N A T I O N A L I N S T I T U T E S O F H E A L T H

N A T I O N A L H E A R T , L U N G , A N D B L O O D I N S T I T U T E

WORKING GROUP

REPORT ON HIGH

BLOOD PRESSURE

IN PREGNANCY

National High Blood Pressure Education Program

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WORKING GROUP

REPORT ON HIGH

BLOOD PRESSURE

IN PREGNANCY

National Institutes of Health

National Heart, Lung,and Blood Institute

National High Blood PressureEducation Program

NIH Publication No. 00-3029Originally Printed 1990Revised July 2000

National High Blood Pressure Education Program

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TABLE OF CONTENTS

The National High Blood Pressure Education Program Working Group on High Blood Pressure in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .v

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vi

The National High Blood Pressure Education Program Coordinating Committee Member Organizations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .vii

Foreword . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .viii

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

Evidence Base . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2

Classification of the Hypertensive Disorders of Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3

Clinical Implications of Classification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .5

Pathophysiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Pathogenic Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Pathophysiology of the Maternal Manifestations of Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .6

Differential Diagnosois . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

Laboratory Tests . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9

Chronic Hypertension in Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Prepregnancy Counseling . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Treatment of Chronic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11

Antihypertensive Drug Selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12

Pregnancy, Hypertension, and Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13

Treating Hypertension That Persists Postpartum . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

Treating Hypertension During Lactation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .14

Fetal Assessment in Chronic Hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

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Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Prevention of Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16

Management of Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Nonpharmacological Management . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17

Postpartum Counseling and Followup . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

Counseling for Future Pregnancies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

Remote Cardiovascular Prognosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .23

Recommendations for Future Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

A Research Diagnosis of Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

Other Research Needs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .25

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .27

Tables

Table 1. Laboratory Evaluation and Its Rationale for Women Who Develop Hypertension After Midpregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .10

Table 2. Fetal Monitoring in Gestational Hypertension and Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . .18

Table 3. Indications for Delivery in Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Table 4. Treatment of Acute Severe Hypertension in Preeclampsia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .22

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THE NATIONAL HIGH BLOOD PRESSURE EDUCATION PROGRAM WORKING

GROUP ON HIGH BLOOD PRESSURE IN PREGNANCY

Ray W. Gifford, Jr., M.D., ChairEmeritusDepartment of Nephrology and HypertensionCleveland Clinic FoundationCleveland, OhioFountain Hills, Arizona

Phyllis A. August, M.D.Professor of Medicine, Obstetrics and GynecologyChief, Hypertension DivisionWeill Medical College of Cornell UniversityNew York Presbyterian HospitalNew York, New York

Gary Cunningham, M.D.Professor and ChairDepartment of Obstetrics and GynecologyUniversity of Texas Southwestern Medical CenterDallas, Texas

Lee A. Green, M.D., M.P.H.Associate Professor and Assistant ChairDepartment of Family MedicineUniversity of MichiganAnn Arbor, Michigan

Marshall D. Lindheimer, M.D.Professor of Medicine, Obstetrics and Gynecology,

and Clinical PharmacologyUniversity of ChicagoChicago, Illinois

Donald McNellis, M.D.Special Assistant for ObstetricsPregnancy and Perinatology BranchCenter for Research for Mothers and ChildrenNational Institute of Child Health and Human

DevelopmentNational Institutes of HealthBethesda, Maryland

James M. Roberts, M.D.Professor and Vice Chair (Research)Department of Obstetrics and Gynecology and

Reproductive SciencesUniversity of PittsburghElsie Hilliard Hillman Chair in Women’s and

Infants’ Health ResearchDirector, Magee-Women’s Research InstituteVice President for Research, Magee-Women’s

HospitalPittsburgh, Pennsylvania

Edward J. Roccella, Ph.D., M.P.H.CoordinatorNational High Blood Pressure Education ProgramOffice of Prevention, Education, and ControlNational Heart, Lung, and Blood InstituteNational Institutes of HealthBethesda, Maryland

Baha M. Sibai, M.D., F.A.C.O.G.Professor and ChairDepartment of Obstetrics and GynecologyUniversity of CincinnatiCincinnati, Ohio

Sandra J. Taler, M.D.Assistant Professor of MedicineConsultant, Division of Hypertension and Internal

MedicineMayo ClinicRochester, Minnesota

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ACKNOWLEDGEMENTS

W e appreciate the advice and contributions provided by:

The American College of Obstetricians and Gynecologists

Committee on Obstetric PracticeMichael F. Greene, M.D., ChairmanDirector of Maternal-Fetal MedicineVincent Memorial Obstetrics DivisionMassachusetts General HospitalHarvard Medical SchoolBoston, Massachusetts

Darrell E. Anderson, M.S.NHBPEP Partnership LeaderProspect Associates, Inc.Silver Spring, Maryland

David J. Birnbach, M.D.Associate Professor of Anesthesiology, Obstetrics

and GynecologyCollege of Physicians and Surgeons of Columbia

UniversityDirector of Obstetric AnesthesiologyImmediate Past President of the Society for

Obstetric Anesthesia and PerinatologySt. Lukes Roosevelt Hospital CenterNew York, New York

Mark A. Brown, M.D.Professor of MedicineSt. George HospitalKogarah NSWAustralia

Claudia Flatau, M.P.H.R.O.W. Sciences, Inc.Rockville, Maryland

Joanne Karimbakas, M.S., R.D. Prospect Associates, Inc.Silver Spring, Maryland

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THE NATIONAL HIGH BLOOD PRESSURE EDUCATION PROGRAM

COORDINATING COMMITTEE MEMBER ORGANIZATIONS

T he NHBPEP Coordinating Committee includesrepresentatives from the following member

organizations:

American Academy of Family Physicians

American Academy of Insurance Medicine

American Academy of Neurology

American Academy of Ophthalmology

American Academy of Physician Assistants

American Association of Occupational HealthNurses

American College of Cardiology

American College of Chest Physicians

American College of Occupational andEnvironmental Medicine

American College of Physicians—AmericanSociety of Internal Medicine

American College of Preventive Medicine

American Dental Association

American Diabetes Association

American Dietetic Association

American Heart Association

American Hospital Association

American Medical Association

American Nurses Association

American Optometric Association

American Osteopathic Association

American Pharmaceutical Association

American Podiatric Medical Association

American Public Health Association

American Red Cross

American Society of Health-System Pharmacists

American Society of Hypertension

Association of Black Cardiologists

Citizens for Public Action on High Blood Pressureand Cholesterol, Inc.

International Society on Hypertension in Blacks

National Black Nurses Association, Inc.

National Hypertension Association, Inc.

National Kidney Foundation, Inc.

National Medical Association

National Optometric Association

National Stroke Association

NHLBI Ad Hoc Committee on MinorityPopulations

Society of Geriatric Cardiology

Society for Nutrition Education

Federal Agencies:

Agency for Health Care Policy and Research

Department of Veterans Affairs

Health Care Financing Administration

Health Resources and Services Administration

National Center for Health Statistics, Centers forDisease Control and Prevention

National Heart, Lung, and Blood Institute

National Institute of Diabetes and Digestive andKidney Diseases

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T his report updates the 1990 National HighBlood Pressure Education Program Working

Group Report on High Blood Pressure inPregnancy and focuses on classification, patho-physiology, and management of the hypertensivedisorders of pregnancy. Using evidence-basedmedicine and consensus, this report updates con-temporary approaches to hypertension control dur-ing pregnancy by expanding on recommendationsmade in the Sixth Report of the Joint NationalCommittee on Prevention, Detection, Evaluation,and Treatment of High Blood Pressure (JNC VI).The recommendations to use K5 for determiningdiastolic pressure and to eliminate edema as a cri-terion for diagnosing preeclampsia are discussed.In addition, the use of blood pressure increases of30 mm Hg systolic or 15 mm Hg diastolic as adiagnostic criterion has not been recommended, asavailable evidence shows that women in this groupare not likely to suffer increased adverse outcomes.Management considerations are made betweenchronic hypertension that is present before preg-nancy and those occurring as part of the pregnan-cy-specific condition preeclampsia, as well as

management considerations in women with comor-bid conditions. A discussion of the pharmacologictreatment of hypertension in pregnancy includesrecommendations for specific agents. The use oflow-dose aspirin, calcium, or other dietary supple-ments in the prevention of preeclampsia isdescribed, and expanded sections on counselingwomen for future pregnancies and recommenda-tions for future research are included. Once againwe thank Dr. Ray Gifford, Jr., and his committeefor volunteering their time to produce this impor-tant report. We hope it helps the busy clinicianprevent and manage a very important problem.

Claude Lenfant, M.D.DirectorNational Heart, Lung, and Blood Instituteand ChairNational High Blood Pressure Education ProgramCoordinating Committee

FOREWORD

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INTRODUCTION

1

H ypertensive disorders during pregnancy are thesecond leading cause, after embolism, of

maternal mortality in the United States, accountingfor almost 15 percent of such deaths.1

Hypertensive disorders occur in 6 to 8 percent ofpregnancies and contribute significantly to still-births and neonatal morbidity and mortality.1

Expectant mothers with hypertension are predis-posed to the development of potentially lethalcomplications, notably abruptio placentae, dissem-inated intravascular coagulation, cerebral hemor-rhage, hepatic failure, and acute renal failure. Theetiology of most cases of hypertension duringpregnancy, particularly preeclampsia, remainsunknown.

The purpose of the National High Blood PressureEducation Program Working Group Report onHigh Blood Pressure in Pregnancy is to provide

guidance to practicing clinicians on managing (1)patients with hypertension who become pregnantand (2) patients who develop hypertensive disor-ders during gestation. The members of the work-ing group recognize that the responsible clinician’sjudgment of the individual patient’s needs remainsparamount. Therefore, this national guidelineshould serve as a tool to be adapted and imple-mented in individual situations. Using evidence-based medicine and consensus, the report updatescontemporary approaches to hypertension controlduring pregnancy. This report expands andupdates recommendations made in The SixthReport of the Joint National Committee onPrevention, Detection, Evaluation, and Treatmentof High Blood Pressure (JNC VI).2

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EVIDENCE BASE

T he studies that provided evidence supportingthe recommendations for treatment sections of

this report were classified and reviewed by themembers of the working group and staff. The fol-lowing classification of references used in JNC VIand originally adapted from Last and Abramson3

will be used in this report:

M Meta-analysis; an analysis of a compendiumof experimental studies

Ra Randomized controlled trials; also known asexperimental studies

Re Retrospective analyses; also known as case-control studies

F Prospective followup; also known as cohortstudies, including historical cohort studiesand long-term followup

X Cross-sectional population studies; alsoknown as prevalence studies

Pr Previous review or position statements

C Clinical interventions (nonrandomized)

These explanatory symbols are appended to someof the references in the reference section of thedocument and to some of the citations in the text.

