Hypertension in Pregnancy

HYPE RTE N SION
PREGNANCY
IN
HYPE RTE N SION IN PREGNANCY

HYPE RTE N SION
IN PREGNANCY
Hypertension in Pregnancy was developed by the Task Force on
Hypertension in Pregnancy. The information in Hypertension in
Pregnancy should not be viewed as a body of rigid rules. The guidelines
are general and intended to be adapted to many different situations,
taking into account the needs and resources particular to the locality,
the institution, or the type of practice. Variations and innovations that
improve the quality of patient care are to be encouraged rather than
restricted. The purpose of these guidelines will be well served if they
provide a firm basis on which local norms may be built.
Library of Congress Cataloging-in-Publication Data

American College of Obstetricians and Gynecologists. Task Force on Hypertension in Pregnancy, author.
Hypertension in pregnancy / developed by the Task Force on Hypertension in Pregnancy.
p. ; cm.
Includes bibliographical references.
ISBN 978-1-934984-28-4
I. American College of Obstetricians and Gynecologists, issuing body. II. Title.
[DNLM: 1. Hypertension, Pregnancy-Induced—Practice Guideline. WQ 244]
RG575.5
618.3'6132—dc23
2013022521
Copyright 2013 by the American College of Obstetricians and Gynecologists,

409 12th Street, SW, PO Box 96920, Washington, DC 20090-6920. All rights
reserved. No part of this publication may be reproduced, stored in a retrieval
system, or transmitted, in any form or by an means, electronic, mechanical,
photocopying, recording, or otherwise, without prior written permission from
the publisher.
12345/76543
Contents
Task Force on Hypertension in Pregnancy v
Endorsements vii
Foreword ix
Executive Summary 1
Chapter 1: Classification of Hypertensive Disorders 13

Preeclampsia–Eclampsia 13
Chronic Hypertension 14
Chronic Hypertension With Superimposed Preeclampsia 14
Gestational Hypertension 14
Postpartum Hypertension 15
Chapter 2: Establishing the Diagnosis of Preeclampsia and Eclampsia 17

Preeclampsia 17
Eclampsia 19
Chapter 3: Prediction of Preeclampsia 21

Definition of an Ideal Predictive Test 21
Epidemiology of and Risk Factors for Preeclampsia 21
Prediction of Preeclampsia Using Uterine Artery Doppler Velocimetry 22
Prediction of Preeclampsia Using Biomarkers 22
Prediction of Adverse Outcomes in Patients With Gestational Hypertension and
Preeclampsia 23
Clinical Considerations 23
Chapter 4: Prevention of Preeclampsia 27

Antiplatelet Agents 27
Antioxidant Supplementation With Vitamin C and Vitamin E 28
Other Nutritional Interventions 28
iii
iv CONTENTS
Dietary Salt Intake 29

Lifestyle Modifications 29
Chapter 5: Management of Preeclampsia and HELLP Syndrome 31

Antepartum Management 31
Intrapartum Management 34
Severe Preeclampsia 36
Route of Delivery in Preeclampsia 40
Eclampsia 40
HELLP Syndrome 41
Anesthetic Considerations 42
Postpartum Hypertension and Preeclampsia 43
Chapter 6: Management of Women With Prior Preeclampsia 47

Preconception Management 47
Antepartum Management 49
Chapter 7: Chronic Hypertension in Pregnancy and Superimposed Preeclampsia 51

Chronic Hypertension in Pregnancy 51
Superimposed Preeclampsia 61
Management of Women With Chronic Hypertension in the Postpartum Period 65
Chapter 8: Later-Life Cardiovascular Disease in Women With Prior Preeclampsia 71
Chapter 9: Patient Education 73

Importance of Patient Education 73
Patient Education Strategies 74
Patient Education Barriers 75
Chapter 10: State of the Science and Research Recommendations 79

Fundamental Advances in the Understanding of Preeclampsia 79
Summary of Fundamental Research Recommendations by the Task Force 83
Task Force on Hypertension in Pregnancy
James M. Roberts, MD, Chair Maurice Druzin, MD

Investigator Magee-Womens Research Institute Professor of Obstetrics and Gynecology and
Professor, Department of Obstetrics, Gynecology and Maternal-Fetal Medicine
Reproductive Sciences, Epidemiology and Clinical Stanford University
Translational Research Stanford, CA
University of Pittsburgh
Robert R. Gaiser, MD
Pittsburgh, PA
Professor of Anesthesiology and Critical Care
Phyllis A. August, MD, MPH University of Pennsylvania
Professor of Medicine in Obstetrics and Gynecology Philadelphia, PA
New York Presbyterian
Joey P. Granger, PhD
Weill Cornell Physicians
Billy S. Guyton Distinguished Professor
New York, NY
Professor of Physiology and Medicine
George Bakris, MD Director, Center for Excellence in Cardiovascular-
Professor of Medicine Renal Research
Director, Comprehensive Hypertension Center Dean, School of Graduate Studies in Health Sciences
University of Chicago University of Mississippi Medical Center
Chicago, IL Jackson, MS
John R. Barton, MD Arun Jeyabalan, MD, MS

Director, Maternal-Fetal Medicine Associate Professor, Department of Obstetrics,
Baptist Health Lexington Gynecology and Reproductive Sciences
Lexington, KY University of Pittsburgh
Pittsburgh, PA
Ira M. Bernstein, MD
John VanSicklen Maeck Professor and Chair Donna D. Johnson, MD
Department of Obstetrics, Gynecology and Lawrence L. Hester Professor and Chair
Reproductive Sciences Department of Obstetrics and Gynecology
Senior Associate Dean for Research Medical University of South Carolina
University of Vermont Charleston, SC
Burlington, VT
v
vi TASK FORCE ON HYPERTENSION IN PREGNANCY
S. Ananth Karumanchi, MD Catherine Y. Spong, MD

Associate Professor of Medicine Director, Extramural Research
Beth Israel Deaconess Medical Center Eunice Kennedy Shriver National Institute of Child
Harvard Medical School Health and Human Development, National
Boston, MA Institutes of Health
Bethesda, MD
Marshall D. Lindheimer, MD
Professor Emeritus, Departments of Obstetrics & Eleni Tsigas
Gynecology, Medicine, and Committee on Clinical Executive Director
Pharmacology and Pharmacogenomics Preeclampsia Foundation
University of Chicago Melbourne, FL
Chicago, IL
James N. Martin Jr, MD
Michelle Y. Owens, MD, MS Ex Officio Task Force Member
Associate Professor Past President, American College of Obstetricians
Vice-Chair of Obstetrics and Gynecology and Gynecologists and American Congress of
University of Mississippi Medical Center Obstetricians and Gynecologists (2011–2012)
Jackson, MS Vice Chair, Research and Academic Development
Director, Division of Maternal-Fetal Medicine
George R. Saade, MD
University of Mississippi Medical Center
Professor, Department of Obstetrics and Gynecology
Jackson, MS
Director, Division of Maternal-Fetal Medicine
University of Texas Medical Branch American College of Obstetricians and Gynecologists
Galveston, TX Staff
Gerald F. Joseph Jr, MD, Vice President of Practice
Baha M. Sibai, MD
Activities
Professor, Department of Obstetrics, Gynecology and
Nancy O’Reilly, MHS
Reproductive Sciences
Alyssa Politzer
University of Texas Health Science Center
Sarah Son, MPH
Houston, TX
Karina Ngaiza
Conflict of Interest Disclosures

The following task force members reported no financial relationships or potential conflicts of interest to disclose:
James M. Roberts, MD; Ira M. Bernstein, MD; Maurice Druzin, MD; Robert R. Gaiser, MD; Joey P. Granger, PhD;
Arun Jeyabalan, MD; Donna D. Johnson, MD; Marshall Lindheimer, MD; Michelle Y. Owens, MD, MS;
George R. Saade, MD; Catherine Y. Spong, MD; and Eleni Tsigas.
George Bakris, MD, has Investigator Initiated grants from Takeda and CVRx paid directly to the University
of Chicago. He received a salary for being National Clinical Trial Principal Investigator for Medtronic (15%),
Relypsa (15%) (the percentage is salary support.) He is a consultant for Takeda, Abbott, CVRx, Johnson&
Johnson, Eli Lilly, Daichi-Sankyo, Boerhinger-Ingelheim, and the U.S. Food and Drug Administration. He is an
editor for the American Journal of Nephrology and the Hypertension section of UpToDate, and an associate editor
for Diabetes Care and Nephrology Dialysis and Transplantation. John R. Barton, MD, provides research support
to Alere and Beckman Coulter. S. Ananth Karumanchi, MD, has served as consultant to Beckman Coulter, Roche
and Siemens; has a financial interest in Aggamin Therapeutics LLC, Co; and is an inventor on patents related to
preeclampsia biomarkers held by Beth Israel Deaconess Medical Center. Baha M. Sibai, MD, is a consultant
for Alere Women’s Health who is investigating a biomarker for preeclampsia.
Endorsements
The following professional organizations have reviewed, endorsed, and support this report:
American Academy of Physician Assistants

American Academy of Neurology*
American College of Occupational and Environmental Medicine
American Optometric Association
American Osteopathic Association
American Society of Hypertension
Preeclampsia Foundation
Society for Maternal-Fetal Medicine
*The American Academy of Neurology has affirmed the value of this report. Please see the American Academy of
Neurology Guideline Endorsement Policy for further information.
vii
Foreword
Hypertensive disorders of pregnancy, including pre- • Preeclampsia is a risk factor for future cardiovascu-
eclampsia, complicate up to 10% of pregnancies lar disease and metabolic disease in women.
worldwide, constituting one of the greatest causes of
• Despite considerable research, the etiology of pre-
maternal and perinatal morbidity and mortality
eclampsia remains unclear.
worldwide. In early 2011, as the 62nd President Elect
of the American College of Obstetricians and Gyne- • Within the past 10 years, substantial advances in
cologists (the College) and the American Congress of the understanding of preeclampsia pathophysiology
Obstetricians and Gynecologists, I decided to make as well as increased efforts to obtain evidence to
this issue a Presidential Initiative for the following guide therapy have emerged. However, this infor-
reasons: mation has not translated into improved clinical
practice.
• The incidence of preeclampsia has increased by
25% in the United States during the past two • New best practice recommendations are greatly
decades (1). needed to guide clinicians in the care of women
with all forms of preeclampsia and hypertension
• Preeclampsia is a leading cause of maternal and
that occur during pregnancy, particularly women
perinatal morbidity and mortality, with an estimated
with acute severe hypertension and superimposed
50,000–60,000 preeclampsia-related deaths per
preeclampsia. Also needed is a system for continu-
year worldwide (2, 3).
ally updating these guidelines and integrating them
• For every preeclampsia-related death that occurs into daily obstetric practice.
in the United States, there are probably 50–100
• Identification of patients with severe forms of pre-
other women who experience “near miss” signifi-
eclampsia continues to challenge clinicians.
cant maternal morbidity that stops short of death
but still results in significant health risk and health • Improved patient education and counseling strate-
care cost (4, 5). gies are needed to convey more effectively the
dangers of preeclampsia and hypertension and the
• What can be considered “less-than-optimal" care of
importance of early detection to women with vary-
patients with preeclampsia and other hypertensive
ing degrees of health literacy.
disorders of pregnancy reportedly occurs with some
frequency worldwide, contributing to maternal and • Research on preeclampsia and other hypertensive
perinatal injury that might have been avoidable (6). disorders of pregnancy in both the laboratory and
clinical arenas requires continued emphasis and
• Hypertensive disorders of pregnancy are major
funding.
contributors to prematurity.
ix
x FOREWORD
To address these important issues, the Task Force In addition, I would like to give special thanks to
on Hypertension in Pregnancy, composed of 17 experts Dr. James M. Roberts of the University of Pittsburgh’s
in the fields of obstetrics, maternal–fetal medicine, Magee-Womens Research Institute for his superb
hypertension, internal medicine, nephrology, anesthe- leadership of the task force and to Nancy O’Reilly,
siology, physiology, and patient advocacy, was created Senior Director of Practice Bulletins, and Dr. Gerald F.
and charged with three tasks: 1) summarize the cur- Joseph Jr, Vice President of Practice Activities, at the
rent state of knowledge about preeclampsia and other College for their support throughout the process.
hypertensive disorders in pregnancy by reviewing and Efforts are now underway to achieve global consen-
grading the quality of the extant world literature; sus on best practice guidelines for the diagnosis and
2) translate this information into practice guidelines management of preeclampsia and other hypertensive
for health care providers who treat obstetric patients disorders of pregnancy. It is my fervent hope that the
affected by these disorders; and 3) identify and priori- work of the Task Force on Hypertension in Pregnancy
tize the most compelling areas of laboratory and clini- serves as a springboard to these efforts and ultimately
cal research to bridge gaps in our current knowledge. translates into improved obstetric care for patients
Members of the task force met three times over 9 with preeclampsia and other hypertensive disorders of
months during 2011 and 2012 at the College head- pregnancy in this country and throughout the world.
quarters in Washington, DC. They spent countless
additional hours writing and deliberating to achieve James N. Martin Jr, MD
consensus on the practice recommendations that fol- Immediate Past President
low in the Executive Summary. The American College of Obstetricians and Gynecologists
I am deeply grateful to each member of the Task 2012–2013
Force on Hypertension in Pregnancy for their hard The American Congress of Obstetricians and Gynecologists
work and dedication to this important endeavor. 2012–2013
References
1. Wallis AB, Saftlas AF, Hsia J, Atrash HK. Secular trends in 4. Callaghan WM, Mackay AP, Berg CJ. Identification of
the rates of preeclampsia, eclampsia, and gestational hyper- severe maternal morbidity during delivery hospitaliza-
tension, United States, 1987–2004. Am J Hypertens tions, United States, 1991–2003. Am J Obstet Gynecol
2008;21:521–6. [PubMed] ^ 2008;199:133.e1–8. [PubMed] [Full Text] ^
2. World Health Organization. The world health report: 5. Kuklina EV, Ayala C, Callaghan WM. Hypertensive disor-
2005: make every mother and child count. Geneva: WHO; ders and severe obstetric morbidity in the United States.
2005. Available at: http://www.who.int/whr/2005/whr Obstet Gynecol 2009;113:1299–306. [PubMed] [Obstet-
2005_en.pdf. Retrieved March 20, 2013. ^ rics & Gynecology] ^
3. Duley L. Maternal mortality associated with hypertensive 6. van Dillen J, Mesman JA, Zwart JJ, Bloemenkamp KW,
disorders of pregnancy in Africa, Asia, Latin America and van Roosmalen J. Introducing maternal morbidity audit
the Caribbean. Br J Obstet Gynaecol 1992;99:547–53. in the Netherlands. BJOG2010;117:416–21. [PubMed]
[PubMed] ^ [Full Text] ^
Executive Summary
T
he American College of Obstetricians and ill. Optimal management requires close observation
Gynecologists (the College) convened a task for signs and premonitory findings and, after establish-
force of experts in the management of hyper- ing the diagnosis, delivery at the optimal time for both
tension in pregnancy to review available data maternal and fetal well-being. More recent clinical evi-
and publish evidence-based recommendations for clin- dence to guide this timing is now available. Chronic
ical practice. The Task Force on Hypertension in Preg- hypertension is associated with fetal morbidity in the
nancy comprised 17 clinician–scientists from the fields form of growth restriction and maternal morbidity
of obstetrics, maternal–fetal medicine, hypertension, manifested as severely increased blood pressure (BP).
internal medicine, nephrology, anesthesiology, physi- However, maternal and fetal morbidity increase dra-
ology, and patient advocacy. This executive summary matically with the superimposition of preeclampsia.
includes a synopsis of the content and task force rec- One of the major challenges in the care of women with
ommendations of each chapter in the report and is in- chronic hypertension is deciphering whether chronic
tended to complement, not substitute, the report. hypertension has worsened or whether preeclampsia
Hypertensive disorders of pregnancy remain a has developed. In this report, the task force provides
major health issue for women and their infants in the suggestions for the recognition and management of
United States. Preeclampsia, either alone or superim- this challenging condition.
posed on preexisting (chronic) hypertension, presents In the past 10 years, there have been substantial
the major risk. Although appropriate prenatal care, advances in the understanding of preeclampsia as well
with observation of women for signs of preeclampsia as increased efforts to obtain evidence to guide therapy.
and then delivery to terminate the disorder, has Nonetheless, there remain areas on which evidence is
reduced the number and extent of poor outcomes, scant. The evidence is now clear that preeclampsia is
serious maternal–fetal morbidity and mortality still associated with later-life cardiovascular (CV) disease;
occur. Some of these adverse outcomes are avoidable, however, further research is needed to determine how
whereas others can be ameliorated. Also, although best to use this information to help patients. The task
some of the problems that face neonates are related force also has identified issues in the management of
directly to preeclampsia, a large proportion are sec- preeclampsia that warrant special attention. First, is
ondary to prematurity that results from the appropri- the failure by health care providers to appreciate the
ate induced delivery of the fetuses of women who are multisystemic nature of preeclampsia. This is in part
1
2 EXECUTIVE SUMMARY
due to attempts at rigid diagnosis, which is addressed based on the values and judgment and underlying
in the report. Second, preeclampsia is a dynamic pro- health condition of a particular patient in a particular
cess, and a diagnosis such as “mild preeclampsia” situation.
(which is discouraged) applies only at the moment the
diagnosis is established because preeclampsia by
Classification of Hypertensive Disorders
nature is progressive, although at different rates.
Appropriate management mandates frequent reevalu- of Pregnancy
ation for severe features that indicate the actions out- The task force chose to continue using the classification
lined in the recommendations (which are listed after schema first introduced in 1972 by the College and
the chapter summaries). It has been known for many modified in the 1990 and 2000 reports of the Working
years that preeclampsia can worsen or present for the Group of the National High Blood Pressure Education
first time after delivery, which can be a major scenario Program. Similar classifications can be found in the
for adverse maternal events. In this report, the task American Society of Hypertension guidelines, as well
force provides guidelines to attempt to reduce mater- as College Practice Bulletins. Although the task force
nal morbidity and mortality in the postpartum period. has modified some of the components of the classifica-
tion, this basic, precise, and practical classification was
used, which considers hypertension during pregnancy
The Approach
in only four categories: 1) preeclampsia–eclampsia,
The task force used the evidence assessment and rec- 2) chronic hypertension (of any cause), 3) chronic
ommendation strategy developed by the Grading of hypertension with superimposed preeclampsia, and
Recommendations Assessment, Development and 4) gestational hypertension. Importantly, the follow-
Evaluation (GRADE) Working Group (available at www. ing components were modified. In recognition of the
gradeworkinggroup.org/index.htm). Because of its syndromic nature of preeclampsia, the task force has
utility, this strategy has been adapted worldwide by a eliminated the dependence of the diagnosis on pro-
large number of organizations. With the GRADE Work- teinuria. In the absence of proteinuria, preeclampsia is
ing Group approach, the function of expert task forces diagnosed as hypertension in association with throm-
and working groups is to evaluate the available evi- bocytopenia (platelet count less than 100,000/microli-
dence regarding a clinical decision that, because of lim- ter), impaired liver function (elevated blood levels of
ited time and resources, would be difficult for the liver transaminases to twice the normal concentra-
average health care provider to accomplish. The expert tion), the new development of renal insufficiency (ele-
group then makes recommendations based on the evi- vated serum creatinine greater than 1.1 mg/dL or a
dence that are consistent with typical patient values doubling of serum creatinine in the absence of other
and preferences. The task force evaluated the evidence renal disease), pulmonary edema, or new-onset cere-
for each recommendation, the implications, and the bral or visual disturbances (see Box E-1). Gestational
confidence in estimates of effect. With this combination, hypertension is BP elevation after 20 weeks of gesta-
the available information was evaluated and recom- tion in the absence of proteinuria or the aforemen-
mendations were made. In this report, the confidence tioned systemic findings, chronic hypertension is
in estimates of effect (quality) of the available evidence hypertension that predates pregnancy, and superim-
is judged as very low, low, moderate, or high. posed preeclampsia is chronic hypertension in associa-
Recommendations are practices agreed to by the tion with preeclampsia.
task force as the most appropriate course of action;
they are graded as strong or qualified. A strong recom-
Establishing the Diagnosis of
mendation is one that is so well supported that it
would be the approach appropriate for virtually all Preeclampsia or Eclampsia
patients. It could be the basis for health care policy. A The BP criteria are maintained from prior recommenda-
qualified recommendation is also one that would be tions. Proteinuria is defined as the excretion of 300 mg
judged as appropriate for most patients, but it might or more of protein in a 24-hour urine collection. Alter-
not be the optimal recommendation for some patients natively, a timed excretion that is extrapolated to this
(whose values and preferences differ, or who have dif- 24-hour urine value or a protein/creatinine ratio of at
ferent attitudes toward uncertainty in estimates of least 0.3 (each measured as mg/dL) is used. Because of
effect). When the task force has made a qualified rec- the variability of qualitative determinations (dipstick
ommendation, the health care provider and patient test), this method is discouraged for diagnostic use
are encouraged to work together to arrive at a decision unless other approaches are not readily available. If
EXECUTIVE SUMMARY 3
BOX E-1. Severe Features of Preeclampsia (Any of these findings) ^
• Systolic blood pressure of 160 mm Hg or higher, or diastolic blood pressure of 110 mm Hg or higher
on two occasions at least 4 hours apart while the patient is on bed rest (unless antihypertensive
therapy is initiated before this time)
• Thrombocytopenia (platelet count less than 100,000/microliter)
• Impaired liver function as indicated by abnormally elevated blood concentrations of liver enzymes
(to twice normal concentration), severe persistent right upper quadrant or epigastric pain unrespon-
sive to medication and not accounted for by alternative diagnoses, or both
• Progressive renal insufficiency (serum creatinine concentration greater than 1.1 mg/dL or a doubling
of the serum creatinine concentration in the absence of other renal disease)
• Pulmonary edema
• New-onset cerebral or visual disturbances
this approach must be used, a determination of 1+ is or adverse outcomes from preeclampsia in unselected
considered as the cutoff for the diagnosis of protein- women at high risk or low risk of preeclampsia. Calci-
uria. In view of recent studies that indicate a minimal um may be useful to reduce the severity of preeclamp-
relationship between the quantity of urinary protein sia in populations with low calcium intake, but this
and pregnancy outcome in preeclampsia, massive pro- finding is not relevant to a population with adequate
teinuria (greater than 5 g) has been eliminated from calcium intake, such as in the United States. The
the consideration of preeclampsia as severe. Also, administration of low-dose aspirin (60–80 mg) to pre-
because fetal growth restriction is managed similarly vent preeclampsia has been examined in meta-analy-
in pregnant women with and without preeclampsia, it ses of more than 30,000 women, and it appears that
has been removed as a finding indicative of severe pre- there is a slight effect to reduce preeclampsia and
eclampsia (Table E-1). adverse perinatal outcomes. These findings are not
clinically relevant to low-risk women but may be rele-
vant to populations at very high risk in whom the num-
Prediction of Preeclampsia ber to treat to achieve the desired outcome will be
A great deal of effort has been directed at the identifi- substantially less. There is no evidence that bed rest or
cation of demographic factors, biochemical analytes, salt restriction reduces preeclampsia risk.
or biophysical findings, alone or in combination, to
predict early in pregnancy the later development of TASK FORCE RECOMMENDATIONS
preeclampsia. Although there are some encouraging • For women with a medical history of early-onset pre-
findings, these tests are not yet ready for clinical use. eclampsia and preterm delivery at less than 34 0/7
weeks of gestation or preeclampsia in more than
TASK FORCE RECOMMENDATION one prior pregnancy, initiating the administration of
daily low-dose (60–80 mg) aspirin beginning in the
• Screening to predict preeclampsia beyond obtain- late first trimester is suggested.*
ing an appropriate medical history to evaluate for
Quality of evidence: Moderate
risk factors is not recommended.
Strength of recommendation: Qualified
*Meta-analysis of more than 30,000 women in randomized
Strength of recommendation: Strong trials of aspirin to prevent preeclampsia indicates a small
reduction in the incidence and morbidity of preeclampsia
and reveals no evidence of acute risk, although long-term
Prevention of Preeclampsia fetal effects cannot be excluded. The number of women to
treat to have a therapeutic effect is determined by preva-
It is clear that the antioxidants vitamin C and vitamin E lence. In view of maternal safety, a discussion of the use of
are not effective interventions to prevent preeclampsia aspirin in light of individual risk is justified.
4 EXECUTIVE SUMMARY
TABLE E-1. Diagnostic Criteria for Preeclampsia ^
Blood pressure • Greater than or equal to 140 mm Hg systolic or greater than or equal to 90 mm Hg
diastolic on two occasions at least 4 hours apart after 20 weeks of gestation in a
woman with a previously normal blood pressure
• Greater than or equal to 160 mm Hg systolic or greater than or equal to 110 mm Hg
diastolic, hypertension can be confirmed within a short interval (minutes) to facilitate
timely antihypertensive therapy
and
Proteinuria • Greater than or equal to 300 mg per 24-hour urine collection (or this amount
extrapolated from a timed collection)
or
• Protein/creatinine ratio greater than or equal to 0.3*
• Dipstick reading of 1+ (used only if other quantitative methods not available)
Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following:
Thrombocytopenia • Platelet count less than 100,000/microliter
Renal insufficiency • Serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum
creatinine concentration in the absence of other renal disease
Impaired liver function • Elevated blood concentrations of liver transaminases to twice normal concentration
Pulmonary edema
Cerebral or visual
symptoms
* Each measured as mg/dL.
• The administration of vitamin C or vitamin E to deaths could be avoided if health care providers remain
prevent preeclampsia is not recommended. alert to the likelihood that preeclampsia will progress.
Quality of evidence: High The same reviews indicate that intervention in acutely
Strength of recommendation: Strong ill women with multiple organ dysfunction is sometimes
delayed because of the absence of proteinuria. Further-
• It is suggested that dietary salt not be restricted dur- more, accumulating information indicates that the
ing pregnancy for the prevention of preeclampsia. amount of proteinuria does not predict maternal or fetal
Quality of evidence: Low outcome. It is for these reasons that the task force has
Strength of recommendation: Qualified recommended that alternative systemic findings with
new-onset hypertension can fulfill the diagnosis of pre-
• It is suggested that bed rest or the restriction of other eclampsia even in the absence of proteinuria.
physical activity not be used for the primary preven- Perhaps the biggest changes in preeclampsia man-
tion of preeclampsia and its complications. agement relate to the timing of delivery in women
Quality of evidence: Low with preeclampsia without severe features, which
Strength of recommendation: Qualified based on evidence is suggested at 37 0/7 weeks of ges-
tation, and an increasing awareness of the importance
of preeclampsia in the postpartum period. Health care
Management of Preeclampsia
providers are reminded of the contribution of nonste-
and HELLP Syndrome roidal antiinflammatory agents to increased BP. It is
Clinical trials have provided an evidence base to guide suggested that these commonly used postpartum pain
management of several aspects of preeclampsia. None- relief agents be replaced by other analgesics in women
theless, several important questions remain unan- with hypertension that persists for more than 1 day
swered. Reviews of maternal mortality data reveal that postpartum.
EXECUTIVE SUMMARY 5
• If evidence of fetal growth restriction is found in

TASK FORCE RECOMMENDATIONS
women with preeclampsia, fetoplacental assess-
• The close monitoring of women with gestational ment that includes umbilical artery Doppler veloci-
hypertension or preeclampsia without severe fea- metry as an adjunct antenatal test is recommended.
tures, with serial assessment of maternal symptoms Quality of evidence: Moderate
and fetal movement (daily by the woman), serial Strength of recommendation: Strong
measurements of BP (twice weekly), and assess-
ment of platelet counts and liver enzymes (weekly) • For women with mild gestational hypertension or
is suggested. preeclampsia without severe features and no indi-
cation for delivery at less than 37 0/7 weeks of ges-
Quality of evidence: Moderate tation, expectant management with maternal and
Strength of recommendation: Qualified fetal monitoring is suggested.
• For women with gestational hypertension, monitor- Quality of evidence: Low
ing BP at least once weekly with proteinuria assess- Strength of recommendation: Qualified
ment in the office and with an additional weekly
measurement of BP at home or in the office is sug- • For women with mild gestational hypertension or
gested. preeclampsia without severe features at or beyond
37 0/7 weeks of gestation, delivery rather than con-
Quality of evidence: Moderate tinued observation is suggested.
• For women with mild gestational hypertension or Strength of recommendation: Qualified
preeclampsia with a persistent BP of less than
160 mm Hg systolic or 110 mm Hg diastolic, it is • For women with preeclampsia with systolic BP of
suggested that antihypertensive medications not be less than 160 mm Hg and a diastolic BP less than
administered. 110 mm Hg and no maternal symptoms, it is sug-
gested that magnesium sulfate not be administered
Quality of evidence: Moderate universally for the prevention of eclampsia.
Quality of evidence: Low
• For women with gestational hypertension or pre- Strength of recommendation: Qualified
eclampsia without severe features, it is suggested
that strict bed rest not be prescribed.* † • For women with severe preeclampsia at or beyond
34 0/7 weeks of gestation, and in those with un-
Quality of evidence: Low stable maternal or fetal conditions irrespective of
Strength of recommendation: Qualified gestational age, delivery soon after maternal stabili-
* The task force acknowledged that there may be situations zation is recommended.
in which different levels of rest, either at home or in the
hospital, may be indicated for individual women. The Quality of evidence: Moderate
previous recommendations do not cover advice regard- Strength of recommendation: Strong
ing overall physical activity and manual or office work.
• For women with severe preeclampsia at less than
† omen may need to be hospitalized for reasons other
W
34 0/7 weeks of gestation with stable maternal and
than bed rest, such as for maternal and fetal surveillance.
The task force agreed that hospitalization for maternal fetal conditions, it is recommended that continued
and fetal surveillance is resource intensive and should be pregnancy be undertaken only at facilities with
considered as a priority for research and future recom- adequate maternal and neonatal intensive care
mendations. resources.
• For women with preeclampsia without severe fea- Quality of evidence: Moderate
tures, use of ultrasonography to assess fetal growth Strength of recommendation: Strong
and antenatal testing to assess fetal status is sug-
• For women with severe preeclampsia receiving
gested.
expectant management at 34 0/7 weeks or less of
Quality of evidence: Moderate gestation, the administration of corticosteroids for
Strength of recommendation: Qualified fetal lung maturity benefit is recommended.
Quality of evidence: High
Strength of recommendation: Strong
6 EXECUTIVE SUMMARY
• For women with preeclampsia with severe hyper- • It is recommended that corticosteroids be given if
tension during pregnancy (sustained systolic BP the fetus is viable and at 33 6/7 weeks or less of
of at least 160 mm Hg or diastolic BP of at least gestation, but that delivery not be delayed after ini-
110 mm Hg), the use of antihypertensive therapy tial maternal stabilization regardless of gestational
is recommended. age for women with severe preeclampsia that is
Quality of evidence: Moderate complicated further with any of the following:
Strength of recommendation: Strong – uncontrollable severe hypertension
– eclampsia
• For women with preeclampsia, it is suggested that a
– pulmonary edema
delivery decision should not be based on the
– abruptio placentae
amount of proteinuria or change in the amount of
– disseminated intravascular coagulation
proteinuria.
– evidence of nonreassuring fetal status
Quality of evidence: Moderate – intrapartum fetal demise
• For women with severe preeclampsia and before Strength of recommendation: Strong
fetal viability, delivery after maternal stabilization is
recommended. Expectant management is not rec- • For women with preeclampsia, it is suggested that
ommended. the mode of delivery need not be cesarean delivery.
The mode of delivery should be determined by fetal
Quality of evidence: Moderate gestational age, fetal presentation, cervical status,
Strength of recommendation: Strong and maternal and fetal conditions.
• It is suggested that corticosteroids be administered Quality of evidence: Moderate
and delivery deferred for 48 hours if maternal and Strength of recommendation: Qualified
fetal conditions remain stable for women with
severe preeclampsia and a viable fetus at 33 6/7 • For women with eclampsia, the administration of
weeks or less of gestation with any of the following: parenteral magnesium sulfate is recommended.
– preterm premature rupture of membranes Quality of evidence: High

