ofmaternal morbidity and mortality, including HELLP syn-drome, cerebrovascular accident, pulmonary edema, renalfailure, placental abruption, and eclampsia. In general, thesecomplications are more common in women with early-onset preeclampsia and in women with prepregnancy med-ical conditions such as diabetes mellitus, chronic renal dis-ease, and thrombophilia.1

CEREBROVASCULAR ACCIDENTAlthough the absolute risk of cerebrovascular accident islow, stroke remains the leading cause of death in womenwith preeclampsia. In the 2003-2005 Confidential Enquiryinto Maternal and Child Health (CEMACH) report,18 deaths were attributed to eclampsia and preeclampsia;67% resulted from a cerebrovascular accident (10 intracra-nial hemorrhages and 2 cerebral infarctions).188 The endo-thelial dysfunction of preeclampsia can promote edema,vascular tone instability, platelet activation, and localthrombosis. Reversible cerebral edema is the mostcommon CNS feature of preeclampsia or eclampsia. Theleading hypothesis regarding the loss of endothelial

TABLE 45-6 Indications for Delivery in Severe Preeclampsia

Maternal Gestational age � 38 weeks*Platelet count < 100,000/mm3

Progressive deterioration in hepatic functionProgressive deterioration in renal functionSuspected placental abruptionPersistent severe headaches or visual changesPersistent severe epigastric pain, nausea, or

vomitingFetal Severe intrauterine growth restriction

Nonreassuring fetal statusOligohydramnios

*Delivery should be based on maternal and fetal conditions as well

as on gestational age.

Adapted from Report of the National High Blood Pressure




integrity is that cerebral lesions are caused by a loss ofcerebral autoregulation, which results in hyperperfusionthat leads to interstitial or vasogenic edema.189,190 The pres-ence of HELLP syndrome or DIC increases the risk for ahemorrhagic event.

There is growing recognition that mean arterial bloodpressure and diastolic blood pressure may not reflect thetrue risk for stroke. A review of 28 case histories of severelypreeclamptic women who suffered a stroke revealed that(1) systolic blood pressure in excess of 160 mm Hg was afar superior predictor of stroke than diastolic hypertensionor mean arterial pressure, (2) the majority of strokes werehemorrhagic (93%) as opposed to thrombotic (7%), and(3) the majority of strokes (57%) occurred in the postpar-tum period.191 Close attention to blood pressure controlthroughout the peripartum period is the mainstay ofstroke prevention.

PULMONARY EDEMAPulmonary edema is a severe complication of preeclampsiathat occurs in approximately 3% of affected women.110 It isrelatively infrequent in younger (previously healthy)women; the risk is higher in older multigravid womenand in women with preeclampsia superimposed on chronichypertension or renal disease. The clinical presentation ischaracterized by worsening dyspnea and orthopnea withconcomitant signs of respiratory compromise, such astachypnea, rales, and hypoxemia. Causes of pulmonaryedema include low colloid osmotic pressure, increasedintravascular hydrostatic pressure, and greater pulmonarycapillary permeability.192 All of these factors may coexist ina single patient. A large proportion of cases of pulmonaryedema occur postpartum, usually within 2 to 3 days ofdelivery, and management is directed toward the underly-ing cause (e.g., fluid overload, sepsis, cardiac failure).193

Echocardiography can be helpful in the diagnosis of cardio-genic causes of pulmonary edema.194,195 Initial treatmentincludes administration of supplemental oxygen, fluidrestriction, and diuretic therapy (e.g., furosemide). A retro-spective study of more than 16,000 deliveries found thatalthough peripartum pulmonary edema was associatedwith extensive radiographic infiltrates and severe hypoxe-mia, resolution was typically rapid, with a limited need forintensive care unit admission.196 Placement of a pulmonaryartery catheter can facilitate management of patients withsevere refractory pulmonary edema; these women shouldbe managed in an intensive care unit. Notably, in the2003-2005 CEMACH report, there were no deaths attribu-ted solely to pulmonary causes.188 Presumably, this trendreflects improvements in the fluid management of womenwith severe preeclampsia.

RENAL FAILUREAcute renal failure is a rare but serious complication ofsevere preeclampsia and HELLP syndrome.197 The trueincidence remains unknown. Acute renal failure is dividedinto three categories: (1) prerenal, which refers to renalhypoperfusion; (2) intrarenal, which suggests intrinsicrenal parenchymal damage; and (3) postrenal, whichimplies obstructive uropathy.198 The majority of cases(83% to 90%) of acute renal failure in preeclampsia resultfrom prerenal and intrarenal disease (most commonlyacute tubular necrosis) and resolve completely after

delivery.199-201 In contrast, bilateral renal cortical necrosisis a rare and serious condition associated with considerablematernal and perinatal morbidity and mortality. It occursmost commonly in association with known renal parenchy-mal disease, chronic hypertension with superimposedpreeclampsia, placental abruption, or DIC.202

PLACENTAL ABRUPTIONPlacental abruption occurs in approximately 2% of womenwith preeclampsia and increases perinatal morbidityand mortality. A retrospective case-control study of161 women with placental abruption and 2000 womenwithout abruption found a threefold higher risk of placentalabruption in women with preeclampsia.203 The incidenceis also increased in women with underlying chronic hyper-tension.193 Management depends on the extent of abrup-tion and associated hypotension, coagulopathy, or fetalcompromise (see Chapter 37). Placental abruption is alsoassociated with the development of DIC.

HELLP Syndrome

HELLP syndrome is a variant of severe preeclampsia char-acterized by rapid clinical deterioration. It is associated witha higher risk of maternal death (1%) and increased rates ofmaternal morbidities, including DIC, placental abruption,pulmonary edema, acute renal failure, liver hemorrhage orfailure, acute respiratory distress syndrome, sepsis, andstroke (Table 45-7).204 Additionally, the syndrome is asso-ciated with a 70% rate of preterm delivery204; prematurity-related neonatal complications increase the risk of perinatalmorbidity and mortality. The onset of HELLP syndromeoccurs antepartum in 70% of cases, and postpartum in30%.204

TABLE 45-7 Serious Maternal Complications in a Series of442 Patients with Hemolysis, Elevated Liver Enzymes, andLow Platelets (HELLP) Syndrome

Patients Affected

Complication* No. Percentage

Disseminated intravascularcoagulation

92 21

Placental abruption 69 16Acute renal failure 33 8Severe ascites 32 8Pulmonary edema 26 6Pleural effusions 26 6Cerebral edema 4 1Retinal detachment 4 1Laryngeal edema 4 1Subcapsular liver hematoma 4 1Acute respiratory distress

syndrome3 1

Maternal death 4 1

*Some women had multiple complications.

Adapted 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

Obstet Gynecol 1993; 169:1000-6.


Because of a lack of universally accepted diagnostic cri-teria for HELLP syndrome, its incidence cannot be deter-mined accurately. The existence of a subset of cases ofpreeclampsia complicated by abnormal peripheral bloodsmear findings, abnormal liver function parameters, andthrombocytopenia has been recognized for decades; in1982, Weinstein205 described a series of 29 cases andcoined the acronym HELLP. Women who do not demon-strate one or more of these clinical features are said to have‘‘partial’’ HELLP syndrome.

The definition and diagnosis of HELLP syndrome remaincontroversial. Hemolysis, defined as the presence ofmicroangiopathic hemolytic anemia, is the hallmark ofHELLP syndrome; peripheral blood smear demonstratesschistocytes, burr cells, and echinocytes.206 Common histo-pathologic findings are periportal hepatic necrosis andhemorrhage.207 Sibai206 has proposed standardized labora-tory diagnostic criteria, as outlined in Table 45-8. Maternalsigns and symptoms include right upper quadrant or epi-gastric pain, nausea and vomiting, headache, hypertension,and proteinuria. Notably, clinical presentation varies; 12%to 18% of women may be normotensive, and proteinuria isabsent in approximately 13%. Diagnosis can be especiallychallenging because numerous medical and surgical disor-ders can mimic HELLP syndrome (Box 45-3). Pregnantwomen who are likely to have preeclampsia, but who dem-onstrate atypical symptoms, should be screened with acomplete blood count, platelet count, and liver enzymeassessment.