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CLASSIFICATION OF THE HYPERTENSIVE DISORDERS OF PREGNANCY

T he most important consideration in the classifi-cation of diseases in which blood pressure rises

abnormally is differentiating hypertensive disor-ders that antedate pregnancy from a potentiallymore ominous disease peculiar to pregnancy:preeclampsia. Preeclampsia is a pregnancy-specif-ic syndrome of reduced organ perfusion secondaryto vasospasm and activation of the coagulation cas-cade. Although our understanding of this syn-drome has increased, the criteria used to identifythe disorder remain a subject of confusion andcontroversy. This doubtless reflects the fact thatpreeclampsia is a syndrome and that attempts atdefinition use arbitrarily selected markers ratherthan changes of pathophysiologic importance. Theeditors of the 1990 version of this document4 elect-ed to modify minimally the criteria presented bythe American College of Obstetricians andGynecologists (ACOG) Committee onTerminology in 1972.5 This decision was prompt-ed by the opinion that this classification was sim-ple and used widely and that much of what wasunderstood about the prevalence of these disordersand their outcomes was based on data generatedwith this classification. Our current opinion islargely the same.

Several groups, including the ACOG,1 theAustralasian Society for the Study of Hypertensionin Pregnancy,6 and the Canadian HypertensionSociety,7 have published classification schemes anddiagnostic criteria that differ from one document tothe other and contrast with those below. Theyinclude recommendations to eliminate edema fromdiagnostic criteria, to abandon the use of changesin blood pressure as diagnostic,1,7 to use only dias-tolic pressures,7 and to add systemic changes toproteinuria as diagnostic markers.8 Of these, wedetermined that only the elimination of edema andchanges in blood pressure as diagnostic criteriacan be justified on the basis of available data.There were also differences in designating theKorotkoff sound that determines diastolic blood

pressure—K4, muffling6,7 or K5, disappearance.4,8

We chose K5 because substantial data now supportits use.9–13

In chronic hypertension, elevated blood pressure isthe cardinal pathophysiologic feature, whereas inpreeclampsia, increased blood pressure is impor-tant primarily as a sign of the underlying disorderand is a potential cause of maternal morbidity. Asmight be expected, the impact of the two condi-tions on mother and fetus is different, as is theirmanagement. Attempts to differentiate the twoconditions have led to confusion in terminologyworldwide. We have modified the ACOG classifi-cation slightly by adding the term “gestationalhypertension” for the woman who has hyperten-sion without proteinuria during pregnancy, reserv-ing “transient hypertension” for a definitivediagnosis made postpartum. According to this ter-minology, women with increased blood pressureare divided into the groups discussed below:

CLASSIFICATION

• Chronic hypertension

• Preeclampsia-eclampsia

• Preeclampsia superimposed upon chronichypertension

• Gestational hypertension: (1) transient hyper-tension of pregnancy if preeclampsia is notpresent at the time of delivery and blood pres-sure returns to normal by 12 weeks postpartum(a retrospective diagnosis) or (2) chronic hyper-tension if the elevation persists.

Chronic Hypertension

Chronic hypertension is defined as hypertensionthat is present and observable before pregnancy orthat is diagnosed before the 20th week of gesta-tion. Hypertension is defined as a blood pressureequal to or greater than 140 mm Hg systolic or

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Classification of the Hypertensive Disorders of Pregnancy

90 mm Hg diastolic. Hypertension that is diag-nosed for the first time during pregnancy and thatdoes not resolve postpartum is also classified aschronic hypertension.

Preeclampsia-Eclampsia

The pregnancy-specific syndrome usually occursafter 20 weeks of gestation (or earlier with tro-phoblastic diseases such as hydatidiform mole orhydrops). It is determined by increased bloodpressure (gestational blood pressure elevation)accompanied by proteinuria. Gestational bloodpressure elevation is defined as a blood pressuregreater than 140 mm Hg systolic or 90 mm Hgdiastolic in a woman normotensive before 20weeks. In the absence of proteinuria the disease ishighly suspect when increased blood pressureappears accompanied by the symptoms ofheadache, blurred vision, and abdominal pain, orwith abnormal laboratory tests, specifically, lowplatelet counts and abnormal liver enzymes.

In the past it has been recommended that an incre-ment of 30 mm Hg systolic or 15 mm Hg diastolicblood pressure be used as a diagnostic criterion,even when absolute values are below 140/90 mmHg. This definition has not been included in ourcriteria because the only available evidence showsthat women in this group are not likely to sufferincreased adverse outcomes.14,15 Nonetheless, it isthe collective clinical opinion of this panel thatwomen who have a rise of 30 mm Hg systolic or15 mm Hg diastolic blood pressure warrant closeobservation, especially if proteinuria and hyper-uricemia (uric acid [UA] greater than or equal to 6mg/dL) are also present.

Diastolic blood pressure is determined as the dis-appearance of sound (Korotkoff 5). Measuring theblood pressure successively may result in very dif-ferent readings. It is recommended that gestationalblood pressure elevation be defined on the basis ofat least two determinations. The repeat bloodpressure should be performed in a manner that willreduce the likelihood of artifact and/or patient anx-iety.2 For database studies, the measurements ofincreased blood pressure should be no more than 1 week apart.

Proteinuria is defined as the urinary excretion of0.3 g protein or greater in a 24-hour specimen.

This will usually correlate with 30 mg/dL (“1+ dipstick”) or greater in a random urine deter-mination with no evidence of urinary tract infec-tion. However, because of the discrepancybetween random protein determinations and 24-hour urine protein in preeclampsia (which maybe either higher or lower),16–18 it is recommendedthat the diagnosis be based on a 24-hour urine if atall possible or a timed collection corrected for cre-atinine excretion if this is not feasible.

Preeclampsia always presents potential danger tomother and baby. Other conditions may increaseblood pressure and even result in proteinuria; thus,as the certainty of the diagnosis increases, therequirements for careful assessment and considera-tion for delivery also increase. The following find-ings increase the certainty of the diagnosis of thepreeclampsia syndrome and indicate such fol-lowup:

• Blood pressure of 160 mm Hg or more systolic,or 110 mm Hg or more diastolic.

• Proteinuria of 2.0 g or more in 24 hours (2+ or3+ on qualitative examination). The proteinuriashould occur for the first time in pregnancy andregress after delivery.

• Increased serum creatinine (>1.2 mg/dL unlessknown to be previously elevated).

• Platelet count less than 100,000 cells/mm3

and/or evidence of microangiopathic hemolyticanemia (with increased lactic acid dehydroge-nase).

• Elevated hepatic enzymes (alanine aminotrans-ferase [ALT] or aspartate aminotransferase[AST]).

• Persistent headache or other cerebral or visualdisturbances.

• Persistent epigastric pain.

Eclampsia is the occurrence, in a woman withpreeclampsia, of seizures that cannot be attributedto other causes.

Edema occurs in too many normal pregnantwomen to be discriminant and has been abandonedas a marker in this and other classificationschemes.1,7,8

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Preeclampsia Superimposed Upon ChronicHypertension

There is ample evidence that preeclampsia mayoccur in women already hypertensive (i.e., whohave chronic hypertension) and that the prognosisfor mother and fetus is much worse than witheither condition alone. Distinguishing superim-posed preeclampsia from worsening chronichypertension tests the skills of the clinician. Forclinical management, the principle of high sensi-tivity and unavoidable overdiagnosis is appropri-ate. The suspicion of superimposed preeclampsiamandates close observation, with delivery indicat-ed by the overall assessment of maternal-fetalwell-being rather than any fixed end point. Thediagnosis of superimposed preeclampsia is highlylikely with the following findings:

• In women with hypertension and no proteinuriaearly in pregnancy (<20 weeks), new-onset pro-teinuria, defined as the urinary excretion of 0.3 g protein or greater in a 24-hour specimen.

• In women with hypertension and proteinuriabefore 20 weeks’ gestation.

• Sudden increase in proteinuria.

• A sudden increase in blood pressure in awoman whose hypertension has previously beenwell controlled.

• Thrombocytopenia (platelet count <100,000cells/mm3).

• An increase in ALT or AST to abnormal levels.

Gestational Hypertension

The woman who has blood pressure elevationdetected for the first time after midpregnancy,without proteinuria, is classified as having gesta-tional hypertension. This nonspecific termincludes women with the preeclampsia syndromewho have not yet manifested proteinuria as well aswomen who do not have the syndrome. Thehypertension may be accompanied by other signsof the syndrome, which will influence manage-ment. The final differentiation that the womandoes not have the preeclampsia syndrome is madeonly postpartum. If preeclampsia has not devel-oped and blood pressure has returned to normal by12 weeks postpartum, the diagnosis of transienthypertension of pregnancy can be assigned. If blood pressure elevation persists, the woman isdiagnosed as having chronic hypertension. Notethat the diagnosis of gestational hypertension isused during pregnancy only until a more specificdiagnosis can be assigned postpartum.

CLINICAL IMPLICATIONS OF CLASSIFICATION

The clinical spectrum of preeclampsia ranges frommild-to-severe forms. In most women, progressionthrough this spectrum is slow, and the disordermay never proceed beyond mild preeclampsia. Inothers, the disease progresses more rapidly, chang-ing from mild to severe in days or weeks. In themost serious cases, progression may be fulminant,with mild preeclampsia evolving to severepreeclampsia or eclampsia within days or evenhours. Thus, for clinical management, preeclamp-sia should be overdiagnosed, because a major goalin managing preeclampsia is the prevention ofmaternal and perinatal morbidity and mortality,primarily through timing of delivery.

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6

P reeclampsia is a syndrome with both maternaland fetal manifestations. The maternal disease

is characterized by vasospasm, activation of thecoagulation system, and perturbations in manyhumoral and autacoid systems related to volumeand blood pressure control. Oxidative stress andinflammatory-like responses may also be impor-tant in the pathophysiology of preeclampsia. Thepathologic changes in this disorder are primarilyischemic in nature and affect the placenta, kidney,liver, and brain. Of importance, and distinguishingpreeclampsia from chronic or gestational hyperten-sion, is that preeclampsia is more than hyperten-sion; it is a systemic syndrome, and several of its“nonhypertensive” complications can be life-threatening when blood pressure elevations arequite mild.

PATHOGENIC MECHANISMS

The cause of preeclampsia is not known. Manyconsider the placenta the pathogenic focus for allmanifestations of preeclampsia because delivery isthe only definitive cure of this disease. Thusresearch has focused on the changes in the mater-nal blood vessels that supply blood to the placenta.