– labor Strength of recommendation: Strong
– low platelet count (less than 100,000/microliter) • For women with severe preeclampsia, the adminis-
– persistently abnormal hepatic enzyme concentra- tration of intrapartum–postpartum magnesium sul-
tions (twice or more the upper normal values) fate to prevent eclampsia is recommended.
– fetal growth restriction (less than the fifth per-
centile)
– severe oligohydramnios (amniotic fluid index
less than 5 cm) • For women with preeclampsia undergoing cesarean
– reversed end-diastolic flow on umbilical artery delivery, the continued intraoperative administra-
Doppler studies tion of parenteral magnesium sulfate to prevent
– new-onset renal dysfunction or increasing renal eclampsia is recommended.
dysfunction
Quality of evidence: Moderate Strength of recommendation: Strong
• For women with HELLP syndrome and before the
gestational age of fetal viability, it is recommended
that delivery be undertaken shortly after initial
maternal stabilization.
EXECUTIVE SUMMARY 7
• For women with HELLP syndrome at 34 0/7 weeks • For all women in the postpartum period (not just
or more of gestation, it is recommended that deliv- women with preeclampsia), it is suggested that dis-
ery be undertaken soon after initial maternal stabi- charge instructions include information about the
lization. signs and symptoms of preeclampsia as well as the
Quality of evidence: Moderate importance of prompt reporting of this information
Strength of recommendation: Strong to their health care providers.
• For women with HELLP syndrome from the gesta-
tional age of fetal viability to 33 6/7 weeks of gesta-
tion, it is suggested that delivery be delayed for • For women in the postpartum period who present
24 – 48 hours if maternal and fetal condition re- with new-onset hypertension associated with head-
mains stable to complete a course of corticosteroids aches or blurred vision or preeclampsia with severe
for fetal benefit.* hypertension, the parenteral administration of mag-
Quality of evidence: Low nesium sulfate is suggested.
Strength of recommendation: Qualified Quality of evidence: Low
*Corticosteroids have been used in randomized controlled Strength of recommendation: Qualified
trials to attempt to improve maternal and fetal condition. • For women with persistent postpartum hyperten-
In these studies, there was no evidence of benefit to
improve overall maternal and fetal outcome (although sion, BP of 150 mm Hg systolic or 100 mm Hg dia-
this has been suggested in observational studies). There is stolic or higher, on at least two occasions that are at
evidence in the randomized trials of improvement of least 4–6 hours apart, antihypertensive therapy is
platelet counts with corticosteroid treatment. In clinical suggested. Persistent BP of 160 mm Hg systolic or
settings in which an improvement in platelet count is con- 110 mm Hg diastolic or higher should be treated
sidered useful, corticosteroids may be justified.
within 1 hour.
• For women with preeclampsia who require analge- Quality of evidence: Low
sia for labor or anesthesia for cesarean delivery and Strength of recommendation: Qualified
with a clinical situation that permits sufficient time
for establishment of anesthesia, the administration
of neuraxial anesthesia (either spinal or epidural Management of Women With
anesthesia) is recommended. Prior Preeclampsia
Quality of evidence: Moderate Women who have had preeclampsia in a prior preg-
Strength of recommendation: Strong nancy should receive counseling and assessments
before their next pregnancy. This can be initiated at the
• For women with severe preeclampsia, it is suggested
postpartum visit but is ideally accomplished at a pre-
that invasive hemodynamic monitoring not be used
conception visit before the next planned pregnancy.
routinely.
During the preconception visit, the previous pregnancy
Quality of evidence: Low history should be reviewed and the prognosis for the
Strength of recommendation: Qualified upcoming pregnancy should be discussed. Potentially
• For women in whom gestational hypertension, pre- modifiable lifestyle activities, such as weight loss and
eclampsia, or superimposed preeclampsia is diag- increased physical activity, should be encouraged. The
nosed, it is suggested that BP be monitored in the current status of medical problems should be assessed,
hospital or that equivalent outpatient surveillance including laboratory evaluation if appropriate. Medical
be performed for at least 72 hours postpartum and problems such as hypertension and diabetes should be
again 7–10 days after delivery or earlier in women brought into the best control possible. The effect of
with symptoms. medical problems on the pregnancy should be dis-
cussed. Medications should be reviewed and their
Quality of evidence: Moderate administration modified for upcoming pregnancy. Folic
Strength of recommendation: Qualified acid supplementation should be recommended. If a
woman has given birth to a preterm infant during a
preeclamptic pregnancy or has had preeclampsia in
more than one pregnancy, the use of low-dose aspirin
in the upcoming pregnancy should be suggested.
8 EXECUTIVE SUMMARY
Women with a medical history of preeclampsia should

be instructed to return for care early in pregnancy.
During the next pregnancy, early ultrasonography • For women with features suggestive of secondary
should be performed to determine gestational age, and hypertension, referral to a physician with expertise
assessment and visits should be tailored to the prior in treating hypertension to direct the workup is sug-
pregnancy outcome, with frequent visits beginning gested.
earlier in women with prior preterm preeclampsia. The
woman should be educated about the signs and symp-
toms of preeclampsia and instructed when and how to
contact her health care provider. • For pregnant women with chronic hypertension
and poorly controlled BP, the use of home BP moni-
toring is suggested.
TASK FORCE RECOMMENDATION
• For women with preeclampsia in a prior pregnancy, Strength of recommendation: Qualified
preconception counseling and assessment is sug-
gested. • For women with suspected white coat hypertension,
the use of ambulatory BP monitoring to confirm the
diagnosis before the initiation of antihypertensive
therapy is suggested.
Chronic Hypertension and Strength of recommendation: Qualified
Superimposed Preeclampsia
• It is suggested that weight loss and extremely low-
Chronic hypertension (hypertension predating preg- sodium diets (less than 100 mEq/d) not be used for
nancy), presents special challenges to health care pro- managing chronic hypertension in pregnancy.
viders. Health care providers must first confirm that
the BP elevation is not preeclampsia. Once this is estab- Quality of evidence: Low
lished, if the BP elevation has not been previously eval- Strength of recommendation: Qualified
uated, a workup should be performed to document • For women with chronic hypertension who are
that BP is truly elevated (ie, not white coat hyperten- accustomed to exercising, and in whom BP is well
sion) and to check for secondary hypertension and controlled, it is recommended that moderate exer-
end-organ damage. The choice of which women to cise be continued during pregnancy.
treat and how to treat them requires special consider-
ations during pregnancy, especially in light of emerg-
ing data that suggest lowering BP excessively might
have adverse fetal effects. • For pregnant women with persistent chronic hyper-
Perhaps the greatest challenge is the recognition of tension with systolic BP of 160 mm Hg or higher or
preeclampsia superimposed on chronic hypertension, a diastolic BP of 105 mm Hg or higher, antihyperten-
condition that is commonly associated with adverse sive therapy is recommended.
maternal and fetal outcomes. Recommendations are Quality of evidence: Moderate
provided to guide health care providers in distinguish- Strength of recommendation: Strong
ing women who may have superimposed preeclampsia
without severe features (only hypertension and protein- • For pregnant women with chronic hypertension
uria) and require only observation from women who and BP less than 160 mm Hg systolic or 105 mm Hg
may have superimposed preeclampsia with severe fea- diastolic and no evidence of end-organ damage, it is
tures (evidence of systemic involvement beyond hyper- suggested that they not be treated with pharmaco-
tension and proteinuria) and require intervention. logic antihypertensive therapy.
EXECUTIVE SUMMARY 9
• For pregnant women with chronic hypertension • For women with chronic hypertension, the use of
treated with antihypertensive medication, it is ultrasonography to screen for fetal growth restric-
suggested that BP levels be maintained between tion is suggested.
120 mm Hg systolic and 80 mm Hg diastolic and Quality of evidence: Low
160 mm Hg systolic and 105 mm Hg diastolic. Strength of recommendation: Qualified
• If evidence of fetal growth restriction is found in
women with chronic hypertension, fetoplacental as-
• For the initial treatment of pregnant women with sessment to include umbilical artery Doppler veloci-
chronic hypertension who require pharmacologic metry as an adjunct antenatal test is recommended.
therapy, labetalol, nifedipine, or methyldopa are Quality of evidence: Moderate
recommended above all other antihypertensive Strength of recommendation: Strong
drugs.
• For women with chronic hypertension complicated
by issues such as the need for medication, other
underlying medical conditions that affect fetal
• For women with uncomplicated chronic hyperten- outcome, or any evidence of fetal growth restric-
sion in pregnancy, the use of angiotensin-converting tion, and superimposed preeclampsia, antenatal
enzyme inhibitors, angiotensin receptor blockers, fetal testing is suggested.
renin inhibitors, and mineralocorticoid receptor Quality of evidence: Low
antagonists is not recommended. Strength of recommendation: Qualified
• For women with chronic hypertension and no addi-
tional maternal or fetal complications, delivery be-
• For women of reproductive age with chronic hyper- fore 38 0/7 weeks of gestation is not recommended.
tension, the use of angiotensin-converting enzyme Quality of evidence: Moderate
inhibitors, angiotensin receptor blockers, renin Strength of recommendation: Strong
inhibitors, and mineralocorticoid receptor antago-
nists is not recommended unless there is a compel- • For women with superimposed preeclampsia who
ling reason, such as the presence of proteinuric receive expectant management at less than 34 0/7
renal disease. weeks of gestation, the administration of cortico-
steroids for fetal lung maturity benefit is recom-
mended.
• For women with chronic hypertension who are at Strength of recommendation: Strong
a greatly increased risk of adverse pregnancy out-
comes (history of early-onset preeclampsia and • For women with chronic hypertension and superim-
preterm delivery at less than 34 0/7 weeks of posed preeclampsia with severe features, the admin-
gestation or preeclampsia in more than one prior istration of intrapartum–postpartum parenteral
pregnancy), initiating the administration of daily magnesium sulfate to prevent eclampsia is recom-
low-dose aspirin (60–80 mg) beginning in the late mended.
first trimester is suggested.* Quality of evidence: Moderate
Quality of evidence: Moderate Strength of recommendation: Strong
Strength of recommendation: Qualified • For women with superimposed preeclampsia with-
* Meta-analysis of more than 30,000 women in randomized out severe features and stable maternal and fetal
trials of aspirin to prevent preeclampsia indicates a small conditions, expectant management until 37 0/7
reduction in the incidence and morbidity of preeclampsia weeks of gestation is suggested.
fetal effects cannot be excluded. The number of women to Quality of evidence: Low
treat to have a therapeutic effect is determined by preva- Strength of recommendation: Qualified
lence. In view of maternal safety, a discussion of the use
of aspirin in light of individual risk is justified.
10 EXECUTIVE SUMMARY
• Delivery soon after maternal stabilization is recom- years provide all of the information that would be
mended irrespective of gestational age or full corti- gained by knowing a woman had a past preeclamptic
costeroid benefit for women with superimposed pregnancy? Would it be valuable to perform this
preeclampsia that is complicated further by any of assessment at a younger age in women who had a
the following: past preeclamptic pregnancy? If the risk was identi-
– uncontrollable severe hypertension fied earlier, what intervention (other than lifestyle
– eclampsia modification) would potentially be useful and would
– pulmonary edema it make a difference? Are there risk factors that could
– abruptio placentae be unmasked by pregnancy other than conventional
– disseminated intravascular coagulation risk factors? Further research is needed to determine
– nonreassuring fetal status how to take advantage of this information relating
preeclampsia to later-life CV disease. At this time, the
task force cautiously recommends lifestyle modifica-
Strength of the recommendation: Strong
tion (maintenance of a healthy weight, increased
• For women with superimposed preeclampsia with physical activity, and not smoking) and suggests early
severe features at less than 34 0/7 weeks of gesta- evaluation for the most high-risk women.
tion with stable maternal and fetal conditions, it is
recommended that continued pregnancy should be
undertaken only at facilities with adequate mater-
nal and neonatal intensive care resources. • For women with a medical history of preeclampsia
Quality of evidence: Moderate who gave birth preterm (less than 37 0/7 weeks of
Strength of evidence: Strong gestation) or who have a medical history of recur-
rent preeclampsia, yearly assessment of BP, lipids,
• For women with superimposed preeclampsia with fasting blood glucose, and body mass index is sug-
severe features, expectant management beyond gested.*
34 0/7 weeks of gestation is not recommended.
Strength of the recommendation: Strong
*Although there is clear evidence of an association be-
tween preeclampsia and later-life CV disease, the value
Later-Life Cardiovascular Disease in and appropriate timing of assessment is not yet estab-
lished. Health care providers and patients should make
Women With Prior Preeclampsia
this decision based on their judgment of the relative value
Over the past 10 years, information has accumulated of extra information versus expense and inconvenience.
indicating that a woman who has had a preeclamptic
pregnancy is at an increased risk of later-life CV disease.
Patient Education
This increase ranges from a doubling of risk in all cas-
es to an eightfold to ninefold increase in women with Patient and health care provider education is key to
preeclampsia who gave birth before 34 0/7 weeks of the successful recognition and management of pre-
gestation. This has been recognized by the American eclampsia. Health care providers need to inform
Heart Association, which now recommends that a women during the prenatal and postpartum periods
pregnancy history be part of the evaluation of CV risk of the signs and symptoms of preeclampsia and stress
in women. It is the general belief that preeclampsia the importance of contacting health care providers if
does not cause CV disease, but rather preeclampsia these are evident. The recognition of the importance
and CV disease share common risk factors. Awareness of patient education must be complemented by the
that a woman has had a preeclamptic pregnancy recognition and use of strategies that facilitate the
might allow for the identification of women not previ- successful transfer of this information to women with
ously recognized as at-risk for earlier assessment and varying degrees of health literacy. Recommended
potential intervention. However, it is unknown if this strategies to facilitate this process include using plain
will be a valuable adjunct to previous information. If nonmedical language, taking time to speak slowly,
this is the case, would the current recommendation of reinforcing key issues in print using pictorially based
assessing risk factors for women by medical history, information, and requesting feedback to indicate that
lifestyle evaluation, testing for metabolic abnormali- the patient understands, and, where applicable, her
ties, and possibly inflammatory activation at age 40 partner.
EXECUTIVE SUMMARY 11
and inflammation, and secondary mediators that

include modifiers of endothelial function and angio-
• It is suggested that health care providers convey genesis. This understanding of preeclampsia patho-
information about preeclampsia in the context of physiology has not translated into predictors or
prenatal care and postpartum care using proven preventers of preeclampsia or to improved clinical
health communication practices. care. This has led to a reassessment of this conceptual
Quality of evidence: Low framework, with attention to the possibility that pre-
Strength of recommendation: Qualified eclampsia is not one disease but that the syndrome
may include subsets of pathophysiology.
Clinical research advances have shown approaches
The State of the Science and to therapy that work (eg, delivery for women with ges-
Research Recommendations tational hypertension and preeclampsia without
In the past 10 years, striking increases in the under- severe features at 37 0/7 weeks of gestation) or do not
standing of the pathophysiology of preeclampsia have work (vitamin C and vitamin E to prevent preeclamp-
occurred. Clinical research advances also have em- sia). However, there are few clinical recommendations
erged that have provided evidence to guide therapy. It that can be classified as “strong” because there are
is now understood that preeclampsia is a multisystem- huge gaps in the evidence base that guides therapy.
ic disease that affects all organ systems and is far more These knowledge gaps form the basis for research rec-
than high BP and renal dysfunction. The placenta is ommendations to guide future therapy.
evident as the root cause of preeclampsia. It is with the
delivery of the placenta that preeclampsia begins to
Conclusion
resolve. The insult to the placenta is proposed as an
immunologically initiated alteration in trophoblast The task force provides evidence-based recommenda-
function, and the reduction in trophoblast invasion tions for the management of patients with hyperten-
leads to failed vascular remodeling of the maternal sion during and after pregnancy. Recommendations
spiral arteries that perfuse the placenta. The resulting are graded as strong or qualified based on evidence of
reduced perfusion and increased velocity of blood effectiveness weighed against evidence of potential
perfusing the intervillous space alter placental func- harm. In all instances, the final decision is made by the
tion. The altered placental function leads to mater- health care provider and patient after consideration of
nal disease through putative primary mediators, the strength of the recommendations in relation to the
including oxidative and endoplasmic reticulum stress values and judgments of the individual patient.
CHAPTER
1
Classification of Hypertensive Disorders
T
he major goals of a hypertension classifica- 1) preeclampsia–eclampsia, 2) chronic hypertension
tion schema, which describes hypertension (of any cause), 3) chronic hypertension with superim-
that complicates pregnancy, are to differ- posed preeclampsia; and 4) gestational hypertension.
entiate diseases preceding conception from It has been suggested that an older category,
those specific to pregnancy, identify the most omi- “unclassified,” be reintroduced or replaced by “sus-
nous causes, and create categories ideal for record pected” or “presumptive” preeclampsia. This may be
keeping and eventual epidemiologic research. Never- useful in management because one should always be
theless, health care professionals continue to be con- prepared for the disorder with the greatest risk. How-
fused by the differences in terminology that abound ever, although these latter terms may help guide clini-
in the literature, especially the differences in publica- cal practice, they may hinder record keeping for
tions from national and international societies. These precise epidemiological research.
latter reports continue to introduce schema that dif-
fer in various documents and may contrast with those
Preeclampsia–Eclampsia
recommended here. This confusion has obviously
affected both management and outcome research Preeclampsia is a pregnancy-specific hypertensive dis-
and recommendations. ease with multisystem involvement. It usually occurs
The American College of Obstetricians and Gyne- after 20 weeks of gestation, most often near term, and
cologists (the College) Task Force on Hypertension in can be superimposed on another hypertensive disor-
Pregnancy chose to continue using the classification der. Preeclampsia, the most common form of high
schema first introduced in 1972 by the College and blood pressure (BP) that complicates pregnancy, is pri-
modified in the 1990 and 2000 reports of the National marily defined by the occurrence of new-onset hyper-
High Blood Pressure Education Program Working tension plus new-onset proteinuria. However, although
Group (1). Similar classifications can be found in the these two criteria are considered the classic definition
American Society of Hypertension guidelines, as well of preeclampsia, some women present with hyperten-
as College Practice Bulletins (2, 3). Although the sion and multisystemic signs usually indicative of dis-
task force has modified some of the components of ease severity in the absence of proteinuria. In the
the classification, it continues with this basic, precise, absence of proteinuria, preeclampsia is diagnosed as
and practical classification, which considers hyper- hypertension in association with thrombocytopenia
tension during pregnancy in only four categories: (platelet count less than 100,000/microliter), impaired
13
14 CLASSIFICATION OF HYPERTENSIVE DISORDERS
liver function (elevated blood levels of liver transami- half of pregnancy and normalizes postpartum, the
nases to twice the normal concentration), the new diagnosis should be changed to “transient hyperten-
development of renal insufficiency (elevated serum sion of pregnancy.” However, because discharge
creatinine greater than 1.1 mg/dL or a doubling of records are rarely modified, the task force recom-
serum creatinine in the absence of other renal dis- mends against instituting this latter terminology.
ease), pulmonary edema, or new-onset cerebral or
visual disturbances.
Chronic Hypertension With
Hypertension is defined as either a systolic BP of
140 mm Hg or greater, a diastolic BP of 90 mm Hg Superimposed Preeclampsia
or greater, or both. Hypertension is considered Preeclampsia may complicate all other hypertensive
mild until diastolic or systolic levels reach or exceed disorders, and in fact the incidence is four to five times
110 mm Hg and 160 mm Hg, respectively. It is recom- that in nonhypertensive pregnant women (4). In such
mended that a diagnosis of hypertension require at cases, prognosis for the woman and her fetus is worse
least two determinations at least 4 hours apart, than either condition alone. Although evidence from
although on occasion, especially when faced with renal biopsy studies suggests that the diagnosis of
severe hypertension, the diagnosis can be confirmed superimposed preeclampsia may be often erroneous
within a shorter interval (even minutes) to facilitate (5), the diagnosis is more likely in the following seven
timely antihypertensive therapy. scenarios: women with hypertension only in early ges-
Proteinuria is diagnosed when 24-hour excretion tation who develop proteinuria after 20 weeks of ges-
equals or exceeds 300 mg in 24 hours or the ratio of tation and women with proteinuria before 20 weeks of
measured protein to creatinine in a single voided urine gestation who 1) experience a sudden exacerbation of
measures or exceeds 3.0 (each measured as mg/dL), hypertension, or a need to escalate the antihypertensive
termed the protein/creatinine ratio. As discussed in drug dose especially when previously well controlled
Chapter 2 “Establishing the Diagnosis of Preeclampsia with these medications; 2) suddenly manifest other
and Eclampsia,” qualitative dipstick readings of 1+ signs and symptoms, such as an increase in liver enzymes
suggest proteinuria but have many false-positive and to abnormal levels; 3) present with a decrement in
false-negative results and should be reserved for use their platelet levels to below 100,000/microliter;
when quantitative methods are not available or rapid 4) manifest symptoms such as right upper quadrant
decisions are required. pain and severe headaches; 5) develop pulmonary
Eclampsia is the convulsive phase of the disorder congestion or edema; 6) develop renal insufficiency
and is among the more severe manifestations of the (creatinine level doubling or increasing to or above 1.1
disease. It is often preceded by premonitory events, mg/dL in women without other renal disease); and 7)
such as severe headaches and hyperreflexia, but it can have sudden, substantial, and sustained increases in
occur in the absence of warning signs or symptoms. protein excretion.
Specific biochemical markers have been linked to If the only manifestation is elevation in BP to levels
increased morbidity in hypertensive complications of less than 160 mm Hg systolic and 110 mm Hg diastolic
pregnancy (eg, hyperuricemia), but these should not and proteinuria, this is considered to be superim-
be used for diagnosis. Although some label preeclamp- posed preeclampsia without severe features. The
sia as “less severe” or “more severe”, or “mild” and presence of organ dysfunction is considered to be
“severe,” these are not specific classifications, and the superimposed preeclampsia with severe features. For
consideration of preeclampsia as “mild” should be classification purposes, both variants are termed
avoided. The task force recommends that the term “superimposed preeclampsia,” but management is
“mild preeclampsia” be replaced by “preeclampsia guided by the subcategory (analogous to “preeclamp-
without severe features.” These points are more exten- sia with severe features” and “preeclampsia without
sively discussed in Chapter 2 “Establishing the Diagno- severe features”).
sis of Preeclampsia and Eclampsia.”
Gestational Hypertension
Chronic Hypertension
Gestational hypertension is characterized most often by
During pregnancy, chronic hypertension is defined as new-onset elevations of BP after 20 weeks of gestation,
high BP known to predate conception or detected often near term, in the absence of accompanying pro-
before 20 weeks of gestation. Previously, some sug- teinuria. The failure of BP to normalize postpartum
gested that when high BP is first diagnosed in the first requires changing the diagnosis to chronic hypertension.
CLASSIFICATION OF HYPERTENSIVE DISORDERS 15
Outcomes in women with gestational hypertension hypertension (usually mild) in a period that ranges
usually are quite successful, although some of these from 2 weeks to 6 months postpartum. Blood pressure
women experience BP elevations to the severe level remains labile for months postpartum, usually normal-
with outcomes similar to women with preeclampsia izing by the end of the first year. Little is known of this
(6). The cause of this entity is unclear, but many of entity, and, like gestational hypertension, it may be a
these women have preeclampsia before proteinuria predictor of future chronic hypertension.
and other organ manifestations have occurred. Thus,
gestational hypertension, even when BP elevations are
mild, requires enhanced surveillance.
References
Gestational hypertension, although transient in 1. Report of the National High Blood Pressure Education
nature, may also be a sign of future chronic hyperten- Program Working Group on High Blood Pressure in Preg-
sion. Thus, even when benign, it is an important nancy. Am J Obstet Gynecol 2000;183:S1–S22.
[PubMed] [Full Text] ^
marker regarding follow-up and preventive medicine
decisions (7). 2. Lindheimer MD, Taler SJ, Cunningham FG. Hyperten-
sion in pregnancy. J Am Soc Hypertens 2010;4:68–78.
[PubMed] ^
Postpartum Hypertension 3. Diagnosis and management of preeclampsia and eclamp-
sia. ACOG Practice Bulletin No. 33. American College of
It is important to remember that preeclampsia— Obstetricians and Gynecologists. Obstet Gynecol 2002;
including preeclampsia with severe systemic organ 99:159–67. [PubMed] [Obstetrics & Gynecology] ^
involvement and seizures—can first develop in the 4. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M,
postpartum period. Because early hospital discharge is Thom E, et al. Low-dose aspirin to prevent preeclampsia
in women at high risk. National Institute of Child Health
the current practice in the United States, this man-
and Human Development Network of Maternal-Fetal-
dates instruction of women at discharge from the hos- Medicine Units. N Engl J Med 1998;338:701–5.
pital to be aware of symptoms (eg, severe headache, [PubMed] [Full Text] ^
visual disturbances, or epigastric pain) that should be 5. Fisher KA, Luger A, Spargo BH, Lindheimer MD. Hyper-
reported to a health care provider. tension in pregnancy: clinical-pathological correlations
Although not recommended in this classification and remote prognosis. Medicine (Baltimore) 1981;60:
schema, the task force calls attention to a phenome- 267–76. ^
non once labeled “late postpartum hypertension,” a 6. Buchbinder A, Sibai BM, Caritis S, Macpherson C, Hauth J,
Lindheimer MD, et al. Adverse perinatal outcomes are
disorder that was more frequently diagnosed when significantly higher in severe gestational hypertension
women in the postpartum period routinely remained than in mild preeclampsia. National Institute of Child
hospitalized for as long as 2 weeks. It was defined as Health and Human Development Network of Maternal-
women with normotensive gestations who develop Fetal Medicine Units. Am J Obstet Gynecol 2002;186:
66–71. [PubMed] [Full Text] ^
7. Williams D. Long-term complications of preeclampsia.
Semin Nephrol 2011;31:111–22. [PubMed] ^
CHAPTER
2
Establishing the Diagnosis of
Preeclampsia and Eclampsia
^
S
pecific criteria must be met to establish the the middle of the cuff on the upper arm is at the level
diagnosis of preeclampsia, preeclampsia with of the right atrium (the midpoint of the sternum). The
severe features, and eclampsia. More recent patient should be instructed to relax and not talk
criteria for the definition of preeclampsia have during the measurement procedure; ideally, 5 minutes
been established based on their association with ad- should elapse before the first reading is taken. If ele-
verse clinical outcomes. Several preexisting criteria for vated on initial assessment, the BP measurement
preeclampsia with severe features have been eliminat- should be repeated after several minutes to attempt to
ed based largely on whether evidence suggests that eliminate spuriously elevated BP determinations (3).
their presence should outline clinical management in It is worth noting that measurement of BP taken in the
the preterm setting. upper arm with the woman in the left lateral position
will falsely lower BP readings because the blood pres-
sure cuff will be above the heart when these readings
Preeclampsia
are made. This approach is discouraged.
Definition Hypertension does not mean that a patient has pre-
Preeclampsia is a syndrome that chiefly includes the eclampsia; other criteria are required. In most cases,
development of new-onset hypertension in the second this will be new-onset proteinuria, but in the absence of
half of pregnancy. Although often accompanied by proteinuria that meets or exceeds the diagnostic thresh-
new-onset proteinuria, preeclampsia can be associated old, any of the following can establish the diagnosis:
with many other signs and symptoms, including visual new-onset thrombocytopenia, impaired liver function,
disturbances, headaches, epigastric pain, and the rapid renal insufficiency, pulmonary edema, or visual or cere-
development of edema. bral disturbances. Proteinuria is defined by the excre-
Diagnostic criteria include the development of tion of 300 mg or more of protein in a 24-hour urine
hypertension, defined as a persistent systolic blood collection (or this amount extrapolated from a timed
pressure (BP) of 140 mm Hg or higher, or a diastolic collection) (4). Alternatively, a protein/creatinine ratio
BP of 90 mm Hg or higher after 20 weeks of gestation of at least 0.3 (each measured as mg/dL) is an equiva-
in a women with previously normal blood pressure (1, lent acceptable threshold for the diagnosis to be estab-
2) (Table 2-1). The optimal measurement of BP is lished because this ratio has been demonstrated to
made with the patient comfortably seated, legs match or exceed a 24-hour urine protein collection of
uncrossed, and the back and arm supported, so that 300 mg (5). A dipstick reading of 1+ also suggests
17
18 ESTABLISHING THE DIAGNOSIS OF PREECLAMPSIA AND ECLAMPSIA
TABLE 2-1. Diagnostic Criteria for Preeclampsia ^
Blood pressure • Greater than or equal to 140 mm Hg systolic or greater than or equal to 90 mm Hg
diastolic on two occasions at least 4 hours apart after 20 weeks of gestation in a
woman with a previously normal blood pressure
• Greater than or equal to 160 mm Hg systolic or greater than or equal to 110 mm Hg
diastolic, hypertension can be confirmed within a short interval (minutes) to facilitate
timely antihypertensive therapy
and
Proteinuria • Greater than or equal to 300 mg per 24 hour urine collection (or this amount
extrapolated from a timed collection)
or
• Protein/creatinine ratio greater than or equal to 0.3*
• Dipstick reading of 1+ (used only if other quantitative methods not available)
Or in the absence of proteinuria, new-onset hypertension with the new onset of any of the following:
Thrombocytopenia • Platelet count less than 100,000/microliter
Renal insufficiency • Serum creatinine concentrations greater than 1.1 mg/dL or a doubling of the serum
creatinine concentration in the absence of other renal disease
Impaired liver function • Elevated blood concentrations of liver transaminases to twice normal concentration
Pulmonary edema
Cerebral or visual
symptoms
* Each measured as mg/dL.
proteinuria, but because this qualitative method has constellation of laboratory findings is often considered
many false-positive and false-negative results, it should a preeclamptic subtype. The segregation of HELLP
be used for diagnosis only when quantitative methods syndrome from thrombotic thrombocytopenic purpura
are not available. Alternatively, the diagnosis may be may be helped by the measurement of serum lactate
established by the presence of hypertension as defined dehydrogenase when additional criteria for pre-
previously in association with thrombocytopenia (plate- eclampsia are absent (7).
let count less than 100,000/microliter), impaired liver
function (elevated blood concentrations of liver trans- Prediagnostic Findings Warranting
aminases to twice the normal concentration), the new Increased Surveillance
development of renal insufficiency (serum creatinine Some maternal symptoms, even in the absence of a
concentration greater than 1.1 mg/dL or a doubling of confirmed diagnosis of preeclampsia, should prompt
the serum creatinine concentration in the absence of the obstetric care provider to closely evaluate mater-
other renal disease), pulmonary edema, or new-onset nal status for specific signs of preeclampsia. These
cerebral or visual disturbances. Proteinuria is not abso- include the new onset of headache or visual distur-
lutely required for the diagnosis of preeclampsia (6). bances, as well as abdominal pain, particularly in the
Preeclampsia with the absence of severe manifesta- right upper quadrant, or epigastric pain.
tions often has been characterized as “mild.” It should Additional findings that warrant close observation
be noted that this characterization can be misleading; for the subsequent development of preeclampsia
even in the absence of severe disease (defined in this include fetal growth restriction or new-onset protein-
chapter), morbidity and mortality are significantly uria in the second half of pregnancy (8, 9). Elevations
increased. Therefore, the task force recommends that in BP during pregnancy (comparing late pregnancy
the term “preeclampsia without severe features” be with early pregnancy) that exceed 15 mm Hg diastolic
used instead. Some pregnant women present with a or 30 mm Hg systolic are common in uncomplicated
specific constellation of laboratory findings—hemoly- pregnancies (10). Nevertheless, women who demon-
sis, elevated liver enzymes, and low platelet count— strate this degree of elevation in BP “warrant close
that has been labeled “HELLP syndrome.” This observation,” as suggested by the National High Blood
ESTABLISHING THE DIAGNOSIS OF PREECLAMPSIA AND ECLAMPSIA 19
Pressure Education Program Working Group (2).