The management of HELLP syndrome is also highly con-troversial. Owing to associated maternal morbidity andmortality, obstetricians have considered HELLP syndrometo be an indication for immediate delivery. There is con-sensus regarding the need for immediate delivery whenHELLP syndrome manifests beyond 34 weeks’ gestationor in the presence of complications such as DIC, liverinfarction or hemorrhage, renal failure, placental abruption,and nonreassuring fetal status. On the other hand, substan-tial disagreement exists regarding the management ofwomen with stable maternal and fetal conditions at orbefore 34 weeks’ gestation. Some authorities have recom-mended the administration of corticosteroids to acceleratefetal lung maturity, followed by delivery 24 hours

later,206,208 and others have recommended prolongation ofpregnancy until the development of complications, untilfetal lung maturity is achieved, or until 34 weeks’ gesta-tion.209-211 Some reports have suggested that in a selectgroup of women, pregnancy can be prolonged fordays—and possibly a few weeks—with associated improve-ment in laboratory measurements.209-212

Women in whom HELLP syndrome is suspected shouldbe immediately hospitalized for observation in a labor anddelivery unit; women who have not reached 35 weeks’ ges-tation should be managed in a tertiary care facility with aneonatal intensive care unit capable of caring for a compro-mised preterm neonate. Clinical management is similar tothat for severe preeclampsia and includes intravenous mag-nesium sulfate for seizure prophylaxis and antihypertensivemedications to maintain a systolic blood pressure below160 mm Hg and a diastolic blood pressure below 105 mmHg.206 The first priority is to assess and stabilize the mater-nal condition, with particular attention given to hyperten-sion and coagulation abnormalities. Next, the fetalcondition should be assessed with FHR monitoring,Doppler ultrasonography of fetal vessels, and/or a biophys-ical profile. Lastly, decisions regarding delivery must bemade. If time permits, the mother should receive a courseof corticosteroids to accelerate fetal lung maturity.

The platelet count can fall precipitously in the presenceof HELLP syndrome, and it should be evaluated prior to theadministration of neuraxial anesthesia. Women with aplatelet count less than 50,000/mm3 are at significantlyhigher risk of bleeding,213 and general anesthesia is themethod of choice for cesarean delivery. O’Brien et al.208

assessed the impact of corticosteroid administration onthe subsequent use of epidural anesthesia in 37 womenwith HELLP syndrome and a pre-corticosteroid plateletcount less than 90,000/mm3; corticosteroid administrationwas followed by greater use of epidural anesthesia,

TABLE 45-8 Diagnostic Criteria for Hemolysis, ElevatedLiver Enzymes, and Low Platelets (HELLP) Syndrome

Criteria Laboratory Findings

Hemolysis Abnormal peripheral blood smearBilirubin > 1.2 mg/dLLactic dehydrogenase > 600 IU/L

Elevated liverenzymeconcentrations

Serum glutamic oxaloacetictransaminase (SGOT) � 70 IU/L

Lactic dehydrogenase > 600 IU/LThrombocytopenia Platelet count < 100,000/mm3

From Sibai BM. The HELLP syndrome (hemolysis, elevated liver

enzymes, and low platelets): Much ado about nothing? Am J


BOX 45-3 Differential Diagnosis of Hemolysis, ElevatedLiver Enzymes, and Low Platelets (HELLP) Syndrome

� Acute fatty liver of pregnancy� Appendicitis� Cholestasis of pregnancy� Diabetes insipidus� Gallbladder disease� Gastroenteritis� Glomerulonephritis� Hemolytic-uremic syndrome� Hepatic encephalopathy� Hyperemesis gravidarum� Idiopathic thrombocytopenia� Kidney stones� Peptic ulcer� Systemic lupus erythematosus� Thrombotic thrombocytopenic purpura� Viral hepatitis

From O’Brien JM, Barton JR. Controversies with the diagnosis and

management of HELLP syndrome. Clin Obstet Gynecol 2005;

48:460-77.


particularly in women in whom the interval between corti-costeroid administration and delivery was at least 24 hours.

Platelet transfusions are indicated in the presence ofsignificant bleeding and in all parturients with a plateletcount lower than 20,000/mm3. Correction of thrombocyto-penia prior to surgery is crucial; for women who have aplatelet count less than 40,000/mm3 and who are scheduledfor cesarean delivery, the preincision administration of 6 to10 units of platelets has been recommended.214

Rupture of a subcapsular hematoma of the liver is alife-threatening complication of HELLP syndrome that canmanifest as abdominal pain, nausea and vomiting, andheadaches; the pain worsens over time and becomes local-ized to the epigastric area or right upper quadrant.Hypotension and shock typically develop, and the liver isenlarged and tender.215 Diagnosis is confirmed with ultra-sonography, computed tomography, or magnetic resonanceimaging of the liver (Figure 45-6). Subcapsular hematomarupture with shock is a surgical emergency that requiresimmediate multidisciplinary treatment consisting of intra-vascular volume resuscitation, blood and plasma transfu-sions, and emergency laparotomy.215 Prompt surgicalintervention and refinements in surgical technique havereduced the maternal mortality rate associated with spon-taneous hepatic rupture from 60% in 1976 to 30% in1997.128,216 Selective arterial embolization by an interven-tional radiologist might allow a further reduction in the riskof maternal death.217-219 The most common causes of deathare coagulopathy and exsanguination.204,220

Conservative management is recommended for hepatichemorrhage without hepatic rupture in stable women.214

Careful monitoring is required. An important componentof conservative management is to avoid all potential traumato the liver, including seizures, vomiting, and manual pal-pation of the abdomen. Patient transport and transfersshould be conducted with care to avoid maneuvers thatmight result in hematoma rupture.

Anesthetic Management

The anesthetic management of the woman with mild pre-eclampsia differs little from the management of a healthypregnant woman. However, the potential for rapid progres-sion to the severe form of the disease mandates carefulobservation of the patient. The anesthesia provider mustrecognize the unpredictability of the development and pro-gression of severe preeclampsia and should be prepared atall times for immediate cesarean delivery.

PREANESTHESIA EVALUATIONThe preanesthesia assessment of women with confirmed orsuspected preeclampsia should focus on the airway exam-ination, maternal hemodynamic and coagulation status, andfluid balance.

Airway

Generalized edema can involve the airway andobscure visualization of anatomic landmarks at laryngos-copy. The anesthesia provider should anticipate the pos-sibility of a difficult airway (see Chapter 30).

Hemodynamic Monitoring

Systemic arterial blood pressure can change rapidly inwomen with severe preeclampsia, both as a result of diseaseprogression and in response to the administration of intra-venous fluids and antihypertensive drugs. In addition, pre-eclampsia is associated with variable degrees ofintravascular volume depletion, and the clinical assessmentof intravascular volume status can be difficult. Therefore,the use of invasive vascular monitoring may be useful in themanagement of some women with severe preeclampsia.

Indications for continuous arterial blood pressure mon-itoring are straightforward and well-accepted. The mostcommon indications for radial artery catheter insertioninclude (1) poorly controlled maternal blood pressure;(2) need for frequent arterial blood gas measurements,especially in the context of pulmonary edema; (3) planneduse of a rapid-acting vasodilator (e.g., nitroprusside, nitro-glycerin); (4) desire to estimate intravascular volume statuswith use of calculated systolic pressure variation (SPV);221

and (5) need for continuous blood pressure monitoringduring the induction of general anesthesia in hypertensivewomen with severe preeclampsia.