Early in gestation the spiral arteries (the terminalbranches of the uterine artery) are transformedfrom thick-walled, muscular vessels to sac-likeflaccid vessels, which eventually accommodate atenfold increase in uterine blood flow. This trans-formation involves invasion of the spiral arteriesby endovascular trophoblast cells of the placen-ta.19–22 There is evidence in women destined todevelop preeclampsia that trophoblastic invasion ofthe uterine spiral arteries is incomplete, the vesselsremaining thick-walled and muscular.20,22,23 Thecause of this may be a failure of cytotrophoblastcells to express the adhesion molecules necessaryfor normal remodeling of the maternal spiral arter-ies.21,22 Failure of the spiral arteries to remodel ispostulated as the morphologic basis for decreased

placental perfusion in preeclampsia, which mayultimately lead to early placental hypoxia.

Research on how alterations in the immuneresponse at the maternal interface might lead topreeclampsia addresses the link between placentaland maternal disease. A nonclassical humanleukocyte antigen (HLA), HLA G, is expressed innormal placental tissue and may play a role inmodulating the maternal immune response to theimmunologically foreign placenta.24,25 Placentaltissue from preeclamptic pregnancies may expressless or different HLA G proteins,26 resulting inbreakdown of maternal tolerance to the placenta.Additional evidence for alterations in immunity inpathogenesis includes the disease’s prominence innulliparous gestations with subsequent normalpregnancies, a decreased prevalence after heterolo-gous blood transfusions, long cohabitation beforesuccessful conception, and observed pathologicchanges in the placental vasculature in preeclamp-sia that resemble allograft rejection.27 Finally,there are increased levels of inflammatorycytokines in the placenta and maternal circulation,as well as evidence of increased “natural killer”cells and neutrophil activation in preeclampsia.27

PATHOPHYSIOLOGY OF THE MATERNAL

MANIFESTATIONS OF PREECLAMPSIA

Blood Pressure in Preeclampsia

Women with preeclampsia do not usually developfrank hypertension until the second half of gesta-tion, but vasoconstrictor influences may be presentearlier. For instance, alterations in vascular reac-tivity may be detected by gestational week 20, andnumerous surveys suggest that women destined todevelop preeclampsia have slightly higher “nor-mal” blood pressure (e.g., diastolic levels >70 mmHg) as early as the second trimester,28 confirmedby ambulatory blood pressure monitoring tech-niques.29,30

PATHOPHYSIOLOGY

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High blood pressure in preeclampsia is due mainlyto a reversal of the vasodilation characteristic ofnormal pregnancy, replaced by marked increases inperipheral vascular resistance.31,32 Normally, thevasculature of normotensive gravidas manifests adecreased pressor responsiveness to severalvasoactive peptides and amines, especially toangiotensin II (AII). The vessels of women withpreeclampsia, however, become hyperresponsive tothese hormones, and in the case of AII, suchchanges may occur months before the appearanceof overt disease,33 although this has not beenobserved by all investigators.30 Hypertension inpreeclampsia can be labile and may be accompa-nied by a blunting and even reversal of normal cir-cadian blood pressure rhythms.34 Blood pressurenormalizes postpartum, usually within the first fewdays of the puerperium, but may take as long as 2to 4 weeks, especially in severe cases.35

The mechanisms underlying vasoconstriction andaltered vascular reactivity in preeclampsia remainobscure. Research has focused on changes in theratio of vasodilating and vasoconstrictingprostanoids, since there is evidence suggestingdecrements and increments in the production ofprostacyclin and thromboxane, respectively.36–38

More recently, investigators have postulated thatthe vasoconstricting potential of pressor substances(e.g., AII and endothelin) is magnified inpreeclampsia as a consequence of a decreasedactivity of nitric oxide (NO) synthase anddecreased production of NO-dependent or -inde-pendent endothelium relaxing factor (EDRF).39–43

Also under investigation is the role of endothelialcells (the site of prostanoid, endothelin, and EDRFproduction), which in preeclampsia may be dys-functional, due perhaps to inflammatory cytokines(e.g., TNF alpha) and increased oxidative stress.44–51

Other factors postulated to play a role inpreeclamptic hypertension are the sympatheticnervous system,52 calciotropic hormones,53,54

insulin,55–58 and magnesium metabolism.59

The Heart

The heart is usually unaffected in preeclampsia,the decrements in cardiac performance represent-ing a normally contracting ventricle against amarkedly increased afterload.31,60 Cardiac decom-pensation may complicate this disorder; however,this is most often due to the presence of preexist-ing heart disease.61

The Kidney

The renal lesion that is characteristic of preeclamp-sia is termed “glomerular endotheliosis.”62–65 Theglomeruli are enlarged and swollen but not hyper-cellular, due primarily to hypertrophy of the intra-capillary cells (mainly endothelial but mesangial aswell), which encroach on the capillary lumina, giv-ing the appearance of a bloodless glomerulus.

Both glomerular filtration rate (GFR) and renalblood flow decrease in preeclampsia, the formermore so than the latter, leading to a decrease in fil-tration fraction.31 The decrement is usually modest(25 percent) even when morphological changes arepronounced. Since renal function normally rises 35to 50 percent during pregnancy, creatinine levels inwomen with preeclampsia may still be below theupper limits of normal for pregnancy (0.8 mg/dL).Renal insufficiency is rarely severe, but acute tubu-lar or cortical necrosis has been linked topreeclampsia.66 Fractional urate clearance decreas-es, producing hyperuricemia, which is an importantmarker of preeclampsia.31 Proteinuria may appearlate in the clinical course and tends to be nonselec-tive.31 Preeclampsia is associated with hypocalci-uria, in contrast with the increased urinary calciumexcretion observed during normal pregnancy.67

Alterations in calcium regulatory hormones, includ-ing reduced plasma levels of 1,25(OH)2D3,

53 andincreased parathyroid hormone54 are also present.

Sodium excretion may be impaired in preeclampsia,although this is variable.68 Some of the severestforms of the disease occur in the absence of edema.Even when edema is marked, plasma volume islower than that of normal gestation, and there is evi-dence of hemoconcentration, believed to be due inpart to extravasation of albumin into the intersti-tium. In addition, central venous pressure (CVP)and pulmonary capillary wedge pressure (PCWP)are often low or low normal. The reductions inintravascular volume and the lack of evidence forelevations in central pressures, along with decre-ments in placental perfusion, are major reasons toavoid diuretic therapy in women with preeclamp-sia.62

The cause of the impaired renal sodium excretion isunclear; the changes in GFR and several volume-sensitive hormones fail to explain this observation.Filtered sodium, though decreased compared withthat in normal pregnancy, is still above that

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Pathophysiology

measured in nonpregnant women. Suppression ofthe renin angiotensin system is a well-documentedfeature of preeclampsia69 and may be a consequencerather than a cause of impaired sodium excretion.Atrial natriuretic hormone is reported to beincreased.70,71

The Coagulation System

Thrombocytopenia, rarely severe, is the most com-monly found hematologic abnormality in pre-eclampsia. Circulating fibrin degradation productsoccasionally may be elevated, and unless the dis-ease is accompanied by placental abruption, plas-ma fibrinogen levels are unaffected.72 However,antithrombin III levels are lower and cellularfibronectin levels higher in women withpreeclampsia compared with normal pregnantwomen—observations consistent with vascularendothelial injury.73,74

Platelet counts below 100,000 cells/mm3 signalserious disease, and if delivery is delayed, levelsmay continue to fall precipitously. Althoughplatelet counts have not been correlated withmaternal hemorrhagic complications, very lowplatelet counts would be expected to increase therisk of bleeding.

The cause of the thrombocytopenia is also unclear.It has been ascribed to platelet deposition at sitesof endothelial damage72 and to an immunologicprocess.75 There is no firm evidence that the fetus-es born to women with severe preeclampsia-eclampsia will develop thrombocytopenia, despitesevere maternal thrombocytopenia.76

The Liver

The pathologic changes in the liver in preeclamp-sia have been well described in the autopsy studiesof Sheehan and Lynch.77 They include periportalhemorrhages, ischemic lesions, and fibrin deposi-tion. Liver damage accompanying preeclampsiamay range from mild hepatocellular necrosis withserum enzyme abnormalities (aminotransferaseand lactate dehydrogenase) to the ominous hemol-ysis, elevated liver enzymes, and low platelet count(HELLP) syndrome, with markedly elevatedenzyme levels and even subcapsular bleeding orhepatic rupture. The latter syndrome representsserious disease and is associated with significantmaternal morbidity.78,79

The Central Nervous System

Eclampsia, the convulsive phase of preeclampsia,remains a significant cause of maternal mortality.Other central nervous system manifestationsinclude headache and visual disturbances includingblurred vision, scotomata, and, rarely, corticalblindness. Occasionally, focal neurologic signsmay develop, which should prompt radiologicinvestigation.

The pathogenesis of eclampsia remains disputedand has been attributed both to coagulopathy andfibrin deposition, as well as hypertensive encephal-opathy. The latter explanation is difficult to recon-cile with the clinical observations that manywomen develop convulsions with only mild ormoderate hypertension. However, vasoconstrictionin eclampsia may be selective, and the results ofstudies using ultrasonographic Doppler techniquessuggest that severe cerebral vasospasm may occureven when peripheral vasoconstriction is less evident.80,81

The best descriptions of gross and microscopicpathology in eclampsia remain those of Sheehanand Lynch,77 in which most autopsies were per-formed within 1 to 2 hours of death, eliminatingmost of the postmortem changes that usually con-found interpretation of brain pathology. There arevarying degrees of hemorrhages and petechiae,vasculopathy with vessel wall damage and fibri-noid necrosis (possibly related to chronic hyper-tension), ischemic brain damage, andmicroinfarcts.77,82

Women with eclampsia have been evaluated withcomputerized axial tomography (CAT) and mag-netic resonance imaging (MRI) techniques.83,84

Some studies have been relatively normal, and oth-ers describe a variety of abnormalities, most ofwhich are usually transient. Lesions consistentwith cerebral edema and hemorrhage, as well ashypodense areas believed to represent localizededema induced perhaps by hypoxia, have beendescribed in the CAT scans.85 Hemorrhage andedema have also been documented by MRI, and ofinterest are reports of changes in the posteriorhemispheres or in the vascular watershed areas,findings consistent with global ischemia inducedby vasospasm.86 Predominance of posterior lesionsmay explain the increased incidence in preeclamp-sia-eclampsia of visual disturbances.

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D ecisions regarding hospitalization and deliverythat have significant impact on maternal and

fetal health are often based on whether the patientis believed to have preeclampsia or a more benignform of high blood pressure, such as chronic orgestational hypertension. The correct diagnosis isimportant when counseling patients regardingfuture pregnancies. (See the PrepregnancyCounseling section.)