Additionally, biochemical markers can be associated
with poorer outcomes in women in whom preeclamp- BOX 2-1. evere Features of Preeclampsia
S
sia has been diagnosed. These markers may have value (Any of these findings) ^
in the management of specific patients, but they do not
contribute to establishing the diagnosis. Among these • Systolic blood pressure of 160 mm Hg or higher, or diastolic
markers is uric acid concentration (11). It is important blood pressure of 110 mm Hg or higher on two occasions at
to note that these findings warn that preeclampsia may least 4 hours apart while the patient is on bed rest (unless
be impending, which may influence patterns of clinical antihypertensive therapy is initiated before this time)
observation, but the findings do not support the initia- • Thrombocytopenia (platelet count less than 100,000/microliter)
tion of specific interventions in and of themselves.
Although clinically evident edema or rapid weight • Impaired liver function as indicated by abnormally elevated
gain, or both, may raise the clinical suspicion for pre- blood concentrations of liver enzymes (to twice normal
eclampsia, it is not a diagnostic criterion. Nondepen- concentration), severe persistent right upper quadrant or
dent edema occurs in 10–15% of women who remain epigastric pain unresponsive to medication and not accounted
normotensive throughout pregnancy, and it is neither for by alternative diagnoses, or both
a sensitive nor specific sign of preeclampsia (12). • Progressive renal insufficiency (serum creatinine concentration
greater than 1.1 mg/dL or a doubling of the serum creatinine
Assessing the Severity of Preeclampsia concentration in the absence of other renal disease)
Some clinical findings increase the risk of morbidity
and mortality in the setting of preeclampsia and, when • Pulmonary edema
present, segregate preeclampsia into a more severe • New-onset cerebral or visual disturbances
category (13). The more severe forms of preeclampsia
are characterized by the certain findings in women
meeting the basic criteria for diagnosing the disorder
(Box 2-1). Additionally, women who have met the basic
criteria for preeclampsia with systolic BP levels of 140–
160 mm Hg or diastolic BP levels of 90–110 mm Hg, References
along with new evidence of thrombocytopenia,
impaired liver dysfunction, renal insufficiency, pulmo- 1. Stone P, Cook D, Hutton J, Purdie G, Murray H, Harcourt L.
Measurements of blood pressure, oedema and protein-
nary edema, or visual loss or cerebral disturbance, also uria in a pregnant population of New Zealand. Aust N Z
should be considered as having severe disease. J Obstet Gynaecol 1995;35:32–7. [PubMed] ^
In view of recent studies that indicate a minimal rela- 2. Report of the National High Blood Pressure Education
tionship between the quantity of urinary protein and Program Working Group on High Blood Pressure in Preg-
pregnancy outcome in preeclampsia, massive protein- nancy. Am J Obstet Gynecol 2000;183:S1–S22.
uria (greater than 5 g) has been eliminated from the [PubMed] [Full Text] ^
consideration of preeclampsia as severe. Also, because 3. Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J,
Hill MN, et al. Recommendations for blood pressure
fetal growth restriction is managed similarly in pregnant measurement in humans and experimental animals: Part
women with and without preeclampsia, it has been 1: blood pressure measurement in humans: a statement
removed as a finding indicating severe preeclampsia. for professionals from the Subcommittee of Professional
and Public Education of the American Heart Association
Council on High Blood Pressure Research. Subcommittee
Eclampsia of Professional and Public Education of the American
Heart Association Council on High Blood Pressure
Eclampsia is defined as the presence of new-onset Research. Hypertension 2005;45:142–61. [PubMed]
grand mal seizures in a woman with preeclampsia. [Full Text] ^
Eclampsia can occur before, during, or after labor. 4. Kuo VS, Koumantakis G, Gallery ED. Proteinuria and its
Other causes of seizures in addition to eclampsia assessment in normal and hypertensive pregnancy. Am J
include a bleeding arteriovenous malformation, rup- Obstet Gynecol 1992;167:723–8. [PubMed] ^
tured aneurysm, or idiopathic seizure disorder. These 5. Wheeler TL 2nd, Blackhurst DW, Dellinger EH, Ramsey PS.
Usage of spot urine protein to creatinine ratios in the
alternative diagnoses may be more likely in cases in evaluation of preeclampsia. Am J Obstet Gynecol 2007;
which new-onset seizures occur after 48–72 hours 196:465.e1–4. [PubMed] [Full Text] ^
postpartum or when seizures occur during use of 6. Homer CS, Brown MA, Mangos G, Davis GK. Non-
antiepileptic therapy with magnesium sulfate. proteinuric pre-eclampsia: a novel risk indicator in
20 ESTABLISHING THE DIAGNOSIS OF PREECLAMPSIA AND ECLAMPSIA
women with gestational hypertension. J Hypertens 2008; 10. MacGillivray I, Rose GA, Rowe B. Blood pressure survey
26: 295–302. [PubMed] ^ in pregnancy. Clin Sci 1969;37:395–407. [PubMed] ^
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Sunesara I, et al. A high LDH to AST ratio helps to differ- Roberts LM, Brown MA. Plasma uric acid remains a
entiate pregnancy-associated thrombotic thrombocyto- marker of poor outcome in hypertensive pregnancy: a
penic purpura (TTP) from HELLP syndrome. J Matern retrospective cohort study. BJOG 2012;119:484–92.
Fetal Neonatal Med 2012;25:1059–63. [PubMed] [Full [PubMed] [Full Text] ^
Text] ^ 12. Thomson AM, Hytten FE, Billewicz WZ. The epidemiology
8. Fox NS, Huang M, Chasen ST. Second-trimester fetal of oedema during pregnancy. J Obstet Gynaecol Br Com-
growth and the risk of poor obstetric and neonatal out- monw 1967;74:1–10. [PubMed] ^
comes. Ultrasound Obstet Gynecol 2008;32:61–5. 13. von Dadelszen P, Payne B, Li J, Ansermino JM, Broughton
[PubMed] [Full Text] ^ Pipkin F, Cote AM, et al. Prediction of adverse maternal
9. Morikawa M, Yamada T, Yamada T, Cho K, Yamada H, outcomes in pre-eclampsia: development and validation
Sakuragi N, et al. Pregnancy outcome of women who de- of the fullPIERS model. PIERS Study Group. Lancet
veloped proteinuria in the absence of hypertension after 2011;377:219–27. [PubMed] [Full Text] ^
mid-gestation. J Perinat Med 2008;36:419–24. [PubMed]
^
CHAPTER
3
Prediction of Preeclampsia
A
great deal of effort has been directed at the preventive approaches and therapeutic interventions
identification of demographic factors, bio- are available or if close follow-up after prediction
chemical analytes, or biophysical findings, demonstrates improved maternal or fetal outcomes.
alone or in combination, to predict early
in pregnancy the later development of preeclampsia.
Epidemiology of and Risk Factors
Evidence relating to the reliability of prediction tests
for preeclampsia is reviewed as follows. for Preeclampsia
A number of clinical circumstances, summarized in
Box 3-1, increase the risk of preeclampsia (3). The risk
Definition of an Ideal Predictive Test
of preeclampsia is increased twofold to fourfold if a
The utility of a predictive test will depend on the over- patient has a first-degree relative with a medical his-
all prevalence of the disease (1). Although sensitivity tory of the disorder and is increased sevenfold if pre-
and specificity have been used to assess how well a test eclampsia complicated a previous pregnancy (3, 4).
is able to identify patients with a disease, they do not Multiple gestation is an additional risk factor; triplet
focus on the meaning of a single test result. In this gestation is a greater risk than twin gestation. Classic
respect, the best way to assess the value of a specific cardiovascular risk factors also are associated with
test result is by use of likelihood ratios (2). The likeli- increased probability of preeclampsia, as are maternal
hood ratio (LR) of a particular test result is the propor- age older than 40 years, diabetes, obesity, and preex-
tion of participants with the target condition who have isting hypertension. The increased prevalence of
a positive test result relative to the proportion without chronic hypertension and other comorbid medical ill-
the target condition who have the same test result. nesses in women older than 35 years may explain the
Because the incidence of preeclampsia is relatively increased frequency of preeclampsia among older
low, screening tests with positive test results require women. Racial differences in the incidence and sever-
high LRs to adequately predict the disease’s probability of preeclampsia have been difficult to assess
ity, and tests with negative results require low LRs to because of confounding by socioeconomic and cultural
confidently exclude the disorder. Thus, useful predic- factors. Nonetheless, it is important to remember that
tion for preeclampsia would require a high LR (greater most cases of preeclampsia occur in healthy nullipa-
than 10) for a positive test as well as a low LR for a rous women with no other obvious risks.
negative result (less than 0.2). Even the most reliable Attempts to predict preeclampsia during early preg-
prediction test will only have clinical utility if effective nancy using clinical risk factors have revealed modest
21
22 PREDICTION OF PREECLAMPSIA
Prediction of Preeclampsia Using

Biomarkers
BOX 3-1. Risk Factors for Preeclampsia ^
Biomarkers for the prediction of preeclampsia are inte-
• Primiparity gral to disease stratification and targeted therapy (1).
• Previous preeclamptic pregnancy Results from mechanistic studies not only have pro-
• Chronic hypertension or chronic renal disease or both vided insights into the pathogenesis of the disease, but
• History of thrombophilia also have created opportunities to study circulating
• Multifetal pregnancy and urinary biomarkers to predict the disease (8).
• In vitro fertilization
• Family history of preeclampsia Angiogenesis-Related Biomarkers
• Type I diabetes mellitus or type II diabetes mellitus Alterations in a number of circulating antiangiogenic
• Obesity proteins (soluble fms-like tyrosine kinase 1 [sFlt-1]
• Systemic lupus erythematosus and soluble endoglin) and proangiogenic proteins
• Advanced maternal age (older than 40 years) (placenta growth factor [PlGF] and vascular endothe-
lial growth factor [VEGF]) have been evaluated as
potential biomarkers for use in preeclampsia (8).
Because alterations in concentrations of sFlt-1, PlGF,
and soluble endoglin in the maternal circulation pre-
predictive values, with detection of 37% of those who cede the clinical onset of preeclampsia by several
developed early-onset preeclampsia and 29% who weeks to months, their predictive potential has been
developed late-onset preeclampsia, with false-positive evaluated. Many of the studies focused on sFlt-1, an
rates of 5% (5). A study, which used an algorithm that antiangiogenic protein, as a potential predictor of
included known risk factors for preeclampsia in nullip- early-onset preeclampsia (9). Examining odds ratios,
arous women, detected 37% of women who devel- sensitivity, and specificity for various sFlt-1 cutoff val-
oped preeclampsia with a false-positive rate of 10% ues in different trimesters led to the conclusion that
(positive LR = 3.6) (6). the higher the sFlt-1 concentration, the more predic-
tive it is of early-onset preeclampsia (1). However,
because sFlt-1 is altered only 4–5 weeks before the
Prediction of Preeclampsia Using
onset of clinical symptoms, it is not useful when used
Uterine Artery Doppler Velocimetry alone as a screening test earlier in gestation. In contrast,
The utility of uterine artery Doppler studies to predict PlGF concentrations begin to decrease 9–11 weeks
preeclampsia has been extensively studied (7). before the appearance of hypertension and protein-
Increased resistance to flow within the uterine arter- uria, which accelerates during the 5 weeks before the
ies results in an abnormal waveform pattern, repre- onset of disease (10). There are several studies evalu-
sented by either an increased resistance or pulsatility ating first-trimester use of PlGF that reveal, at most,
indices or by the persistence of a unilateral or bilateral modest predictive values for early-onset preeclampsia.
diastolic notch (1). In general, uterine artery Doppler However, combining PlGF concentrations with other
studies are better at predicting early preeclampsia than biochemical markers, uterine artery Doppler studies,
term preeclampsia (7). Several studies have assessed or both, substantially improves the predictive value.
the predictive value for early-onset preeclampsia and One study evaluated 7,797 women with singleton
have noted positive LRs that ranged from 5.0 to 20 and pregnancies during 11–13 weeks of gestation (11).
negative LRs that ranged from 0.1 to 0.8 (7). It appears An algorithm developed by logistic regression that
that irrespective of the index or combinations of indices combined the logs of uterine pulsatility index, mean
used, uterine artery Doppler studies alone have a low arterial pressure, pregnancy-associated plasma pro-
predictive value for the development of early-onset tein A (PAPP-A), serum-free PlGF, body mass index,
preeclampsia. Major pitfalls with this technique are the and presence of nulliparity or previous preeclampsia
wide variability (likely related to operator expertise) revealed the following: at a 5% false-positive rate,
and poor predictive accuracy. A review of the literature the detection rate for early preeclampsia was 93.1%;
found no randomized clinical trials that demonstrated more impressively, the positive LR was 16.5 and the
improved maternal outcomes or fetal outcomes or both negative LR was 0.06 (11). Although the results of
in patients who have undergone uterine artery Doppler these studies are promising, the task force does not
screening. recommend using this for clinical practice because
PREDICTION OF PREECLAMPSIA 23
evidence that maternal–fetal outcomes are improved lating angiogenic factors also have been evaluated in
by early screening is still lacking. the triage setting in women with suspicion of pre-
Because PlGF is a small protein, it is easily filtered eclampsia and have been found to be of potential use
by the normally functioning kidney; therefore, mea- in identifying subsequent adverse maternal–fetal out-
suring urinary PlGF combined with confirmation by comes (23–25). Among participants who presented
measuring the circulating sFlt-1/PlGF ratio has been preterm (less than 34 weeks of gestation), an sFlt-1/
proposed as another strategy for the prediction of PlGF ratio of 85 or greater had a positive predictive
preterm preeclampsia (12). In one study, researchers value of 86.0% and a positive LR of 12.2 for predicting
measured sFlt-1, PlGF, and soluble endoglin in 1,622 adverse maternal–fetal outcomes occurring within
consecutive pregnant women with singleton gesta- 2 weeks of presentation (24).
tions during early pregnancy and in midtrimester and The greatest utility of these tests would be to rule
found superior performances for the PlGF/soluble out progression of gestational hypertension to pre-
endoglin ratio during midtrimester with sensitivity of eclampsia or adverse outcomes. Angiogenic factors
100% and specificity of 98% for early-onset pre- also have been evaluated for this purpose. In one
eclampsia (positive LR, 57.6; 95% confidence interval, study, among participants who were evaluated in the
37.6–57.6, and negative LR, 0.0; 95% confidence triage unit before 34 weeks of gestation (n=176), a
interval, 0.0–0.3) (13). Other studies that used angio- plasma sFlt-1/PlGF ratio of less than 85 had a negative
genic markers in high-risk populations have found predictive value of 87.3% and a negative LR of 0.29
more modest results (14, 15). None of these findings (24). A total of 16 women had false-negative test
have been validated in an independent cohort. Future results; 10 of them had adverse outcomes that could
studies to evaluate the clinical utility of early predic- not be attributed to preeclampsia. Another study
tion using biomarkers as it relates to preeclampsia- found that a PlGF/sFlt-1 ratio of 0.033 multiples of the
related adverse maternal–fetal outcomes are needed. median had a 93% sensitivity with a negative LR of
0.09 for the identification of patients who presented at
Placental Protein-13 and Other Markers less than 34 weeks of gestation and who gave birth
A few studies have suggested first-trimester circulating within 14 days because of preeclampsia (25). The
levels of placental protein-13 are significantly lower in availability of biomarkers to quickly and accurately
women who go on to develop early-onset preeclamp- assess at initial presentation the risk of progression to
sia and preterm birth (16, 17). Combining first- preeclampsia or to adverse outcomes could greatly aid
trimester placental protein-13 with other predictive in the management of patients with gestational hyper-
markers may further improve predictive performance. tension. Similarly, being able to differentiate pre-
One study suggested that 14 different plasma metabo- eclampsia that would or would not be associated with
lites have robust discriminatory power in identifying adverse outcomes would be useful to guide manage-
preeclampsia at 15 weeks of gestation (18). Larger ment. However, both of these demand high certainty
prospective studies are needed to determine whether (negative predictive value and low negative LRs) that
these novel biomarkers will be valuable for the predic- the patient will not progress to adverse outcomes.
tion of early preeclampsia. Large prospective trials evaluating the clinical utility of
biomarkers in this context are needed before recom-
mendations can be made.
Prediction of Adverse Outcomes in
Patients With Gestational Hypertension
and Preeclampsia Clinical Considerations
Biomarkers also may be useful to evaluate adverse As of 2012, no single test reliably predicts preeclamp-
outcomes in patients who present with gestational sia. Extensive work clearly identifies angiogenic fac-
hypertension or preeclampsia. Uric acid has been tors—especially sFlt-1, PlGF, and soluble endoglin
extensively studied in this setting, and elevated con- early in the second trimester—as likely tools for the
centrations have been suggested as useful in identify- prediction of early-onset preeclampsia; however, this
ing women with gestational hypertension who may requires further investigation (1). Current evidence
progress to preeclampsia, develop adverse maternal– suggests that a combination of these biomarkers along
fetal outcomes, or both (19–21). A recent prospective with uterine artery Doppler studies may provide the
study suggested that uric acid might be an accurate best predictive accuracy for the identification of early-
predictor in this population, with a positive predictive onset preeclampsia (26). It also is important for prac-
value of 91.4% for a cutoff of 5.2 mg/dL (22). Circu- ticing obstetricians to realize that these biomarkers are
24 PREDICTION OF PREECLAMPSIA
not approved by the U.S. Food and Drug Administra- genic factors and implications for later cardiovascular dis-
tion and, therefore, are not available for clinical use. ease. Circulation 2011;123:2856–69. [PubMed] [Full
Text] ^
Standardization of these assays across the various
9. Lam C, Lim KH, Karumanchi SA. Circulating angiogenic
automated platforms and prospective studies that
factors in the pathogenesis and prediction of preeclamp-
demonstrate clinical utility are needed. No evidence sia. Hypertension 2005;46:1077–85. [PubMed] [Full
was located to support the hypothesis that accurate Text] ^
prediction of early-onset preeclampsia can be followed 10. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu
by interventions or close follow-up that improve KF, et al. Circulating angiogenic factors and the risk of-
maternal outcome or fetal outcome or both. The use of preeclampsia. N Engl J Med 2004;350:672–83. [PubMed]
[Full Text] ^
predictors to differentiate women with gestational
11. Poon LC, Kametas NA, Maiz N, Akolekar R, Nicolaides
hypertension who are at risk of progression to pre-
KH. First-trimester prediction of hypertensive disorders
eclampsia or adverse outcomes would be useful. Tests in pregnancy. Hypertension 2009;53:812–8. [PubMed]
for this purpose demand high certainty that outcomes [Full Text] ^
will not be bad and demand rigorous testing for clini- 12. Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF,
cal utility, which has not yet taken place. et al. Urinary placental growth factor and risk of pre-
eclampsia. JAMA 2005;293:77–85. [PubMed] [Full Text]
^
TASK FORCE RECOMMENDATION 13. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O,
Mittal P, Vaisbuch E, et al. A prospective cohort study of
• Screening to predict preeclampsia beyond obtain- the value of maternal plasma concentrations of angio-
ing an appropriate medical history to evaluate for genic and anti-angiogenic factors in early pregnancy and
risk factors is not recommended. midtrimester in the identification of patients destined to
develop preeclampsia. J Matern Fetal Neonatal Med
Quality of evidence: Moderate 2009;22:1021–38. [PubMed] [Full Text] ^
Strength of recommendation: Strong 14. Powers RW, Jeyabalan A, Clifton RG, Van Dorsten P,
Hauth JC, Klebanoff MA, et al. Soluble fms-like tyrosine
kinase 1 (sFlt1), endoglin and placental growth factor
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CHAPTER
4
Prevention of Preeclampsia
S
trategies to prevent preeclampsia have been A follow-up Cochrane meta-analysis of 59 trials
studied extensively over the past 20 years. No with more than 37,000 women found a 17% reduction
intervention to date has been proved unequiv- in risk of preeclampsia associated with use of anti-
ocally effective. platelet agents, with a significant increase in absolute
risk reduction in women who are at high risk of the
disease (7). Concern remains that this finding may
Antiplatelet Agents
reflect publication bias (ie, a small, early, positive trial
It has been hypothesized that alterations in systemic is more likely to be published than a small, negative
prostacyclin–thromboxane balance contribute to pre- trial) or chance findings because the largest trials in
eclampsia. Furthermore, inflammation is increased in the analysis did not show a significant protective
preeclampsia (1). Low-dose aspirin (81 mg or less), an effect. Nevertheless, low-dose aspirin appears to be
antiinflammatory agent that blocks the production of safe with no major adverse effects or evidence of
thromboxanes, has been studied in dozens of trials for increased bleeding or abruptio placentae. The number
the prevention of preeclampsia, both in high-risk of patients needed to treat is determined by the dis-
groups and in healthy nulliparous women. For women ease prevalence and the effect size of the treatment.
at high risk of preeclampsia, several small, early trials For low-risk women with a prevalence of 2%, it would
suggested daily aspirin had a significant protective be necessary to treat 500 women to prevent one case
effect (2, 3). These initially promising findings were of preeclampsia. In contrast, among high-risk women
not confirmed in three large randomized controlled with a prevalence of 20%, it would be necessary to
trials (4–6). All three studies found a nonsignificant treat 50 women to prevent one case of preeclampsia
trend toward a lower incidence of preeclampsia in the (see Table 4-1 for numbers needed to treat based on
aspirin-treated groups with no major adverse effects. A prevalence.) Several high-risk conditions (chronic
subsequent comprehensive meta-analysis of antiplate- hypertension, previous preterm preeclampsia, and dia-
let agents to prevent preeclampsia that included more betes) exhibit this degree of risk. Given the modest but
than 30,000 women from 31 trials at varying risk sta- significant protective effect, low-dose aspirin prophy-
tuses suggested that antiplatelet agents have a modest laxis may be considered as primary prevention for pre-
benefit, with a relative risk (RR) of preeclampsia of eclampsia in women at high baseline risk and, if used,
0.90 (95% confidence interval [CI], 0.84–0.97) for should be initiated in the late first trimester (8).
aspirin-treated participants (7).
27
28 PREVENTION OF PREECLAMPSIA
TABLE 4-1. PARIS number needed-to-treat with sample baseline event rates ^
Sample baseline PARIS relative risk Number needed-to-treat
event rate (95%CI) (95% CI)
Pre-eclampsia 18% 0·90 (0·84–0·97) 56 (35–185)
6% 167 (104–556)
2% 500 (313–1667)
Preterm <34 weeks 20% 0·90 (0·83–0·98) 50 (29–250)
10% 100 (59–500)
2% 500 (294–2500)
Perinatal death 7% 0·91 (0·81–1·03) 159 (75–476)
4% 278 (132–833)
1% 1111 (526–3333)
Small for gestational age baby 15% 0·90 (0·81–1·01) 67 (35–667)
10% 100 (53–1000)
1% 1000 (526–10 000)
Pregnancy with serious adverse outcome 25% 0·90 (0·85–0·96) 40 (27–100)
15% 67 (44–167)
7% 143 (95–357)
Reprinted from The Lancet, Vol. 369, Askie LM, Duley L, Henderson-Smart DJ, Stewart LA, Antiplatelet agents for prevention of pre-
eclampsia: a meta-analysis of individual patient data, PARIS Collaborative Group. 1791–98, Copyright 2007, with Permission from Elsevier.
various populations (9–12). A recent Cochrane sys-

tematic review of 15 randomized controlled trials
• For women with a medical history of early-onset pre- (20,748 women) that used vitamin C and vitamin E
eclampsia and preterm delivery at less than 34 0/7 for the prevention of preeclampsia found no benefit
weeks of gestation or preeclampsia in more than (RR, 0.94; 95% CI, 0.82–1.07) (13).
one prior pregnancy, initiating the administration
of daily low-dose (60–80 mg) aspirin beginning in
the late first trimester is suggested.*
Quality of evidence: Moderate • The administration of vitamin C or vitamin E to
Strength of recommendation: Qualified prevent preeclampsia is not recommended.
*Meta-analysis of more than 30,000 women in randomized Quality of evidence: High

trials of aspirin to prevent preeclampsia indicates a small Strength of recommendation: Strong
reduction in the incidence and morbidity of preeclampsia
fetal effects cannot be excluded. The number of women to Other Nutritional Interventions
treat to have a therapeutic effect is determined by preva-
lence. In view of maternal safety, a discussion of the use of Several studies have examined the effectiveness of cal-
aspirin in light of individual risk is justified. cium supplementation to prevent preeclampsia. In a
large U.S. cohort of healthy primiparous women, calci-
um supplementation did not reduce incidence of pre-
Antioxidant Supplementation With
eclampsia (14). However, calcium supplementation
Vitamin C and Vitamin E might be expected to be of greater benefit in women
Because oxidative stress appears to contribute to the who have a nutritional deficiency of calcium. A
pathogenesis of preeclampsia, it has been suggested meta-analysis of 13 trials that involved 15,730 women
that antioxidants may prevent preeclampsia. Despite reported a significant reduction in preeclampsia risk
initial enthusiasm for using a combination of the anti- with calcium supplementation (RR, 0.45; 95% CI,
oxidants vitamin C and vitamin E for this purpose, 0.31–0.65), with the greatest effect among women
large randomized, placebo-controlled trials conducted with low baseline calcium intake (RR, 0.36; 95% CI,
during pregnancy found that supplementation with 0.20–0.65) (15). Thus, calcium supplementation (1.5–
vitamin C and vitamin E did not reduce the risk of pre- 2 g) may be considered in pregnant women from pop-
eclampsia or improve maternal and fetal outcomes in ulations with low baseline calcium intake (less than
PREVENTION OF PREECLAMPSIA 29
600 mg/d). This is not the case in the United States or randomized controlled clinical trials are needed that
other developed countries. can evaluate whether moderate exercise can reverse
Vitamin D deficiency has been suggested as a factor markers of endothelial dysfunction and prevent
contributing to preeclampsia (16); however, whether adverse pregnancy outcomes.
supplementation with vitamin D is helpful is unknown.
Evidence is insufficient for reliable conclusions with
regard to other nutritional interventions, such as fish
oil or garlic, which have been used to prevent pre- • It is suggested that bed rest or the restriction of
eclampsia. Protein and calorie restriction for obese other physical activity not be used for the primary
pregnant women shows no reduction in the risk of pre- prevention of preeclampsia and its complications.
eclampsia or gestational hypertension and may Quality of evidence: Low
increase the risk of intrauterine growth restriction and Strength of recommendation: Qualified
should be avoided.
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arly, meta-analysis of approximately 7,000 random- nancy-induced hypertension and lower the ratio of
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• It is suggested that dietary salt not be restricted gravidae. Lancet 1986;1:1–3. [PubMed] ^
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vention and treatment of pre-eclampsia among 9364
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343:619–29. [PubMed] ^
Although bed rest has been suggested as a preventive
6. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M,
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min C and vitamin E in pregnant women at risk for
uated the utility of modest exercise for the prevention pre-eclampsia(VIP trial): randomised placebo-controlled
of preeclampsia, but the CIs were too wide to make trial. Vitamins in Pre-eclampsia (VIP) Trial Consortium.
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30 PREVENTION OF PREECLAMPSIA
10. Roberts JM, Myatt L, Spong CY, Thom EA, Hauth JC, 17. Duley L, Henderson-Smart DJ, Meher S. Altered dietary
Leveno KJ, et al. Vitamins C and E to prevent complications salt for preventing pre-eclampsia, and its complications.
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Shriver National Institute of Child Health and Human Art. No.: CD005548. DOI: 10.1002/14651858.CD005548.
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N Engl J Med 2010;362:1282–91. [PubMed] [Full Text] 18. Collins R, Yusuf S, Peto R. Overview of randomised trials
^ of diuretics in pregnancy. Br Med J (Clin Res Ed)
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^ preventing pre-eclampsia and its complications. Cochrane
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CHAPTER
5
Management of Preeclampsia and
HELLP Syndrome
^49 ^83
T
he first consideration in the management of • 34 0/7 weeks or more of gestation, plus any of the
women with mild gestational hypertension following:
or preeclampsia without severe features is – Progressive labor or rupture of membranes
always safety of the woman and her fetus. – Ultrasonographic estimate of fetal weight less
The second is delivery of a mature newborn that will than fifth percentile
not require intensive or prolonged neonatal care (1). – Oligohydramnios (persistent amniotic fluid index
Once the diagnosis of mild gestational hypertension less than 5 cm)
or preeclampsia without severe features is established, – Persistent BPP 6/10 or less (normal 8/10–
subsequent management will depend on the results of 10/10)
maternal and fetal evaluation, gestational age, pres-
ence of labor or rupture of membranes, vaginal bleed- For women who have not given birth, management
ing, and wishes of the woman (Fig. 5-1). can occur in the hospital or at home with restricted
activity and serial maternal and fetal evaluation.
Antepartum Management
Continued Evaluation
Initial Evaluation Continued evaluation of women who have not given
At time of diagnosis, all women should have a com- birth who have mild gestational hypertension or pre-
plete blood count (CBC) with platelet count and assess- eclampsia without severe features consists of the fol-
ment of serum creatinine and liver enzyme levels, be lowing:
evaluated for urine protein (24-hour collection or
• Fetal evaluation includes daily kick count, ultraso-
protein/creatinine ratio), and be asked about symptoms
nography to determine fetal growth every 3 weeks,
of severe preeclampsia. Fetal evaluation should include
and amniotic fluid volume assessment at least
ultrasonographic evaluation for estimated fetal weight
once weekly. In addition, an NST once weekly for
and amniotic fluid index (calculated in centimeters),
patients with gestational hypertension and an NST
nonstress test (NST), and biophysical profile (BPP) if
twice weekly for patients with preeclampsia with-
NST is nonreactive. Best practice indicates hospitaliza-
out severe features is suggested. The presence of
tion and delivery for one or more of the following:
a nonreactive NST requires BPP testing. The fre-
• 37 0/7 weeks or more of gestation quency of these tests may be modified based on
• Suspected abruptio placentae subsequent clinical findings.
31
32 MANAGEMENT OF PREECLAMPSIA AND HELLP SYNDROME
Maternal and Fetal Findings
• 37 0/7 weeks or more of gestation

or
• 34 0/7 weeks or more of gestation with:
– Labor or rupture of membranes
Yes
– Abnormal maternal–fetal test results • Delivery
– Ultrasonographic estimate of fetal • Prostaglandins if needed for induction
weight less than fifth percentile
– Suspected abruptio placentae
No
• Less than 37 0/7 weeks of gestation