Invasive central monitoring has been advocated in theassessment of oliguria and to monitor patient responses tofluid administration. Anesthesiologists have debated therelative merits and risks of placement of a central venouspressure (CVP) catheter compared with a pulmonaryartery catheter. The poor correlation between the centralvenous and pulmonary capillary wedge pressures (inpatients with a CVP greater than 6 mm Hg) has beencited as the rationale for the preferential use of the pul-monary artery catheter for accurate assessment of the leftventricular preload.222,223 However, this lack of correlationis an expected finding in the presence of decreased intra-vascular volume and varying levels of increased left ven-tricular afterload.109

The use of a pulmonary artery catheter has not beendemonstrated to improve patient outcome. Studies in avariety of populations have not found a benefit to therapydirected by pulmonary artery catheter measurements rather

FIGURE 45-6 Contrast-enhanced computed tomography scanshowing a large area of parenchymal hemorrhage with hepaticrupture (arrow) and subcapsular hematoma (star) in the right lobe ofthe liver. (From Das CJ, Srivastava DN, Debnath J, et al. Endovascularmanagement of hepatic hemorrhage and subcapsular hematoma inHELLP syndrome. Indian J Gastroenterol 2007; 26:244-5.)


than standard care.224 The American Society ofAnesthesiologists (ASA) Task Force on Pulmonary ArteryCatheterization has stated:

Evidence regarding the effectiveness of pulmonary arterycatheterization in obstetrics and gynecology is lacking.Pulmonary catheterization has been recommended forsevere preeclampsia, case reports have supported itsvalue, and its use in critical illness seems common, butcontrolled clinical outcome studies have not beenreported.225

Further, the placement of an invasive CVP or pulmonaryartery catheter is not a benign procedure. Well-recognizedrisks include arterial trauma, pneumothorax, venous airembolism, neuropathy, and cardiac arrhythmias.Additional risks of an indwelling pulmonary artery catheterinclude potentially fatal pulmonary artery hemorrhage,thromboembolism, sepsis, and endocardial damage.225

The 1991-1993 Report on Confidential Enquiries intoMaternal Deaths in the United Kingdom226 described thepostpartum death of a woman after several unsuccessfulattempts at internal jugular line placement and a likely car-otid artery puncture. Despite digital pressure and applica-tion of a pressure dressing after vessel puncture, necktightness and dyspnea developed 4 hours later. Attemptsat re-intubation and resuscitation were unsuccessful, andshe expired. In the 2003-2005 CEMACH report, ananesthesia-related maternal death occurred in a womanwith fulminant preeclampsia and HELLP syndrome.188

Shortly after a subclavian line insertion, she had a cardiacarrest and could not be resuscitated. Autopsy showed alarge right hemothorax. Because both immediate anddelayed227 maternal deaths have been attributed to theuse of invasive central catheters, they should be insertedonly after careful consideration of the risks and benefits.

The frequency of pulmonary artery catheter use in obstet-ric anesthesia practice is low.228 When invasive central mon-itoring is desired, a CVP catheter is adequate in the majorityof cases. A CVP catheter provides a reliable method ofcentral venous drug administration, and assessment ofchanges in CVP over time may guide fluid administration.

Timing of the use of invasive central monitoring isimportant and requires clinical judgment. Many patientsare better served by immediate transfer to the operatingroom for delivery rather than delay of delivery for centralline placement. In one study of a critical care unit inan academic hospital, the time from the decision to proceedwith placement of a pulmonary artery catheter until the firstpressure measurement was obtained was always more than45 minutes.229 Insertion time would probably exceed45 minutes in most labor and delivery settings, where theprocedure is rarely performed and qualified assistance maynot be available. In the majority of cases, the preoperativeplacement of an invasive central line will not change theintraoperative anesthetic management. Similarly, manyobstetricians prefer to deliver women with persistent oligu-ria (defined as less than 400 mL of urine output in 24 hours)and to optimize fluid status postoperatively.230

In summary, the presence of severe preeclampsia per seis not an indication for CVP or pulmonary artery pressuremonitoring. There is no indication for central hemodynam-ic monitoring that is unique to preeclampsia. Preeclampsiais a disorder of the peripheral circulation, not the central

circulation. Indications for invasive central monitoring aresimilar to those in other multisystem disorders, such assevere sepsis, multisystem organ dysfunction, pulmonaryedema, and cardiomyopathy. Some women require transferto an intensive care unit for specialized nursing care andmanagement directed by a critical care medicine specialist.

NEURAXIAL ANALGESIA FOR LABOR AND DELIVERYDuring labor, early administration of epidural analgesia isrecommended (1) to avoid general anesthesia and the pos-sibility of airway catastrophe in the event of emergencycesarean delivery, (2) to optimize the timing of epiduralcatheter placement in the setting of a declining plateletcount, and (3) to obtain the beneficial effects of epiduralanalgesia on uteroplacental perfusion.

Continuous lumbar epidural analgesia and combinedspinal-epidural (CSE) analgesia are the preferred methodsof pain management during labor in women with pre-eclampsia. Advantages include (1) provision of high-qualityanalgesia, which attenuates the hypertensive response topain231-233; (2) a reduction in levels of circulating cate-cholamines and stress-related hormones234; (3) possibleimprovement in intervillous blood flow235; and (4) provi-sion of a means of administering local anesthetic for emer-gency cesarean delivery, thus obviating the need for generalanesthesia with its attendant risks.

One disadvantage of the CSE technique is that epiduralcatheter function cannot be fully evaluated until after res-olution of the intrathecal analgesia. For this reason, manyanesthesia providers avoid the CSE technique in favor of astandard epidural technique in women with severe pre-eclampsia who have a higher risk for emergency cesareandelivery. Use of a standard epidural technique allows forimmediate verification of catheter function.

Continuous epidural analgesia has been used in theantepartum period to optimize uteroplacental blood flowin the hope of prolonging pregnancy and avoiding pretermdelivery in preeclamptic women remote from term.Kanayama et al.236 studied 20 severely preeclampticwomen at 28 to 32 weeks’ gestation, who were assignedby physician choice to receive either long-term epiduralbupivacaine combined with routine supportive manage-ment or routine supportive management alone.Gestational age at delivery and birth weight were greaterin the treatment group, and maternal blood pressure andplatelet count were also improved, when compared with theroutine management group. Although this study was notwell controlled, its results suggest that antepartum epiduralanalgesia may have the potential to prolong pregnancy andperhaps avoid preterm delivery in women with preeclamp-sia; further studies are warranted.

For the most part, the clinical administration of epidu-ral analgesia to women with preeclampsia does not differfrom that in healthy pregnant women without preeclamp-sia (see Chapter 23). The choice of local anesthetic,method of epidural space identification, and maintenanceof analgesia are not affected by the presence of preeclamp-sia. However, the following four special considerationsapply to preeclamptic women: (1) assessment of coagula-tion status, (2) intravenous hydration prior to the epiduraladministration of a local anesthetic, (3) treatment of hypo-tension, and (4) use of an epinephrine-containing localanesthetic solution.


Coagulation Status

Platelets contribute to coagulation and hemostasis in twoimportant ways. First, their adhesive and cohesive functionslead to the formation of the hemostatic plug. Second, theyactivate the coagulation process by exposing a phospholipidsurface and acting as a catalytic site for subsequent coagu-lation and consolidation of the initial platelet plug. Activatedplatelets release adenosine diphosphate, serotonin, throm-boxane A2, and other adhesive proteins, coagulation factors,and growth factors.237 Women with mild preeclampsia areusually hypercoagulable relative to women with an uncom-plicated pregnancy and should not be denied neuraxial laboranalgesia.

Women with severe preeclampsia (particularly those withHELLP syndrome) may have thrombocytopenia, whichincreases the risk of bleeding into the epidural or spinalspace with a neuraxial procedure (see Chapter 32).Neuraxial hematoma formation can have permanent neu-rologic sequelae. Therefore, documentation of the plateletcount is necessary prior to provision of epidural analgesia inwomen with severe preeclampsia. The incidence of neurax-ial hematoma is small but cannot be precisely determinedbecause not all cases are reported and because there is noaccurate method to determine the denominator of all pre-eclamptic women who have received neuraxial anesthesia.

In the past, a platelet count of at least 100,000/mm3 wasconsidered necessary for the safe administration of neurax-ial anesthesia. This threshold probably originated from theresults of a 1972 study that correlated platelet counts withbleeding times.238 Critical appraisal of 1083 human studiesconcluded that the bleeding time is no longer considered areliable method of assessing the risk of bleeding for a singleindividual.239 In addition, platelet counts of 70,000/mm3 to100,000/mm3 occur during normal pregnancies. A system-atic review by Douglas213 proposed a platelet count thresh-old of 80,000/mm3 as adequate for the administration ofneuraxial anesthesia in pregnant women without other riskfactors. Further coagulation testing is not required formildly preeclamptic women with a platelet count exceed-ing 100,000/mm3, because coagulopathy is rare in pre-eclamptic women with a normal platelet count.137 For awoman with a platelet count less than 100,000/mm3, otherhemostatic abnormalities, including prolonged prothrom-bin time (PT), prolonged partial thromboplastin time(PTT), and reduced fibrinogen concentration can be pres-ent.137 Further coagulation studies may be useful, particu-larly if risk factors for DIC are present (e.g., placentalabruption, HELLP syndrome).137 In patients at risk forcoagulopathy, a normal or nearly normal international nor-malized ratio (INR) is required for the safe performance ofneuraxial anesthesia.240,241

Many obstetric anesthesia providers consider a plateletcount of 75,000/mm3 to 80,000/mm3 to be adequate foradministration of neuraxial anesthesia. In this setting,many anesthesia providers believe that spinal needle place-ment is less traumatic (and less risky) than epidural needleplacement because of the smaller size of the spinal needle,although supporting data are lacking.