The period in gestation when hypertension is firstdocumented is helpful in determining the correctdiagnosis. Documentation of hypertension beforeconception, or before gestational week 20, favors adiagnosis of chronic hypertension (either essentialor secondary). High blood pressure presenting atmidpregnancy (weeks 20 to 28) may be due eitherto early preeclampsia (rare before 24 weeks), tran-sient hypertension, or unrecognized chronic hyper-tension. Concerning the latter, blood pressurenormally falls in the initial trimesters, and this“physiologic” decrement may even be exaggeratedin patients with essential hypertension, maskingthe diagnosis in pregnancy. Hypertension may benoted later in pregnancy, however, as part of thenormal third trimester rise in blood pressure orwhen superimposed preeclampsia occurs.

LABORATORY TESTS

Laboratory tests recommended to diagnose ormanage hypertension in pregnancy serve primarilyto distinguish preeclampsia from either chronic ortransient hypertension. They are also useful inassessing the severity of disease, particularly in thecase of preeclampsia, which is usually associatedwith laboratory abnormalities that deviate signifi-cantly from those of normal pregnant women.These same measurements are usually normal inwomen with uncomplicated chronic or transienthypertension.

Efforts to identify an ideal screening or predictivetest for preeclampsia have not been successful todate.7 Several parameters, such as midpregnancyblood pressure, ambulatory blood pressure moni-toring, serum ß-hCG, AII sensitivity, urinary calci-um excretion, urinary kallikrein, uterine arteryDoppler, plasma fibronectin, and platelet activa-tion, have been shown to be statistically valid earlymarkers of disease; however, they have not beendemonstrated to have sufficient predictive value orpractical utility for application to individualpatients.87

High-Risk Patients Presenting With NormalBlood Pressure

Pregnant women whose gestations are considered“high risk” for preeclampsia (e.g., history ofincreased blood pressure before conception or in aprevious gestation, especially before week 34, orwhen the subject is multiparous; women with dia-betes, collagen vascular disease, or underlyingrenal vascular or renal parenchymal disease; andthose with a multifetal pregnancy) will benefitfrom a database of laboratory tests performed inearly gestation.88,89 Tests that by later comparisonwill help establish an early diagnosis of pre-eclampsia (pure or superimposed) include hemat-ocrit, hemoglobin, and platelet count as well asserum creatinine and uric acid levels. Observationof 1 plus protein by routine urine analysis, docu-mented by a clean-catch specimen, should be fol-lowed by a 24-hour collection for measurement ofprotein as well as creatinine content (to determineaccuracy of collection and to permit calculation ofthe creatinine clearance). High-risk patientsrequire accurate dating and assessment of fetalgrowth. If conditions are not optimal for clinicaldating, sonographic dates should be established asearly in pregnancy as possible. A baseline sono-gram for evaluating fetal growth should be consid-ered at 25 to 28 weeks in these circumstances.

DIFFERENTIAL DIAGNOSIS

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Differential Diagnosis

Patients Presenting With Hypertension BeforeGestation Week 20

Most women presenting with hypertension beforegestation week 20 have, or will develop, essentialhypertension; their management is discussed in thenext section. Some may be already under the careof primary physicians and screened for secondaryhypertension. Young women with preexisting orearly gestational hypertension are among the popu-lation in which secondary hypertension is more aptto be found (e.g., renal disease, renovascularhypertension, primary aldosteronism, Cushing syn-drome, and pheochromocytoma). Thus, furtherevaluation with noninvasive testing may be war-ranted, especially when there is suspicion of thoseforms of secondary hypertension that are associat-ed with more maternal and fetal complications.

The same database described above (high-riskwomen presenting with normal blood pressure) ishelpful in determining whether further incrementsin pressure in the third trimester represent the“physiologic” increments or the onset of superim-posed preeclampsia. Since these fetuses are at

higher risk for the development of intrauterinegrowth restriction, early baseline sonography fordating and fetal size is also indicated for thesepatients.

Patients Presenting With Hypertension AfterMidpregnancy

Table 1 summarizes the laboratory tests that arerecommended in the evaluation of women withhypertension after midpregnancy and the rationalefor testing them biweekly or more often if clinicalcircumstances lead to hospitalization of the patient.Not only do such tests help to distinguish pre-eclampsia from chronic and transient hypertension,but they are useful in assessing disease progressionand severity. It is important to recognize that inwomen with preeclampsia, one or more abnormali-ties may be present even when blood pressure ele-vation is minimal. If there is a life-threateningabnormality such as coagulopathy or abnormalhepatic or renal function, it may be necessary toterminate the pregnancy despite only mild hyper-tension. (See the section on Management ofPreeclampsia.)

TABLE 1. LABORATORY EVALUATION AND ITS RATIONALE FOR WOMEN

WHO DEVELOP HYPERTENSION AFTER MIDPREGNANCY

Test Rationale

Hemoglobin and hematocrit Hemoconcentration supports diagnosis of preeclampsia and is anindicator of severity. Values may be decreased, however, ifhemolysis accompanies the disease.

Platelet count Thrombocytopenia suggests severe preeclampsia.

Quantification of protein excretion Pregnancy hypertension with proteinuria should be consideredpreeclampsia (pure or superimposed) until it is proved otherwise.

Serum creatinine level Abnormal or rising serum creatinine levels, especially inassociation with oliguria, suggest severe preeclampsia.

Serum uric acid level Increased serum uric acid levels suggest the diagnosis ofpreeclampsia.

Serum transaminase levels Rising serum transaminase values suggest severe preeclampsiawith hepatic involvement.

Serum albumin, lactic acid For women with severe disease, these values indicate the extentdehydrogenase, blood smear, of endothelial leak (hypoalbuminemia), presence of hemolysisand coagulation profile (latic acid dehydrogenase level increase, schizocytosis,

spherocytosis), and possible coagulopathy, includingthrombocytopenia.

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PREPREGNANCY COUNSELING

W omen with hypertension should be evaluatedbefore pregnancy to define the severity of

their hypertension and to facilitate planning forpotential lifestyle changes that a pregnancy mayrequire. As recommended in JNC VI,2Pr the diag-nosis should be confirmed by multiple measure-ments and may incorporate home or otherout-of-office blood pressure readings. If hyperten-sion is confirmed and particularly if it is severe(stage 3: systolic pressure ≥ 180 mm Hg or dias-tolic pressure ≥ 110 mm Hg), a woman should beevaluated for potentially reversible causes.Angiotensin-converting enzyme inhibitors and AIIreceptor antagonists should be discontinued. (Fora discussion of drug therapy, see the next section.)

Women with a history of hypertension for severalyears should be evaluated for target organ damageincluding left ventricular hypertrophy, retinopathy,and renal disease. If damage is present, thewoman should be advised that pregnancy mayexacerbate the condition. Women with chronichypertension are at higher risk for adverse neonataloutcomes independent of the development ofpreeclampsia, if proteinuria is present early inpregnancy.88F The risks of fetal loss and accelerat-ed deterioration of maternal renal disease areincreased if serum creatinine is above 1.4 mg/dL atconception, although it may be difficult to separatethe effects of the pregnancy from progression ofthe underlying renal disease.90F,91F In patients withimpaired renal function, relative risk of fetal losshas been reported to be increased tenfold whenhypertension is present and not controlled at con-ception, compared with pregnancy without hyper-tension or with well-controlled hypertension.92F,93Re

Chronic hypertension before pregnancy requiresplanning for lifestyle changes. For example, preg-nant women with hypertension may need to restricttheir activities at work and home and refrain from

vigorous exercise. Although regular exercise isbeneficial for hypertensive individuals who are notpregnant and may be safe for normotensive preg-nant women,94F,95F there are no data on safety in thesetting of chronic hypertension and pregnancy. Inview of the theoretical concerns with maintainingadequate placental blood flow in hypertensivewomen who are at increased risk for preeclampsia,our recommendation is to discourage aerobic exer-cise in hypertensive pregnant women until moredata are available. Weight reduction during preg-nancy, even in obese women, is not recommended.Although obesity may be a risk factor for superim-posed preeclampsia, there is no evidence that lim-iting weight gain reduces its occurrence. Althoughthe evidence is sparse in pregnant women, manyexperts recommend restriction of sodium intake tothe same 2.4 g sodium intake recommended foressential hypertension. Women who already fol-low a more restricted sodium intake may continueto follow that dietary approach.

The use of alcohol and tobacco during pregnancyshould be strongly discouraged. Both have a deleterious effect on the fetus and the mother.Excessive consumption of alcohol can cause oraggravate maternal hypertension. Tobacco is asso-ciated with a substantive risk for placental abrup-tion and fetal growth restriction.

TREATMENT OF CHRONIC HYPERTENSION

The majority of women with chronic hypertensionin pregnancy have Stage 1 to 2 hypertension(defined as systolic blood pressure of 140 to 179 mm Hg or diastolic blood pressure of 90 to109 mm Hg) and are at low risk for cardiovascularcomplications within the short timeframe of preg-nancy. Among women with Stage 1 to 2 preexist-ing essential hypertension and normal renalfunction, most pregnancies will have good mater-nal and neonatal outcomes. These women are can-didates for nondrug therapy because, to date, there

CHRONIC HYPERTENSION IN PREGNANCY

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Chronic Hypertension in Pregnancy

is no evidence that pharmacologic treatment resultsin improved neonatal outcomes.96Ra,97Ra Since bloodpressure usually falls during the first half of preg-nancy, hypertension may be easier to control withless or no medication.

The value of continued administration of antihy-pertensive drugs to pregnant women with chronichypertension continues to be an area of debate.Although it may be beneficial for the mother withhypertension to reduce her blood pressure, lowerpressure may impair uteroplacental perfusion andthereby jeopardize fetal development.98,99M

Although it is not generally agreed whether antihy-pertensive therapy is beneficial or detrimental topregnancy outcome, several studies offer someclinical guidance. Over the past 30 years, at leastseven studies have compared antihypertensive ther-apy with either no medication or a placebo in preg-nant women with mild chronic hypertension.100Pr

Higher fetal losses during the second trimesterwere noted among untreated women in severalearly trials, but this finding was not confirmed.Indeed, overall prevalence rates of these adverseoutcomes were very low. Rey and Couturier retro-spectively evaluated the course of 298 pregnantwomen with chronic hypertension whose antihy-pertensive medications had been discontinued orwhose doses were reduced early in pregnancy.101F

Treatment did not decrease the frequency of super-imposed preeclampsia, preterm delivery, abruptioplacentae, or perinatal death when compared withuntreated groups. Much uncertainty about the ben-efits of lowering blood pressure in pregnantwomen with mild chronic hypertension stems frompublished trials that are too small to detect modestreductions in obstetrical complications.

Evidence from several studies indicates the effec-tiveness of antihypertensive drugs in preventingexacerbation of chronic hypertension to severehypertension during pregnancy.96Ra,100Pr These trialshave included heterogeneous populations ofwomen with preexisting hypertension and gesta-tional hypertension, different thresholds for treat-ment by gestational age, and the presence orabsence of proteinuria, and they often includedmultiple treatment agents.