• Inpatient or outpatient management
Maternal evaluation: twice weekly
Fetal evaluation
– With preeclampsia: twice weekly
nonstress test
– With gestational hypertension:
weekly nonstress test
• 37 0/7 weeks or more of gestation Yes

• Worsening maternal or fetal condition*
• Labor or premature rupture of membranes
FIGURE 5-1. Management of mild gestational hypertension or preeclampsia without severe features. ^
• At the time of office or clinic visit for antenatal test- • Patients are instructed to have a regular diet with
ing, blood pressure (BP) is to be assessed. In patients no salt restriction.
with gestational hypertension, an additional BP de-
• At the time of diagnosis and at each subsequent
termination should be performed in addition to
visit, women are instructed to report symptoms of
that obtained at the weekly NST. This additional BP
severe preeclampsia (severe headaches, visual
determination may be performed in the office or changes, epigastric pain, and shortness of breath).
at home. Further, women with gestational hyper- They also are advised to immediately come to the
tension are to be evaluated for proteinuria at each hospital or office if they develop persistent symp-
antenatal visit, but following the diagnosis of pre- toms, abdominal pain, contractions, vaginal spot-
eclampsia, additional evaluation of proteinuria is ting, rupture of membranes, or decreased fetal
no longer necessary. movements.
• Maternal laboratory evaluation includes a CBC and • During management outside of the hospital, the
liver enzyme and serum creatinine level assess- onset of decreased fetal movement or abnormal
ment at least once a week. The frequency of these fundal height growth (less than 3 cm of what is
tests may be modified based on subsequent clini- expected for gestational age) requires prompt
cal findings. fetal testing with NST and estimation of amniotic
MANAGEMENT OF PREECLAMPSIA AND HELLP SYNDROME 33
fluid volume. The development of new signs or [CI], 0.41–0.61) but no effect on the development of
symptoms of severe preeclampsia or severe or progression to preeclampsia (RR, 0.97; 95% CI,
hypertension (systolic BP of 160 mm Hg or higher 0.83–1.13), eclampsia, pulmonary edema, fetal or
or diastolic BP of 110 mm Hg or higher on repeat neonatal death (RR, 0.73; 95% CI, 0.50–10.8),
measurements) or evidence of fetal growth preterm birth (RR, 1.02; 95% CI, 0.89–1.16), or
restriction require immediate hospitalization. In small-for-gestational-age infants (RR, 1.04; 95% CI,
addition, an increased concentration of liver 0.84–1.27) (7). Of 29 trials that evaluated oral
enzymes or thrombocytopenia requires hospital- β-blockers, these agents were found to be associated
ization. with a decrease in risk of severe hypertension (RR,
0.37; 95% CI, 0.26–0.53) but with an increase in the
In women with mild gestational hypertension, the
rate of small-for-gestational-age infants (RR, 1.36;
progression to severe gestational hypertension or pre-
95% CI, 1.02–1.82) (7). These reviews concluded
eclampsia often develops within 1–3 weeks after diag-
that there was insufficient evidence that treatment of
nosis, whereas in women with preeclampsia without
nonsevere hypertension improves maternal and neo-
severe features, the progression to severe preeclamp-
natal outcomes (4, 7). The National Institute for
sia could happen within days (2).
Health and Clinical Excellence guidelines recom-
mended treatment at BP levels at 150 mm Hg systolic
TASK FORCE RECOMMENDATIONS or 100 mm Hg diastolic, or both (8). Given the rarity
• The close monitoring of women with gestational of cerebral hemorrhage and congestive heart failure
hypertension or preeclampsia without severe fea- and their lack of association with gestational hyper-
tures with serial assessment of maternal symptoms tension, antihypertensive therapy for this outcome is
and fetal movement (daily by the woman) and not beneficial in patients with mild to moderate ges-
serial measurements of BP (twice weekly), and tational hypertension, and treatment exposes the
assessment of platelet counts and liver enzymes woman and her fetus to potentially harmful medica-
(weekly) is suggested. tions without clear evidence of benefit (9, 10).
In addition, concern exists that reducing maternal
Quality of evidence: Moderate BP may compromise blood flow to the fetoplacental
Strength of recommendation: Qualified unit (11).
• For women with gestational hypertension, monitor-
ing at least once weekly with proteinuria assess- TASK FORCE RECOMMENDATION
ment in the office and with an additional weekly
measurement of BP at home or in the office is sug- • For women with mild gestational hypertension or
gested. preeclampsia with a persistent BP of less than 160
mm Hg systolic or 110 mm Hg diastolic, it is sug-
gested that antihypertensive medications not be
administered.
Antihypertensive Therapy Quality of evidence: Moderate
Antihypertensive therapy is used to prevent severe Strength of recommendation: Qualified
gestational hypertension and maternal hemorrhagic
strokes. Overall, there is no consensus regarding the Bed Rest
management of nonsevere hypertension; prior trials Complete or partial bed rest has been recommended
have not been designed to define the maternal and to improve pregnancy outcome in women with gesta-
perinatal benefits and risks. Therapy may decrease tional hypertension or preeclampsia without severe
progression to severe hypertension but also may be features. However, a Cochrane review of four random-
associated with impairment of fetal growth (3–6). A ized trials that compared bed rest with no rest in preg-
recent systematic review of 46 trials (4,282 women) nant women with mild hypertension found insufficient
evaluated BP control in women with mild to moder- evidence to provide guidance for clinical practice,
ate hypertension (4, 6). The authors concluded that it suggesting that bed rest should not routinely be
is unclear whether antihypertensive therapy is worth- recommended for management of hypertension in
while. In trials that compared therapy with placebo, pregnancy (12). In addition, prolonged bed rest for
the risk of developing severe hypertension was cut in the duration of pregnancy increases the risk of throm-
half (risk ratio [RR], 0.50; 95% confidence interval boembolism.
risks associated with expectant management include

the development of severe hypertension (10–15%),
• For women with gestational hypertension or preeclampsia (0.2–0.5%), HELLP (hemolysis, elevated
eclampsia without severe features, it is suggested liver enzymes, and low platelet count) syndrome
that strict bed rest not be prescribed.*† (1–2%), abruptio placentae (0.5–2%), fetal growth
Quality of evidence: Low restriction (10–12%), and fetal death (0.2–0.5%)
Strength of recommendation: Qualified (15). However, immediate delivery is associated with
increased rates of admission to the neonatal intensive
*The task force acknowledged that there may be situations
care unit, neonatal respiratory complications, and a
in which different levels of rest, either at home or in the
hospital, may be indicated for individual women. The slight increase in neonatal death compared with
previous recommendations do not cover advice regarding infants born at or beyond 37 0/7 weeks of gestation.
overall physical activity and manual or office work. Therefore, considering the risk–benefit ratio between
†
Women may need to be hospitalized for reasons other than the two management plans, available retrospective
bed rest, such as for maternal and fetal surveillance. The data suggest that the balance should be in favor of
task force agreed that hospitalization for maternal and fetal
continued monitoring and delivery to 37 0/7 weeks of
surveillance is resource intensive and should be considered
as a priority for research and future recommendations. gestation in the absence of abnormal fetal testing or
other severe conditions (eg, premature rupture of
Fetal Testing membranes, preterm labor, or vaginal bleeding) (15).
Maternal hypertension or preeclampsia is a known risk
factor for perinatal death and is a common indication TASK FORCE RECOMMENDATION
for antenatal testing. Limited to no data exist regard-
ing when to start fetal testing, the frequency of testing, • For women with mild gestational hypertension or
and which test to use in the absence of fetal growth preeclampsia without severe features and no indi-
restriction (13). In the absence of randomized trials cation for delivery at less than 37 0/7 weeks of
comparing testing versus no testing, it remains unclear gestation, expectant management with maternal
whether antenatal fetal testing improves outcome in and fetal monitoring is suggested.
these pregnancies (14). Quality of evidence: Low
TASK FORCE RECOMMENDATIONS In women with mild gestational hypertension or
• For women with preeclampsia without severe fea- preeclampsia without severe features, a large multi-
tures, use of ultrasonography to assess fetal growth center trial from the Netherlands was conducted,
and antenatal testing to assess fetal status is sug- which included 756 women with singleton gestations
gested. at 36–41 6/7 weeks of gestation who were allocated
to induction of labor or expectant monitoring (16).
The primary outcome was a composite of adverse
maternal outcome (new-onset severe preeclampsia,
• If evidence of fetal growth restriction is found in HELLP syndrome, eclampsia, pulmonary edema, or
women with preeclampsia, fetoplacental assess- abruptio placentae). Secondary outcomes were neo-
ment that includes umbilical artery Doppler veloci- natal morbidities and rate of cesarean delivery. Induc-
metry as an adjunct antenatal test is recommended. tion of labor was associated with a significant
Quality of evidence: Moderate reduction in composite adverse maternal outcome
Strength of the recommendation: Strong (RR, 0.71; 95% CI, 0.59–0.86) but no differences in
rates of neonatal complications or cesarean delivery.
Intrapartum Management
Timing of Delivery
In women with mild gestational hypertension or pre- • For women with mild gestational hypertension or
eclampsia without severe features between 34 0/7 preeclampsia without severe features at or beyond
weeks of gestation and 37 0/7 weeks of gestation, 37 0/7 weeks of gestation, delivery rather than
there are no randomized controlled trials that indicate continued observation is suggested.
that expectant management will either improve peri- Quality of evidence: Moderate
natal outcomes or increase maternal or fetal risks. The Strength of recommendation: Qualified
Magnesium Sulfate Prophylaxis Antihypertensive Drugs to Treat Severe

There are only two double-blind, placebo controlled Hypertension in Pregnancy
trials that have evaluated the use of magnesium sul- The objectives of treating severe hypertension are to
fate in women with preeclampsia without severe fea- prevent potential cardiovascular (congestive heart fail-
tures (17, 18). No instances of eclampsia occurred ure and myocardial ischemia), renal (renal injury or
among 181 women assigned to placebo, and no dif- failure), or cerebrovascular (ischemic or hemorrhagic
ferences occurred in the percentage of women who stroke) complications related to uncontrolled severe
progressed to severe preeclampsia (12.5% in magne- hypertension. No randomized trials in pregnancy
sium group versus 13.8% in the placebo group; RR, could be identified to determine the level of hyperten-
0.90; 95% CI, 0.52–1.54). However, the number of sion to treat to prevent these complications. Data from
women enrolled in these trials is too limited to draw case series—as well as from developing countries
any valid conclusions (17, 18). Based on a rate of where antihypertensive medications were not used in
eclampsia of 0.5%, and assuming a 50% reduction women with severe gestational hypertension or severe
by magnesium sulfate (0.25% rate) (a = .05 and preeclampsia—reveal increased rates of heart failure,
β = 0.2) approximately 10,000 women would need to pulmonary edema, and death. These life-threatening
be enrolled in each group to find a significant reduc- maternal complications justify recommending the use
tion in eclampsia in women with preeclampsia with- of medications to lower BP to a safe range even though
out severe features treated with magnesium sulfate the magnitude of this risk is unknown.
(17). The number of women necessary to be studied Several randomized trials compared different anti-
to address serious maternal morbidity other than hypertensive drugs in pregnancy. In these trials, paren-
eclampsia is even higher (18). teral hydralazine was compared with labetalol or oral
Although the universal use of magnesium sulfate nifedipine. An updated Cochrane systematic review of
therapy in preeclampsia without severe features is 35 trials that involved 3,573 women found no signifi-
not recommended, certain signs and symptoms cant differences regarding either efficacy or safety
(headache, altered mental state, blurred vision, sco- between hydralazine and labetalol, or between hydral-
tomata, clonus, and right upper quadrant abdominal azine and any calcium channel blocker (19). The
pain) have traditionally been considered as premoni- results of these trials suggest that hydralazine, labeta-
tory to seizures and should be considered in the lol, or oral nifedipine can be used to treat acute severe
choice for initiation of magnesium sulfate therapy. hypertension in pregnancy as long as the medical pro-
Because the clinical course of women with pre- vider is familiar with the drug to be used, including
eclampsia without severe features can suddenly dosage, expected time of onset of action, and potential
change during labor, all women with preeclampsia adverse effects and contraindications (19).
without severe features who are in labor must be Theoretical concern exists that the combined use of
monitored closely for early detection of progression nifedipine and magnesium sulfate can result in exces-
to severe disease. This should include monitoring of sive hypotension and neuromuscular blockade. A
BP and maternal symptoms during labor and delivery review on the subject concluded that the combined use
as well as immediately postpartum. Magnesium sul- of these drugs does not increase such risks; however,
fate therapy should then be initiated if there is pro- this recommendation was based on limited data (20).
gression to severe disease. In women requiring antihypertensive medications
for severe hypertension, the choice and route of
administration of drugs should be based primarily on
the physician’s familiarity and experience, adverse
• For women with preeclampsia with systolic BP of effects and contraindications to the prescribed drug,
less than 160 mm Hg and a diastolic BP of less than local availability, and cost.
110 mm Hg and no maternal symptoms, it is sug-
gested that magnesium sulfate not be administered
universally for the prevention of eclampsia.
Quality of evidence: Low • For women with preeclampsia with severe hyperten-
Strength of recommendation: Qualified sion during pregnancy (sustained systolic BP of at
least 160 mm Hg or diastolic BP of at least 110 mm
Hg), the use of antihypertensive therapy is recom-
mended.
Severe Preeclampsia ery (7.1 days versus 1.3 days; P<.05) and gestational
age at delivery (223 days versus 221 days; P<.05)
Severe preeclampsia can result in both acute and long-
were both greater with expectant management,
term complications for both the woman and her new-
whereas total neonatal complications were reduced
born (1, 4, 21–23). Maternal complications of severe
(33% versus 75%; P<.05) compared with planned
preeclampsia include pulmonary edema, myocardial
delivery. Another group of researchers studied 95
infarction, stroke, acute respiratory distress syndrome,
women with severe preeclampsia and no concurrent
coagulopathy, severe renal failure, and retinal injury.
medical (renal disease, type 1 diabetes mellitus, or
These complications are more likely to occur in the
connective tissue disease) or obstetric (vaginal bleed-
presence of preexistent medical disorders and with
ing, premature rupture of membranes, multifetal ges-
acute maternal organ dysfunction related to pre-
tation, or preterm labor) complications at 28–32
eclampsia (1, 21–23). Fetal and newborn complica-
weeks of gestation (25). Those randomized to receive
tions of severe preeclampsia result from exposure to
expectant management gave birth at a more advanced
uteroplacental insufficiency or from preterm birth, or
gestational age (32.9 weeks of gestation versus 30.8
both (1, 21–23).
weeks of gestation; P=.01) and had newborns who
The clinical course of severe preeclampsia is often
required less frequent neonatal intensive care unit
characterized by progressive deterioration of maternal
admission (76% versus 100%; P<.01), had less fre-
and fetal conditions if delivery is not pursued (21–23).
quent respiratory distress syndrome (22.4% versus
Therefore, in the interest of the woman and her fetus,
50%; P=.002), and had less frequent necrotizing
delivery is recommended when gestational age is at or
enterocolitis (0% versus 10.9%; P=.02), but more fre-
beyond 34 0/7 weeks. In addition, prompt delivery is
quent small-for-gestational-age birth weight (30.1
the safest option for the woman and her fetus when
versus 10.9; P=.04). No cases of maternal eclampsia
there is evidence of pulmonary edema, renal failure,
or pulmonary edema were reported in either trial.
abruptio placentae, severe thrombocytopenia, dissem-
Cases of abruptio placentae were similar in frequency
inated intravascular coagulation, persistent cerebral
between the randomized groups in both studies;
symptoms, nonreassuring fetal testing, or fetal demise
HELLP syndrome complicated only two expectantly
irrespective of gestational age in women with severe
managed cases and one aggressively managed case in
preeclampsia at less than 34 0/7 weeks of gestation
the latter study (4.1% versus 2.1%).
(21–23) (Fig. 5-2).
Observational Studies
TASK FORCE RECOMMENDATION Observational studies of expectant management of
severe preeclampsia have varied in their inclusion
• For women with severe preeclampsia at or beyond
criteria and indications for delivery (21–23, 26).
34 0/7 weeks of gestation, and in those with unsta-
Some included only women who remained stable
ble maternal–fetal conditions irrespective of gesta-
after 24 – 48 hours of observation, whereas others
tional age, delivery soon after maternal stabilization
included women expectantly managed from the time
is recommended.
of diagnosis. In one review, maternal outcomes for
Quality of data: Moderate expectant management of severe preeclampsia at less
Strength of recommendation: Strong than 34 weeks of gestation (presented as median per-
centile; interquartile range) included intensive care
Expectant Management unit admission, 27.6 (1.5, 52.6); HELLP syndrome,
Randomized Trials 11.0 (5.3, 17.6); recurrent severe hypertension, 8.5
The task force found only two published randomized (3.3, 27.5); abruptio placentae, 5.1 (2.2, 8.5); pul-
trials of delivery versus expectant management of monary edema, 2.9 (1.4, 4.3); eclampsia, 1.1 (0,
preterm severe preeclampsia (24, 25). One group of 2.0); subcapsular liver hematoma, 0.5 (0.2, 0.7); and
researchers studied 38 women with severe preeclamp- stroke, 0.4 (0, 3.1) (26). Perinatal outcomes in this
sia between 28 weeks of gestation and 34 weeks of study included stillbirth, 2.5 (0, 11.3); neonatal
gestation (24). Eighteen women received antenatal death, 7.3 (5.0, 10.7); perinatal asphyxia, 7.4 (5.0,
corticosteroids for fetal maturation and were then 10.0); and any neonatal complication, 65.9 (39.7,
treated expectantly, with delivery only for specific 75.7) (26). Small-for-gestational-age infants were
maternal or fetal indications. Another 20 patients common (30–50%) after expectant management.
were assigned to receive antenatal corticosteroids Indications for delivery with expectant management
with planned delivery after 48 hours. Latency to deliv- of severe preeclampsia at less than 34 weeks of gesta-
• Observe in labor and delivery for first 24–48 hours

• Corticosteroids, magnesium sulfate prophylaxis, and
antihypertensive medications
• Ultrasonography, monitoring of fetal heart rate, symptoms,
and laboratory tests
Contraindications to continued expectant management

• Eclampsia • Nonviable fetus
Delivery once maternal Yes • Pulmonary edema • Abnormal fetal test results
condition is stable • Disseminated intravascular • Abruptio placentae
coagulation • Intrapartum fetal demise
• Uncontrollable severe
hypertension
Are there additional expectant complications?

• Greater than or equal to 33 5/7 weeks of gestation
• Persistent symptoms
Corticosteroids for fetal Yes • HELLP or partial HELLP syndrome
maturation • Fetal growth restriction (less than fifth percentile)
Delivery after 48 hours • Severe oligohydramnios
• Reversed end-diastolic flow (umbilical artery Doppler studies)
• Significant renal dysfunction
Expectant management
• Facilities with adequate maternal and neonatal intensive
care resources
• Fetal viability–33 6/7 weeks of gestation
• Inpatient only and stop magnesium sulfate
• Daily maternal–fetal tests
• Vital signs, symptoms, and blood tests
• Oral antihypertensive drugs
• Achievement of 34 0/7 weeks of gestation

Yes • New-onset contraindications to expectant management
Delivery
• Abnormal maternal–fetal test results
FIGURE 5-2. Management of severe preeclampsia at less than 34 weeks of gestation. ^

Abbreviation: HELLP, hemolysis, elevated liver enzymes, and low platelet count.
tion were fetal (36%), maternal (40%), or maternal proteinuria (defined as 5 g/24 h or greater), signifi-
and fetal (8.8%) (26). The frequency of these compli- cant pregnancy prolongation occurred, maternal com-
cations, however, is unknown in the absence of plications were not increased, and resolution of renal
expectant management. dysfunction occurred in all women by 3 months after
delivery (29). A second study categorized women with
severe preeclampsia according to the severity of pro-
teinuria as mild (less than 5 g/24 h), severe (5–9.9 g/
• For women with severe preeclampsia at less than 24 h), or massive (more than 10 g/24 h) (30). No dif-
34 0/7 weeks of gestation with stable maternal and ferences in the rates of eclampsia, abruptio placentae,
fetal conditions, it is recommended that continued pulmonary edema, HELLP syndrome, neonatal death,
pregnancy be undertaken only at facilities with or neonatal morbidity were identified between these
adequate maternal and neonatal intensive care groups. Although the amount of proteinuria increases
resources. over time with expectant management, this change is
Quality of evidence: Moderate not predictive of pregnancy prolongation or perinatal
Strength of recommendation: Strong outcomes (29). On the basis of these data, severe pro-
teinuria alone and the degree of change in proteinuria
Corticosteroids for Fetal Lung Maturity should not be considered criteria to avoid or terminate
Although data specific to expectantly managed severe expectant management.
preeclampsia are limited, randomized controlled trials
that involved pregnancies complicated by hyperten- TASK FORCE RECOMMENDATION
sion syndromes have found antenatal corticosteroid
treatment to result in less frequent respiratory distress • For women with preeclampsia, it is suggested that
syndrome (RR, 0.50; 95% CI, 0.35–0.72), neonatal a delivery decision should not be based on the
death (RR, 0.50; 95% CI, 0.29–0.87), and intraven- amount of proteinuria or change in the amount of
tricular hemorrhage (RR, 0.38; 95% CI, 0.17–0.87) proteinuria.
(27). In a single placebo-controlled study of weekly Quality of evidence: Moderate
betamethasone for women with severe preeclampsia Strength of recommendation: Strong
between 26 weeks of gestation and 34 weeks of gesta-
tion, treatment (mean exposure 1.7 doses) reduced Management Before the Limit of Fetal Viability
the frequency of respiratory distress syndrome (RR, Severe preeclampsia that develops near the limit of fetal
0.53; 95% CI, 0.35–0.82) and intraventricular hemor- viability is associated with a high likelihood of peri-
rhage (RR, 0.35; 95% CI, 0.15–0.86), among other natal morbidities and mortality, regardless of expect-
complications (28). If not previously given, and if it is ant management (21–23, 26, 31, 32). However, data
anticipated that there will be time for fetal benefit regarding outcomes with expectant management cat-
from this intervention, antenatal corticosteroid admin- egorized by gestational week at diagnosis are limited.
istration should be considered regardless of a plan for Survival rates of 0/34 (0%), 4/22 (18.2%), and
expectant management. 15/26 (57.7%) have been reported after expectant
management of severe preeclampsia initiated before
TASK FORCE RECOMMENDATION 23 0/7 weeks of gestation, at 23 0/7 weeks of gesta-
tion, and at 24 0/7 weeks of gestation, respectively
• For women with severe preeclampsia receiving (21, 23, 31). Other reports also have suggested rare
expectant management at 34 0/7 weeks or less of survival with expectant management of severe pre-
gestation, the administration of corticosteroids for eclampsia at less than 23–24 weeks of gestation (32).
fetal lung maturity benefit is recommended. Explicit counseling regarding the likelihood of poor
Quality of evidence: High perinatal outcomes—including severe respiratory
Strength of recommendation: Strong distress syndrome, chronic lung disease, and severe
intraventricular hemorrhage—with expectant man-
Severe Proteinuria agement should be provided. This is especially
The presence of severe proteinuria in women with important in the presence of severe fetal growth
severe preeclampsia undergoing expectant manage- restriction at less than 23 0/7 weeks of gestation,
ment is not associated with worse outcomes. In one when the perinatal mortality rate approaches 100%
study of 42 expectantly managed women with severe (31, 32). Further, maternal complications such as
HELLP syndrome, pulmonary edema, and renal fail- nausea, or vomiting; and those who develop preterm
ure must be balanced with poor perinatal outcome. labor or premature rupture of membranes (21, 23).
Maternal indications for delivery
TASK FORCE RECOMMENDATION • Recurrent severe hypertension
• Recurrent symptoms of severe preeclampsia
• For women with severe preeclampsia and before • Progressive renal insufficiency (serum creatinine
fetal viability, delivery after maternal stabilization concentration greater than 1.1 mg/dL or a dou-
is recommended. Expectant management is not bling of the serum creatinine concentration in the
recommended. absence of other renal disease)
Quality of evidence: Moderate • Persistent thrombocytopenia or HELLP syndrome
Strength of recommendation: Strong • Pulmonary edema
• Eclampsia
Maternal and Fetal Monitoring • Suspected abruptio placentae
During expectant management, maternal and fetal • Progressive labor or rupture of membranes
conditions should be frequently monitored as follows: Fetal indications for delivery
Maternal assessment • Gestational age of 34 0/7 weeks
• Vital signs, fluid intake, and urine output should be • Severe fetal growth restriction (ultrasonographic
monitored at least every 8 hours estimate of fetal weight less than the fifth percentile)
• Symptoms of severe preeclampsia (headaches, • Persistent oligohydramnios (maximum vertical
visual changes, retrosternal pain or pressure, short- pocket less than 2 cm)
ness of breath, nausea and vomiting, and epigastric • BPP of 4/10 or less on at least two occasions
pain) should be monitored at least every 8 hours 6 hours apart
• Presence of contractions, rupture of membranes, • Reversed end-diastolic flow on umbilical artery
abdominal pain, or bleeding should be monitored Doppler studies
at least every 8 hours • Recurrent variable or late decelerations during NST
• Laboratory testing (CBC and assessment of platelet • Fetal death
count, liver enzyme, and serum creatinine levels)
should be performed daily. (These tests can then be
spaced to every other day if they remain stable and
the patient remains asymptomatic.) • It is suggested that corticosteroids be administered
and delivery deferred for 48 hours if maternal and
Fetal assessment
fetal conditions remain stable for women with se-
• Kick count and NST with uterine contraction moni-
vere preeclampsia and a viable fetus at 33 6/7
tored daily
weeks or less of gestation with any of the following:
• Biophysical profile twice weekly
• Serial fetal growth should be performed every 2 – preterm premature rupture of membranes
weeks and umbilical artery Doppler studies should – labor
be performed every 2 weeks if fetal growth restric- – low platelet count (less than 100,000/micro-
tion is suspected liter)
– persistently abnormal hepatic enzyme concen-
Indications for Delivery During Expectant trations (twice or more the upper normal val-
Management ues)
In the published studies of preterm severe preeclampsia – fetal growth restriction (less than the fifth per-
managed expectantly, delivery has typically been pur- centile)
sued at approximately 34 weeks of gestation. However, – severe oligohydramnios (amniotic fluid index
deterioration of maternal or fetal conditions before this less than 5 cm)
gestational age is the most common reason for delivery – reversed end-diastolic flow on umbilical artery
(21, 23, 27). Maternal indications for delivery are delin- Doppler studies
eated in Figure 5-2. Delivery should also be considered – new-onset renal dysfunction or increasing renal
for women whose health is declining or who are nonad- dysfunction
herent with ongoing inpatient observation; those devel- Quality of evidence: Moderate
oping persistent epigastric or right upper quadrant pain, Strength of recommendation: Qualified
• It is recommended that corticosteroids be given if oping countries (36). For many years, these were
the fetus is viable and at 33 6/7 weeks or less of treated with several different anticonvulsants, and
gestation, but delivery not be delayed after initial attempts to prevent eclamptic seizures were exercised
maternal stabilization regardless of gestational age sporadically (37).
for women with severe preeclampsia that is compli- Systematic reviews of magnesium sulfate for the
cated further with any of the following: treatment of eclampsia have demonstrated its superi-
– uncontrollable severe hypertension ority to phenytoin and diazepam (38). For women
– eclampsia with eclampsia, magnesium sulfate should be contin-
– pulmonary edema ued for at least 24 hours after the last convulsion. Fur-
– abruptio placentae thermore, a systematic review of six randomized trials
– disseminated intravascular coagulation that included more than 11,000 women demonstrated
– evidence of nonreassurring fetal status that in women with preeclampsia, magnesium de-
– intrapartum fetal demise creases the rate of eclampsia by 50% (RR, 0.41; 95%
CI, 0.29–0.58) (39). In this review, the regimens of
Quality of evidence: Moderate magnesium sulfate used included an intravenous load-
Strength of recommendation: Strong ing dose of 4–6 g followed by a maintenance dose of
1–2 g/h for at least 24 hours. In addition, some studies
Route of Delivery in Preeclampsia used an intramuscular maintenance regimen that is
not used in the United States. Women treated with
When delivery is indicated, vaginal delivery can often magnesium sulfate to prevent or treat eclamptic sei-
be accomplished, but this is less likely with decreasing zures should receive an intravenous loading dose of
gestational age. With labor induction, the likelihood of 4–6 g followed by a maintenance dose of 1–2 g/h con-
cesarean delivery increases with decreasing gestational tinued for at least 24 hours.
age (range, 93–97% at less than 28 weeks of gestation, Several observational and retrospective studies
53–65% at 28–32 weeks of gestation, and 31–38% at found that expectant management of eclampsia to
32–34 weeks of gestation) (23, 33, 34). prolong gestation for fetal benefit is associated with a
substantial increase of maternal and perinatal mor-
TASK FORCE RECOMMENDATION bidity and mortality (40). One retrospective study,
however, found that expectant management of
• For women with preeclampsia, it is suggested that eclampsia (antepartum onset before 34 weeks of ges-
the mode of delivery does not need to be cesarean tation) for 24–48 hours to administer corticosteroids
delivery. The mode of delivery should be deter- for fetal benefit can be undertaken if meticulous
mined by fetal gestational age, fetal presentation, maternal and fetal monitoring remains reassuring
cervical status, and maternal–fetal condition. while continuously infused magnesium sulfate and
Quality of evidence: Moderate antihypertensive agents to prevent severe hyperten-
Strength of recommendation: Qualified sion are administered for maternal stabilization;
however, the safety of such an approach has not been
proved (41). In all other circumstances, there is gen-
Eclampsia
eral agreement that women with eclampsia should
Eclampsia is defined as the presence of new-onset undergo delivery following stabilization. Patients
grand mal seizures in a woman with preeclampsia. with severe preeclampsia undergoing cesarean deliv-
Eclampsia is preceded by a wide range of signs and ery remain at risk of developing eclampsia. The
symptoms, ranging from severe to absent or minimal induction of anesthesia and the stress of delivery may
hypertension, massive to no proteinuria, and promi- reduce their seizure threshold and increase the likeli-
nent to no edema (35). Several clinical symptoms are hood of eclampsia. Discontinuing magnesium sulfate
potentially helpful in predicting impending eclampsia. infusions in the operative suite will not abate the
These include persistent occipital or frontal headaches, potential interactions of magnesium sulfate with
blurred vision, photophobia, epigastric or right upper anesthetic agents and furthermore increases the like-
quadrant pain or both, and altered mental status (35, lihood of a subtherapeutic serum magnesium level in
36). Eclamptic seizures contribute substantially to the recovery room or postpartum suite, placing the
maternal morbidity and mortality, especially in devel- patient at risk of postpartum eclampsia.
with HELLP syndrome. Because a significant fetal