The trend in the platelet count is also important; a rap-idly falling platelet count is a cause for concern because thenadir in the platelet count cannot be identified prospec-tively. How often should the anesthesia provider obtain aplatelet count? Platelet count measurement every 6 hours is

adequate when platelet numbers are relatively stable; a mea-surement obtained as recently as within the last 1 to 3 hoursbefore the neuraxial procedure may be required when theplatelet count shows evidence of a significant decline.

The risk of epidural hematoma formation exists notonly during placement of an epidural catheter but alsoduring its removal. In patients with thrombocytopenia,the catheter should not be withdrawn from the epiduralspace until there is evidence of an acceptable (and rising)platelet count. A platelet count of 75,000/mm3 to 80,000/mm3 seems reasonable for epidural catheter removal. In theabsence of corticosteroid administration, the platelet countin women with HELLP syndrome usually reaches a nadir onthe second or third postpartum day and then graduallyreturns to the patient’s normal baseline.

Although thromboelastography (TEG) has shown somepromise in the assessment of overall coagulation status inpregnant patients with thrombocytopenia,242 the techniquehas been criticized for its inability to diagnose a specificcoagulation defect. Further, the hypothetical potential ofthromboelastography to predict the risk for epidural hema-toma after the administration of neuraxial anesthesia inpregnant patients is unproven and requires further study.243

There is a consensus among anesthesia providers that aplatelet count lower than 50,000/mm3 precludes the admin-istration of neuraxial anesthesia. For women with a plateletcount between 50,000/mm3 and 80,000/mm3, the risks andbenefits of neuraxial anesthesia must be weighed against therisks of general anesthesia for the individual patient if emer-gency cesarean delivery is required. If the decision is madeto proceed with a neuraxial technique, the following sug-gestions may help reduce the risk of epidural hematomaand its sequelae:

1. The most skilled anesthesia provider available shouldperform the neuraxial procedure.

2. A spinal technique may be preferable to an epiduraltechnique (when appropriate) because of the smallerneedle size.

3. Use of a flexible wire–embedded epidural cathetermay reduce epidural vein trauma.

4. The patient should be carefully monitored after deliveryfor neurologic signs that may signal bleeding into theepidural space.

5. The platelet count should be checked for evidence ofa return toward normal measurements (at least75,000/mm3 to 80,000/mm3) before removal of theepidural catheter. Epidural vein trauma at the time ofcatheter discontinuation can result in epidural bleedingand perhaps epidural hematoma.

6. Imaging studies and neurologic or neurosurgicalconsultation should be obtained immediately ifthere is any question of an epidural hematoma.Prompt surgical intervention may be required to avoidpermanent neurologic injury.

Intravenous Hydration

In the past, when higher concentrations of local anestheticsolution (e.g., 0.25% to 0.5% bupivacaine) were administeredduring labor, intravenous crystalloid hydration preceded epi-dural local anesthetic administration to prevent or amelioratepost–epidural anesthesia hypotension. In contemporary


practice, lower concentrations of local anesthetic are used(e.g., 0.0625% to 0.125% bupivacaine in combination with anopioid), hypotension is less common, and fluid preloading isof less clinical importance. Although the risk of pulmonaryedema secondary to fluid preloading has decreased with cur-rent techniques for labor analgesia, careful attention to intra-venous fluid infusion rates is necessary in women with severepreeclampsia because of the increased risk of pulmonaryedema in these patients (as discussed earlier).

Treatment of Hypotension

The incidence of hypotension after the initiation of epidurallabor analgesia has declined in modern practice. Womenwith mild preeclampsia may be treated with routine dosesof either ephedrine or phenylephrine. There is an often-expressed concern that severely preeclamptic womenmay have an exaggerated response to vasopressors thatmight result in a sharp rise in blood pressure.244,245

However, supportive data are lacking. The anesthesia pro-vider should initiate treatment with small doses of ephed-rine (e.g., 2.5 mg) or phenylephrine (e.g., 25 to 50 mg) toassess maternal blood pressure response before administra-tion of a larger dose. With careful dosing, greater sensitivityto vasopressors is rarely a clinical problem.

Epinephrine

It has been suggested that local anesthetic solutionscontaining epinephrine (including the standard epineph-rine-containing test dose) should be avoided during theadministration of epidural analgesia in preeclampticwomen. This concern arises from observations that pre-eclamptic women exhibit a greater sensitivity to vasopres-sors, including angiotensin II,79,246 norepinephrine andepinephrine,117,247 and a thromboxane A2–mimeticagent.248 Also, clinical studies have demonstrated that smal-ler doses of ephedrine and phenylephrine are required torestore maternal blood pressure during spinal anesthesiain preeclamptic women than in pregnant women withoutpreeclampsia.244,245,249,250 One case has been reported of ahypertensive crisis in a preeclamptic woman after the incre-mental administration of 30 mL of 2% lidocaine with freshlyadded epinephrine 5 mg/mL (1:200,000) for planned cesar-ean delivery.251 However, the timing of the onset and dura-tion of hypertension was atypical, and a drug error could notbe excluded.251 In contrast, several other case series haveused the same solution without adverse effects in womenwith preeclampsia.252,253

No randomized controlled trials have assessed the effectsof epidural epinephrine in women with severe preeclamp-sia. However, epinephrine is unlikely to pose a significantrisk of hypertensive crisis, given the absence of confirmedreports after decades of its use in obstetric anesthesia prac-tice. In the absence of malignant hypertension, it seemsreasonable to administer the routine epinephrine-contain-ing test dose to exclude intravascular placement of theepidural catheter. Notably, patients who have receivedbeta-adrenergic receptor antagonists (e.g., labetalol) donot demonstrate the typical tachycardic response to intra-vascular administration of epinephrine.254

There is no compelling reason to include epinephrinein epidural labor analgesic solutions because its administra-tion (in combination with epidural bupivacaine) inwomen without preeclampsia has only a modest local

anesthetic–sparing effect.255 In contemporary practice,most anesthesia providers administer an epidural solutionof local anesthetic in combination with an opioid whenproviding epidural labor analgesia.

ANESTHESIA FOR CESAREAN DELIVERYThe administration of neuraxial anesthesia for cesareandelivery in women with preeclampsia does not differ greatlyfrom that in healthy pregnant women (see Chapter 26).Hepatic dysfunction can result in reduced drug clearancebut has little clinical impact on choice of anesthetic or anal-gesic agents.

The choice of local anesthetic, method of epidural spaceidentification, and maintenance of anesthesia are notaffected by the presence of preeclampsia. However, thereare three special considerations in preeclamptic womenundergoing cesarean delivery: (1) choice of anesthetic tech-nique, (2) technique for induction of general anesthesia, and(3) the interaction between magnesium sulfate and nonde-polarizing muscle relaxants.

Neuraxial Anesthesia

In the 2003-2005 CEMACH report, the leading cause ofdeath in women with preeclampsia was intracranial hem-orrhage.188 Disadvantages of general anesthesia in the pres-ence of preeclampsia include the risk of intracranialhemorrhage from the hypertensive response to intubationand the possibility of difficult intubation secondary toairway edema. Therefore, neuraxial anesthesia is preferredwhenever clinical circumstances permit its use.

Epidural anesthesia has long been considered the optimalanesthetic technique for cesarean delivery in women withsevere preeclampsia. Its advantages include relatively stablematernal blood pressure (Figure 45-7),256 optimization ofuteroplacental perfusion,235 and the ability to titrate theadministration of local anesthetic and intravenous fluidsslowly to achieve the desired level of anesthesia without aprecipitous decrease in maternal blood pressure. Thismethod of local anesthetic administration also permits theanesthesia provider to minimize fluid administration toreduce the possibility of fluid overload and pulmonaryedema.