Most of the increased risk associated with chronichypertension occurs in the setting of superimposedpreeclampsia.88F Preeclampsia is more common in

women with chronic hypertension and complicatesalmost 25 percent of such pregnancies. The inci-dence is even higher if the high blood pressure isassociated with renal insufficiency, the presence ofhypertension for at least 4 years, and a history ofhypertension in a previous pregnancy.88F,90F,91F Theincidence of placental abruption is markedlyincreased in the presence of superimposedpreeclampsia.102Pr

On the basis of available data, some centers cur-rently manage women with chronic hypertensionby stopping antihypertensive medications underclose observation.101F,103Pr In patients with hyperten-sion for several years, with evidence of targetorgan damage, or on multiple antihypertensiveagents, medications may be tapered on the basis ofblood pressure readings but should be continued ifneeded to control blood pressure. End points forreinstituting treatment include exceeding thresholdblood pressure levels of 150 to 160 mm Hg sys-tolic or 100 to 110 mm Hg diastolic or the pres-ence of target organ damage such as leftventricular hypertrophy or renal insufficiency.Methyldopa is preferred by most practitioners.Alternatively, women who are well controlled onantihypertensive therapy before pregnancy may bekept on the same agents (with the exception ofangiotensin-converting enzyme inhibitors, AIIreceptor antagonists) during pregnancy.

ANTIHYPERTENSIVE DRUG SELECTION

While the goal of treating chronic hypertension isto reduce maternal risk, the agents selected mustbe efficacious and safe for the fetus, especially inregard to acute and long-range neurologic effects.Methyldopa is preferred by many physicians asfirst-line therapy, on the basis of reports of stableuteroplacental blood flow and fetal hemodynam-ics,104F and one followup study after 7.5 years, in alimited number of infants, showed no long-termadverse effects on development of childrenexposed to methyldopa in utero.105F Methyldopacauses somnolence in many individuals. If thisagent cannot be tolerated, alternatives such aslabetalol are selected based on more limited clini-cal experience. If methyldopa is ineffective, alter-natives can be substituted (see below) based onrational considerations of mechanisms of action.In the latter respect, salt retention may cause

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refractoriness to vasodilator therapy, in which casea diuretic added to the regimen restores bloodpressure control and permits prolongation of thepregnancy.

Most of the published experience with other agentscomes from trials using adrenergic-blocking drugsincluding beta-blockers and the alpha-beta-blockerlabetalol.106M There is a suggestion that beta-block-ers prescribed early in pregnancy, specificallyatenolol, may be associated with growth restric-tion.106M,107Re,108F,109Ra On the other hand, none ofthese agents has been associated with any consis-tent ill effects; however, long-term followup stud-ies are lacking.

Experience with calcium antagonists is limited,with most reported uses being late in pregnancy. A multicenter prospective cohort study of firsttrimester drug exposures reported no increase inmajor teratogenicity from these agents.110F Arecent multicenter study randomizing patients toslow-release nifedipine or no treatment beginningin the second trimester reported neither benefitsnor evidence of harm from nifedipine treatment.97Ra

The use of diuretic agents in pregnancy is contro-versial. The primary concern is theoretical. It isknown that preeclampsia is associated with areduction of plasma volume111F and that fetal out-come is worse in women with chronic hyperten-sion who fail to expand plasma volume.112Ra

Whether this is a cause-and-effect relationship isnot clearly established. Nonetheless, women usingdiuretics from early pregnancy do not increasetheir blood volume to the degree usually occurringin normal pregnancy.113Ra Because of the theoreti-cal concerns, diuretics are usually not used as first-line drugs. A meta-analysis of nine randomizedtrials involving more than 7,000 subjects receivingdiuretics revealed a decrease in the tendency of thewomen to develop edema and/or hypertension114M

and confirmed no increased incidence of adversefetal effects. However, if their use is indicated,they are safe and efficacious agents, can markedlypotentiate the response to other antihypertensiveagents, and are not contraindicated in pregnancyexcept in settings where uteroplacental perfusion isalready reduced (preeclampsia and intrauterinegrowth restriction). Although data concerning theuse of diuretics in pregnant women with essentialhypertension are sparse, this working group

concluded that gestation does not preclude use ofdiuretic drugs to reduce or control blood pressurein women whose hypertension predated conceptionor manifested before midpregnancy.

Angiotensin-converting enzyme inhibitors are con-traindicated during pregnancy because of associa-tions with fetal growth restriction, oligohydram-nios, neonatal renal failure, and neonataldeath.115Pr,116,117Re,118 Although no data are availableon human use of angiotensin II receptor antago-nists, adverse effects are likely to be similar tothose reported with angiotensin converting enzymeinhibitors, and these agents should be avoided.

There are no placebo-controlled trials examiningthe treatment of severe hypertension in pregnancy,and none are likely to be performed, because ofethical considerations. Early reports of experiencewith severe chronic hypertension in the firsttrimester described fetal loss of 50 percent and sig-nificant maternal mortality.119F Most of the pooroutcomes were in pregnancies complicated bysuperimposed preeclampsia.119F Antihypertensivetherapy is indicated for maternal benefit but mayalso permit prolongation of the pregnancy andthereby improve fetal maturity.

PREGNANCY, HYPERTENSION, AND

RENAL DISEASE

Among pregnant women with mild renal disease(serum creatinine less than 1.4 mg/dL), fetal sur-vival is moderately reduced, and the underlyingdisease does not generally worsen.120Pr Womenwith renal diseases that tend to progress should beencouraged to complete their childbearing whiletheir renal function is well preserved. The pres-ence of hypertension before conception or early inpregnancy increases the incidence of maternal andfetal complications, with a tenfold higher relativerisk of fetal loss.92F,121Re

Moderate or severe renal insufficiency may accel-erate during pregnancy and jeopardize fetal sur-vival.90F,91F,120Pr,121Re Hypertension occurs in morethan half of these pregnancies.122Pr A decrease inbirthweight correlates directly with rising maternalserum creatinine concentration.91F As renal failureprogresses, the hypertension has a component ofvolume overload and may require sodium restric-tion, use of loop diuretics, or dialysis.

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Chronic Hypertension in Pregnancy

Recognition of superimposed preeclampsia may bedifficult because proteinuria commonly increasesin women with glomerular disease during pregnan-cy. Chronic dialysis during pregnancy is associat-ed with significant maternal morbidity, andconception should be discouraged. Infant survivalrates are higher in pregnancies where dialysis isstarted after conception (74 to 80 percent) than inthose women who conceived while on mainte-nance dialysis (40 to 50 percent),123X,124Re presum-ably because the former are women with greaterresidual renal function. Infant survival mayimprove with greater duration of dialysis eachweek. Although low birthweight and pretermdelivery are the rule, prognosis appears to beimproving.

Clinical Note: Magnesium sulfate is hazardous inwomen with severe renal failure, and maintenancedoses must be reduced. The usual loading dosecan be given as this distributes to total body waterand is not influenced by renal function. Thenmagnesium should be administered at a gram perhour maintenance, with therapy guided by hourlyto two hourly magnesium levels until steady stateis reached. Phenytoin may be considered as analternative. (See the Anticonvulsive Therapy section.)

Renal transplant recipients are advised to wait 1.5 to 2 years after successful transplantation toundertake pregnancy and only if renal function isstable with creatinine of 2.0 mg/dL or less.122Pr,125Pr

Although pregnancies may be complicated, 92 per-cent of infants survive in those pregnancies that gobeyond the first trimester. From the NationalTransplantation Pregnancy Registry, in 115 renaltransplant patients who received cyclosporine, highrisks to the newborn were reported in settings ofmaternal hypertension and serum creatinine levelsgreater than 1.5 mg/dL. Rates of prematurityapproach 55 percent; thus, all pregnancies in trans-plant recipients are considered high risk.126Re

TREATING HYPERTENSION THAT PERSISTS

POSTPARTUM

Women with chronic hypertension can developencephalopathy, heart failure and pulmonaryedema, and renal failure in the postpartum period.Risk factors include underlying cardiac disease,

chronic renal disease, superimposed preeclampsiain the second trimester, placental abruption com-plicated by disseminated intravascular coagulation,and requirement for multiple antihypertensiveagents.127C,128F Acute hypertensive changes inducedby pregnancy usually dissipate rapidly, within thefirst several days after delivery. Resolution ofhypertension is more rapid in patients with gesta-tional hypertension and may lag in those withpreeclampsia, especially those with longer durationof preeclampsia and greater extent of renal impair-ment.35F This delay in resolution may reflect thetime needed for endothelial recovery.

Oral antihypertensive agents may be required afterdelivery to help control maternal blood pressure, inparticular, for women who were hypertensivebefore pregnancy. If prepregnancy blood pressureswere normal or unknown, it is reasonable to stoporal medication after 3 to 4 weeks and observe the blood pressure at 1- to 2-week intervals for 1 month, then at 3- to 6-month intervals for 1 year.If hypertension recurs, it should be treated.

TREATING HYPERTENSION DURING

LACTATION

Breastfeeding should be encouraged and can bedone safely with certain limits on antihypertensivedrug choices. In mildly hypertensive mothers whowish to breastfeed for a few months, the clinicianmay consider withholding medication, with closemonitoring of blood pressure. After discontinua-tion of nursing, antihypertensive therapy can bereinstituted. For patients with more severe bloodpressure elevation and taking a single antihyper-tensive agent, the clinician may consider reducingthe dosage, then closely observing both the motherand the infant.

Little information is available regarding excretionof antihypertensive agents in human breast milkand effects on the newborn.129Pr Further, there areno data concerning long-term effects of thesedrugs on infants exposed through breastfeeding.The reader is referred to the text by Briggs andcolleagues130Pr and recommendations of theCommittee on Drugs of the American Academy ofPediatrics.131Pr The available data suggest that allstudied agents are excreted into human breastmilk, although differences in the milk/plasma ratio

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are related to lipid solubility and extent of ioniza-tion of the drug at physiologic pH.132Pr No short-term adverse effects have been reported fromexposure to methyldopa or hydralazine. Althoughthe Committee on Drugs considers atenolol com-patible with breastfeeding, this beta-blocker, aswell as metoprolol and nadolol, appears to be con-centrated in breast milk. This property is notshared by propranolol or labetalol; for that reasonthese agents have been recommended if a beta-blocker is indicated. No data on calcium-channelblockers and lactation have been reported.Diuretics may reduce milk volume and suppresslactation.133,134 Angiotensin-converting enzymeinhibitors and angiotensin receptor antagonistsshould be avoided on the basis of reports ofadverse fetal and neonatal renal effects. Given thescarcity of data, breastfed infants of mothers tak-ing antihypertensive agents should be closely mon-itored for potential adverse effects.