benefit of corticosteroid administration exists for
• For women with eclampsia, the administration of women with severe preeclampsia, similar fetal bene-
parenteral magnesium sulfate is recommended. fit should exist for women with antepartum HELLP
syndrome.
Several observational and retrospective studies
have found that in combination with magnesium sul-
• For women with severe preeclampsia, the adminis- fate therapy and control of severe hypertension, differ-
tration of intrapartum–postpartum magnesium sul- ent regimens of steroids have been associated with a
fate to prevent eclampsia is recommended. major maternal morbidity–related decrease in HELLP
Quality of evidence: High syndrome (44, 45). However, data on maternal bene-
Strength of recommendation: Strong fits of dexamethasone in women with HELLP syn-
drome are conflicting (46, 47). A 2010 Cochrane
• For women with preeclampsia undergoing cesarean meta-analysis of 11 randomized controlled trials eval-
delivery, the continued intraoperative administra- uated the effect of antenatal maternal corticosteroid
tion of parenteral magnesium sulfate to prevent treatment on perinatal outcomes during expectant
eclampsia is recommended. management of HELLP syndrome (48). Among these
Quality of evidence: Moderate trials, only four trials (362 women) reported maternal
Strength of recommendation: Strong death; three trials (278 women) reported maternal
death or severe maternal morbidity; two trials (91
women) reported maternal liver hematoma, rupture,
HELLP Syndrome
or failure; and three trials (297 women) reported
Hemolysis, abnormal liver function tests, and throm- maternal pulmonary edema. This systematic review
bocytopenia have been recognized as complications of found significantly improved maternal platelet counts
preeclampsia and eclampsia for many years. The term when corticosteroids are given, but no evidence of
“HELLP syndrome” is an acronym for the following improvements in maternal mortality or severe mater-
presentation: hemolysis, elevated liver enzymes, and nal morbidities was reported. More robust and pro-
low platelet count (42). perly performed randomized trials are needed to
The development of HELLP syndrome may occur clarify what value this intervention may bring to
antepartum or postpartum (43). The clinical course of HELLP syndrome management.
women with HELLP syndrome is often characterized
by progressive and sometimes sudden deterioration in
maternal and fetal condition. Because the presence of
this syndrome has been associated with increased • For women with HELLP syndrome and before the
rates of maternal morbidity and mortality, many gestational age of fetal viability, it is recommended
authors consider its presence to be an indication for that delivery be undertaken shortly after initial
immediate delivery. A consensus of opinion is that maternal stabilization.
prompt delivery is indicated if the syndrome develops
beyond 34 weeks of gestation or earlier if there is dis-
seminated intravascular coagulation, liver infarction
or hemorrhage, renal failure, pulmonary edema, sus- • For women with HELLP syndrome at 34 0/7 weeks
pected abruptio placentae, or nonreassuring fetal sta- or more of gestation, it is recommended that deliv-
tus (43). Because the management of patients with ery be undertaken soon after initial maternal stabi-
HELLP syndrome requires the availability of neonatal lization.
and obstetric intensive care units and personnel with Quality of evidence: Moderate
special expertise, patients with HELLP syndrome who Strength of recommendation: Strong
are remote from term should receive care at a tertiary
care center (43). • For women with HELLP syndrome from the gesta-
The task force found no randomized trials that tional age of fetal viability to 33 6/7 weeks of ges-
evaluated the benefits versus risks of a short course of tation, it is suggested that delivery be delayed for
corticosteroids for fetal lung maturation in women 24–48 hours if maternal and fetal condition remain
stable to complete a course of corticosteroids for development of an epidural hematoma. The enlarged
fetal benefit.* epidural veins accompanying pregnancy increase the
Quality of evidence: Low risk of puncture of these vessels during needle or
Strength of recommendation: Qualified catheter placement. Risk factors for hematoma
include difficult placement, coagulopathy, and cathe-
*Corticosteroids have been used in randomized controlled
trials to attempt to improve maternal and fetal condition. ter removal (52). The task force found no studies that
In these studies, there was no evidence of benefit to im- examined the safe limit for platelet count and neurax-
prove overall maternal and fetal outcome (although this ial anesthesia. There are numerous case reports of
has been suggested in observational studies). There is evi- epidural placement in patients with low platelet
dence in the randomized trials of improvement of platelet counts (as low as 20,000/microliter). These case
counts with corticosteroid treatment. In clinical settings
in which an improvement in platelet count is considered reports do not establish a safe limit. The American
useful, corticosteroids may be justified. Society of Anesthesiologists has not recommended a
safe limit for the platelet count in parturient women
with preeclampsia, relying on the health care provid-
Anesthetic Considerations er’s judgment following review of the laboratory val-
Hypotension ues (53). A review article of case series and case
Spinal anesthesia results in hypotension secondary to reports on epidural and spinal anesthesia in patients
sympathetic blockade, which decreases uteroplacental with thrombocytopenia concluded that 80,000/
blood flow. The incidence and severity of hypotension microliter is a safe platelet count for the placement of
following spinal anesthesia was compared in parturi- epidural or spinal anesthesia and for the removal of
ent women with severe preeclampsia (65 patients) an epidural catheter. This conclusion by these authors
and women without the disease process (71 patients) is dependent on a stable platelet count and the
(49). Hypotension, defined as a 30% decrease in mean absence of coagulopathy (54).
arterial pressure, was less common in the parturient
women with severe preeclampsia (24.6% versus Magnesium Sulfate
40.8%), with no difference in the severity of the Magnesium sulfate has significant anesthetic implica-
hypotension. tions. It prolongs the duration of nondepolarizing
The task force found no meta-analyses that com- muscle relaxants and has led to practitioners stopping
pared spinal anesthesia with general anesthesia for magnesium sulfate administration during surgical pro-
cesarean delivery in women with severe preeclampsia. cedures. However, because magnesium has a half-life
However, there is one randomized trial that compared of 5 hours, discontinuing the intravenous infusion of
spinal anesthesia with epidural anesthesia for women magnesium sulfate before cesarean delivery minimally
with severe preeclampsia who underwent cesarean reduces magnesium concentration at the time of deliv-
delivery (50). The spinal group consisted of 53 patients, ery and possibly increases the risk of seizure (55).
and 47 patients were in the epidural group. Hypoten- Women with preeclampsia who require cesarean deliv-
sion was defined as a systolic BP less than 100 mm Hg. ery should continue magnesium sulfate infusion
The incidence of hypotension was higher in the spinal during the delivery.
group (51% versus 23%) but was easily treated and of
short duration (less than 1 minute). There were no Invasive Hemodynamic Monitoring
adverse effects on the woman or the neonate. Invasive monitoring allows for the direct measure-
ment of BP as well as cardiac filling pressure. The use
Thrombocytopenia of an arterial catheter for direct measurement of BP is
Thrombocytopenia is the most common hematologic used in parturient women who may require frequent
abnormality in women with preeclampsia. Its inci- arterial specimens for pH and blood gas analysis. It
dence depends on the severity of the disease and the also may be indicated in patients who receive continu-
presence or absence of abruptio placentae. In one ous infusions of potent vasoactive drugs. With proper
survey, a platelet count of less than 150,000/microli- use, the risk of arterial catheterization is low, primarily
ter was found in 50% of parturient women with pre- including infection (dependent on location of arterial
eclampsia and a platelet count of less than 100,000/ catheter, with femoral placement having a greater
microliter in 36% of the women (51). The major risk) and thrombosis (56). There are, however, no spe-
concern with neuraxial anesthesia and analgesia in cific data concerning the risk of arterial catheterization
parturient women with thrombocytopenia is the in the parturient woman.
Placement of a catheter in a central vein for deter- Postpartum Hypertension and

mination of a central venous pressure (CVP) or of a Preeclampsia
pulmonary artery catheter allows for the administra-
tion of medication, improved venous access, and The exact incidence of postpartum hypertension and
hemodynamic monitoring. These monitors may allow preeclampsia is difficult to ascertain because most
for the measurement of filling pressure of the heart women in the postpartum period will not have their
and assessment of vascular resistance, cardiac func- BP checked until the 6-week postpartum visit (61). In
tion, and oxygen uptake and delivery. The correlation addition, most women with hypertension usually are
between CVP and pulmonary artery occlusion pres- asymptomatic, and those with symptoms frequently
sure in preeclampsia is moderate, which limits the are seen and managed in emergency departments.
usefulness of CVP determinations (57). In 30 parturi- Several studies have reported that many women will
ent women with severe preeclampsia, the correlation be hospitalized postpartum because of severe hyper-
coefficient between CVP and pulmonary artery occlu- tension and preeclampsia, and a 2010 large popula-
sion pressure was 0.64, if the patient did not receive tion-based study reported that 0.3% of all postpartum
treatment. Treatment of the disease process reduced visits to emergency departments were due to hyper-
the correlation coefficient to 0.53. This lack of cor- tension and preeclampsia (62). Postpartum hyperten-
relation is further confounded by the lack of data sion and preeclampsia are either secondary to
from randomized controlled trials that demonstrate persistent hypertension or exacerbation of hyperten-
the usefulness of pulmonary artery catheters (58), sion in women with previous gestational hypetension,
but pulmonary artery catheterization is not without preeclampsia, chronic hypertension or because of a
risk (59). Four of the 100 patients who were reviewed new-onset condition (61). In women with preeclamp-
retrospectively had either a venous thrombosis or cel- sia or superimposed preeclampsia, BP usually de-
lulitis. A retrospective case series of patients who creases within 48 hours following delivery, but the BP
received central venous catheters was performed. Of increases again 3–6 days postpartum (61). Several
85 patients, 20 had preeclampsia. A high incidence of studies have emphasized the potential value of educat-
infection (14%) was reported in those parturient ing patients and health care providers to report signs
women who received central venous catheters (60). and symptoms of preeclampsia that commonly pre-
Other complications included superficial and deep cede eclampsia, hypertensive encephalopathy, pulmo-
vein thrombosis, hematoma, ventricular tachycardia, nary edema, or stroke (63–66). However, it remains
and discomfort. unclear whether such reporting will lead to the pre-
vention of eclampsia and adverse maternal outcomes.
Several retrospective studies have found that most
TASK FORCE RECOMMENDATIONS women who presented with eclampsia and stroke in
• For women with preeclampsia who require analge- the postpartum period had these symptoms for hours
sia for labor or anesthesia for cesarean delivery and and days before presentation (63–66). In addition,
with a clinical situation that permits sufficient time many of these symptoms were not considered import-
for establishment of anesthesia, the administration ant by patients or medical providers. The group also
of neuraxial anesthesia (either spinal or epidural believed that many medical providers (nurses, obste-
anesthesia) is recommended. tricians, nurse–midwives, emergency department phy-
sicians, and internists) may not be aware that
preeclampsia and eclampsia can develop up to 4 weeks
postpartum. Health care providers are reminded of the
• For women with severe preeclampsia, it is sug- contribution of nonsteroidal antiinflammatory agents
gested that invasive hemodynamic monitoring not to increase BP. It is suggested that these commonly
be used routinely. used postpartum pain relief agents be replaced by
other analgesics in women with hypertension that per-
sists for more than 1 day postpartum.
• For women in whom gestational hypertension, pre-

eclampsia, or superimposed preeclampsia is diag-
nosed, it is suggested that BP be monitored in the
hospital or that equivalent outpatient surveillance
be performed for at least 72 hours postpartum and Quality of evidence: Low

again 7–10 days after delivery or earlier in women Strength of recommendation: Qualified
with symptoms.
• For women with persistent postpartum hypertension,
Quality of evidence: Moderate BP of 150 mm Hg systolic or higher or 100 mm Hg
Strength of recommendation: Qualified diastolic or higher, on at least two occasions that are
at least 4–6 hours apart, antihypertensive therapy is
• For all women in the postpartum period (not just
suggested. Persistent BP of 160 mm Hg systolic or
women with preeclampsia), it is suggested that dis-
100 mm Hg diastolic or higher should be treated
charge instructions include information about the
within 1 hour.
signs and symptoms of preeclampsia as well as the
importance of prompt reporting of this information Quality of evidence: Low
to their health care providers. Strength of recommendation: Qualified
Strength of recommendation: Qualified References
1. Sibai BM. Diagnosis and management of gestational hyper-
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CHAPTER
6
Management of Women With
Prior Preeclampsia
T
he primary objectives in the management of including the presence of infertility and preexisting
patients with a history of preeclampsia are comorbidities such as obesity, chronic hypertension,
to reduce risk factors for recurrence by opti- renal disease, diabetes mellitus, connective tissue dis-
mizing maternal health before conception, to orders, and acquired thrombophilias. A baseline labo-
detect obstetric complications, and to achieve optimal ratory evaluation could include a complete blood
perinatal outcome during subsequent pregnancy. These count, metabolic profile, and urinalysis. A detailed
objectives can be achieved by formulating a rational obstetric history should include maternal as well as
approach that includes preconception evaluation and perinatal outcomes in the previous pregnancy (2, 3).
counseling, early antenatal care, frequent antepartum Therefore, information should be obtained from
visits to monitor both maternal and fetal well-being, medical records concerning the gestational age at
and timely delivery (see Box 6-1) (1). onset of preeclampsia, maternal complications
(HELLP [hemolysis, elevated liver enzymes, and low
platelet count] syndrome, eclampsia, pulmonary ede-
Preconception Management
ma, renal failure, and abruptio placentae), perinatal
Treatment of a patient with a previous pregnancy com- complications (fetal growth restriction, perinatal mor-
plicated by preeclampsia ideally should begin before bidity, and perinatal death), and laboratory test val-
conception. If the patient is unlikely to have a precon- ues, including those for acquired thrombophilia and
ception visit, this assessment should be conducted at connective tissue disorders as well as placental pathol-
the 6-week postpartum visit, including patient coun- ogy, if available.
seling on risk of preeclampsia recurrence and risk- The status of maternal comorbidities ideally should
modification strategies. Results should be forwarded be optimized before conception. High body mass index
to her primary health care provider. is a risk factor for preeclampsia. Overweight or obese
For women who present before conception, man- patients should be counseled on the potential benefit
agement should include a thorough medical history of of weight loss as a modifiable risk factor. They should
preexisting risk factors and medical conditions report- be referred for nutritional counseling in an attempt to
edly associated with preeclampsia to allow appropri- achieve a healthy body mass index. Weight loss and
ate counseling as to the magnitude of the risk of lifestyle modification also may reduce the likelihood of
preeclampsia in subsequent pregnancy. Also, attention chronic hypertension and type 2 diabetes mellitus.
should be given to the outcome of the previous preg- Because the risk of preeclampsia correlates with the
nancy as well as assessment of maternal risk factors, severity of maternal hypertension and glycemic control,
47
48 MANAGEMENT OF WOMEN WITH PRIOR PREECLAMPSIA
BOX 6-1. Evaluation and Management of Women at Risk of Preeclampsia Recurrence ^

Preconception
• Identify risk factors (ie, type 2 diabetes mellitus, obesity, hypertension, and family history).
• Review outcome of previous pregnancy (abruptio placentae, fetal death, fetal growth restriction,
and gestational age at delivery).
• Perform baseline metabolic profile and urinalysis.
• Optimize maternal health.
• Supplement with folic acid.
First Trimester
• Perform the following:
– Ultrasonography for assessment of gestational age and fetal number
– Baseline metabolic profile and complete blood count
– Baseline urinalysis
• Continue folic acid supplementation.
• Offer first-trimester combined screening.
• For women with prior preeclampsia that led to delivery before 34 weeks of gestation or occurring in
more than one pregnancy, offer low-dose aspirin late in the first trimester and discuss the risks and
benefits of low-dose aspirin with other women.
Second Trimester
• Counsel patient about signs and symptoms of preeclampsia beginning at 20 weeks of gestation;
reinforce this information with printed handouts.
• Monitor for signs and symptoms of preeclampsia.
• Monitor blood pressure at prenatal visits, with nursing contacts, or at home.
• Perform ultrasonography at 18–22 weeks of gestation for fetal anomaly evaluation and to rule out
molar gestation.
• Hospitalize for severe gestational hypertension, severe fetal growth, or recurrent preeclampsia.
Third Trimester
• Monitor for signs and symptoms of preeclampsia.
• Monitor blood pressure at prenatal visits, with nursing contacts, or at home.
• Perform the following as indicated by clinical situation:
– Laboratory testing
– Serial ultrasonography for fetal growth and amniotic fluid assessment
– Umbilical artery Doppler with nonstress test, biophysical profile, or both
• Hospitalize for severe gestational hypertension or recurrent preeclampsia.
Modified from Barton JR, Sibai BM. Prediction and prevention of recurrent preeclampsia. Obstet Gynecol 2008;112:359–72.
women with chronic hypertension, diabetes mellitus, come as well as the effect of pregnancy on these con-
or both, should have their blood pressure, blood glu- ditions. In addition, if the patient is taking medications
cose, or both, optimized before conception. It is for a chronic medical disorder, there should be a
unknown, however, whether amelioration of altered review of these medications with special emphasis on
hemodynamics or optimization of glucose control will those to be avoided, such as angiotensin receptor
definitively reduce the recurrence risk of preeclamp- blockers and some immunosuppressive agents. As for
sia. During the preconception visit, discussion should any woman contemplating conception, folic acid sup-
include the effects of these diseases on pregnancy out- plementation should be prescribed.
MANAGEMENT OF WOMEN WITH PRIOR PREECLAMPSIA 49
Early and frequent prenatal visits are the key for a suc- BOX 6-2. Symptoms of Preeclampsia^
cessful pregnancy outcome in women with preeclamp-
sia in a previous pregnancy, particularly those with • Swelling of the face or hands
early-onset disease. First-trimester ultrasound exam- • Headache that will not go away
ination is essential to determine accurate gestational
• Seeing spots or changes in eyesight
age and establish fetal number. For women with prior
preeclampsia leading to delivery before 34 weeks of • Pain in upper right quadrant or stomach
gestation or occurring in more than one pregnancy, • Nausea or vomiting (in second half of
low-dose aspirin should be offered late in the first tri- pregnancy)
mester, and the risks and benefits of low-dose aspirin
• Sudden weight gain
should be discussed with other women with prior pre-
eclampsia. • Difficulty breathing
During each antepartum visit, the woman should
be monitored closely for signs and symptoms of pre-
eclampsia (Box 6-2). She also should be educated
about symptoms of organ dysfunction and instructed
to report any symptoms, such as severe headache, TASK FORCE RECOMMENDATION
visual change, right upper quadrant or epigastric pain,
nausea and vomiting, and changes in fetal movement. • For women with preeclampsia in a prior pregnancy,
The frequency of antepartum visits may be modified preconception counseling and assessment is sug-
according to the gestational age at the onset of pre- gested.
eclampsia in the previous pregnancy as well as the Quality of evidence: Low
results of maternal and fetal surveillance. Health care Strength of recommendation: Qualified
providers must be cautioned that these recommenda-
tions concerning antepartum management and assess-
References
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randomized studies addressing this subject. Fetal 1. Barton JR, Sibai BM. Prediction and prevention of recur-
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CHAPTER
7
Chronic Hypertension in Pregnancy
and Superimposed Preeclampsia
C
hronic hypertension presents special chal- 110 mm Hg or higher), although a distinction is not
lenges to health care providers. Health made between chronic, gestational, or preeclamptic
care providers must first confirm that blood hypertension. Most women with chronic hypertension
pressure (BP) elevation is not preeclampsia. will have essential (also called primary) hypertension,
Perhaps the greatest challenge is the recognition of but as many as 10% may have underlying renal or
preeclampsia superimposed on chronic hypertension, endocrine disorders (ie, secondary hypertension).
a condition that is commonly associated with adverse The diagnosis of chronic hypertension is easily
maternal and fetal outcomes. established when prepregnancy hypertension is well
documented and in women already receiving antihy-
pertensive medications. Chronic hypertension also is
Chronic Hypertension in Pregnancy
the most likely diagnosis when hypertension is present
Definition and Diagnosis in the first trimester. Difficulties may arise when preg-
Chronic hypertension in pregnancy is defined as hyper- nant women with prepregnancy, undiagnosed hyper-
tension present before pregnancy or before 20 weeks of tension initially present in the second trimester with
gestation (1). Chronic hypertension is present in up to normal BP after having experienced the pregnancy-
5% of pregnant women; rates vary according to the associated physiologic decrease in BP. These women
population studied and the criteria used to establish will have been presumed to be normotensive, and if BP
the diagnosis (1–3). Chronic hypertension complicating increases in the third trimester, they may be errone-
pregnancy is diagnosed when high BP is known to pre- ously diagnosed with either gestational hypertension
date pregnancy. When prepregnancy BP is not known, or, if proteinuria is present, with preeclampsia rather
elevated BP detected before 20 weeks of gestation is than superimposed preeclampsia. Thus, chronic hyper-
often due to chronic hypertension. However, if BP was tension may not be diagnosed until well after delivery.
normal in the first trimester and then increases before In other instances, women with well-documented
20 weeks of gestation, gestational hypertension or early hypertension before pregnancy will demonstrate nor-
preeclampsia also should be considered (4). Hyperten- mal BP throughout the entire pregnancy only to return
sion is defined as either a systolic BP of 140 mm Hg or to prepregnancy hypertensive levels postpartum.
greater, or a diastolic BP of 90 mm Hg or greater, or both.
In pregnancy, BP is categorized as mild to moderate Maternal and Fetal Outcomes
(systolic, 140–159 mm Hg or diastolic, 90–109 mm Hg) Reports of outcomes of pregnancies complicated by
or severe (systolic, 160 mm Hg or higher, diastolic chronic hypertension have not uniformly distinguished
51
52 CHRONIC HYPERTENSION IN PREGNANCY AND SUPERIMPOSED PREECLAMPSIA
between women with superimposed preeclampsia and ated with chronic hypertension in pregnancy is the
those with uncomplicated chronic hypertension. Pre- exposure to antihypertensive medications in utero that
existing hypertension is a recognized risk factor for may cause growth restriction and fetal malformations;
preeclampsia. Superimposed preeclampsia develops in this has been extensively evaluated. Although most
13– 40% of women with chronic hypertension, depend- antihypertensive agents considered safe in pregnancy
ing on diagnostic criteria, etiology (essential versus have not been shown to be associated with fetal mal-
secondary), duration, and the severity of hypertension formations, the question of whether they have an
(5, 6). A major reason for this wide range in incidence effect on growth is still controversial. Clinical trials
is that the definition of superimposed preeclampsia is that evaluated long-term outcomes of exposed off-
used liberally in some studies. spring have been conducted with a limited number of
Women with chronic hypertension who develop agents, primarily, methyldopa.
superimposed preeclampsia have higher rates of
adverse maternal–fetal outcomes, but the indepen- Chronic Hypertension With Superimposed
dent risks associated with uncomplicated chronic Preeclampsia
hypertension are less clear. An analysis of 1,807 Preexisting hypertension is a recognized risk factor for
deliveries in women with chronic hypertension found preeclampsia, and superimposed preeclampsia is asso-
that uncomplicated chronic hypertension was still ciated with considerable maternal–fetal morbidity and
associated with a greater risk of cesarean delivery mortality. Superimposed preeclampsia develops in
(odds ratio [OR], 2.7; 95% confidence interval [CI], 13–40% of women with chronic hypertension, depend-
2.4–3.0) and postpartum hemorrhage (OR, 2.2; ing on diagnostic criteria, etiology (essential versus
95% CI, 1.4–3.7) compared with women without secondary), duration, and the severity of hypertension
hypertension (2). Other adverse maternal outcomes (5, 6). A major reason for this wide range in incidence
in women with chronic hypertension include acceler- is that the definition of superimposed preeclampsia is
ated hypertension with resultant target organ dam- liberally used in some studies.
age (eg, to the heart, brain, and kidneys), although in
the absence of preeclampsia, this is extremely uncom- Preconception Counseling
mon. Women with higher prepregnancy BP or those Preconception counseling should include explanation
with secondary hypertension are at greater risk of of the risks associated with chronic hypertension and
developing severe hypertension during pregnancy. education about the signs and symptoms of preeclamp-
Chronic hypertension is associated with an increased sia. Maternal characteristics that increase the risk of
risk of gestational diabetes (OR, 1.8; 95% CI, 1.4 –2) superimposed preeclampsia include the presence of
(2, 7, 8). This may reflect similar risk factors for both diabetes, obesity, or renal disease; history of pre-
conditions (eg, obesity) as well as similar pathoge- eclampsia, particularly early preeclampsia; severity
netic mechanisms (eg, insulin resistance). The risk of and duration of hypertension before pregnancy; and
abruptio placentae is increased threefold in women presence of secondary hypertension, such as pheo-
with chronic hypertension, although most of the chromocytoma and renovascular hypertension (5, 11).
increased risk is associated with superimposed pre- Medications with known fetal adverse effects often
eclampsia (5, 9, 10). Women with chronic hyperten- prescribed to women with chronic hypertension
sion in pregnancy are more likely to be hospitalized should be discontinued before conception. In particu-
for hypertension (8). lar, angiotensin-converting enzyme (ACE) inhibitors,
Perinatal mortality is higher in pregnancies associ- angiotensin receptor blockers, and mineralocorticoid
ated with chronic hypertension, most of this increased antagonists are contraindicated. Statins, which are
attributable risk is the result of superimposed pre- widely used in individuals with hypertension who also
eclampsia (5, 10). The relative risk of perinatal death have elevated cholesterol, should be avoided because
is reported to be approximately 3.6 in women with there is conflicting evidence about the safety of their
superimposed preeclampsia compared with those with use in pregnancy (12).
uncomplicated chronic hypertension (8). Perinatal
death also is higher in women with uncomplicated
hypertension compared with normotensive controls
(relative risk, 2.3) (8). Initial Evaluation of Women With Known or
Fetal growth restriction is more frequent with Suspected Chronic Hypertension
chronic hypertension and is usually associated with All women with preexisting hypertension should be as-
superimposed preeclampsia (6). Another risk associ- sessed either before pregnancy or early in pregnancy
CHRONIC HYPERTENSION IN PREGNANCY AND SUPERIMPOSED PREECLAMPSIA 53
as outlined by the Seventh Report of the Joint National