The traditional view has been that spinal anesthesia isrelatively contraindicated in severe preeclampsia becauseof the possibility of marked hypotension due to the rapidonset of spinal anesthesia–induced sympathetic blockade.However, there is growing support for the use of spinalanesthesia in women with severe preeclampsia undergoingcesarean delivery, on the basis of results of more recentstudies and clinical experience. Wallace et al.257 randomlyassigned 80 women with severe preeclampsia who requiredcesarean delivery to receive general, epidural, or CSE anes-thesia. Notably, the initial spinal dose in the CSE group(hyperbaric bupivacaine 11.25 mg) is a dose comparable tothat often used for a single-shot spinal technique. Therewas no significant difference between the CSE and epidu-ral anesthesia groups in maternal mean arterial pressureover time (Figure 45-8). Another small prospective studyrandomly assigned women with severe preeclampsia toreceive either spinal or epidural anesthesia, with similarresults.258 Hood and Curry, 259 in a retrospective reviewof cesarean delivery records for 138 women with severepreeclampsia who received either spinal or epidural


anesthesia, found that the lowest mean blood pressuremeasurements did not differ between the groups.Because of the retrospective study design, the possibilitythat the groups were dissimilar cannot be excluded(i.e., the anesthesia providers may have chosen to admin-ister epidural anesthesia to the more severely ill women).Nonetheless, the marked hypotension expected after spinalanesthesia did not occur. These studies lend support tothe safety of spinal anesthesia in women with severepreeclampsia.

In two prospective cohort studies of women undergoingcesarean delivery, Aya et al.244,249 compared women withsevere preeclampsia to healthy pregnant women (both pre-term244 and at term249) and found that the risk of significantspinal anesthesia–induced hypotension (defined as

requiring the administration of ephedrine) was significantlylower in the preeclampsia groups than in the controlgroups. The researchers speculated that the known greatervascular sensitivity to vasoconstrictors may explain theinfrequent incidence of post–spinal anesthesia hypotensionand the ease with which mean arterial blood pressure canbe restored to baseline with small doses of vasopressor.

Lastly, a randomized multicenter study comparing thehemodynamic effects of spinal anesthesia with epiduralanesthesia for cesarean delivery in women with severepreeclampsia found that significantly more women inthe spinal anesthesia group experienced hypotension.260

However, the duration of hypotension was less than1 minute in both groups and, although there was moreephedrine use in the spinal group than the epidural

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FIGURE 45-7 A, Mean ± SEM of mean arterial pressure (MAP), pulmonary artery pressure (PAP), and pulmonary wedge pressure (PWP) in 10preeclamptic patients who underwent cesarean delivery under thiopental, nitrous oxide (40%), and halothane (0.5%) anesthesia. Measurementsbefore the induction of anesthesia are indicated at �60 to �10 minutes. The start of induction is indicated by the first 0. The second 0 refers tothe start of suction and extubation. Time gap refers to the time elapsed between the completion of the first 30 minutes of anesthesia and thestart of suction and extubation. B, Mean ± SEM of MAP, PAP, and PWP in 10 preeclamptic patients who underwent cesarean delivery underepidural bupivacaine anesthesia. Measurements before epidural injection of bupivacaine (at 0 minutes) are indicated at �60 to �10 minutes, andmeasurements during epidural anesthesia are indicated at 2 to 60 minutes. (From Hodgkinson R, Husain FJ, Hayashi RH. Systemic and pulmonaryblood pressure during caesarean section in parturients with gestational hypertension. Can Anaesth Soc J 1980; 27:389-94.)


group, hypotension was easily treated in both groups. Inaddition, there was no significant difference in neonataloutcome between infants whose mothers received spinalanesthesia and those whose mothers received epiduralanesthesia.261

Although the evidence to date is not conclusive, it doessuggest that a reappraisal of the use of spinal anesthesia forcesarean delivery in women with severe preeclampsia isappropriate. In the absence of large prospective randomizedtrials with tight control of inclusion criteria (i.e., antihyper-tensive medications, magnesium sulfate), it seems reason-able to use spinal anesthesia in women with severepreeclampsia to avoid the risks associated with emergencyadministration of general anesthesia.262,263

General Anesthesia

General anesthesia is less desirable than neuraxial anes-thesia because of (1) the possibility of difficult intubationsecondary to airway edema and (2) the transient butsevere hypertension that accompanies endotracheal intu-bation (see Figure 45-7). Nonetheless, there are timeswhen general anesthesia is the best anesthetic option.Clinical indications include severe ongoing maternalhemorrhage, sustained fetal bradycardia with a reassuringmaternal airway examination, and severe thrombocytope-nia or other coagulopathy. The platelet count can fall dra-matically with rapidly progressing severe preeclampsia orHELLP syndrome and may mandate administration ofgeneral anesthesia. Major placental abruption, intrauterinefetal demise, and preeclampsia all increase the risk of DIC.The safe administration of general anesthesia in womenwith preeclampsia requires both careful preparation whentime permits and an advanced state of readiness whentime is limited.

Once the decision has been made to proceed with gen-eral anesthesia, the anesthesia provider faces three specificchallenges: (1) the potential difficulty of securing the airway,(2) the hypertensive response to direct laryngoscopy andendotracheal intubation, and (3) the effects of magnesiumsulfate on neuromuscular transmission and uterine tone. Asuggested technique for the administration of general anes-thesia is described in Box 45-4.

Airway Considerations Before the induction of generalanesthesia, careful airway examination is mandatory.Airway edema may be present even with relatively reassur-ing airway findings; thus many anesthesia providers try toavoid emergency administration of general anesthesia ifthere is any suspicion of a difficult airway. Endotrachealtubes in various sizes and difficult airway equipmentshould be immediately available (see Chapter 30). In unusu-ally difficult situations, it may be prudent to have an oto-laryngology surgeon immediately available to establish asurgical airway. One of the dangers of repeated intubationattempts is the risk of traumatic bleeding in the airway,which may make ventilation difficult or impossible. It iswise to avoid repeated attempts and to proceed with inser-tion of a laryngeal mask airway (LMA)—while maintaininggentle cricoid pressure—before the airway is irretrievablylost. Because the LMA does not protect the patient frompulmonary aspiration of gastric contents, the obstetricianshould be encouraged to complete the procedure as quicklyas possible.

Hypertensive Response to Laryngoscopy The hemodynamicinstability associated with rapid-sequence induction andendotracheal intubation presents a serious problem in thepatient with preeclampsia. The transient but severe hyper-tension that may accompany intubation can result in cere-bral hemorrhage or pulmonary edema, both of which arepotentially fatal complications. Continuous arterial bloodpressure monitoring is required for severely hypertensivewomen to monitor the effects of antihypertensive drugsadministered before and after intubation and to allowrapid detection of adverse hemodynamic responses tolaryngoscopy.

Antihypertensive medications that have been used toblunt the hemodynamic response to laryngoscopy includelabetalol, esmolol, nitroglycerin, sodium nitroprusside, andremifentanil.264-268 The goal of treatment is to reduce thearterial blood pressure to approximately 140 mm Hg sys-tolic/90 mm Hg diastolic prior to the induction of generalanesthesia. When possible, the FHR should be monitoredduring intravenous antihypertensive therapy.

Most anesthesia providers regard labetalol as the drug ofchoice for attenuating the hypertensive response to laryn-goscopy in women with severe preeclampsia. Ramanathanet al.266 compared intravenous labetalol with no treatmentin a randomized study of preeclamptic women whoreceived general anesthesia for cesarean delivery. Maternalmean arterial pressure rose following intubation in bothstudy groups, but the hypertensive response was signifi-cantly less pronounced in the labetalol group. Women inthe control group also developed tachycardia (in responseto laryngoscopy and intubation), which did not occur in thelabetalol group. Labetalol has been administered both via abolus technique and as a continuous intravenous infusion.

MA

P (

mm

Hg)

Spinal–epiduralEpiduralGeneral

Time posts

TOR TIN TT TOTIN5 TIN10 TIN20 TSKI TD TSKC

120

110

100

90

FIGURE 45-8 The profiles of average mean arterial pressure(MAP) were significantly different over the five common time posts(P < .001). However, only at skin incision does the general groupdiffer from the two regional groups (P = .003). TOR, time intooperating room; TIN, time of induction; TSKI, time of skin incision;TD, time of delivery; TSKC, time of skin closure; TT, time of intubation;TO, time of extubation. Regional groups: TIN5, time of induction + 5minutes; TIN10, time of induction + 10 minutes; TIN20, time ofinduction + 20 minutes. (From Wallace DH, Leveno KJ, CunninghamFG, et al. Randomized comparison of general and regional anesthesiafor cesarean delivery in pregnancies complicated by severepreeclampsia. Obstet Gynecol 1995; 86:193-9.)