FETAL ASSESSMENT IN CHRONIC

HYPERTENSION

Much of the increased perinatal morbidity andmortality associated with chronic hypertension canbe attributed to superimposed preeclampsia and/or

fetal growth restriction. A plan of antepartum fetalassessment is directed by these findings. Effortsshould, therefore, be directed at the early detectionof superimposed preeclampsia and fetal growthrestriction. If these are excluded, then extensivefetal antepartum testing is less essential.

An initial sonographic assessment of fetal size anddating should be performed at 18 to 20 weeks’ ges-tation. Fetal growth should be carefully assessedthereafter. If this is not possible with usual clinicalestimation of fundal height (e.g., maternal obesityor multiple examiners), sonographic assessmentshould be performed at 28 to 32 weeks and month-ly until term. If there is evidence of growthrestriction, fetal well-being should be assessed bynonstress tests or biophysical profiles as usual forthe growth-restricted fetus. Similarly, if pre-eclampsia cannot be excluded, then fetal assess-ment as appropriate for the fetus of a woman withpreeclampsia is mandatory. If the infant is normal-ly grown and preeclampsia can be excluded, how-ever, there is no indication for these studies.

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PREVENTION OF PREECLAMPSIA

T he ability to prevent preeclampsia is limited bylack of knowledge of its underlying cause.

Prevention has focused on identifying women athigher risk, followed by close clinical and labora-tory monitoring to recognize the disease process inits early stages. These women can then be select-ed for more intensive monitoring or delivery.Although these measures do not prevent pre-eclampsia, they may be helpful for preventingsome adverse maternal and fetal sequelae.

Use of Low-Dose Aspirin To PreventPreeclampsia

Benefits of low-dose aspirin prophylaxis areunproven for most women, including nulliparas.The prevailing opinion is that women without riskfactors do not benefit from treatment, despite earli-er prospective studies that suggested that aspirinadministration reduced the incidence of pre-eclampsia. The basis for this opinion is the resultsof eight large trials in different populations aroundthe world. Overall, the results of these trials,which included more than 27,000 pregnantwomen, demonstrate minimal to no reduction inthe incidence of preeclampsia with low-doseaspirin.89Ra,135Ra,136Ra,137Ra,138Ra,139Ra,140Ra,141Ra,142Pr

An important study on low-dose aspirin prophylax-is in 2,539 women at higher risk for preeclampsiawas published recently by the National Institutesof Health (NIH).89Ra Included were four subgroupsof women with pregestational insulin-treated dia-betes mellitus, chronic hypertension, multifetalgestation, or preeclampsia in a previous pregnancy.The incidence of preeclampsia, perinatal death,preterm delivery, and fetal growth restriction wasthe same in the aspirin- and placebo-treatedpatients, with no significant differences in out-comes for any of the four subgroups at higher risk.

Calcium Supplementation

There are no data indicating that dietary supple-mentation with calcium will prevent preeclampsiain low-risk women in the United States. Certainly,a diet that provides 1,000 mg elemental calciumdaily is recommended for general health.143Pr

Whether an enriched calcium diet beyond thisamount may have benefit is unproven.

Results from a large NIH trial in 4,589 healthynulliparous women randomized at 13 to 21 weeksto 2 g elemental calcium daily or placebo indicatethat calcium supplementation neither reduced theincidence or severity of preeclampsia nor delayedits onset.144Ra There were no differences in theprevalence of nonproteinuric hypertension. Evenwithin the subgroup of women with the lowestquintile of dietary calcium intake, similar to thatreported for women in many developing countries,no benefit of calcium supplementation was demon-strated.145Ra,146Ra

Still, randomized trials of calcium supplementationin nulliparous women considered at high riskdemonstrated significant reductions in incidence ofpreeclampsia.147Ra,148Ra,149Ra,150Ra,151Ra

Other Dietary Supplements

Prophylactic magnesium supplementation has notbeen shown to be beneficial in preventingpreeclampsia.152Ra,153Ra

The results of three randomized trials of fish oilsupplementation in women at high risk for pre-eclampsia revealed no reduction in incidence ofpreeclampsia.154Ra,155Ra,156Ra A recent study showingthe benefits of vitamins C and E to prevent pre-eclampsia was encouraging but needs further confirmation.157Ra,158

PREECLAMPSIA

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MANAGEMENT OF PREECLAMPSIA

Rationale for Treatment

The objectives of therapy for preeclampsia arebased on a philosophy of management arisingfrom the knowledge of the pathology, pathophysi-ology, and prognosis of the disorder for motherand baby. The following three important tenetsunderlie management schemes:

1. Delivery is always appropriate therapy for themother but may not be so for the fetus. Formaternal health, the goal of therapy is to pre-vent eclampsia as well as other severe compli-cations of preeclampsia. These disorders arecompletely reversible and usually begin to abatewith delivery. Thus, if only maternal well-being was considered, the delivery of allwomen with preeclampsia, regardless of theseverity of preeclampsia or duration of gesta-tion, would be appropriate. Conversely, deliv-ery induction is not indicated for a pretermfetus with no evidence of fetal compromise inwomen with mild disease. There are twoimportant corollaries of this statement. First,any therapy for preeclampsia other than deliv-ery must have as its successful end point thereduction of perinatal morbidity and mortality.Second, the cornerstone of obstetric manage-ment of preeclampsia is based on whether thefetus is more likely to survive without signifi-cant neonatal complications in utero or in thenursery.

2. The pathophysiologic changes of severepreeclampsia indicate that poor perfusion is themajor factor leading to maternal physiologicderangement and increased perinatal morbidityand mortality. Attempts to treat preeclampsiaby natriuresis or by lowering blood pressuremay exacerbate the important pathophysiologicchanges.

3. The pathogenic changes of preeclampsia arepresent long before clinical diagnostic criteriaare manifest. Several studies indicate thatchanges in vascular reactivity, plasma volume,and renal tubular function antedate—in somecases by weeks—the increases in blood pres-sure, protein excretion, and sodium retention.These findings suggest that irreversible changes

affecting fetal well-being may be present beforethe clinical diagnosis. If there is a rationale formanagement other than delivery, it would be topalliate the maternal condition to allow fetalmaturation and cervical ripening.

NONPHARMACOLOGICAL MANAGEMENT

Fetal Evaluation

Fetal surveillance is indicated for the woman withpreeclampsia. (See the section on High-RiskPatients Presenting With Normal Blood Pressure.)

Nonstress testing (NST), ultrasound assessment offetal activity and amniotic fluid volume (biophysi-cal profile [BPP]), and fetal movement counts con-stitute the most common fetal surveillancetechniques. If determination of pulmonary maturi-ty would influence management, amniocentesisshould be done to determine this before the inter-ruption of pregnancy.

For all women with preeclampsia, daily fetalmovement assessment is a useful screening assess-ment. More formal testing is indicated if move-ments are not normal. Formal testing (NST, BPP)should be performed periodically with even normalfetal activity. The frequency of formal testing willbe dictated by the clinical condition. Althoughweekly to biweekly assessment will usually suf-fice, for women with severe preeclampsia who arebeing managed expectantly, daily testing is appro-priate. (See Table 2.)

If possible fetal compromise is indicated by fetalsurveillance, then decision-making for deliveryrequires judgment heavily weighted by fetal age.

Maternal Evaluation

Antepartum monitoring has two goals. The first isto recognize preeclampsia early; the second is toobserve progression of the condition, both to pre-vent maternal complications by delivery and todetermine whether fetal well-being can be safelymonitored with the usual intermittent observations.

At present, clinical management of preeclampsia isdirected by overt clinical signs and symptoms.Although rapid weight increase and facial edemamay indicate the fluid and sodium retention ofpreeclampsia, they are neither universally presentnor uniquely characteristic of preeclampsia.

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Preeclampsia

These signs are, at most, a reason for closer moni-toring of blood pressure and urinary protein. Earlyrecognition of impending preeclampsia is basedprimarily on blood pressure increases in the latesecond and early third trimesters. Once bloodpressure starts to rise (this may be the first sign ofdeveloping preeclampsia), a repeat examinationwithin 1 to 3 days is recommended. In selectedpatients, blood pressure and urinary protein maybe checked at home. In either case, the womanshould be evaluated for symptoms suggestive ofpreeclampsia—headaches, blurred vision, rightupper quadrant or epigastric pain—and shouldundergo laboratory testing for platelet count, renalfunction, and liver enzymes. Quantification of a12- to 24-hour urine sample for proteinuria is rec-ommended. (See Table 1.) These measures deter-mine how fast the condition is progressing toensure that it is not following a fulminant course.The frequency of subsequent observations is deter-mined by the initial observations and the ensuingclinical progression. If the condition appears sta-ble, weekly observations may be appropriate. Theinitial appearance of proteinuria is an especiallyimportant sign of progression and dictates frequentobservations.

Often, hospitalization is initially recommended forwomen with new-onset preeclampsia. After mater-nal and fetal conditions are serially assessed,

subsequent management may be continued in-hos-pital, at a day-care unit, or at home on the basis ofthe initial assessment. Prolonged hospitalizationfor the duration of pregnancy allows rapid inter-vention in case of fulminant progression to hyper-tensive crisis, eclampsia, or abruptio placentae.159Pr

These complications are rare in compliant womenwho have mild hypertension, minimal proteinuria,no symptoms, and normal platelet counts andserum liver enzyme levels. Recently, ambulatorymanagement at home or at a day-care unit hasbeen evaluated as an option for monitoring womenwith mild gestational hypertension or preeclampsiaremote from term. A number of observation-al160F,161F,162F,163F,164F and randomized studies165F,166Ra,167Ra

suggest a place for ambulatory management ofselected women. If day care or home managementis selected, it should include frequent maternal andfetal evaluation and access to health careproviders.159Pr If worsening of preeclampsia isdiagnosed, as determined by laboratory findings,symptoms, and clinical signs, hospitalization isindicated.

Hospitalization for the duration of pregnancy isindicated for preterm onset of severe gestationalhypertension or preeclampsia. The decision to pro-long the pregnancy in these women is determinedday by day. The women should receive intensivematernal and fetal surveillance, usually at a tertiary

TABLE 2. FETAL MONITORING IN GESTATIONAL HYPERTENSION AND PREECLAMPSIA

Gestational Hypertension (hypertension only without proteinuria, with normal laboratory test results, and without symptoms)

• Estimation of fetal growth and amniotic fluid status should be performed at diagnosis. If results arenormal, repeat testing only if there is significant change in maternal condition.

• Nonstress test (NST) should be performed at diagnosis. If NST is nonreactive, perform biophysicalprofile (BPP). If BPP value is eight or if NST is reactive, repeat testing only if there is significant changein maternal condition.