Committee on Prevention, Detection, Evaluation, and
Treatment of High Blood Pressure and the National
BOX 7-1. indings Suggestive of
F
Secondary Hypertension ^
High Blood Pressure Education Program guidelines
to rule out secondary (and potentially curable)
Any of the following findings are suggestive
hypertension if appropriate and to seek out evidence
of secondary hypertension:
of target organ damage, unless such evaluations were
previously performed. Baseline concentrations of • Resistant hypertension
serum creatinine, electrolytes, uric acid, liver • Hypokalemia (potassium level less than
enzymes, platelet count, and urine protein (either 3.0 mEq/L)
dipstick test or quantification of urine protein) should
• Elevated serum creatinine level (greater
be documented to use as comparators if superim-
than 1.1 mg/dL)
posed preeclampsia is suspected later in pregnancy.
Glucose tolerance testing should be performed early • Strong family history of kidney disease
in pregnancy for women at risk of gestational diabe-
tes (obese, history of gestational diabetes, or strong
family history of type 2 diabetes mellitus). Good clin-
ical practice suggests performing assessment of left
ventricular function with either echocardiography or TASK FORCE RECOMMENDATION
electrocardiography in women with severe hyperten-
• For women with features suggestive of secondary
sion of long duration (eg, more than 4 years).
hypertension, referral to a physician with expertise
Screening for Secondary Hypertension in treating hypertension to direct the workup is
The most common cause of secondary hypertension suggested.
is chronic kidney disease, and screening is easily Quality of evidence: Low
accomplished with routine blood chemistries and uri- Strength of recommendation: Qualified
nalysis. If proteinuria is detected on urinalysis (1+ or
greater), either a 24-hour urine should be collected Monitoring Blood Pressure
or a protein/creatinine ratio measured in a spot urine Blood pressure is checked monthly in all pregnant
to quantify the level of proteinuria. If evidence of women as part of standard obstetric practice. Although
chronic kidney disease is detected (abnormal urinaly- increased frequency of BP monitoring has not been
sis or elevated serum creatinine), or if there is a evaluated as a strategy for improving pregnancy out-
strong family history of kidney disease, then renal comes, good clinical practice dictates increased moni-
ultrasonography should be performed to rule out toring for women with BP above desired targets.
polycystic kidney disease, the most common genetic Although most superimposed preeclampsia occurs
type of kidney disease. Other causes of secondary near term, it can occur before 24 weeks of gestation,
hypertension that may be present in women of child- and there are even anecdotal reports of its occurrence
bearing age include primary aldosteronism, renovas- before 20 weeks of gestation. Therefore, increased
cular hypertension, pheochromocytoma, and Cushing monitoring may be particularly useful in the second
disease. Suggestive clinical features of secondary half of pregnancy. Because of a considerable body of
hypertension (resistant hypertension, hypokalemia, literature of hypertension in patients who are not
palpitations, lack of family history of hypertension, pregnant, which documents the use of home BP moni-
and age younger than 35 years) warrant consider- toring as an aid to achieving BP targets and monitor-
ation of further diagnostic workup. Case series and ing responses to treatment, the task force suggests this
case reports suggest that particular diagnoses such as approach for pregnant women.
pheochromocytoma and renovascular hypertension
are associated with adverse maternal and fetal out- TASK FORCE RECOMMENDATION
comes, and that if the underlying disorder is treated,
outcomes are improved. There is variability in the • For pregnant women with chronic hypertension
recommended strategies for diagnosing secondary and poorly controlled BP, the use of home BP mon-
hypertension; therefore, the task force suggests refer- itoring is suggested.
ral to a hypertension specialist if secondary hyperten- Quality of evidence: Moderate
sion is a consideration (Box 7-1). Strength of recommendation: Qualified
White coat hypertension, defined as elevated BP primar- exercise, maintaining ideal body weight, moderation
ily in the presence of health care providers, may of alcohol intake, adopting specific diets (such as the
account for up to 10–15% of individuals with office DASH [Dietary Approaches to Stop Hypertension]
hypertension. The prevalence in pregnancy is not diet, a diet with abundant fruits and vegetables, low-
known. Ambulatory BP monitoring is the preferred test fat dairy products, and high fiber), and reducing
to diagnose white coat hypertension in an individual sodium intake. Some of these approaches are either
who is not pregnant. White coat hypertension should not appropriate for pregnancy or have not been eval-
be suspected if BP is higher in the doctor’s office com- uated in the context of pregnancy. Weight loss and
pared with other settings. Failure to recognize white regular aerobic exercise have been shown to be bene-
coat hypertension may result in overtreatment of BP ficial in hypertensive individuals who are not preg-
and unnecessary adverse effects of treatment. nant because it lowers BP and favorably affects weight
and insulin sensitivity (13, 14). Exercise regimens
have been tested in pregnancy, primarily as a strategy
for preventing excessive weight gain (15), and mod-
• For women with suspected white coat hyperten- erate-level physical activity in pregnant women
sion, the use of ambulatory BP monitoring to confirm without medical and obstetric complications is recom-
the diagnosis before the initiation of antihyperten- mended (16). This approach has not been assessed as
sive therapy is suggested. a strategy for lowering BP in pregnant women with
chronic hypertension. Observational research and
small clinical trials suggest that exercise may be bene-
ficial in preventing preeclampsia (16, 17); however,
Treatment these studies have not specified the effect in women
Hypertension is a strong risk factor for stroke, coronary with chronic hypertension. Whether any exercise or
heart disease, congestive heart failure, kidney disease, vigorous aerobic exercise is harmful in women
and death; lowering BP has been conclusively shown with chronic hypertension has not been adequately
to prevent these complications in hypertensive individ- studied.
uals who are not pregnant. The course of vascular
damage and cardiovascular (CV) complications associ-
ated with hypertension is years; stage 1 hypertension
(BP, 140–159 mm Hg, systolic/90–99 mm Hg, diastolic) • It is suggested that weight loss and extremely
is associated with a 40% increased risk of stroke (com- low-sodium diets (less than 100 mEq/d) not be used
pared with age-matched individuals without hyperten- for managing chronic hypertension in pregnancy.
sion), which is usually apparent after 10 years of Quality of evidence: Low
untreated hypertension. In populations of individuals Strength of recommendation: Qualified
who are not pregnant, demonstration of such benefits
requires years of treatment, whereas in pregnancy, the • For women with chronic hypertension who are
goals of treatment are more focused on preventing accustomed to exercising, and in whom BP is well
acute complications of hypertension in the woman and controlled, it is suggested that moderate exercise
maintaining a healthy pregnancy for as long as possi- be continued during pregnancy.
ble. The goals of therapy also include minimizing risks Quality of evidence: Low
to the fetus that are attributable to hypertension, Strength of recommendation: Qualified
vascular disease, and the possible effects of antihyper-
Antihypertensive pharmacologic treatment. Treatment
tensive medications that may alter maternal hemo-
of severe hypertension—The task force found limited
dynamics and reduce uteroplacental perfusion, or that
evidence regarding the precise BP level at which anti-
may cross the placenta and be harmful to the fetus.
hypertensive therapy is indicated during pregnancy in
Preventing long-term maternal CV morbidity and mor-
women with chronic hypertension. Severe elevations
tality is not the primary concern during pregnancy.
in BP are associated with acute maternal cerebrovas-
Nonpharmacologic treatment. Treatment of hyperten- cular and coronary events, although the BP level at
sive individuals who are not pregnant is focused which risk of these adverse events increases is not pre-
on two basic strategies: 1) lowering BP and 2) mini- cisely known and is likely to vary and depend on
mizing additional CV risk factors. Nonpharmacologic comorbidities and other factors such as baseline B P,
approaches that have successfully lowered BP in indi- and rate of increase. In an adult who is not pregnant,
viduals who are not pregnant include regular aerobic antihypertensive therapy is recommended when the
systolic BP is 140 mm Hg or higher or the diastolic BP

is 90 mm Hg or higher, and this approach is supported
by large clinical trials that have clearly demonstrated • For pregnant women with persistent chronic hyper-
benefits of treatment (18). tension with systolic BP of 160 mm Hg or higher or
Few clinical trials have been performed that diastolic BP of 105 mm Hg or higher, antihyperten-
specifically address the optimum level of BP during sive therapy is recommended.
pregnancy in women with preexisting (chronic)
hypertension. Most studies that address this have not
been limited to women with chronic hypertension
and also have included women with gestational Treatment of mild to moderate hypertension—When
hypertension or preeclampsia. Antihypertensive ther- and how to use antihypertensive drugs in women with
apy has been compared with placebo or no therapy, chronic hypertension in pregnancy who do not have
and outcomes assessed in these studies have been severely elevated levels of BP is less clear. To justify the
variable (eg, development of superimposed pre- use of antihypertensive therapy during pregnancy in
eclampsia, progression of hypertension, and fetal women with chronic hypertension with mild to moder-
weight and survival.) A Cochrane systematic review ately elevated BP (systolic BP of 140 mm Hg or higher
of drug treatment for severe hypertension during and less than 160 mm Hg or diastolic BP of 90 mm Hg
pregnancy, which included 35 trials involving 3,573 or higher and less than 110 mm Hg), the maternal
women, included few women with chronic hyperten- benefit and improvement in perinatal outcomes that
sion (19). Drug therapy was instituted when diastolic are due to treatment must outweigh the potential risk
BP levels reached or exceeded 100–110 mm Hg, and of adverse effects on fetal and neonatal safety, includ-
in the majority of the studies, not until the third tri- ing the possibility that pharmacologic reductions in
mester. Women with chronic hypertension were gener- maternal systemic BP result in compromised uteropla-
ally excluded, and if included, no subgroup analysis cental blood flow.
was reported. Thus, there is a paucity of evidence Results from seven placebo-controlled randomized
addressing thresholds for initiating antihypertensive trials that involved 650 women with mild to moderate
drugs in pregnant women with chronic hypertension. chronic hypertension did not demonstrate an improve-
Future placebo-controlled trials addressing the treatment in either maternal or perinatal outcomes with
ment of severe hypertension are unlikely to be init- antihypertensive therapy (6, 20–26). Published in
iated and are not recommended given ethical consid- 2007, a Cochrane systematic review of antihyperten-
erations. Therefore, recommendations for treating sive drug therapy for mild to moderate hypertension in
women with chronic hypertension with severely ele- pregnancy (including all diagnoses) that included 46
vated BP are based on indirect evidence from treating trials (4,282 women) concluded that treatment
pregnant women with new acute onset of severe ges- reduced the risk of developing severe hypertension but
tational hypertension or preeclampsia (19). Given the had no effect on the incidence of preeclampsia (27).
limitations of the data as well as the higher likelihood There were no effects, either positive or negative, on
of outpatient therapy with less frequent BP monitor- perinatal outcomes such as preterm birth, small-for-ges-
ing among pregnant women with chronic hyperten- tational-age (SGA) infants, or fetal death. Of the stud-
sion, treatment is suggested at a lower diastolic BP ies included, only five trials focused exclusively on
threshold of 105 mm Hg. Most of these trials focused women with chronic hypertension. Similar to the over-
on diastolic BP, and specific cutoff values for the treat- all findings, there was a risk reduction in progression
ment of elevated systolic BP are not as well defined; to severe hypertension with treatment in this subgroup
however, if indirect evidence from these trials and the (RR, 0.57; 95% CI, 0.34–0.98) but no effect on perina-
Seventh Report of the Joint National Committee on Pre- tal outcomes (27). No harm was associated with treat-
vention, Detection, Evaluation, and Treatment of High ment. Thus, the currently available evidence suggests
Blood Pressure recommendations for adults who are potential maternal benefit of antihypertensive treat-
not pregnant are applied to pregnant women with ment by reducing the progression to severe hyperten-
chronic hypertension, pharmacologic treatment sion, but no direct fetal benefit or significant
should be used to maintain systolic BP below 160 improvement in perinatal outcomes among women
mm Hg (18, 19). Overly aggressive BP lowering is with chronic hypertension.
discouraged because of concerns that uteroplacental Although the 2007 Cochrane review did not find
blood flow may be compromised at pharmacologi- evidence of fetal harm associated with lowering BP,
cally induced low BP. two meta-regression analyses evaluated the effect of
lowering BP specifically on fetal birth weight; there pertensive therapy is initiated in pregnant women
were seven trials of women with chronic hypertension with chronic hypertension. Two pilot randomized tri-
and 38 trials of women with late-onset hypertension in als that included women with either mild to moderate
pregnancy (27–29). A decrease of 10 mm Hg (mean chronic or gestational hypertension were included in a
arterial pressure) was associated with an average Cochrane review (256 women) that compared “tight”
decrease in infant birth weight of 145 g; however, the (systolic BP less than 130 mm Hg and diastolic BP less
relationship between a decrease in BP and SGA was less than 80 mm Hg) BP with “less tight” (systolic BP less
convincing in women with chronic hypertension, possi- than 140 mm Hg and diastolic BP less than 90 mm Hg)
bly because of the limited power of the overall study. A BP control (34–37). No significant adverse outcomes
2010 case–control analysis of the Quebec Pregnancy were identified, and the evidence was insufficient to
Registry data reported that after adjusting for potential determine optimal BP control needed to improve
confounders, antihypertensive medication use during maternal and fetal or neonatal outcomes.
the second trimester or third trimester of the pregnancy
was significantly associated with an increased risk of
SGA (OR, 1.53; 95% CI, 1.17–1.99) (30). Another
important issue regarding treatment of maternal hyper- • For pregnant women with chronic hypertension
tension during pregnancy is the risk of teratogenicity treated with antihypertensive medication, it is
attributable to drugs. There is conflicting evidence; two suggested that BP levels be maintained between
population-based studies suggest that exposure to any 120 mm Hg systolic and 80 mm Hg diastolic, and
antihypertensive medication may be associated with 160 mm Hg systolic and 105 mm Hg diastolic.
an increased risk of fetal cardiac abnormalities (31, Quality of evidence: Low
32), but these findings were not corroborated by oth- Strength of recommendation: Qualified
ers (30, 33).
Many limitations exist to these population-based Treatment of women receiving antihypertensive
studies, including the small numbers of malformations therapy prior to pregnancy—In women who enter preg-
overall; furthermore, it is not possible to discern nancy with well-controlled or mild hypertension with
whether these are specific medication effects, effects of medication, there are minimal data to guide decisions
elevated BP, or, alternatively, effects of low BP second- as to continuing or discontinuing therapy. A review of
ary to treatment. Although the increased number of 298 women in whom medication dosage was reduced
malformations are modest, these data support the gen- or stopped reported no increase in preeclampsia, abrup-
eral strategy of being cautious when prescribing any tio placentae, and perinatal death compared with
drug during pregnancy, particularly during the first untreated groups (8). A recent case–control study also
trimester, and emphasize the need for additional, found no difference in preeclampsia or eclampsia with
well-conducted prospective trials to clarify risks and discontinuation of antihypertensive drugs in the first tri-
benefits. Therefore, in the absence of strong evidence mester (37). Although decision making must be individ-
supporting use of antihypertensive therapy for mild to ualized, discontinuing medications during the first
moderate chronic hypertension during pregnancy, trimester and restarting them if BP approaches the
initiation of therapy is not suggested unless BP approach- severe range is reasonable practice. For women with
es 160 mm Hg systolic or higher or 105 mm Hg dia- end-organ damage, such as chronic renal disease or car-
stolic or higher, or both). diac disease, BP goals are lower (systolic BP less than
140 mm Hg and diastolic BP less than 90 mm Hg) to
avoid progression of disease during pregnancy and
TASK FORCE RECOMMENDATION associated complications. As noted previously, end-or-
• For pregnant women with chronic hypertension gan damage of the kidney and heart should be assessed
and BP less than 160 mm Hg systolic or 105 mm Hg before pregnancy or during early pregnancy, or both. A
diastolic and no evidence of end-organ damage, it detailed review of the medical history as well as base-
is suggested that they not be treated with pharma- line assessment of renal function (serum creatinine, cre-
cologic antihypertensive therapy. atinine clearance, and urinary protein excretion) and
cardiac function (echocardiography or electrocardiog-
raphy) is useful, and women should be monitored close-
ly if medications are withdrawn. This is clearly a case in
Blood pressure targets for antihypertensive treatment— which an informed discussion with the pregnant patient
Minimal data address the ideal target BP once antihy- should guide the choice of therapy or no therapy.
Types of Antihypertensive Medication ine and intravenous magnesium sulfate can result in
When choosing an antihypertensive medication to use hypotension and neuromuscular blockade. One review
for the treatment of chronic hypertension in preg- concluded that the combined use of these drugs does
nancy, an important consideration is the goal of therapy, not increase such risks (38); however, given the plausi-
which is either 1) acute lowering of severe hyperten- bility of the mechanism (both are calcium antagonists),
sion in the hospital setting (Table 7-1) or 2) chronic careful monitoring of women receiving both is advis-
treatment of BP to keep levels below the severe range, able. In view of these data, in women requiring antihy-
often in the outpatient setting (Table 7-2). pertensive medications for severe hypertension, the
choice and route of administration of drugs should
Drugs for urgent lowering of blood pressure. Thirty-
be based primarily on the physician’s familiarity and
five randomized controlled trials that involved 3,573
experience, adverse effects and contraindications to
women were included in a Cochrane systematic review
the prescribed drug, local availability, and cost.
that compared antihypertensive medications with each
other for acute lowering of severely elevated BP in Drugs for continuous management. Oral agents are
pregnancy (19). Most of these trials included only used for outpatient treatment of pregnant women
women with preeclampsia or gestational hypertension with chronic hypertension (39). Randomized con-
in the third trimester and excluded women with known trolled trials of drug therapy have focused on methyl-
chronic hypertension or previous antihypertensive dopa (included in five trials) (20–22, 24, 26) and
therapy use. Hydralazine, labetalol, and calcium chan- labetalol (included in one trial) (26). The largest trial
nel blockers are among the medications that were com- that included pregnant women with chronic hyperten-
pared with each other. Based on the findings of the sion randomized 263 women to labetalol, methyldopa,
systematic review, evidence is inadequate to demon- or no treatment; there were no differences in out-
strate the superior safety or efficacy of any of these comes or safety (29). Commonly used oral agents for
medications (19). Therefore, the authors conclude that chronic hypertension management in pregnancy are
the choice of antihypertensive medication should summarized in Table 7-2.
depend on the potential adverse effects and contraindi- Methyldopa, a centrally acting alpha-2 adrenergic
cations as well as the individual clinician’s experience agonist, remains a commonly used drug mainly
and familiarity with a particular drug (19). Given the because of the long history of use in pregnancy and
unlikelihood of future trials focusing specifically on childhood safety data. Blood pressure control is grad-
acute treatment of pregnant women with chronic ual, over 6–8 hours, as a result of the indirect mecha-
hypertension, it is reasonable to extrapolate manage- nism of action. Methyldopa has been prospectively
ment recommendations based on these data. Intrave- studied specifically in chronic hypertension com-
nous labetalol, intravenous hydralazine, or oral pared with placebo (20–22, 24, 26), as well as in a
nifedipine are reasonable first-line agents for acute mixed group of hypertensive women (40–42). There
lowering of BP in the hospital setting (Table 7-1). There are no apparent adverse effects on uteroplacental or
is theoretical concern that the combined use of nifedip- fetal hemodynamics or on fetal well-being (26, 43).
TABLE 7-1. Antihypertensive Agents Used for Urgent Blood Pressure Control in Pregnancy ^
Drug Dose Comments
Labetalol 10–20 mg IV, then 20–80 mg Considered a first-line agent
every 20–30 min to a maximum Tachycardia is less common and fewer
dose of 300 mg adverse effects
or Contraindicated in patients with asthma,
Constant infusion 1–2 mg/min IV heart disease, or congestive heart failure
Hydralazine 5 mg IV or IM, then 5–10 mg IV Higher or frequent dosage associated with
every 20–40 min maternal hypotension, headaches, and fetal
or distress—may be more common than other
Constant infusion 0.5–10 mg/h agents
Nifedipine 10–20 mg orally, repeat in May observe reflex tachycardia and headaches
30 minutes if needed; then
10–20 mg every 2–6 hours
Abbreviations: IM, intramuscularly; IV, intravenously.
TABLE 7-2. Common Oral Antihypertensive Agents in Pregnancy ^

Drug Dosage Comments
Labetalol 200–2,400 mg/d orally in two to Well tolerated
three divided doses Potential bronchoconstrictive effects
Avoid in patients with asthma and
congestive heart failure
Nifedipine 30–120 mg/d orally of a slow- Do not use sublingual form
release preparation
Methyldopa 0.5–3 g/d orally in two to three Childhood safety data up to 7 years of age
divided doses May not be as effective in control of severe
hypertension
Thiazide diuretics Depends on agent Second-line agent
Angiotensin-converting Associated with fetal anomalies
enzyme inhibitors/ Contraindicated in pregnancy and
angiotensin receptor preconception period
blockers
Birth weight, neonatal complications, and develop- pregnancy, in which nifedipine was the most com-
ment at 1 year were similar in infants exposed to monly prescribed calcium channel blocker, indicates
methyldopa in utero compared with no therapy (44, no increase in adverse perinatal outcomes (26, 48).
45). A follow-up study of children at 7 years of age Furthermore, nifedipine does not appear to adversely
did not show any difference in neurocognitive devel- affect uterine or umbilical blood flow (49, 50).
opment or intelligence compared with controls (46). Diuretics are generally considered second-line
Serious adverse effects include hepatic dysfunction drugs for the treatment of hypertension in pregnancy
and necrosis as well as hemolytic anemia. Methyldo- (51). Theoretical concern has been raised regarding
pa may be less effective in preventing severe hyper- the potential for diuretics to cause intravascular vol-
tension based on the Cochrane analysis of a subset of ume depletion and thereby lead to fetal growth restric-
studies compared with β-blocker and calcium chan- tion. However, this is not supported based on data
nel blocker classes combined (OR, 0.75; 95% CI, from a meta-analysis of nine randomized trials as well
0.59–0.94) (27). as a Cochrane systematic review of diuretics for the
Labetalol, a nonselective β-blocker with vascular prevention of preeclampsia (52, 53). Thus, diuretics
alpha receptor-blocking ability, is commonly used in may be used in pregnancy with dose adjustments to
pregnancy. In women with chronic hypertension, minimize adverse effects and risks such as hypokale-
there were no significant differences in perinatal out- mia. They may be especially useful in women with
comes when compared with placebo or methyldopa known salt-sensitive hypertension, particularly in the
(26, 42). Based on comparisons with placebo or setting of reduced renal function.
other antihypertensive agents for mild to moderate Angiotensin-converting enzyme inhibitors and
hypertension in pregnancy, labetalol is a reasonable angiotensin receptor blockers used in the second and
choice in women with chronic hypertension (27). third trimesters of pregnancy are associated with fetal
Adverse effects include lethargy, fatigue, sleep distur- abnormalities (including renal failure, oligohydram-
bances, and bronchoconstriction. Labetalol should be nios, pulmonary hypoplasia, calvarial abnormalities,
avoided in women with asthma, heart disease, or and fetal growth restriction) as well as postdelivery
congestive heart failure. Beta-blockers alone have effects such as oliguria and anuria (54). Serious con-
been used extensively in pregnancy and are effective cerns also have been raised regarding first-trimester
in lowering BP (27). However, β-blockers may be exposure and congenital anomalies. Based on a review
associated with an increase in SGA infants (RR, 1.34; of 29,096 Tennessee Medicaid records, 209 infants
95% CI, 1.01–1.79) compared with placebo or no were exposed to ACE inhibitors in the first trimester
treatment (47). with an RR for congenital malformations of 2.71
Calcium channel blockers are a class of drugs that (95% CI, 1.72–4.27) compared with women not tak-
has not been extensively studied in pregnant women ing antihypertensive drugs (55). Cardiac and central
with chronic hypertension. Extrapolation from the nervous system anomalies were most common. In the
comparison trials for mild to moderate hypertension in Kaiser Northern California database, first-trimester
ACE inhibitor use was associated with a higher rate of The task force could locate few studies that have been
cardiac malformations compared with normal controls performed exclusively in women with chronic hyperten-
(adjusted OR, 1.54; 95% CI, 0.9–2.62), but not signifi- sion; however, hypertensive women have been included
cantly higher than women with chronic hypertension as subgroups in trials of high-risk women.
with or without other medications (adjusted OR, 1.14; Meta-analysis and systematic reviews have demon-
95% CI, 0.65–1.98). strated that the use of antiplatelet agents (eg, low-
Based on the currently available data, the task force dose aspirin) is associated with a small but statistically
recommends discontinuation of ACE inhibitors and significant reduction (17%) in preeclampsia (56).
angiotensin-receptor blockers, as well as associated Women considered to be at high risk (including those
classes of medications such as the renin inhibitors and with chronic hypertension) may experience a benefit
mineralocorticoid receptor antagonists, during preg- as great as a 25% reduction (95% CI, 34–15% reduc-
nancy (33). Because 50% of pregnancies are un- tion) (57). Small effects (approximately a 10% reduc-
planned, these medications should be avoided in tion) on fetal outcomes (fetal survival or preterm
women of reproductive age. If these medications are birth) also were observed. Another meta-analysis sug-
unavoidable or strongly indicated (eg, proteinuric gested that benefits were greater when low-dose aspi-
renal disease), then women should be counseled rin was initiated earlier in pregnancy (58).
regarding risks and effective contraception recom- Calcium supplementation also has been extensively
mended. In select and rare cases in which there is a studied for the prevention of preeclampsia. A Cochrane
compelling reason to continue ACE inhibitors until con- meta-analysis of 13 studies (more than 15,000 women)
ception, extensive counseling of risk and benefits is concluded that calcium supplementation of 1 g or
warranted. greater was associated with an approximate 50%
reduction in BP and development of preeclampsia
(17). The effect was greatest for high-risk women (five
trials, 587 women; risk ratio [RR], 0.22; 95% CI, 0.12–
• For the initial treatment of pregnant women with 0.42) and those with low baseline calcium intake
chronic hypertension who require pharmacologic (eight trials, 10,678 women; RR, 0.36; 95% CI, 0.20–
therapy, labetalol, nifedipine, or methyldopa are 0.65). Preterm birth was reduced modestly (RR, 0.76;
recommended above all other antihypertensive 95% CI, 0.60–0.97) and among women at high risk of
drugs. developing preeclampsia recruited to four small trials
Quality of evidence: Moderate (568 women; RR, 0.45; 95% CI, 0.24–0.83). Addi-
Strength of recommendation: Strong tional preventive strategies that have been tested, pri-
marily in low-risk women, have not been shown to
• For women with uncomplicated chronic hyper- reduce the rate of preeclampsia or improve maternal
tension in pregnancy, the use of ACE inhibitors, and fetal outcomes.
angiotensin receptor blockers, renin inhibitors, and
mineralocorticoid receptor antagonists is not rec- • For women with chronic hypertension who are at a
ommended. greatly increased risk of adverse pregnancy out-
comes (history of early-onset preeclampsia and
preterm delivery at less than 34 0/7 weeks of
gestation or preeclampsia in more than one prior
• For women of reproductive age with chronic hyper- pregnancy), initiating the administration of daily
tension, the use of ACE inhibitors, angiotensin low-dose aspirin (60–80 mg) beginning in the late
receptor blockers, renin inhibitors, and mineralo- first trimester is suggested.*
corticoid receptor antagonists is not recommended Quality of evidence: Moderate
unless there is a compelling reason, such as the Strength of recommendation: Qualified
presence of proteinuric renal disease.
*Meta-analysis of more than 30,000 women in randomized
trials of aspirin to prevent preeclampsia indicates a small
Strength of recommendation: Qualified reduction in the incidence and morbidity of preeclampsia
Prevention of superimposed preeclampsia. Various nutri-
fetal effects cannot be excluded. The number of women to
tional modifications, addition of supplemental vitamins, treat to have a therapeutic effect is determined by preva-
and medications have been evaluated in large random- lence. In view of maternal safety, a discussion of the use of
ized controlled trials designed to prevent preeclampsia. aspirin in light of individual risk is justified.
Fetal Surveillance for Women With Chronic antenatal testing to determine the optimal timing of
Hypertension delivery in a fetus with growth restriction. Absent
The risk of fetal growth restriction is higher in preg- end-diastolic flow and reversed end-diastolic flow are
nant women with chronic hypertension. In patients indicative of fetal compromise. If umbilical artery Dop-
with mild chronic hypertension, the incidence of SGA pler velocimetry is abnormal, timing of the delivery is
infants is 8–15.5%, but in women with severe chronic based on the gestational age and the severity of the
hypertension, the incidence may be as high as 40% Doppler velocimetry abnormality.
(1, 8, 59). Fetuses with growth restriction are at an In a systematic review of 10,156 high-risk pregnan-
increased risk of perinatal morbidity (60). cies from 18 randomized studies, the use of umbilical
Ideally, identification of fetal growth restriction artery Doppler testing compared with either no Dop-
should allow obstetric interventions to decrease peri- pler or nonstress test (NST) alone reduced perinatal
natal risks. Two methods primarily used to screen for mortality by 29% (RR, 0.71; 95% CI, 0.52–0.98) with-
fetal growth restriction are 1) measurement of fundal out increasing rates of induction of labor (RR, 0.89;
height and 2) ultrasonographic estimation of fetal 95% CI, 0.80–0.99) or cesarean delivery (RR, 0.92;
weight. Fundal height measurements are more suit- 95% CI, 0.84–0.97). Studies incorporated into this
able in women who are at low risk of fetal growth analysis were not of high quality and were not limited
restriction. The sensitivity for fundal height measure- to patients with hypertension with or without fetal
ment to detect fetal growth restriction is inadequate growth restriction (65).
for high-risk women (61). In pregnancies at high risk
of fetal growth restriction based on maternal disease TASK FORCE RECOMMENDATION
such as hypertension, the preferred method for
screening is ultrasonography. Based on observational • If evidence of fetal growth restriction is found in
data, the best predictor of fetal growth restriction is women with chronic hypertension, fetoplacental
serial ultrasonographic assessments of either fetal assessment to include umbilical artery Doppler
weight or abdominal circumference (62). The opti- velocimetry as an adjunct antenatal test is recom-
mal timing and frequency of examinations is not mended.
known. The timing and frequency of ultrasonography Quality of evidence: Moderate
for fetal growth is based on the clinical scenario, such Strength of recommendation: Strong
as prior obstetric history, severity of hypertension,
Fetal antenatal surveillance with either an NST, bio-
and coexisting morbidities.
physical profile (BPP), or a modified BPP may be bene-
It remains unclear whether the antenatal detection
ficial in reducing perinatal morbidity and mortality in
of fetal growth restriction decreases perinatal mor-
high-risk pregnancies (66). In patients with chronic
tality. In a systematic review of more than 27,000 low-
hypertension, data for the specific time to initiate ante-
risk women, screening compared with no screening
natal testing, the testing interval, and the most effec-
with ultrasonography after 24 weeks of gestation did
tive antenatal test to use are lacking. Based on
not improve perinatal outcomes (63). In high-risk
observational studies in populations at high risk of
pregnancies, no data exist to address this issue. Based
intrauterine fetal demise, antepartum fetal surveillance
on expert opinion, early detection and appropriate
with either is often recommended to decrease perinatal
management of fetal growth restriction is expected to
morbidity. Patients with chronic hypertension at high-
decrease the stillbirth rate by 20% (64).
est risk of perinatal mortality have either fetal growth
restriction or superimposed preeclampsia.
TASK FORCE RECOMMENDATION A systematic review of NSTs compared with no or
• For women with chronic hypertension, the use of concealed NSTs in 2,105 high-risk women from six
ultrasonography to screen for fetal growth restric- randomized or quasi-randomized trials showed no dif-
tion is suggested. ference in perinatal mortality (RR, 2.05; 95% CI,
Quality of evidence: Low 0.95–4.42) or potentially preventable deaths (RR,
Strength of recommendation: Qualified 2.46; 95% CI, 0.96–6.30) (65). When BPPs were com-
pared with NSTs or modified BPPs in a systematic
Doppler velocimetry studies of the fetoplacental unit review of five trials that involved 2,974 high-risk
can be used antenatally to detect increased placental women, there was no significant difference in perina-
resistance and fetal vascular response. Umbilical artery tal deaths between the groups (RR, 1.33; 95% CI,
Doppler velocimetry is often used in conjunction with 0.60–2.98) (67).
Superimposed Preeclampsia
Definition and Diagnosis
• For women with chronic hypertension complicated
Superimposed preeclampsia refers to women with
by issues such as the need for medication, other
chronic hypertension who develop preeclampsia. Dis-
underlying medical conditions that affect fetal out-
tinguishing superimposed preeclampsia from benign
come, any evidence of fetal growth restriction, and
gestational increases in BP and proteinuria that are
superimposed preeclampsia, antenatal fetal testing
often observed in women with chronic hypertension
is suggested.
can be quite challenging. Given the higher risk of
Quality of evidence: Low adverse pregnancy outcomes with superimposed pre-
Strength of recommendation: Qualified eclampsia, overdiagnosis may be preferable, with the
goal of increasing vigilance and preventing catastro-
Intrapartum Management phic maternal and fetal outcomes. Alternatively, a
The optimal delivery time to reduce maternal and fetal more specific and stratified approach based on severity
morbidity and mortality in women with chronic hyper- and predictors of adverse outcome may be useful in
tension, with or without maternal or fetal complica- guiding clinical management and avoiding unneces-
tions, has not been studied. Trials that have been sary preterm births.
conducted included women with hypertensive disor- Based on these considerations, the task force pro-
ders of pregnancy, such as gestational hypertension poses that superimposed preeclampsia be stratified
and preeclampsia with or without preexisting hyper- into two groups to guide management: 1) superim-
tension. Hypertensive disorders of pregnancy affect a posed preeclampsia and 2) superimposed preeclamp-
heterogeneous population, but data are often extrapo- sia with severe features.
lated to women with chronic hypertension. Superimposed preeclampsia is likely when any of
In women with chronic hypertension and without the following are present:
any obstetric complications, a small clinical trial sug-
gests that the risk of adverse perinatal outcomes is • A sudden increase in BP that was previously well
similar to women without chronic hypertension (59). controlled or escalation of antihypertensive medi-
Findings in a population-based cohort study suggest cations to control BP
that the optimal timing for women with uncomplicated • New onset of proteinuria or a sudden increase in
hypertension is between 38 weeks of gestation and proteinuria in a woman with known proteinuria
39 weeks of gestation (68). Delivery in this gestational before or early in pregnancy
age group optimizes fetal outcomes while decreasing
neonatal morbidity. In a systematic review of 22 stud- The diagnosis of superimposed preeclampsia with
ies that involved almost 30 million infants, late severe features is established when any of the follow-
preterm birth is associated with increased neonatal ing are present:
complications and death within the first year of life • Severe-range BP despite escalation of antihyper-
(69). Without a known maternal or fetal benefit but tensive therapy
with known risk of neonatal complications, delivery
before 38–39 weeks of gestation is not warranted in • Thrombocytopenia (platelet count less than
patients with only isolated, uncomplicated chronic 100,000/microliter)
hypertension (70). • Elevated liver transaminases (two times the upper
limit of normal concentration for a particular labo-
TASK FORCE RECOMMENDATION ratory)
• For women with chronic hypertension and no ad- • New-onset and worsening renal insufficiency
ditional maternal or fetal complications, delivery • Pulmonary edema
before 38 0/7 weeks of gestation is not recom-
mended. • Persistent cerebral or visual disturbances
Quality of evidence: Moderate Clinicians should recognize that there is often