There is also evidence of safe short-term administrationof esmolol in this setting. A randomized double-blind studyof 80 hypertensive women presenting for cesarean deliverydemonstrated that intravenous esmolol—in doses as high as2 mg/kg—can be safely used to dampen the hemodynamicresponse to laryngoscopy and intubation.269

Nitroglycerin has many desirable properties for blunt-ing the hypertensive response to intubation. It is a directvasodilator with a rapid onset, is rapidly metabolized, andhas no apparent maternal or fetal toxicity. In a randomizedcontrolled trial, Hood et al.265 administered intravenousnitroglycerin (200 mg/mL), which was titrated to lowermean arterial blood pressure by 20% prior to induction ofgeneral anesthesia. The maximal blood pressure with endo-tracheal intubation was significantly lower in the nitroglyc-erin group than in women who did not receivenitroglycerin. Both Apgar scores and umbilical cord bloodgas and acid-base measurements were similar in the twogroups.

Sodium nitroprusside infusions have also been used toattenuate hemodynamic responses to intubation in womenwith severe preeclampsia. An intravenous infusion can beinitiated at 0.5 mg/kg/min and then titrated to blood pres-sure response. Short-term infusions are considered safe forthe fetus (as discussed earlier).

The short-acting opioid remifentanil, which is rapidlymetabolized in both mother and neonate by nonspecificblood and tissue esterases, has been administered to pre-eclamptic women. A clear advantage of remifentanil overother opioids is the rapid onset and short duration of thedrug; the limited duration of action should not interfere

with the resumption of spontaneous ventilation if intuba-tion is unsuccessful. Ngan Kee et al.268 randomly assigned40 pregnant women without preeclampsia who requiredgeneral anesthesia for cesarean delivery to receive either aone-time intravenous dose of remifentanil 1 mg/kg or salineimmediately prior to induction. The primary outcome wasthe maximum increase in systolic blood pressure (in com-parison with a baseline measurement). Administration ofremifentanil significantly reduced the maximum increasein maternal systolic pressure. However, remifentanil crossesthe placenta, and two neonates in the remifentanil grouprequired naloxone administration for poor respiratoryeffort.

Effects of Magnesium Sulfate Most severely preeclampticwomen present to the operating room after varying dura-tions of exposure to magnesium sulfate for seizure prophy-laxis. The primary anesthetic considerations for womenreceiving magnesium sulfate are (1) interaction with non-depolarizing muscle relaxants, (2) effects on uterine tone,and (3) interaction with calcium entry–blocking agents,specifically nimodipine.

Magnesium inhibits the release of acetylcholine at theneuromuscular junction, decreases the sensitivity of theneuromuscular junction to acetylcholine, and depressesthe excitability of the muscle fiber membrane.Magnesium sulfate has been demonstrated to increase thepotency and duration of vecuronium, rocuronium, andmivacurium.270-272 Several case reports have described arequirement for overnight mechanical ventilation afteradministration of routine doses of vecuronium in women

BOX 45-4 Administration of General Anesthesia in Women with Severe Preeclampsia

1. Place a radial arterial cannula for continuous bloodpressure monitoring in the woman with severehypertension.

2. Place an additional intravenous catheter.3. Make certain that smaller-sized endotracheal tubes and

laryngeal mask airways are immediately available.Equipment needed for management of a difficult airwayshould also be immediately available.

4. Administer an H2-receptor antagonist and metoclopramideIV between 30 and 60 minutes before induction ofanesthesia.

5. Administer 30 mL of 0.3 M sodium citrate by mouth lessthan 30 minutes before induction of anesthesia.

6. Denitrogenate (3 minutes of tidal-volume breathing or8 vital capacity breaths with an FIO2 of 1.0 and atight-fitting face mask).

7. Give labetalol (10-mg bolus doses) IV; titrate to desiredeffect before induction of anesthesia.

8. Continue to monitor the fetal heart rate during labetaloladministration.

9. Consider alternative antihypertensive agents for patientswho showed no response to labetalol (or those with acontraindication to labetalol). Alternatives includeremifentanil (1 mg/kg as a single bolus), sodiumnitroprusside infusion (starting at 0.5 mg/kg/min andtitrated to effect), or nitroglycerin infusion (starting at0.1 mg/kg/min and titrated to effect).

10. Perform rapid-sequence induction with either propofol2 to 2.5 mg/kg or sodium thiopental 4 to 5 mg/kg andsuccinylcholine 1.0 to 1.5 mg/kg.

11. Maintain anesthesia with 50% nitrous oxide and a volatilehalogenated agent. After delivery, consider giving anopioid with or without a benzodiazepine. If additionalmuscle relaxation is required, administer a reduced doseof a short-acting nondepolarizing muscle relaxant.

12. At the end of surgery, reverse neuromuscular blockadeand give labetalol 5 to 10 mg IV to prevent hypertensionduring emergence and extubation.

IV, intravenously.

Adapted from Ramanathan J, Bennett K. Preeclampsia: Fluids, drugs, and anesthetic management. Anesthesiol Clin North Am 2003;21:145-63.


receiving magnesium sulfate.270,273 Because of this interac-tion, if nondepolarizing muscle relaxants are used, theyshould be administered in very small doses and theresponse should be monitored carefully with a peripheralnerve stimulator.

Even though succinylcholine mimics acetylcholine at thenerve terminal, the onset and duration of a single intubatingdose of succinylcholine is not prolonged when administeredconcurrently with a magnesium sulfate infusion274; a rou-tine intubating dose of 1 to 1.5 mg/kg should be used duringrapid-sequence induction.

Used for many years as a tocolytic agent, magnesiumdepresses smooth muscle contractions and inhibits CNScatecholamine release.275-277 After a prolonged magnesiumsulfate infusion, it seems intuitive that the risk of uterineatony and excessive blood loss might be increased.172

However, studies have not found an increased risk ofblood loss in women receiving magnesium sulfate.166,172

A blood sample for type and screen should be sent to theblood bank prior to cesarean delivery, and uterotonic agentsshould be immediately available.

The calcium entry–blocking agent nifedipine may inter-act with magnesium sulfate to have adverse effects. Apossibly greater hypotensive effect of nifedipine and neuro-muscular blockade has been reported when the drugs wereadministered concomitantly.159-162 Severe hypotension andfetal compromise have also been reported with use of thetwo drugs.159,160

Postoperative Analgesia

Options for postoperative analgesia are the same as foruncomplicated pregnancies. They include patient-con-trolled intravenous opioids, neuraxial opioids (single injec-tion), and continuous epidural infusion of analgesic agents.Many anesthesia providers prefer neuraxial opioid admin-istration for postcesarean analgesia (see Chapter 28). Inthe rare case of a woman with continuing severe refrac-tory hypertension, continuous epidural analgesia is attrac-tive for its blood pressure–modulating properties.

Regardless of the postoperative analgesic technique, allpreeclamptic women should be carefully monitored withpulse oximetry for signs of respiratory depression orairway obstruction.

Postpartum Management

The risks of severe preeclampsia do not end with delivery.Postpartum women are at significant risk for pulmonaryedema, sustained hypertension, stroke, venous thromboem-bolism, airway obstruction, and seizures, and should receiveclose monitoring of blood pressure, fluid intake, and urineoutput. In addition, severe preeclampsia, HELLP syndrome,and eclampsia can present for the first time in the postpar-tum period. A study of almost 4000 women diagnosed withpreeclampsia found that the incidence of postpartum dis-ease onset was 5.7%.104

The risk of pulmonary edema is also highest in thepostpartum period. Resolution of preeclampsia usuallyoccurs within 5 days of delivery and is heralded by amarked diuresis that follows mobilization of extracellularfluid and an increase in the intravascular volume. As aconsequence, women with severe preeclampsia, particularlythose with early-onset disease, renal insufficiency, or

pulmonary capillary leak, are at higher risk for the develop-ment of pulmonary edema.16

In contrast to women with gestational hypertension, whotypically become normotensive within a week of delivery,women with severe preeclampsia may have a longer dura-tion of hypertension; the risk of cerebral vascular accidentis highest during this time.191,278 Antihypertensive therapyshould be started or resumed for these women, and bloodpressure should be carefully monitored during therapy.