Mild Preeclampsia (mild hypertension, normal platelet count, normal liver enzyme values, and no maternal symptoms)

• Estimation of fetal growth and amniotic fluid status should be performed at diagnosis. If results arenormal, repeat testing every 3 weeks.

• NST, BPP, or both should be performed at diagnosis. If NST is reactive or if BPP value is eight, repeatweekly. Testing should be repeated immediately if there is abrupt change in maternal condition.

• If estimated fetal weight by ultrasound is <10th percentile for gestational age or if there isoligohydramnios (amniotic fluid index ≤ 5 cm), then testing should be performed at least twice weekly.

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care facility.168F,169Ra,170Ra Laboratory studies are per-formed at frequent intervals and include serial deter-minations of platelet count, serum liver enzymelevels, renal function, and urinary protein.Assiduous attention is given for worsening hyper-tension; evidence of central nervous system involve-ment that includes severe headache, disorientation,or visual symptoms; and hepatic involvement indi-cated by epigastric pain and tenderness.

Antepartum Management of Preeclampsia

There is little to suggest that any therapy alters theunderlying pathophysiology of preeclampsia.Therapeutic efforts that may be palliative, slowprogression of the disorder, and permit continua-tion of pregnancy have not been shown to reversethe underlying disorder. Restricted activity is ausual and reasonable recommendation for womenwith preeclampsia, although its efficacy is notclearly established. Strict sodium restriction anddiuretic therapy appear to have no role in manage-ment. Finally, results of several randomized trialssuggest that antihypertensive therapy for womenwith gestational hypertension or preeclampsia doesnot improve perinatal outcomes.97Ra,100Pr,171Ra

Indications for Delivery

Delivery is the only definitive treatment forpreeclampsia, and some suggested indications arelisted in Table 3. All women with this diagnosisshould be considered for delivery at 40 weeks’ ges-tation. Delivery may be indicated for women with

mild disease and a favorable cervix for inductionat 38 weeks’ gestation and should be considered inwomen who have severe preeclampsia beyond 32to 34 weeks’ gestation. At gestational week 33 to34, the fetus may benefit from corticosteroidadministration.

Prolonged antepartum management in women withsevere preeclampsia is possible in a select group ofwomen with fetal gestational age between 23 and32 weeks. In some women, preeclampsiaimproves after hospitalization and treatment withmagnesium sulfate and antihypertensive agentsgiven acutely.96Ra,169Ra,170Ra Such management mayprolong pregnancy, with a decrease in perinatalmorbidity and mortality. It should be attemptedonly in centers equipped to provide close maternaland fetal surveillance.172Pr Delivery in thesepreterm pregnancies is indicated by worseningmaternal symptoms, laboratory evidence of end-organ dysfunction, or fetal deterioration.

Route of Delivery

Vaginal delivery is preferable to caesarean deliveryfor women with preeclampsia, thus avoiding theadded stress of surgery to multiple physiologicaberrations. Acute palliation for several hoursdoes not increase maternal risk if performedappropriately. Labor induction should be carriedout aggressively once the decision for delivery ismade. In gestation remote from term in whichdelivery is indicated and with fetal and maternal

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

TABLE 3. INDICATIONS FOR DELIVERY IN PREECLAMPSIA*

Maternal Fetal

Gestational age ≥ 38 weeks Severe fetal growth restriction

Platelet count <100,000 cells/mm3 Nonreassuring fetal testing results

Progressive deterioration in hepatic function Oligohydramnios

Progressive deterioration in renal function

Suspected abruptio placentae

Persistent severe headaches or visual changes

Persistent severe epigastric pain, nausea, or vomiting

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Preeclampsia

conditions stable enough to permit pregnancy to beprolonged 48 hours, glucocorticoids can be safelyadministered to accelerate fetal pulmonary maturi-ty. (See Table 3.)

The aggressive approach to induction includes a clear end point for delivery, usually within 24 hours of the decision to induce labor. Mostexperts recommend a trial of induction regardlessof cervical condition. If vaginal delivery cannot beeffected within a reasonable time, caesarean deliv-ery is considered and is also performed for otherusual obstetrical indications.

Neuraxial (epidural, spinal, and combined spinal-epidural) techniques offer many advantages forlabor analgesia and can be safely administered tothe preeclamptic parturient. Dilute epidural infu-sions of local anesthetic plus opioid produce ade-quate sensory block without motor block orclinically significant sympathectomy. When neu-raxial techniques are used for cesarean delivery,however, there is a possibility of extensive sympa-tholysis with profound hypotension which maylead to decreased cardiac output and further dimin-ished uteroplacental perfusion. This may be morelikely with single-shot spinal anesthesia, whichalthough considered acceptable by some experts, isstill considered by others to be relatively con-traindicated in women with severe preeclampsia.A recent analysis, however, suggests that spinalanesthesia can be used safely in the severelypreeclamptic patient undergoing cesarean section,since the magnitude of maternal blood pressuredeclines appear to be similar after spinal or epidur-al anesthesia.173Re Hypotension can usually beavoided by meticulous attention to anesthetic tech-nique and careful volume expansion. In oneunblinded study of 80 women with severepreeclampsia randomized to receive epidural, com-bined spinal-epidural, or general anesthesia, allthree regimens appeared equally safe.174Ra

With general anesthesia, significant hypertensionmay occur at the time of laryngoscopy and trachealintubation and again during emergence and extuba-tion. These responses can usually be blocked byappropriate pretreatment with hydralazine, nitro-glycerin, or labetalol. Airway edema may be seenin the preeclamptic patient and may increase therisks of a “difficult airway” situation leading tofailed intubation and ventilation. Because general

anesthesia poses considerably greater risk to par-turients than regional anesthesia,175X the risk of afailed intubation must be weighed against the riskof transient hypotension when deciding betweengeneral and regional anesthesia for cesarean sectionin the severely preeclamptic/eclamptic patient.Although neuraxial techniques have become thepreferred method to provide labor analgesia oranesthesia for cesarean section in women withsevere preeclampsia-eclampsia, they are relativelycontraindicated in the presence of coagulopathy.Early consultation with an anesthesiologist is sug-gested for parturients with severe preeclampsia.

Anticonvulsive Therapy

Anticonvulsive therapy is usually indicated either toprevent recurrent convulsions in women witheclampsia or to prevent convulsions in women withpreeclampsia. There is universal agreement thatwomen with eclampsia should receive anticonvulsivetherapy.176Ra Several randomized studies indicate thatparenteral magnesium sulfate reduced the frequencyof eclampsia more effectively than phenytoin in amixed group of gestational hypertensive andpreeclamptic women.177Pr,178M Parenteral magnesiumsulfate is given during labor, delivery, and for vari-able durations postpartum. There is not clear agree-ment concerning the use of prophylactic magnesiumsulfate for women with preeclampsia.179Ra Theresults of two large randomized trials showed thatparenteral magnesium sulfate reduces the frequencyof eclampsia in women with either pregnancy-induced hypertension or severe preeclampsia.179Ra,180Ra

Although parenteral magnesium sulfate should begiven peripartum to women with severe preeclamp-sia, its benefits with mild gestational hypertension orpreeclampsia remain unclear. A multicenter ran-domized trial to answer this question is urgentlyneeded. Precautions regarding the use of magne-sium sulfate during pregnancy in women with renalfailure are discussed in the section on Pregnancy,Hypertension, and Renal Disease.

Invasive Hemodynamic Monitoring

Some investigators recommend the use of invasivehemodynamic monitoring in managing womenwith severe preeclampsia-eclampsia. It has beenused to monitor fluid therapy during plasma vol-ume expansion;181Re in managing women with pul-monary edema, persistent oliguria unresponsive tofluid challenge, and intractable severe

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hypertension; and in some patients receivingepidural anesthesia.182Pr There is no published evi-dence that the use of invasive hemodynamic moni-toring is indicated for the purposes mentionedabove.

Treatment of Acute Hypertension

Antihypertensive therapy is indicated when bloodpressure is dangerously high or rises suddenly inwomen with preeclampsia, especially intrapartum.Antihypertensive agents can be withheld as long asmaternal pressure is only mildly elevated. Someexperts would treat persistent diastolic levels of105 mm Hg or higher. Others would withholdtreatment until diastolic blood pressure levelsreach 110 mm Hg.103Pr In adolescents whose dias-tolic pressures were recently below 75 mm Hg,treating persistent levels of 100 mm Hg or highermay be considered. When treatment is required,the ideal drug that reduces pressures to a safe levelshould act quickly, reduce pressure in a controlledmanner, not lower cardiac output, reverse uteropla-cental vascular constriction, and result in noadverse maternal or fetal effects. The medicationsused to treat hypertensive crises in pregnancy, andtheir route of administration, are summarized inTable 4. Details of their pharmacology and safetyare discussed elsewhere.183Pr

The most commonly used drug is hydralazine,administered as either intravenous (IV) or intra-muscular (IM), which, if given cautiously, is suc-cessful in most instances. It has been shown to beeffective against preeclamptic hypertension.184F,185Re

Although this drug is sometimes given as an intra-venous infusion, the pharmacokinetics (maximaleffect at 20 minutes, duration of action 6 to 8 hours) indicate intermittent bolus injections aremore sensible. A 5 mg bolus is given intravenous-ly over 1 to 2 minutes. After 20 minutes,

subsequent doses are dictated by the initialresponse. Once the desired effect is obtained, thedrug is repeated as necessary (frequently in severalhours).185Re Parenteral labetalol has been shown tobe effective for the treatment of acute severe hy-pertension in pregnancy.106M,184F The drug may beused as intravenous bolus injections of 20 mg or40 mg, or as continuous intravenous infusion of 1 mg/kg as needed. Labetalol is usually used as asecond-line drug. It should be avoided in womenwith asthma and in those with congestive heart failure.

The use of oral nifedipine has been described in alimited number of women with acute severe hyper-tension during pregnancy.186F Details of thesereports are summarized elsewhere.100Pr Nifedipineacts rapidly, causing significant reduction in arteri-al blood pressure within 10 to 20 minutes of oraladministration. Although it has favorable hemody-namic effects,186F physicians should be advised thatrapidly acting nifedipine (in capsules containingthe liquid form) has never been approved by theFood and Drug Administration for treating hyper-tension or hypertensive emergencies. The JNCVI2Pr has recommended that it not be used for thispurpose because it has been associated with fataland nonfatal untoward cardiovascular events, espe-cially in older patients.187Pr Of the 16 case reportsreviewed by Grossman and colleagues,187Pr, 188 onewas a 37-year-old pregnant woman whose bloodpressure was reduced from 150/118 to 90/55, pre-cipitating the need for caesarean section becauseof fetal distress. Care should be exercised whenusing nifedipine or any calcium antagonist withmagnesium sulfate.189,190Pr,191

In the rare case, sodium nitroprusside may be indi-cated after the failure of hydralazine, nifedipine,and labetalol for acute hypertensive emergency.