Strength of recommendation: Strong ambiguity in the diagnosis of superimposed pre-
eclampsia and that the clinical spectrum of disease is
broad. Furthermore, women with superimposed pre-
eclampsia can progress and develop end-organ
involvement and adverse outcomes. Therefore, lished. Therefore, recommendations regarding anti-
increased surveillance but not intervention (eg, deliv- hypertensive treatment in this group are extrapolated
ery) is warranted even if the diagnosis is suspected from the evidence based on chronic hypertension in
and not definitive. Future investigation is needed to pregnancy and preeclampsia. Pharmacologic antihy-
further refine the diagnosis, potentially including pertensive therapy should be used for women with
markers that are predictive of adverse outcome. hypertension (systolic BP 160 mm Hg or higher or
diastolic BP 105 mm Hg or higher) or at even lower
Initial Evaluation of Women With levels if there is evidence of end-organ involvement to
Superimposed Preeclampsia prevent acute maternal cerebrovascular and coronary
Initial evaluation of women with superimposed pre- events (19). Treatment of women with systolic BP
eclampsia should occur in a hospital setting to con- 140–160 mm Hg or diastolic BP 90–105 mm Hg has
firm the diagnosis, evaluate maternal–fetal status, not been shown to be beneficial in decreasing adverse
and monitor for progressive worsening of the disease. perinatal outcomes but reduces progression to severe
The clinical workup should include questions about hypertension (27). Initiation of antihypertensive
symptoms associated with preeclampsia (neurologic medications or an increase in dosages because of
symptoms, epigastric or right upper quadrant pain, worsening BP in the setting of superimposed pre-
nausea and vomiting, vaginal bleeding, and fetal eclampsia should occur in the hospital setting while
movement). Serial BP measurements should be monitoring for worsening maternal–fetal status.
obtained. Physical examination should be performed Acute lowering of severe hypertension may be accom-
with attention to signs of preeclampsia and associated plished by intravenous or oral medications (intrave-
complications. Proteinuria should be assessed by a nous labetalol, intravenous hydralazine, or oral
protein/creatinine ratio or 24-hour urine collection. nifedipine) (Table 7-1). Long-term treatment of BP
Laboratory evaluation should also include a complete that maintains levels below the severe range generally
blood count with platelets, liver transaminases, lactic involves the use of oral agents such as labetalol, nifed-
dehydrogenase, and creatinine assessment. Uric acid ipine, or methyldopa as initial agents (Table 7-2).
assessment also may be helpful if uric acid concentra-
tions are known from early pregnancy because hyper- Antepartum Management of Superimposed
uricemia is associated with adverse outcomes in Preeclampsia
superimposed preeclampsia and also with early renal General considerations in the antepartum manage-
dysfunction, which may be present with chronic ment of women with superimposed preeclampsia
hypertension (71, 72). Ideally, these laboratory include the administration of antenatal corticosteroids
results are compared with baseline information and use of magnesium sulfate for seizure prophylaxis.
obtained in early pregnancy. If abnormalities are of Ongoing management and timing of delivery is based
new-onset, then the diagnosis of superimposed pre- on gestational age and the severity of disease.
eclampsia; end-organ involvement; or hemolysis, ele-
vated liver enzymes, and low platelet count (HELLP) Antenatal Corticosteroids
syndrome can be confirmed. If abnormalities are Women with superimposed preeclampsia diagnosed
long-standing or of unknown duration, results should before 37 weeks of gestation are at increased risk of
be cautiously interpreted before a definitive diagno- preterm delivery. Therefore, antenatal corticosteroids
sis is established. Although not included in the diag- should be administered at less than 34 weeks of gesta-
nostic criteria for superimposed preeclampsia, fetal tion for fetal lung maturity benefit to decrease neona-
growth and well-being should be assessed when tal morbidity and mortality (73).
superimposed preeclampsia is suspected. Additional
testing or interventions or both may be warranted if TASK FORCE RECOMMENDATION
there are concerns regarding fetal status.
• For women with superimposed preeclampsia who
Antihypertensive Treatment for receive expectant management at less than 34 0/7
Superimposed Preeclampsia weeks of gestation, the administration of cortico-
Clinical trials that have evaluated antihypertensive steroids for fetal lung maturity benefit is recom-
therapy that included women with chronic hyperten- meded.
sion have not specifically addressed lowering BP once Quality of evidence: High
the diagnosis of superimposed preeclampsia is estab- Strength of the recommendation: Strong
Magnesium Sulfate for Seizure Prophylaxis Gestational age of 37 weeks or older. Delivery is sug-
Eclampsia is associated with maternal mortality in the gested for superimposed preeclampsia diagnosed at
range of 0.3–1% and serious morbidity, including renal term (37 weeks of gestation or more). Neonatal out-
failure, pulmonary edema, aspiration pneumonia, comes are favorable, and continuation of pregnancy
stroke, and cardiopulmonary arrest (74). There also is incurs risk to the woman and her fetus (70).
evidence of long-term maternal sequelae, such as per-
Gestational age of less than 37 weeks. In the absence of
sistence of white-matter lesions and impaired cognitive
severe features and with reassuring fetal status, expect-
function (75, 76). Magnesium sulfate has been shown
ant management with ongoing close maternal and fetal
to be superior to a number of other agents for the pre-
surveillance is reasonable. There is a paucity of data to
vention of seizures in women with preeclampsia.
support outpatient management of superimposed pre-
The frequency of eclampsia in women with chronic
eclampsia. However, if an outpatient approach is
hypertension and superimposed preeclampsia is not
undertaken, maternal adherence to home BP monitor-
well defined but ranges from 0% to 2.4% as reported
ing, reporting of symptoms, physician visits one to two
in observational and small retrospective studies (77,
times a week, weekly laboratory testing, and fetal sur-
78). Currently, no data appear to specifically address
veillance are important. Women with superimposed
the use of magnesium sulfate for seizure prophylaxis
preeclampsia with worsening disease, severe features,
for the subgroup of women with superimposed pre-
or concern for fetal well-being should be monitored as
eclampsia. Therefore, evidence from the general
inpatients (see the following section “Management of
preeclampsia literature must be used to guide manage-
Superimposed Preeclampsia With Severe Features”).
ment. For women with chronic hypertension and
Optimal delivery timing between 34 weeks of ges-
superimposed preeclampsia with severe features, the
task force recommends the administration of intrapar- tation and 37 weeks of gestation in superimposed pre-
tum–postpartum parenteral magnesium sulfate to preeclampsia without any evidence of severe features or
vent eclampsia. In the absence of data that specifically worsening disease is unclear. A retrospective cohort
address superimposed preeclampsia without any study that used a perinatal database found no differ-
severe features, the collective opinion of the task force ence in perinatal outcomes between superimposed
is against the use of magnesium sulfate for seizure pro- preeclampsia and preeclampsia; however, there was a
phylaxis during labor and delivery in this subgroup. higher rate of delivery at less than 34 weeks of gesta-
However, signs and symptoms that have traditionally tion (17.3% versus 8.7%; P<0.001), cesarean delivery
been considered premonitory to eclampsia (eg, neuro- (46.2% versus 36.3%; P<0.001), and neonatal in-
logic symptoms, clonus, and right upper quadrant tensive care unit admission (16.3% versus 11.4%;
pain), as well as worsening clinical course to severe P<0.002) (79). These data indicate a higher risk of
disease, should be considered in the decision to initiate intervention-related events and morbidity among
magnesium during labor and delivery. women with superimposed preeclampsia compared
with women with preeclampsia, thus raising the issue
of potentially unnecessary iatrogenic preterm births
with superimposed preeclampsia. If extrapolated from
• For women with chronic hypertension and super- the general preeclampsia literature, delivery for severe
imposed preeclampsia with severe features, the preeclampsia (expectantly managed) is suggested at
administration of intrapartum–postpartum paren- 34 weeks of gestation and at 37 weeks of gestation for
teral magnesium sulfate to prevent eclampsia is preeclampsia without severe features (70, 80, 81).
recommended. The task force suggests that superimposed preeclamp-
sia with severe features be managed in a manner
similar to severe preeclampsia and superimposed pre-
eclampsia without severe features be managed in a
Timing and Indications for Delivery manner similar to preeclampsia without severe fea-
Indications for and timing of delivery in superimposed tures. Future research and investigation is needed to
preeclampsia are based on gestational age, severity of better delineate the risk–benefit balance of pregnancy
disease, progression of disease, and ongoing assess- continuation between 34 weeks of gestation and 37
ment of maternal and fetal well-being. With any weeks of gestation among women with superimposed
attempts to prolong pregnancy, the potential fetal– preeclampsia. If the disease has remained stable with-
neonatal benefits must be weighed against maternal out evidence of progression or severe features, deliv-
and fetal morbidity and mortality. ery at 37 weeks of gestation is suggested.
regarding expectant management beyond the 48 hours

to achieve steroid benefit are limited. Thus, manage-
• For women with superimposed preeclampsia with- ment is based on extrapolation of indirect evidence
out severe features and stable maternal and fetal from management of severe preeclampsia, as well as
conditions, expectant management until 37 0/7 direct evidence from retrospective studies of expectant
weeks of gestation is suggested. management of superimposed preeclampsia. Expect-
ant management beyond the 48 hours of antenatal cor-
ticosteroid administration in two randomized trials of
Strength of the recommendation: Qualified
severe preeclampsia at less than 34 weeks of gestation
Management of Superimposed Preeclampsia was associated with significant prolongation of preg-
With Severe Features nancy, reduction in neonatal respiratory distress syn-
Before 34 weeks of gestation, management options drome, fewer days in the neonatal intensive care units,
for superimposed preeclampsia with severe features and higher birth weight with reasonable maternal safe-
are as follows: immediate delivery after maternal sta- ty in the expectantly managed group (80–82). Women
bilization, short-term prolongation to achieve steroid with severe preeclampsia were candidates for expect-
benefit for the fetus, or long-term prolongation ant management if BP was controlled, there was no
(expectant management) to increase gestational age evidence of severe end-organ involvement, and fetal
and improve neonatal outcomes. Given the paucity of status was reassuring without growth restriction.
clinical trials and prospective studies in women with The subgroup of women with superimposed pre-
superimposed preeclampsia, the indications and tim- eclampsia diagnosed before 34 weeks of gestation is
ing of delivery are based on indirect evidence from typically excluded from studies focusing on the expect-
the management of preeclampsia (11). Two random- ant management of preeclampsia, and if included,
ized trials that included 133 women and a number of their outcomes are generally not reported separately
observational studies provide the basis for manage- (81, 82, 86, 87). Prospective studies of women with
ment of severe preeclampsia (80–82). Because of the chronic hypertension allude to expectant management
significant maternal–fetal or maternal–neonatal mor- of women with superimposed preeclampsia, but this
bidity, immediate delivery after maternal stabiliza- issue is not clearly addressed. For example, in a pro-
tion is recommended if any of the following are spective cohort of 861 women with chronic hyperten-
present: uncontrollable severe hypertension, eclamp- sion enrolled in the Vitamins in Preeclampsia Trial, the
sia, pulmonary edema, disseminated intravascular incidence of superimposed preeclampsia was 22%,
coagulation, new or increasing renal dysfunction or and 51% of these women gave birth before 37 weeks
both, abruptio placentae, or nonreassuring fetal sta- of gestation (77). The average antenatal inpatient stay
tus. Many of these studies do not clearly differentiate was 7.3 days, suggesting that an expectant manage-
between immediate delivery and an attempt to ment approach was taken in at least a subset of
achieve some level of steroid benefit (80, 83). Given patients with superimposed preeclampsia. A retro-
the neonatal benefit of antenatal corticosteroids and spective case series of expectant management of pre-
some data supporting the expectant management of eclampsia specifically reported on a subset of 29
HELLP syndrome and fetal growth restriction (80, women with superimposed preeclampsia (88). Com-
83–85), it is reasonable to delay delivery in a subset pared with women with severe preeclampsia in this
of women with severe disease to achieve the benefits series, women with superimposed preeclampsia had
of antenatal corticosteroid use (48 hours). Women similar latency periods (8.4 days versus 8.5 days) and
with neurologic or epigastric pain symptoms, HELLP no difference in the rates of abruptio placentae, oligu-
syndrome or partial HELLP syndrome, thrombocyto- ria, or HELLP syndrome.
penia, elevated liver transaminases, or fetal growth Another retrospective review focused on women
restriction are potential candidates for short-term with superimposed preeclampsia at a single institu-
pregnancy prolongation with close inpatient moni- tion in the United States who were expectantly man-
toring and readily available tertiary obstetric, neona- aged beyond 48 hours to achieve steroid benefit and
tal, and anesthesia services. Delivery is recommended gave birth before 37 weeks of gestation (78). In this
if there is worsening of maternal or fetal status. Par- series of 41 women, the median gestational age at
enteral magnesium sulfate is recommended for sei- diagnosis was 31.6 weeks, and the mean time from
zure prophylaxis. diagnosis to delivery was 9.7 days, with a wide range
For women with superimposed preeclampsia diag- of 2–34 days. There were no perinatal deaths, and
nosed before 34 weeks of gestation, published data adverse outcomes included two cases of abruptio
placentae, one pulmonary edema, one case of pro- • For women with superimposed preeclampsia with
gression to HELLP syndrome, and an average neona- severe features, expectant management beyond
tal intensive care unit stay of 17.9 days. Although 34 0/7 weeks of gestation is not recommended.
these studies are small and fraught with limitations, Quality of evidence: Moderate
they suggest that the rate of adverse outcomes and Strength of the recommendation: Strong
latency periods are comparable with those observed
with expectant management of preterm severe pre-
eclampsia (80). Thus, expectant management in Management of Women With Chronic
women with superimposed preeclampsia before 34 Hypertension in the Postpartum Period
weeks of gestation in the hospital setting, as espoused Women with chronic hypertension before and during
with preterm severe preeclampsia, appears reason- pregnancy will usually require treatment with antihy-
able. Prospective studies are needed to quantify the pertensive medications in the postpartum period, even
risks and benefits of this approach. if they were not treated during pregnancy. Because the
For women with superimposed preeclampsia with American College of Obstetricians and Gynecologists
severe features undergoing expectant management encourages all women to breastfeed their infants, anti-
before 34 weeks of gestation, inpatient management is hypertensive medications that are safe for breastfeed-
recommended with delivery at 34 weeks of gestation. ing (ie, they tend not to be secreted into breast milk)
This is based on the morbidity associated with severe should be prescribed.
preeclampsia and the approach taken in randomized The task force is not aware of clinical trials that
clinical trials (80, 82, 83). As with the expectant man- specifically address management of postpartum hyper-
agement of severe preeclampsia, parenteral magne- tension in women with any form of hypertension in
sium sulfate is recommended during the initial pregnancy. Blood pressure in the postpartum period is
evaluation and stabilization period (generally 24 hours) often higher compared with antepartum levels, partic-
before expectant management. ularly in the first 1–2 weeks (89, 90). Medication
As with severe preeclampsia, if superimposed pre- should be adjusted to maintain BP in a safe range (less
eclampsia with severe features is newly diagnosed than 160 mm Hg systolic and 100 mm Hg diastolic).
after 34 weeks of gestation, delivery should be accom- Use of nonsteroidal antiinflammatory agents should
plished after stabilization of maternal status. be avoided in the postpartum period in women with
chronic hypertension, particularly those with superim-
TASK FORCE RECOMMENDATIONS posed preeclampsia. Extensive documentation exists
that nonsteroidal antiinflammatory agents increase BP
• Delivery soon after maternal stabilization is recom-
and sodium retention in patients who are not preg-
mended irrespective of gestational age or full corti-
nant. Although use of these medications have not been
costeroid benefit for women with superimposed
investigated in the postpartum period, alternative
preeclampsia that is complicated further by any of
strategies are recommended.
the following:
Magnesium sulfate is indicated if there are signs
– uncontrollable severe hypertension and symptoms of persistent or new-onset superim-
– eclampsia posed preeclampsia, such as severe headache, visual
– pulmonary edema disturbances, shortness of breath, and signs of HELLP
– abruptio placentae syndrome. Older women, women with comorbidities
– disseminated intravascular coagulation (obesity, diabetes, or kidney disease), and those with
– nonreassuring fetal status an onset of hypertension at an earlier gestational age
Quality of evidence: Moderate may be at greater risk of prolonged elevations in BP
Strength of the recommendation: Strong postpartum (89). It also has been observed that
eclampsia and adverse cerebrovascular events associ-
• For women with superimposed preeclampsia with ated with pregnancy are more likely to occur in the
severe features at less than 34 0/7 weeks of gesta- postpartum period (90). The role of BP control in
tion with stable maternal and fetal conditions, it is preventing these outcomes has not been well studied;
recommended that continued pregnancy be under- however, antihypertensive medications may be used
taken only at facilities with adequate maternal and more liberally in the postpartum period, and if cere-
neonatal intensive care resources. bral symptoms are present, BP should be lowered.
Quality of evidence: Moderate If hypertension in the postpartum period remains
Strength of evidence: Strong severe despite adequate doses of two antihypertensive
medications, the woman should be referred to a hyper- 6. Ferrer RL, Sibai BM, Mulrow CD, Chiquette E, Stevens
tension specialist to rule out secondary causes. KR, Cornell J. Management of mild chronic hypertension
during pregnancy: a review. Obstet Gynecol 2000;96:
849–60. [PubMed] [Obstetrics & Gynecology] ^
Breastfeeding
7. Zetterstrom K, Lindeberg SN, Haglund B, Hanson U.
Good clinical practice suggests that women with Maternal complications in women with chronic hyper-
chronic hypertension should be encouraged to breast- tension: a population-based cohort study. Acta Obstet
feed, although the task force is not aware of clinical Gynecol Scand 2005;84:419–24. [PubMed] [Full Text]
trials that have assessed either maternal or fetal out- ^
comes in this patient population. Many, if not most, 8. Rey E, Couturier A. The prognosis of pregnancy in wom-
en with chronic hypertension. Am J Obstet Gynecol
types of antihypertensive medications are detectable,
1994;171:410–6. [PubMed] ^
albeit at low concentrations, in breast milk.
9. Williams MA, Mittendorf R, Monson RR. Chronic hyper-
In general, drugs that are bound to plasma proteins tension, cigarette smoking, and abruptio placentae.
are not transferred to breast milk. Lipid-soluble drugs Epidemiology 1991;2:450–3. [PubMed] ^
may achieve higher concentrations compared with 10. Ananth CV, Savitz DA, Bowes WA Jr, Luther ER. Influence
water-soluble drugs. Methyldopa is considered safe, of hypertensive disorders and cigarette smoking on pla-
and concentrations in breast milk are low. Several cental abruption and uterine bleeding during pregnancy.
β-blockers are concentrated in breast milk, with ateno- Br J Obstet Gynaecol 1997;104:572–8. [PubMed] ^
lol and metoprolol resulting in high concentrations, 11. Sibai BM, Koch MA, Freire S, Pinto e Silva JL, Rudge MV,
Martins-Costa S, et al. The impact of prior preeclampsia
and propranolol and labetalol resulting in low concen-
on the risk of superimposed preeclampsia and other ad-
trations. Both captopril and enalapril concentrations verse pregnancy outcomes in patients with chronic hy-
in breast milk have been reported as low, and many pertension. Am J Obstet Gynecol 2011;204:345.e1–6.
consider these drugs to be safe for breastfeeding; how- [PubMed] [Full Text] ^
ever, in women who require high doses, other agents 12. Taguchi N, Rubin ET, Hosokawa A, Choi J, Ying AY,
are appropriate. There are only limited reports of cal- Moretti ME, et al. Prenatal exposure to HMG-CoA reduc-
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cium channel blockers and their transfer into breast
Reprod Toxicol 2008;26:175–7. [PubMed] [Full Text] ^
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13. Siebenhofer A, Jeitler K, Berghold A, Waltering A,
the concentration of diuretics in breast milk is usually Hemkens LG, Semlitsch T, et al. Long-term effects of
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that evaluate outcomes of children exposed to antihy-
14. Blumenthal JA, Babyak MA, Sherwood A, Craighead L,
pertensive medications in breast milk.
Lin PH, Johnson J, et al. Effects of the dietary approaches
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CHAPTER
8
Later-Life Cardiovascular Disease
in Women With Prior Preeclampsia
S
everal large epidemiologic studies demonstrate stroke, and congestive heart failure) (3) and, therefore,
that all women with a history of preeclampsia should be advised to 1) maintain ideal body weight;
have an increased risk of cardiovascular (CV) 2) engage in aerobic exercise regularly (five times per
diseases later in life. For many years, the older week); 3) eat a diet high in fiber, vegetables, and fruits
literature was misinterpreted to suggest that women and low in fat (the Dietary Approaches to Stop Hyper-
with preeclampsia only in a first pregnancy were not tension diet); and 4) avoid tobacco. Evaluation for risk
at increased risk. However, more recent studies with of later-life CV disease requires health care provider
larger numbers of participants and longer follow-up and patient consideration (Box 8-1).
indicate an increased risk of later-life CV disease even
with preeclampsia in a first pregnancy (1). This risk is
much greater if the woman has recurrent preeclampsia
(2), gave birth preterm (less than 37 weeks of gesta- • For women with a medical history of preeclampsia
tion), or had a pregnancy with fetal growth restriction who gave birth preterm (less than 37 0/7 weeks of
(1, 3, 4), with risk rates at least equaling the CV risk gestation) or who have a medical history of recur-
with obesity or smoking (5). In 2011, the American rent preeclampsia, yearly assessment of blood pres-
Heart Association added preeclampsia to its list of risk sure, lipids, fasting blood glucose, and body mass
factors for CV disease (6). Prepregnancy risk factors index is suggested.*
and preeclampsia may both contribute to the develop- Quality of evidence: Low
ment of long-term CV disease risk (7). Preeclampsia, Strength of recommendation: Qualified
particularly when associated with preterm delivery,
should be considered as a strong risk factor for CV dis- *Although there is clear evidence of an association
between preeclampsia and later-life CV disease, the value
ease (data exist to support that it is quantitatively sim-
and appropriate timing is not yet established. Health care
ilar in magnitude to the increase in the risk of having providers and patients should make this decision based
diabetes) (7). These individuals are at increased risk on their judgment of the relative value of extra informa-
of hypertension and CV disease (myocardial infarction, tion versus expense and inconvenience.
71
72 LATER-LIFE CARDIOVASCULAR DISEASE IN WOMEN WITH PRIOR PREECLAMPSIA
BOX 8-1. valuation for Risk Factors ^

E
• How many pregnancies have you had?
• How many miscarriages have you had?
• Were any of your babies born early (more than 3 weeks before your due date)?
– How many?
– Did this occur spontaneously or were the babies delivered early because you were ill?
• Did you have preeclampsia in any of your pregnancies?
– Which pregnancy?
– How many times?
– Was the baby delivered early because you had preeclampsia?
– How many weeks before your due date was the baby delivered?
• Did you have high blood pressure in any pregnancy?
– Did you have protein in your urine in that pregnancy?
– Do you have a family history of preeclampsia? Is there a history of preeclampsia in your partner’s
family?
• Did you have gestational diabetes?
– Were you treated with insulin or blood glucose-lowering pills?
• What were the birth weights of your babies, and how many weeks before your due date were they
delivered?
• Do you have a medical history of high blood pressure or chronic kidney disease?
Modified from Roberts JM, Catov JM. Pregnancy is a screening test for later life cardiovascular disease: now what? Research
recommendations. Womens Health Issues 2012;22:e123–8.
References 4. Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA. Car-
diovascular health after maternal placental syndromes
1. Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term (CHAMPS): population-based retrospective cohort study.
mortality of mothers and fathers after pre-eclampsia: Lancet 2005;366:1797–803. [PubMed] [Full Text] ^
population based cohort study. BMJ 2001;323:1213–7. 5. Roberts JM, Hubel CA. Pregnancy: a screening test for
[PubMed] [Full Text] ^ later life cardiovascular disease. Womens Health Issues
2. Funai EF, Paltiel OB, Malaspina D, Friedlander Y, Deutsch 2010;20:304–7. [PubMed] [Full Text] ^
L, Harlap S. Risk factors for pre-eclampsia in nulliparous 6. Mosca L, Benjamin EJ, Berra K, Bezanson JL, Dolor RJ,
and parous women: the Jerusalem perinatal study. Lloyd-Jones DM, et al. Effectiveness-based guidelines for
Paediatr Perinat Epidemiol 2005;19:59–68. [PubMed] ^ the prevention of cardiovascular disease in women--2011
3. Mongraw-Chaffin ML, Cirillo PM, Cohn BA. Preeclamp- update: a guideline from the American Heart Associa-
sia and cardiovascular disease death: prospective evi- tion. American Heart Association [published erratum
dence from the child health and development studies appears in J Am Coll Cardiol 2012;59:1663]. J Am Coll
cohort. Hypertension 2010;56:166–71. [PubMed] [Full Cardiol 2011;57:1404–23. [PubMed] [Full Text] ^
Text] ^ 7. Romundstad PR, Magnussen EB, Smith GD, Vatten LJ.
Hypertension in pregnancy and later cardiovascular risk:
common antecedents? Circulation 2010;122:579–84.
CHAPTER
9
Patient Education
M
any millions of dollars have been spent literacy skills have been researched and described in
on clinical and laboratory research in an the literature. These can be applied to patient educa-
effort to discover the pathogenesis of pro- tion about preeclampsia with the goal of ensuring that
phylactic measures for and optimal treat- the best possible outcomes are achieved with the
ment of preeclampsia. Although these goals are of the resources currently available.
utmost importance, a more effective use of currently
available information and resources may reduce the
Importance of Patient Education
burden of morbidity and mortality that arises in asso-
ciation with preeclampsia. Health services interven- In the developed world, the frequency of adverse
tions, including patient education, may not only help maternal and perinatal events related to preeclampsia
to reduce this burden, particularly among populations remains markedly lower than in developing countries,
at greatest risk (eg, those with low health literacy or largely because of the greater number of available
at highest risk of developing preeclampsia), but also resources and routine hypertension and proteinuria
may reach that goal at a relatively low cost. Patient screening (3–5). Interventions for women with disease
and health care provider education is key to the suc- include increased monitoring, magnesium sulfate,
cessful recognition and management of preeclampsia. antihypertensive medications, corticosteroids for fetal
Health care providers need to inform women during lung maturation, and delivery. To maximally benefit
the prenatal and postpartum periods of the signs and from these resources, however, women must first seek
symptoms of preeclampsia and stress the importance medical care in a timely fashion.
of contacting health care providers if these are evi- The possibility that women do not seek timely care
dent. This can be accomplished without increasing may be increased if they have a poor understanding of
patient anxiety (1). the signs and symptoms of preeclampsia. Several recent
Little is understood about how to best educate studies emphasized the potential value of educating
women about preeclampsia and provide them with the patients to report and their health care providers to act
information needed to seek prompt and appropriate on signs and symptoms of severe preeclampsia that
care. What is known is that the population, in general, commonly precede eclampsia, hypertensive encepha-
has difficulty understanding even basic health infor- lopathy, pulmonary edema, or stroke (6–11). This
mation, and preeclampsia, specifically, is a poorly hypothesis is further supported by studies of women in
understood complication of pregnancy (2). Education whom preeclampsia was diagnosed, received timely
techniques that are appropriate for patients with poor and proper surveillance, and had fewer adverse events
73
74 PATIENT EDUCATION
than those with delayed diagnosis (12). Regardless of viders can effect change in the practice environment as
literacy level and understanding of preeclampsia, this it relates to patient education when considering a pop-
knowledge deficit appears to be modifiable because ulation with limited health literacy (16). A summary
women who acknowledge receiving information about of recommendations is listed in Box 9-1.
the disease demonstrate greater preeclampsia-specific Predicting who is affected by inadequate health lit-
knowledge (2). eracy skills is challenging because the problem is ubiq-
Beyond improving outcomes, it is the ethical uitous, spanning all races and income and education
responsibility of the health care system and the health levels. Certainly, an obstetric care provider can relay
care providers who work within that system to ensure both the symptoms of preeclampsia in nonmedical lan-
that patients have been educated about the implica- guage (Box 9-1) and the appropriate actions that
tions and complications of a specific health state, should be taken should those symptoms arise; how-
including pregnancy. According to the American Med- ever, if that message is relayed in a manner that is
ical Association, “Patients have the right to understand poorly understood by the patient, it is of little to no
healthcare information that is necessary for them to value. Hence, any educational intervention should be
safely care for themselves, and to choose among avail- created so that patients with even limited literacy skills
able alternatives. Health care providers have a duty to can understand and act on the information.
provide information in simple, clear and plain lan- It is not only important that medical care providers
guage and to check that the patients have understood offer easy-to-understand and straightforward verbal
the information before ending the conversation” (13). communication, but also that appropriate aids are
used for women to take with them that offer visual
reminders at home. These should be written at no
Patient Education Strategies
greater than a fifth-grade or sixth-grade reading level,
Although few would debate the importance of patient be graphic-based, and be culturally sensitive (16–21).
education, the question still remains as to how best to For example, relaying to a patient that she should no-
provide such education about preeclampsia. The solu- tify her health care provider if she experiences right
tion is complex because it is estimated that approxi- upper quadrant pain, headache, or visual alterations
mately one half of the American population has a may be confusing to the patient and her family. The
limited capacity to obtain, process, and understand health care provider should instead explain that the
basic health information and services needed to make patient should notify her health care provider if she
appropriate health decisions (14, 15). In addition, an has pain in her stomach, has a headache, or sees spots.
overall paucity of published research addresses patient The health care provider could then point to the areas
education in the context of pregnancy. Consequently, of concern (abdomen, head, and eyes) and provide a
models for successful interventions that address graphic-based tool intended to relay the same concept
health-related outcomes are found outside the context (22, 23). A group of researchers found that after dis-
of pregnancy. In 2007, the American Medical Associa- tributing a card depicting pictures of preeclampsia
tion Foundation published a monograph summarizing signs and symptoms to women in certain Jamaican
research related to health literacy. The publication also parishes, women from these parishes had lower rates
provided recommendations on how health care pro- of preeclampsia-related morbidity than women from
BOX 9-1. ey Components of Effective Health Communication and Patient Education ^

K
• Do not assume a patient’s literacy level or understanding based on her appearance.