Venous thromboembolism (VTE) has an estimatedincidence of 0.5 per 1000 cesarean deliveries279 and is aleading cause of maternal death in pregnancy.280 The riskfactors for antepartum and postpartum events differ, sug-gesting a different pathophysiology for each.281 Both cesar-ean delivery281-284 and preeclampsia281,282 are independentrisk factors for postpartum VTE. An emergency cesareandelivery doubles the risk of VTE compared with a non-emergency cesarean delivery.285 The 2008 AmericanCollege of Chest Physicians Evidence-Based ClinicalPractice Guidelines recommend that women at increasedrisk for post–cesarean delivery VTE (because of the pres-ence of an additional risk factor such as preeclampsia)receive either pharmacologic thromboprophylaxis ormechanical prophylaxis (e.g., intermittent pneumatic com-pression devices) while in the hospital after cesareandelivery.286

A review of eight anesthesia-related maternal deaths inMichigan found that all anesthesia-related deaths fromairway obstruction or hypoventilation occurred in thepostoperative period and that system errors, lapses in post-operative monitoring, and inadequate supervision by theanesthesia providers played a role in these deaths.287 Oneof the women who died had severe preeclampsia and sleep-disordered breathing and was found pulseless and apneic inher hospital room. In another study, investigators foundgreater upper airway resistance in women with preeclampsiaduring sleep than in women without preeclampsia.288 Bothstudies highlight the need for close monitoring and consis-tent vigilance in the postoperative care of women withsevere preeclampsia—particularly those with generalizededema, known airway swelling, snoring, and obesity.

Long-Term Outcomes

There is mounting evidence that women with a history ofpreeclampsia are at increased risk of chronic hypertensionand cardiovascular disease in later life,47-49,53,289,290 and foran earlier onset of cardiovascular disease during theirlives.47-49,51,53,289,290 Ischemic heart disease and stroke arethe most common manifestations of cardiovascular mor-bidity. Also, mortality in women with a history of pre-eclampsia is double that in women whose pregnancieswere not complicated by a maternal placental syndrome;Funai et al.51 concluded that excess risk of death was pri-marily the result of cardiovascular disease. In the first 10 to15 years after the occurrence of preeclampsia, the risk ofcardiovascular disease and death appears to be low, but itincreases markedly thereafter.52

In addition, there is evidence of a dose-response relation-ship between preeclampsia and cardiovascular disease.Women who have severe preeclampsia or early-onset pre-eclampsia and whose pregnancies are complicated by bothpreeclampsia (the maternal syndrome) and intrauterine


growth restriction (the fetal syndrome) are at higher riskthan women with mild preeclampsia or gestational hyper-tension.50 Women with preeclampsia in both their first andsecond pregnancies are at even greater risk for future ische-mic heart disease.49

The mechanism of the greater risk of cardiovascular dis-ease in preeclampsia is unclear. It is possible that pre-eclampsia causes permanent damage to the endotheliumand hastens the onset of cardiovascular disease. Womenwith a history of preeclampsia have persistent impairmentof brachial artery endothelium-dependent vascular relax-ation at 1 to 3 years after delivery, a finding not seen incontrols.291,292 A more likely explanation is that preeclamp-sia and cardiovascular disease have a common pathogenesisowing to shared risk factors. Common risk factors for pre-eclampsia and atherosclerosis include hypertension, obesity,insulin resistance, advanced age, hypercholesterolemia, anddyslipidemia.53,293,294 Cigarette smoking is the notableexception, in that it is an established risk factor for cardio-vascular disease but is protective against preeclampsia.55,56

Preeclampsia may be a cardiovascular risk marker inwomen with an underlying predisposition to vascular dis-ease; the metabolic stress of pregnancy causes the predispo-sition to manifest as preeclampsia. After pregnancy womenreturn to a normal state until the threshold for disease devel-opment is exceeded in later life. This hypothesis is illustratedin Figure 45-9.

Regardless of the mechanism of increased risk, theseobservations represent an opportunity for primary diseaseprevention and risk factor modification. In a 2004 multina-tional study, 90% of the risk of a first myocardial infarctionwas attributed to potentially modifiable risk factors.295

Possible interventions include earlier cardiovascular diseasescreening and individual counseling about the importanceof smoking cessation, regular exercise, and a diet low insaturated fat and high in antioxidants.

In contrast, a history of preeclampsia has been associatedwith a decreased risk of cancer. Several studies have sug-gested that women who have been diagnosed with pre-eclampsia have a slightly lower risk for breast cancer inlater life than other parous women.296-300 In contrast, asystematic review and meta-analysis of almost 200,000women with a history of preeclampsia found no associationbetween preeclampsia and future cancer risk.52

Preliminary evidence indicates that preeclampsia mayalso have psychological sequelae. Post-traumatic stress dis-order (PTSD) is an anxiety disorder that can develop afterexposure to one or more terrifying events that threatenedor caused grave physical harm.301 A woman with a historyof severe preeclampsia (particularly with early-onset diseaseand preterm delivery) has experienced a serious complica-tion that threatened her life and the life of her child. Casereports have described the onset of PTSD after pregnanciescomplicated by severe preeclampsia or HELLP syn-drome.302 In an exploratory study, approximately onefourth of women experienced PTSD after early-onset pre-eclampsia.303 Further research is required to define womenat risk for PTSD and to investigate strategies for its preven-tion and intervention.

ECLAMPSIA

Eclampsia is defined as the new onset of seizures or unex-plained coma during pregnancy or the postpartum periodin a woman with signs and symptoms of preeclampsia andwithout a preexisting neurologic disorder.304-306

Epidemiology

Findings of population-based studies in the past 10 yearssuggest that the incidence of eclampsia varies from 0.1 to5.5 per 10,000 pregnancies in western countries.1,17,307-310

On average, studies have shown a decrease in the incidenceof eclampsia over time (i.e., from 1.04 to 0.8 per 10,000pregnancies in the United States, and from 4.9 to 2.7 per10,000 pregnancies in the United Kingdom).17,309 The vari-ation in rates of eclampsia among studies likely reflectsreporting differences among countries or differences intreatment for severe preeclampsia.309,311

Eclampsia can occur suddenly at any point in the puer-perium; however, most seizures occur intrapartum orwithin the first 48 hours after delivery. Late eclampsia isdefined as seizure onset from 48 hours after delivery to lessthan 4 weeks postpartum.305,312 The majority of eclampticwomen have evidence of severe preeclampsia, but in 10% to15% of cases, hypertension is absent or modest and/or pro-teinuria is not detected.312 Recent data indicate that animportant risk factor for eclampsia is maternal age lessthan 20 years.17 Other reported risks include nulliparity,multiple gestation, molar pregnancy, triploidy, preexistinghypertension or renal disease, previous severe preeclampsiaor eclampsia, nonimmune hydrops fetalis, and systemiclupus erythematosus.313 Major maternal complications ofeclampsia include pulmonary aspiration, pulmonaryedema, cerebral vascular accident, cardiopulmonary arrest,acute renal failure, and death.9,308,309 Eclampsia is associat-ed with a high perinatal death rate and can be associatedwith placental abruption, severe intrauterine growth restric-tion, and extreme prematurity.304,308,309

Clinical Presentation and Diagnosis

Any of the pathophysiologic changes of preeclampsia canbe present in eclampsia. Premonitory signs and symptomsinclude persistent occipital or frontal headaches, blurredvision, photophobia, epigastric or right upper quadrant

Time

Vas

cula

r ris

k fa

ctor

s

Women with preeclampsia during pregnancyWomen with uncomplicated pregnancyThreshold for vascular or metabolic disease

Pregnancies Middle age

FIGURE 45-9 Vascular risk factors versus time. (From Sattar N, GreerIA. Pregnancy complications and maternal cardiovascular risk:Opportunities for intervention and screening? Br Med J 2002;325:157-60.)


pain, hyperreflexia, and altered mental status304,312; thesesymptoms can occur before or after the onset of seizures.304

Seizures have an abrupt onset, typically beginning asfacial twitching that is followed by a tonic phase persistingfor 15 to 20 seconds. This progresses to a generalized clonicphase characterized by apnea, which lasts approximately1 minute. Breathing generally resumes with a long sterto-rous inspiration, and the patient enters a postictal state witha variable period of coma. Cardiorespiratory arrest and pul-monary aspiration of gastric contents can complicate a sei-zure. Although the definitive diagnosis for eclampsia is asudden seizure in a pregnant woman who has signs andsymptoms of preeclampsia, a woman who lapses intocoma without witnessed convulsions can also be classifiedas eclamptic.304

The mechanism of eclamptic seizures remains poorlyunderstood.95,306 One hypothesis involves a loss of thenormal cerebral autoregulatory mechanism that results inhyperperfusion and leads to interstitial or vasogenic cere-bral edema and decreased cerebral blood flow.7,189,190,306