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Preeclampsia

* Side effects: See Physicians Desk Reference (53rd edition).

Caution: Sudden and severe hypotension can result from the administration of any of these agents, especially short-acting oral nifedipine.The goal of blood pressure reduction in emergency situations should be a gradual reduction of blood pressure to the normalrange. (See Treatment of Acute Hypertension section.)

Clinical Note: In managing hypertensive emergencies, the IV route is safer than oral or IM administration because it is easier to combatinadvertent hypotension by stopping an IV injection or infusion than it is to stop intestinal or intramuscular absorption of an orallyor IM-administered drug.

TABLE 4. TREATMENT OF ACUTE SEVERE HYPERTENSION IN PREECLAMPSIA*

BP ≥ 160 mm Hg systolic and/or ≥ 105 mm Hg diastolic if sustained

• Hydralazine: Start with 5 mg IV or 10 mg IM. If blood pressure is not controlled, repeat at 20-minuteintervals (5 to 10 mg depending on response). Once BP control is achieved, repeat as needed (usuallyabout 3 hours). If no success by 20 mg IV or 30 mg IM total, consider another drug.

• Labetalol: Start with 20 mg IV as a bolus; if effect is suboptimal, then give 40 mg 10 minutes later and80 mg every 10 minutes for two additional doses. Use a maximum of 220 mg. If desired bloodpressure levels are not achieved, switch to another drug. Avoid giving labetalol to women with asthmaor congestive heart failure.

• Nifedipine: Start with 10 mg orally and repeat in 30 minutes if necessary. See precautions, in Treatmentof Acute Hypertension section. (Short-acting nifedipine is not approved by FDA for managinghypertension.)

• Sodium nitroprusside is rarely needed for hypertension not responding to the drugs listed above and/orif there are clinical findings of hypertensive encephalopathy. Start at a rate of 0.25 µg/kg/min to amaximum dose of 5 µg/kg/min. Fetal cyanide poisoning may occur if used for more than 4 hours.

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W omen who develop hypertension during preg-nancy should be carefully reevaluated during

the immediate postpartum months and counseledwith respect to future gestations and remote car-diovascular risks as well. Any laboratory abnor-mality or physical finding that has not returned tonormal before postdelivery discharge should bereassessed at postpartum followup. The expecta-tion is that hypertension and other signs or symp-toms of organ dysfunction associated withpreeclampsia will have remitted by the 6-weekpostpartum examination, but if abnormalities per-sist, the patients should be reexamined 6 weekslater, when persisting pathology will probably bechronic.

COUNSELING FOR FUTURE PREGNANCIES

Women who have had preeclampsia are moreprone to hypertensive complications in subsequentpregnancies. Risk is best established for nulliparaswith a history of preeclampsia, the magnitude ofthe recurrence rate increasing the earlier the dis-ease manifested during the index pregnancy. Forinstance, when preeclampsia presents clinicallybefore gestational week 30, the recurrence ratemay be as high as 40 percent.192F,193F Preeclampsiareappearance rates may also be population-specif-ic. For example, in white woman with well-defined disease after gestational week 36,recurrence is barely 10 percent,194Pr but it may besubstantially greater in black patients.192F Therecurrence rate for women with one episode ofHELLP is almost 5 percent.195F

Recurrence rates are higher for those experiencingpreeclampsia as multiparas compared with nulli-parous women.196Re Risk is also increased in multi-paras who conceive with a new father even whentheir first pregnancy was normotensive, the inci-dence being intermediate between that of primi-parous women and monogamous multiparous

women who have not had a preeclamptic pregnancy.196Re

Of interest are data indicating that women withearly-onset severe preeclampsia harbor metabolicabnormalities or risk factors associated with vascu-lar thrombosis. These include activated protein Cresistance (Factor V Leiden), antiphospholipidantibodies, hyperhomocysteinemia, and protein Sdeficiency.197F,198F,199,200Re Therefore, patients with ahistory of early-onset severe preeclampsia shouldbe evaluated for evidence of prior thromboembolicdiseases and, if they have such a history, should be tested for the above-described abnormalities(which when present jeopardize not only futurepregnancies but the patients’ general health as well).

REMOTE CARDIOVASCULAR PROGNOSIS

Preeclampsia-Eclampsia

The remote prognosis of women experiencingpreeclampsia or eclampsia is best summarized asfollows: The more certain the diagnosis ispreeclampsia alone (e.g., nulliparity, especially ifcomplicated by eclampsia or confirmed by renalbiopsy), the lower the prevalence of remote cardio-vascular disorders. Prevalence of remote hyperten-sion, however, is increased in nulliparous womenwith preeclampsia or eclampsia manifesting hyper-tension in subsequent gestations, multiparas whodevelop the disorder, and women with severeearly-onset disease of any parity. The literaturefurther suggests that preeclampsia-eclampsia, byitself, is not a cause of essential hypertension. Inessence, it is the hypertension in subsequent gesta-tions, presence of preeclampsia in a multipara, orearly-onset disease in any pregnancy that signalsthat the disease has occurred in a patient with anincreased probability of essential hypertensionlater in life.89Ra,192F,193F,194Pr,201F

POSTPARTUM COUNSELING AND FOLLOWUP

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Postpartum Counseling and Followup

In summary, it is reasonable to counsel patients asfollows: If preeclampsia occurred late in an initialgestation, there is no evidence of remote cardio-vascular risk, but subsequent pregnancies will helpus define risk more accurately. Women with early-onset disease, multiparous women with preeclamp-sia or only hypertension, and those manifesting

gestational hypertension in any pregnancy are atincreased cardiovascular risk—information ofimportance for long-term health care strategies.The best news, however, is that women experienc-ing normotensive births have a reduced risk forremote hypertension.

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A RESEARCH DIAGNOSIS OF

PREECLAMPSIA

T he clinical definitions used in this documentaim to protect both mother and fetus from

adverse outcome. They were purposely chosen tohave a high sensitivity rather than specificitybecause overdiagnosis is a safe strategy thatensures closer scrutiny of the patient and avoidsmorbidity. In the process, however, many womenreceiving the clinical diagnosis do not, in reality,have true preeclampsia. The use of patientslabeled preeclamptic by the clinical definition maylead to erroneous findings in studies designed todetermine outcome and epidemiologic associa-tions. Thus, more stringent criteria must be usedfor selecting cases for research in preeclampsia.Specifically, cases should be documented to benormotensive before pregnancy or 12 weeks afterpregnancy.

Studies of nulliparous women are important inorder to distinguish unique pathologic features ofpreeclampsia from other preexisting or futurepathophysiology, which is often present in multi-paras who appear to develop the disorder. Thereare situations in which studies of multiparas areuseful, mainly those designed to understand factorsthat predispose to preeclampsia (and that shouldeventually provide targets to prevent the disease orimprove management strategies). Included hereare subsets of patients such as those with a varietyof metabolic disorders and women with a historyof early-onset preeclampsia.193

OTHER RESEARCH NEEDS

Studies To Establish Appropriate DiagnosticCriteria for Preeclampsia

Large prospective multicenter trials designed todetect markers that uniquely predict and/or specifi-cally accompany the preeclamptic syndrome and

are absent from other hypertensive disorders areneeded. Ideally, the clinical diagnosis of pre-eclampsia would be based on sensitive and specificdiagnostic tests derived directly from the causativemechanism of the disease. No such tests exist, andnone is likely until we understand the pathogenesisof the syndrome more completely. Lacking suchtests, clinical diagnosis should be based on therelationship of findings to outcomes or those find-ings’ ability to predict development of frank clini-cal preeclampsia. Estimates of the prevalence ofpreeclampsia at different threshhold values ofblood pressure or change in pressure, and the mag-nitude of overlap using the different criteria, mustbe developed. Ideally, receiver-operating charac-teristic curves should be defined for both absoluteblood pressure and change over baseline so thatthe most appropriate criterion values can be chosenand the need for revising current definitionsassessed. Use of current estimates of qualitativeand quantitative protein excretion should be ana-lyzed similarly, and these prospective studiesshould also be designed to determine the predictivevalue of other signs and symptoms to diagnosepreeclampsia when proteinuria is absent (e.g.,platelets, liver function, abdominal and neurologicsymptoms, markers of endothelial activation58).Such data may help improve both the clinical andresearch diagnoses of preeclampsia.

A substantial subset of the desired data, at least forblood pressures if not for other tests, may beobtained by reanalyzing the original data sets ofthe large prospective trials of aspirin or calciumsupplementation for prophylaxis. That may be themost cost-effective approach in the short term.

Clinical Trials Regarding Prevention andManagement of the Hypertensive Complications

There are few trials to guide choices of antihyper-tensive agents in pregnancy, and all appear to haveone or more major flaws. Large multicenter ran-domized trials, carefully designed to determine the

RECOMMENDATIONS FOR FUTURE RESEARCH

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Recommendations for Future Research

teratogenicity of any prescribed medication andother aspects of fetal jeopardy as well as maternalwell-being, are needed. Such studies shouldinclude substantial periods of neonatal followup.Given both their importance and costs, such trialscan rarely rely on industry funding; they requireGovernment support.

Attempts To Identify Subsets of Women With thePreeclampsia Syndrome

Efforts should be made to recognize different sub-sets of women with preeclampsia and to examine

them separately for both outcome and pathophysi-ology. This approach has increased our under-standing of other complex syndromes (e.g., type 1and type 2 diabetes). Criteria for determining sub-sets could include gestational age at delivery, asso-ciation with intrauterine growth restriction, as wellas research into the genetic predisposition ofpreeclampsia including both population geneticsand biochemical markers for women at risk forpreeclampsia. Such studies should identify womenat adverse risk for maternal and fetal outcome as aresult of preeclampsia.

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Discrimination Prohibited: Under provisions of applicable public laws enacted by Congresssince 1964, no person in the United States shall,on the grounds of race, color, national origin,handicap, or age, be excluded from participationin, be denied the benefits of, or be subjected todiscrimination under any program or activity(or, on the basis of sex, with respect to any edu-cation program or activity) receiving Federalfinancial assistance. In addition, ExecutiveOrder 11141 prohibits discrimination on thebasis of age by contractors and subcontractorsin the performance of Federal contracts, andExecutive Order 11246 states that no federallyfunded contractor may discriminate against anyemployee or applicant for employment because of race, color, religion, sex, or national origin.Therefore, the National Heart, Lung, and BloodInstitute must be operated in compliance with theselaws and Executive Orders.

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U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

Public Health ServiceNational Institutes of HealthNational Heart, Lung, and Blood Institute

NIH Publication No. 00-3029Originally Printed 1990Revised July 2000

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