Neuroradiologic studies suggest that eclampsia might be aform of reversible posterior leukoencephalopathy syndrome(PLES)314 or posterior reversible encephalopathy syndrome(PRES).315 The difference between PLES and PRES is thatsignificant blood pressure elevations are not necessarilypresent in PRES.316

Until proven otherwise, the occurrence of seizuresduring pregnancy should be considered eclampsia.Conditions that simulate eclampsia include seizure disor-der, stroke, hypertensive encephalopathy, ischemia orhypoxia, cerebral space-occupying lesion, systemic disease(e.g., systemic lupus erythematosus, sickle cell anemia),infection (e.g., meningitis, encephalitis), electrolyte andendocrine disturbances, PRES or PLES, vasculitis or angio-pathy, amniotic fluid embolism, medications (withdrawal,illicit drug use), and organ failure.95,305

Obstetric Management

Immediate goals are to stop convulsions, establish a patentairway, and prevent major complications (e.g., hypoxemia,aspiration). Further obstetric management consists of anti-hypertensive therapy, induction or augmentation of labor,and expeditious (preferably vaginal) delivery. Fetal brady-cardia typically occurs during and/or immediately after aseizure but does not mandate immediate delivery unless itis persistent.

Resuscitation and Seizure Control

During the seizure, oxygenation may prove impossible,but supplemental oxygen should be delivered by meansof an Ambu bag and face mask (Box 45-5). Attempts toinsert an oral airway should be withheld until the seizureabates, but insertion of a soft nasopharyngeal airway mayfacilitate oxygenation. As soon as breathing resumes, ven-tilation may be gently augmented with a bag-mask device.Pulse oximetry should be used to assess maternal oxygen-ation. Blood pressure and electrocardiography should bemonitored to identify hypertension, arrhythmia, or cardiacarrest. While initial resuscitation is under way, an assis-tant should establish intravenous access, which can bedifficult in a combative postictal woman. Judicious

sedation might be required to allow further treatment insome patients.

Magnesium sulfate is the preferred drug worldwide forthe prevention of further seizures in eclampsia (as discussedearlier).163,166,317 The administration of magnesium sulfatein eclamptic women is also associated with significantlylower maternal death rates. An initial intravenous bolusof 4 to 6 g is administered, followed by an infusion at1 to 2 g/hr, assuming the patient has adequate urineoutput.318 Recurrent convulsions should prompt adminis-tration of an additional bolus of 2 to 4 g, infused over 5 to10 minutes.318 The patient should be carefully monitoredfor signs of magnesium toxicity.

Anesthetic Management

The preanesthetic management of an eclamptic womanparallels that of a patient with severe preeclampsia (as dis-cussed earlier). Management considerations specific to thewoman with eclampsia are as follows180,304,319:

1. Assessment of seizure control and neurologic func-tion. The possibility of increased intracranial pressure isnot a cause for concern if the patient remains conscious,alert, and seizure-free. Persistent coma and localizingsigns may indicate major intracranial pathology, whichcould affect anesthetic management (see later).

2. Maintenance of fluid balance. Intake should berestricted to 75 to 100 mL/hr to minimize the risk ofexacerbating cerebral edema.

3. Blood pressure control. Antihypertensive therapyshould be instituted if the systolic pressure exceeds 160mm Hg, or if the diastolic pressure exceeds 110 mm Hg.

4. Continuous pulse oximetry monitoring of maternaloxygenation.

BOX 45-5 Eclampsia: The ABCs of Seizure Control

Airway� Turn patient to left side; apply jaw thrust.� Attempt bag and mask ventilation (FIO2 = 1.0).� Insert soft nasopharyngeal airway if necessary.

Breathing� Continue bag and mask ventilation (FIO2 = 1.0).� Apply pulse oximeter and monitor SaO2.

Circulation� Secure intravenous access.� Check blood pressure at frequent intervals.� Monitor electrocardiogram.

Drugs� Magnesium sulfate:� 4 to 6 g IV over 20 minutes� 1 to 2 g/hr IV for maintenance therapy� 2 g IV, over 10 minutes, for recurrent seizures

� Antihypertensive agents:� Labetalol 10 to 20 mg IV or hydralazine 5 to 10 mg

IV as needed to treat hypertension

IV, intravenously.


5. Continuous FHR monitoring.

6. Laboratory investigations are the same as in pre-eclampsia, with the addition of coagulation studies,which should be obtained regardless of the plateletcount.

The anesthesia plan is tailored to the individual case. Inconscious eclamptic women with no evidence of increasedintracranial pressure and whose seizures are well-con-trolled, epidural analgesia/anesthesia can be considered.In a retrospective review of 66 stable South Africanwomen with eclampsia, Moodley et al.320 found no differ-ence in maternal and neonatal outcomes between epiduralanesthesia and general anesthesia for cesarean delivery.

Eclamptic seizures are likely associated with an increasein intracranial pressure. In the rare instance of requirementfor immediate delivery in a woman with ongoing seizures,a neuroanesthetic technique should be considered.Intravenous induction agents such as propofol321 and pen-tothal322 reduce both cerebral metabolic rate and cerebralblood flow, with consequent decreases in cerebral bloodvolume and intracranial pressure. These agents are alsoeffective in terminating seizures.323,324 Because hyperventi-lation reduces cerebral blood flow without a reduction incerebral metabolic rate, it should be employed with caution.On the other hand, hypoventilation is associated withhypercarbia, which can lower the seizure threshold. Inorder to prevent further neurologic injury, it is importantnot to be overly aggressive in the reduction of systemicpressure, because cerebral perfusion pressure equals meanarterial pressure minus intracranial pressure.325 Avoidanceof hypoxia, hyperthermia, and hyperglycemia are alsoimportant in avoiding an exacerbation of neurologicinjury.326 Patients who have not recovered neurologicallyshould remain intubated and should be monitored in anintensive care unit. If unconsciousness persists, further neu-rologic evaluation, including electroencephalography andcomputed tomography, should be performed.

Long-Term Outcomes

Neurologic abnormalities occurring in patients witheclampsia (e.g., cortical blindness, focal motor deficits,coma) do not usually result in permanent neurologic defi-cits.95 However, a study by Aukes et al.327 found that for-merly eclamptic women had significantly more cognitivefailures several (7.6 ± 5.0) years after the index pregnancy;the investigators hypothesized that cognitive failures mightbe related to some degree of white matter change.

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KEY POINTS

� Preeclampsia is a multisystem disorder of pregnancycharacterized by a maternal syndrome with orwithout a fetal syndrome.� Preeclampsia is a leading cause of maternal and

perinatal morbidity and mortality worldwide,particularly in developing countries.

� The etiology of preeclampsia remains unknown.

� The pathophysiology of preeclampsia involvessuperficial placentation related to abnormal

angiogenesis, placental hypoxia, and release ofsoluble substances toxic to vascular endothelium.

� Management of preeclampsia is supportive, anddelivery of the fetus and placenta is the onlydefinitive cure.

� Preeclampsia likely consists of more than onedisease; early-onset disease (less than 34 weeks’gestation) carries a worse prognosis than late-onsetdisease.

� Systemic disease manifestations result fromwidespread maternal vascular endothelialdysfunction.

� Complications of severe preeclampsia include severerefractory hypertension, cerebrovascular accident,pulmonary edema, placental abruption, renal failure,and HELLP syndrome.

� Important hematologic changes that may occur inpreeclamptic women include thrombocytopenia,hypercoagulability (with mild disease),hypocoagulability (with severe disease), anddisseminated intravascular coagulation.

� There are no indications for invasive centralmonitoring that are unique to preeclampsia;indications are similar to those in other multisystemdisorders, such as severe sepsis and multisystemorgan dysfunction.

� Preeclamptic women are at risk for airway edema.The anesthesia provider should anticipate thepossibility of a difficult airway.

� The hypertensive response to direct laryngoscopyand intubation can cause intracranial hemorrhage inwomen with severe preeclampsia.

� Spinal anesthesia is acceptable for women withsevere preeclampsia, especially as an alternative togeneral anesthesia for emergency cesarean delivery.

� The risks of pulmonary edema, cerebrovascularaccident, and venous thromboembolism are higherin the postpartum period.


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chapter 45 - hypertensive disorders - vanderbilt … disorders in pregnancy. gestational...

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