• In both oral and written communication, use plain, nonmedical language.
• Speak slowly.
• Organize information into two or three components.
• Ask the patient to “teach back” information to confirm understanding.
Data from Nielsen-Bohlman L, Panzer AM, Kindig DA, editors. Health literacy: a prescription to end confusion. Committee
on Health Literacy, Board on Neuroscience and Behavioral Health, Institute of Medicine. Washington, D.C.: The National
Academies Press; 2004. p. 345.
PATIENT EDUCATION 75
parishes who had not received the card (22). The fifth-grade to sixth-grade reading level. Group prenatal
health care provider should also ask the patient to care, often called “centering pregnancy,” has been found
“teach back” the information to confirm the patient’s to be effective in conveying information and improving
understanding. An example would include, “We have perinatal outcomes at no added cost (26).
gone over a lot of information. In your own words, can
you tell me what we discussed today? What would
Patient Education Barriers
make you call your health care provider or come to the
hospital?” This should take the place of close-ended There are several barriers that may preclude a health
questions such as, “Did you understand the material care provider’s ability to educate patients about pre-
discussed today?” (16). eclampsia (Box 9-3). The amount of time available for
Grouping information together and then checking each prenatal visit is limited, and a great deal of infor-
for understanding—“chunk and check”—also is a way mation has to be relayed in a typical prenatal appoint-
to provide information that is easier to understand and ment. It is important to note that many of the
remember. When applying this concept to preeclamp- aforementioned techniques actually require little time.
sia, a health care provider could break down the con- If they are spread out over several visits starting as
versation by explaining the syndrome, its implications, early as 15 weeks of gestation, but no later than 20
the associated symptoms, and the appropriate actions weeks of gestation, and reviewed several times during
that should be used if a patient experiences symptoms. the course of the pregnancy, it would only take a few
Each of these broad ideas could include two or three minutes to discuss this information. In some settings,
details (Box 9-2). The health care provider should health care systems have successfully used a centering
check for understanding using the teach-back method pregnancy model, whereby women are grouped
before moving on to the next idea (16). together by due dates for prenatal education and sup-
Mobile applications are increasingly being used to port (27–29). Some may believe that providing a
reach diverse populations. More than 85% of Ameri- patient with information about preeclampsia will pro-
cans own a cell phone, and 72% of cell phone users duce unnecessary anxiety. There is evidence to the
send or receive text messages (24). Text4Baby, a contrary because failure to educate patients about pre-
text-messaging program that sends out timed prenatal eclampsia may cause women to experience greater
and postpartum information to registered mobile fear because of lack of information (1).
phones, recently reported positive results since its Evidence suggests that health care providers who
launch in February 2010 (25). Time spent in the patient fail to inform patients about preeclampsia may do so
reception area can be used to convey information by because the health care provider is underinformed. A
way of TV monitors and print material written at the 2002 survey of obstetrician–gynecologists revealed
BOX 9-2. hunk-and-Check ^

C
What is it?
Definition of preeclampsia in layman’s terms: “Preeclampsia is a serious disease related to high blood
pressure. It can happen to any pregnant woman.”
Why should you care?

Explanation of risks to the patient and her infant, emphasizing the seriousness of responding in a
timely manner: “There are risks to you: seizures, stroke, organ damage, or death; and to your baby:
premature birth or death.”
What should you pay attention to?

Explanation of potentially concerning signs and symptoms accompanied by graphics and simply
written description: “Symptoms include…”
What should you do?

Explanation of appropriate actions that should be taken if a patient experiences symptoms:
"If you experience any concerning symptoms, call you health care provider right away. Finding
preeclampsia early is important for you and your baby.”
76 PATIENT EDUCATION
BOX 9-3. ost Commonly Reported Barriers to Providing Preeclampsia Education ^

M
• Health care providers have too many important issues to address and not enough time.
• Information overload is causing women to be too anxious about their pregnancies.
• Materials that are written simply, available in other languages, and affordable, are not available.
• Health care providers are unsure about what information needs to be provided that will affect out-
comes.
great disparities in their knowledge and clinical man- prescribed management. This all leads to improved
agement of hypertensive disorders of pregnancy (30). pregnancy outcomes.
Health care providers need to understand that pre-
eclampsia without severe features can progress quickly
and unexpectedly; that proteinuria is not always pres-
ent, even in severe forms of preeclampsia; that women • It is suggested that health care providers convey in-
remain at risk of preeclampsia postpartum; and that a formation about preeclampsia in the context of pre-
woman’s symptoms should not be dismissed without a natal care and postpartum care using proven health
proper assessment. This is corroborated by thousands communication practices.
of patient experiences reported to the Preeclampsia Quality of evidence: Low
Foundation (31). Many clinicians and patients are Strength of recommendation: Qualified
unaware that preeclampsia can still occur after deliv-
ery. Postpartum hypertension or preeclampsia either is This chapter was developed with the assistance of
a new-onset condition or is secondary to persistence or Whitney You, MD.
exacerbation of hypertension in women with previous
gestational hypertension, preeclampsia, or chronic References
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CHAPTER
10
State of the Science and
Research Recommendations
A
n important charge of the American Col- includes a cascade of secondary effector mechanisms,
lege of Obstetricians and Gynecologists’ including altered proangiogenic and antiangiogenic
Task Force on Hypertension in Pregnancy factor balance, increased maternal oxidative stress, and
was to review the state of the science and endothelial and immunological dysfunction (5, 6). Fur-
to develop corresponding research recommendations ther elucidation of these mechanisms will hopefully
relating to management of hypertension during preg- lead to a more complete understanding of the patho-
nancy. The last such formal review of scientific data physiology of preeclampsia and to specific and success-
dates back to the National High Blood Pressure Ed- ful therapeutic intervention.
ucation Program’s presentation in 2000 (1). Summa-
rized as follows is the progress of research from 2000 Abnormal Implantation and Vasculogenesis
through 2012, with suggested areas in which focused Although the underlying molecular mechanisms that
investigations are needed or should continue. lead to the preeclampsia syndrome are not clear, a
major mechanism is believed to be placental insuffi-
ciency due to inadequate remodeling of the maternal
Fundamental Advances in the
vasculature perfusing the intervillous space. During
Understanding of Preeclampsia normal pregnancy, fetally derived cytotrophoblasts
Preeclampsia, at least early-onset preeclampsia, is invade the maternal uterine spiral arteries, replacing
believed to evolve in two stages (2–7). The first stage their endothelium, and differentiating into an endo-
(less than 20 weeks of gestation) involves poor placen- thelial-like phenotype (8). This complex process
tation, at which time there are neither signs nor symp- results in a conversion of the high-resistance,
toms of the disorder. The second stage involves the small-diameter vessels into high-capacitance, low-
consequences of poor placentation, probably evoked by resistance vessels and ensures adequate delivery of
relative placental hypoxia and hypoxia reperfusion, maternal blood to the developing uteroplacental
resulting in a damaged syncytium and limited fetal unit. In the woman destined to develop preeclamp-
growth, with these and other events leading to the clin- sia, poorly understood errors in this carefully orches-
ical findings of preeclampsia. The link between the rel- trated scheme lead to inadequate delivery of blood to
atively hypoxic placenta and the maternal syndrome the developing uteroplacental unit and increase the
79
80 STATE OF THE SCIENCE AND RESEARCH RECOMMENDATIONS
degree of hypoxemia and oxidative and endoplasmic Endothelial Activation and Dysfunction
reticulum stress. The maternal vascular endothelium of women destined
The exact mechanisms responsible for the abnor- to develop preeclampsia appears to be an important tar-
mal trophoblast invasion and vascular remodeling in get of factors that are presumably generated through
preeclampsia are unclear, but a series of studies have placental ischemia and hypoxia (5, 6, 11). The vascular
now appeared that are enhancing the understanding endothelium has many important functions, including
of these important adaptations and of potential mech- control of smooth muscle tone through the release of
anisms that may lead to maladaptations (2–7). In vasoconstrictors and vasodilators and the regulation of
one study, researches provided evidence that Notch anticoagulation, antiplatelet, and fibrinolytic functions
signaling may be a crucial component of the process by release of different soluble factors. Alterations in the
whereby fetal trophoblast cells invade and remodel circulating concentration of many markers of endo-
maternal blood vessels (9). They reported that failure thelial dysfunction have been reported in women that
of this physiologic transformation in the absence of develop preeclampsia (5, 6, 11). This suggests that the
Notch2 is associated with reduced vessel diameter and disease is an endothelial cell disorder. The fact that this
placental perfusion. Their findings that perivascular endothelial dysfunction can be demonstrated before
and endovascular cytotrophoblasts often fail to express overt disease supports a causal role.
the Notch ligand, JAG1, in preeclampsia provides fur- Maternal status may influence the endothelial
ther evidence that defects in Notch signaling may be response to factors triggered by placental ischemia and
an important part of the pathogenesis of this preg- hypoxia in preeclampsia. There is compelling evidence,
nancy complication. for example, that obesity, a major epidemic in devel-
Other studies also have suggested that variability of oped countries, including the United States, increases
immune system genes that code for major histocom- the risk of preeclampsia. A body mass index (calculated
patibility complex molecules and natural killer recep- as weight in kilograms divided by height in meters
tors also may affect human placentation (10). They squared) characteristic of obesity (greater than 39)
reported that specific combinations of fetal major his- increases this risk threefold (12). Despite this and
tocompatibility complex molecules and maternal natu- many other studies linking obesity to preeclampsia, the
ral killer receptor genes in humans correlate with the pathophysiologic mechanisms whereby obesity in-
risk of preeclampsia, recurrent miscarriage, and fetal creases the risk of developing preeclampsia are unclear.
growth restriction. Researchers have begun to explore Thus, further research into how obesity and metabolic
the similarities and differences between human and factors such as leptin, insulin, and free fatty acids,
mice natural killer cells and potential trophoblast affect the various stages of preeclampsia is warranted.
ligands with the aim of developing mouse models that
will elucidate how natural killer cell–trophoblast inter- Factors Linking Placental Ischemia and
actions contribute to placentation. Hypoxia With the Maternal Syndrome
Studies like the aforementioned studies, have Angiogenic Factors
established abnormalities in vasculogenic and angio- In response to placental hypoxia, the placenta is pro-
genic signaling pathways as important candidates to posed to produce pathogenic factors that enter the
explain mechanisms by which placentation goes awry maternal blood stream and are responsible for the endo-
in preeclampsia, leading the task force to strongly rec- thelial dysfunction and other clinical manifestations of
ommend the need for more emphasis on the study of the disorder. A variety of molecules are released but
placentation during pregnancy and preeclampsia. amongst them, antiangiogenic and autoimmune or
Although genetic manipulation in mouse models can inflammatory factors have recently received the greatest
be an important tool in providing insights into the pro- attention (13, 14). In these respects, perhaps the most
cess of placentation, the placentas of these animals intensely studied pathway in the manifestation of pre-
differ significantly from those in women, underscoring eclampsia is that related to vascular endothelial growth
a critical need to perform such research in primates, factor (VEGF) signaling. Vascular endothelial growth
where placentation is similar to that in humans. factor and placental growth factor (PlGF-1), besides
In addition, use of state-of-the-art technologies and their role in angiogenesis, also are important in the
experimental approaches such as genomic, proteomic, maintenance of proper endothelial cell function. This
metabolomic, and microRNA analyses should provide signaling pathway came to prominence with the discov-
new and important information regarding molecular ery of elevated circulating and placental concentrations
pathways involved in the process of placentation. of the soluble form of the VEGF receptor Flt-1 (sFlt-1).
STATE OF THE SCIENCE AND RESEARCH RECOMMENDATIONS 81
The soluble form of the VEGF receptor Flt-1 is a circulat- which includes both exosomes and microvesicles.
ing soluble receptor for both VEGF and PlGF, that when They speculate that changes not only in the numbers,
increased in maternal plasma leads to less circulating but also in the size (beneficial syncytiotrophoblast exo-
free-VEGF and free-PlGF, thus preventing their availabil- somes and harmful microvesicles), might be important
ity to stimulate angiogenesis and maintain endothelial in the maternal syndrome of preeclampsia.
integrity. In the kidney, this inactivation of free-VEGF is Another area related to the immune component of
believed to cause glomerular endotheliosis with conse- preeclampsia is research relating to the agonistic anti-
quent proteinuria (13, 14). Studies of the regulation of body AT1-AA (18, 19). These autoantibodies, isolated
sFlt-1 in cell culture and placental tissue in vitro have more than a decade ago in women who had preeclamp-
demonstrated that sFlt-1 is released from placental villi sia, have been studied more intensively recently,
and trophoblast cells in response to reduced oxygen ten- including their identification in the circulation of rats
sion similar to that seen in an ischemic placenta. A undergoing placental ischemia. These antibodies
promising pilot study demonstrated that sFlt-1 could be appear to be induced by the production of the cyto-
removed from the maternal circulation by apheresis kine, tumor necrosis factor (TNF)-α because infusion
safely, and that this therapy reduced both blood of TNF-α into pregnant rats also results in production
pressure (BP) and proteinuria, with a trend toward of the antibody at concentrations comparable to that
increased gestational duration (15). seen in pregnant women with preeclampsia and the
Although compelling data derived from animal and Reduced Uterine Perfusion Pressure (RUPP) rat (20).
human studies suggest an important role for angio- It also has been demonstrated that infusion of AT1-AA
genic imbalance in the pathophysiology of preeclamp- directly into pregnant rats results in moderate hyper-
sia, there are many unanswered questions and many tension. However, the pathogenic importance of these
opportunities for future research. For example, the antibodies remains to be fully elucidated because their
molecular mechanisms involved in the regulation of presence has been noted postpartum in a subset of
sFlt-1 production have yet to be fully elucidated. More- patients who had preeclampsia with no discernible
over, although sFlt-1 appears to play an important role phenotype. Further studies are needed, including
in the pathogenesis of preeclampsia, specific inhibitors determining how these unique antibodies are produced
of sFt-1 production are not available at this time. Thus, and how they interact with the other pathogenic agents
research into the discovery of inhibitors of sFlt-1, or in preeclampsia to produce the clinical phenotype.
ways to stimulate greater production of VEGF and
PlGF, is of critical importance. Endothelin
There is growing evidence to suggest an important
Immune Factors and Inflammation role for endothelin-1 (ET-1) in the pathophysiology of
One of the earliest and most persistent theories about preeclampsia. Given the myriad experimental models
the origins of preeclampsia was that it is a disorder of of preeclampsia (placental ischemia, sFlt-1 infusion,
immunity and inflammation (16). Of interest is work TNF-α infusion, and AT1-AA infusion) that have
that suggests the inflammatory response is triggered proved susceptible to ETA antagonism, could the ET-1
by particles shed from the syncytial surface of the system be a potential therapeutic target for the treat-
human placenta ranging from large deported multinu- ment of preeclampsia (21)? Because there is evidence
clear fragments to subcellular components. These cir- that interfering with the ETA receptor in early animal
culating particles are increased in preeclampsia. In this pregnancy may abort the pregnancy or lead to devel-
respect, researchers have proposed that the fragments opmental anomalies, research here should focus later
include proinflammatory proteins that may contribute in gestation where ETA-receptor antagonists might
to the systemic inflammatory response in normal preg- prove safe and efficacious, which is started when
nancy and the exaggerated inflammatory response in symptoms appear. Alternatively, development of ETA-
preeclampsia (16). There is new evidence from the receptor antagonists, which do not cross the placental
same researchers of a large hidden population of barrier, would be welcome. Researchers recently
microvesicles and nanovesicles (including exosomes), reported that a selective ETA-receptor antagonist had
not easily studied because of their small size (17). limited access to the fetal compartment during chronic
Using nanoparticle tracking analysis to measure the maternal administration late in pregnancy (22).
size and concentration of syncytiotrophoblast vesicles
prepared by placental perfusion, they found that vesi- Nitric Oxide
cles range in size from 50 nanometers to 1 micrometer Studies have suggested important roles for nitric oxide
with the majority being less than 500 nanometers, as a regulator of arterial pressure under various physi-
ologic and pathophysiologic conditions (6). Nitric oxide eclampsia should help shed further light into the
production is elevated in normal pregnancy, and these importance of oxidative stress in the pathophysiology
increments appear to play an important role in the vaso- of preeclampsia and perhaps allow the identification
dilatation of pregnancy. Thus, it was postulated that of useful antioxidant strategies. It remains to be seen
nitric oxide deficiency during preeclampsia might be whether reactive oxygen species production is a pri-
involved in the disease process. Studies from several mary or secondary cause of preeclampsia pathophysi-
laboratories have found that chronic nitric oxide syn- ology, and how effective manipulation of the system
thase inhibition in pregnant rats produces hypertension will be in the search for effective therapies.
associated with peripheral and renal vasoconstriction, There also appears to be an excess of endoplasmic
proteinuria, intrauterine growth restriction, and in- reticulum stress in placentas from women with early-
creased fetal morbidity, a pattern resembling the find- onset preeclampsia (26). Endoplasmic reticulum stress
ings of preeclampsia (6). However, whether there is a activates a number of signaling pathways aimed at
reduction in nitric oxide production during preeclamp- restoring homeostasis. Researchers have proposed that
sia is controversial. Much of the uncertainty originates this homeostatic mechanism fails and apoptotic path-
from the difficulty in directly assessing the activity of ways are activated to alter placental function in
the nitric oxide system in a clinical setting. Assessment women who develop preeclampsia (26). In addition
of whole-body nitric oxide production by measurement chronic, low concentrations of endoplasmic reticulum
of 24-hour nitrate–nitrite excretion has yielded variable stress during the second trimester and third trimester
results because of difficulties in controlling for factors may result in a growth restricted phenotype. They also
such as nitrate intake, thus, the relative importance of propose that higher concentrations of endoplasmic
nitric oxide deficiency in the pathogenesis of preeclamp- reticulum stress lead to activation of proinflammatory
sia has yet to be fully elucidated. pathways that may contribute to maternal endothelial
cell activation. Although endoplasmic reticulum stress
Oxidative and Endoplasmic Reticulum Stress is known to occur in preeclampsia, the importance of
Oxidative stress also has been implicated in pre- this abnormality in the pathophysiology has yet to be
eclampsia because increased concentration of several fully elucidated.
oxidative stress markers also have been reported sys-
temically in women with preeclampsia, among these Hemeoxygenase
peroxynitrites (23, 24). Peroxynitrite concentrations in It also appears that the stress response gene, heme-
vascular endothelium were much higher in women oxygenase-1 (HO-1), and its catalytic product, carbon
with preeclampsia compared with women with nor- monoxide also may be involved in the pathogenesis of
mal pregnancies, concurrent with decreased concen- preeclampsia (27). Genetic or pharmacologic block-
trations of superoxide dismutase and nitric oxide ade of HO-1 in pregnant animals lead to preeclampsia-
synthase (25). There also is evidence of increased oxi- like phenotypes (27). It also appears that induction of
dative stress during gestation in the RUPP rat hyper- the HO-1 gene may be involved and, thus, this too is
tensive model, suggesting a link between placental an area in which to explore therapeutic approaches.
ischemia and hypoxia with the production of reactive There are several lines of evidence that HO-1 and its
oxygen species (6). Treating this model with two dif- catalytic products may protect against the progression
ferent antioxidants, 1) vitamin C and 2) vitamin E, had of preeclampsia by interfering at sites in the pathway
no effect on the gestational hypertension. The super- that links placental hypoxia and hypertension (28–
oxide dismutase mimetic drug, tempol, however, led 30). Of interest, in this respect, are studies suggesting
to significant attenuation of the hypertensive response. that combustion products of tobacco, such as carbon
In a related study, administration of the reduced form monoxide, reduce the risk of preeclampsia by more
of nicotinamide adenine dinucleotide phospate oxi- than 35% (29). In addition, TNF-α mediated cellular
dase inhibitor, apocynin, also significantly attenuated damage in placental villous explants can be prevented
RUPP-induced gestational hypertension, implicating by up-regulating HO-1 enzyme activity (28). Heme
that enzyme as an important source of pathogenic oxygenase pathways have also been shown to inhibit
reactive oxygen species in the RUPP animal (6). Fail- the release of sFlt-1 in several in vitro models (30).
ure of the drug to fully normalize BP, however, leaves Induction of the HO-1 enzyme or chronic administra-
open the possibility that alternative reactive oxygen tion of HO-1 metabolites have also been reported to
species production pathways are at work in the RUPP ameliorate hypertension in several animal models of
model. Further studies into the mechanism of reactive hypertension that involve BP regulatory factors similar
oxygen species production in animal models of pre- to that observed in women with preeclampsia. More
compelling evidence that supports the concept that the management of preeclampsia. Cogent examples
HO-1 and its catalytic products may protect against are the clinical trials of magnesium sulfate to prevent
the progression of preeclampsia are data that indicate and treat eclampsia that resolved decades of contro-
that chronic administration of an HO-1 enzyme inducer versy. Obstetricians in the United Sates used magne-
(cobalt protoporphyrin IX chloride) or carbon monox- sium sulfate for almost 70 years with little attention
ide releasing molecule-A1 significantly attenuates from other parts of the world and with scorn from the
hypertension in response to placental ischemia (31). neurological community. However, studies in the past
These findings, taken together, make heme oxygenase two decades have now established that magnesium
a potential target for studies to improve the treatment sulfate can be used safely, including administering it in
of preeclampsia. In this respect, the cardiovascular (CV) developing countries. Magnesium sulfate therapy was
drugs, statins, have been shown to stimulate HO-1 shown to be superior to phenytoin or diazepam for
expression and inhibit sFlt-1 release in vivo and in vitro; treating eclampsia and is more effective than phenyto-
thus, they have the potential to ameliorate early-onset in or placebo for preventing preeclampsia (32–34).
preeclampsia. The pavaStatin to Ameliorate Early This has had a major effect on modifying treatment
Onset Pre-eclampsia trial is underway to address this outside the United States. In the United States magne-
and, if positive, its outcome could lead to therapeutic sium sulfate is accepted as the drug of choice but the
intervention to prolong affected pregnancies. answer to the question of whom to treat remains
unclear. In Chapter 5 “Management of Preeclampsia
and HELLP Syndrome,” the available data are reviewed
Summary of Fundamental Research
and recommendations are made to guide rational use
Recommendations by the Task Force of the drug.
As noted, there has been enormous progress toward At times empirically guided, but also guided by
understanding the pathophysiology of preeclampsia research results, a plethora of potential predictive tests
during the past two decades, but many unresolved and have been examined. None of these have been shown
critical questions remain. The full elucidation of the to be clinically useful, although current investigations
molecular and cellular mechanisms involved in the using combinations of tests has engendered cautious
various stages of the disease process will hopefully optimism that clinically useful ways to predict pre-
lead to a more complete understanding of the etiology eclampsia may be on the horizon (35, 36). In this
of preeclampsia and eventually lead to successful ther- respect, the use of combinations of analytes and bio-
apeutic intervention through the targeted disruption physical testing (eg, uterine artery Doppler velocime-
of new and novel pathways. As follows are basic sci- try) has encouraging preliminary results (35).
ence research recommendations to attempt to resolve Prevention is another critical focus of clinical stud-
some of these unsolved questions over the next several ies. Several strategies have been tested, retested, or
years: reanalyzed with, at best, minimal evidence of success.
• More research on the study of placentation, in- The latest entry into prevention testing was the use of
cluding immunological abnormalities and abnor- antioxidant vitamins. The presence of oxidative stress
malities of angiogenic signaling pathways during in preeclampsia has been evident for many years in
pregnancy and preeclampsia, is needed. multiple tissues (although there has been some contro-
versy) (37, 38). By the late 1990s the evidence seemed
• Continued research on the role of genetic and epi- sufficient to warrant a trial of the antioxidants vitamin
genetic factors in preeclampsia is warranted. C and vitamin E, to modify the pathophysiology of pre-
• Research on the molecular mechanisms involved in eclampsia. In a small pilot study, performed in England,
the regulation of proangiogenic and antiangiogenic vitamin C and vitamin E were administered in phar-
factors also is needed. macologic doses (far exceeding those present in prena-
tal vitamins) with the intent of reducing evidence of
• Research into the discovery of novel inhibitors of
endothelial activation (39). Antioxidant vitamin treat-
sFlt-1 is of critical importance.
ment was associated not only with reduced endothe-
• Further development of animal models is needed. lial activation and reduced oxidative stress, but also
with a significant reduction in the frequency of pre-
Advances in Clinical Research eclampsia. The findings stimulated large trials in
Clinical research stimulated by and performed follow- England, Canada, Australia, and the United States and
ing the last National High Blood Pressure Education in developing countries. Both low-risk and high-risk
Program report also has led to important advances in women were studied. However, none of the studies
demonstrated any evidence of a beneficial effect (40). calcium success, it could be postulated that there
Whether the lack of success was due to timing, dosage, might be a subset of women with preeclampsia in
or the particular antioxidant used is not known, but it whom low-dose aspirin therapy would be effective.
is clear that the use of vitamin C and vitamin E in unse- This was studied using an approach termed “individu-
lected low-risk or high-risk women is not indicated for al patient meta-analysis” in which the data from stud-
the prevention of preeclampsia. ies are brought together for reanalysis. In this study, it
The findings with vitamin C and vitamin E mirror was not possible to identify any subset of patients in
the findings of studies that used low-dose aspirin and whom therapy was uniquely effective (48). The study
calcium to prevent preeclampsia. In all studies, these did confirm the significant effects of aspirin therapy
agents were successful in initial small studies, but that reported in standard meta-analysis to prevent pre-
success was not validated in larger trials (41–45). The eclampsia, and to reduce prematurity and perinatal
most likely explanation for this discrepancy is that the mortality. However, the effects of aspirin were not clin-
small studies are underpowered and reflect publica- ically useful in these analyses because the usual preva-
tion bias. That is, small studies that are successful are lence of preeclampsia in low-risk populations was
reported, whereas small studies that do not succeed 2–3%; therefore, 500 women would need to be treated
are not likely to be reported and published. There are in order to prevent one case of preeclampsia. However,
other interesting possibilities. One treatment may not it is important to remember that as the prevalence of a
be effective for all cases of preeclampsia. Thus, suc- disease increases, the number of patients necessary to
cesses in small studies in homogenous populations are treat for a successful outcome reduces. Thus, in indi-
not substantiated in larger studies, which characteris- viduals who have preexisting risk factors that increase
tically are not only larger but also more heterogeneous preeclampsia prevalence to 20%, it would only require
because they are usually performed in several centers. treating 50 patients to prevent one case of preeclamp-
This was a consideration in the studies of calcium to sia. For this reason the task force suggests low-dose
prevent preeclampsia where the early small successful aspirin prophylaxis in patients at high risk of pre-
trials largely took place in developing countries where eclampsia. Specifically, low-dose aspirin is recom-
many women had low calcium intake, whereas the mended beginning late in the first trimester for women
large unsuccessful trial was conducted in the United with a medical history of preeclampsia in more than
States where the vast majority of women had ade- one prior pregnancy or in whom preeclampsia in a
quate calcium intake (40, 41). The World Health Orga- prior pregnancy resulted in the birth of an infant at
nization tested this possibility in a study in which less than 34 weeks of gestation. These women have a
calcium was supplemented in pregnant women from prevalence of preeclampsia of at least 40%. Thus,
populations known to have a low calcium intake (46). approximately 20 women would need to be treated to
There was no reduction in the incidence of preeclamp- prevent one case of preeclampsia. Additionally, the
sia with calcium treatment. However, the frequency of treatment of 35,000 women with low-dose aspirin in
severe adverse outcomes, including eclampsia and the numerous previous trials indicated no acute
severe hypertension was lower. Further, treatment adverse outcomes for the woman or her infant. How-
reduced a composite outcome of adverse maternal ever, there is no information on the long-range safety
outcomes. Although the body of the calcium studies of the drug. Based on this information, it would seem
supports the concept of prevention with a particular reasonable to discuss the possibility of low-dose aspi-
agent being pertinent in some, but not all, popula- rin therapy with an individual woman at less extreme
tions, it also indicates calcium supplementation is not risk, pointing out the potential benefit to her and the
useful in a population with adequate calcium intake as established safety of the drug acutely, but also the
occurs in the United States. unknown long-term safety. The decision for therapy
An attempt was made to evaluate the efficacy of would then be based on the importance of these par-
low-dose aspirin by meta-analysis of approximately ticular factors to the particular woman.
35,000 women who had been included in trials of Another possibility that arises from the failure of
aspirin to prevent preeclampsia. There was no evi- predictors to predict preeclampsia and therapy based
dence of significant reduction in preeclampsia in any on well-established pathophysiology to prevent pre-
of the large individual trials. However, in the eclampsia is that preeclampsia may actually be more
meta-analysis of this large number of participants, than one disease. This possibility certainly is supported
there was a significant reduction in the frequency of by clinical and epidemiologic data, which indicate pro-
preeclampsia, premature births, and perinatal mortal- foundly different effects of the disorder in different
ity with low-dose aspirin therapy (47). Based on the women and at different times in pregnancy and differ-
ent long-term CV outcome with early-onset preeclamp- weeks of gestation have an 8–10-fold increased risk,
sia and late-onset preeclampsia (49). Thus, the task and women with recurrent preeclampsia have an
force encourages attempts to identify subtypes of pre- increase in death from CV disease earlier in life than
eclampsia as one of the targets for future research. The women who only have preeclampsia in their first preg-
analogy of diabetes in which the disease is recognized nancies (55). It seems most likely that the increase in
as insulin-resistant or is insulinopenic with each subset CV disease in later life in women with preeclampsia is
that requires different therapy indicates the value of due to common risk factors for both conditions
this approach. although a component of residual injury from pre-
In a clinical trial performed in the Netherlands, eclampsia cannot be completely excluded. The Ameri-
investigators examined whether in women with mild can Heart Association recognized the relationship of
preeclampsia or mild gestational hypertension (hyper- preeclampsia and later-life CV disease in its recent
tension, but no proteinuria) it is safer for them to give guidelines (56). These guidelines list a pregnancy his-
birth at 37 weeks of gestation or it is safer to observe tory as a part of the assessment of CV risk for women.
them (50). The study showed a reduction in adverse They also state that preeclampsia and gestational dia-
maternal outcomes with delivery at 37 weeks of gesta- betes should be part of the risk score for CV disease.
tion compared with observation. There was no increase The challenge is to determine how to use this informa-
in neonatal morbidity. For this reason the task force tion (57). This raises the idea that a history of pre-
recommends delivery at 37 weeks of gestation in eclampsia might suggest that these women be tested
women with mild preeclampsia and mild gestational for CV disease earlier than age 40 years.
hypertension. Nonetheless, this study should be repli- In reviewing the recommendations that the task
cated in a U.S. population. force has prepared, it becomes evident that there are
A problem inherent in this recommendation must few clinical issues for which there is strong evidence.
be resolved by future research. There is abundant evi- Therefore, the task force has prepared the following
dence that gestational hypertension is not simply a lists of research recommendations to attempt to
mild form of preeclampsia. Twenty five percent of resolve some of these problems in the near future.
women in whom gestational hypertension is diag-
nosed at 34 weeks of gestation will later develop pro- Task Force Recommendations for Clinical
teinuria and thus preeclampsia (51). It also is likely Research
that another portion of the women have preeclampsia Prediction and Risk Stratification
without developing proteinuria by the time they give
birth. Another portion of women with gestational • Prospective clinical trials should be performed to
hypertension have chronic hypertension that was demonstrate the clinical utility of biomarkers or their
masked by the decrease of BP in early pregnancy. combinations with biophysical variables that can
However, it is also evident there is another group of directly affect management decisions as follows:
women with mild gestational hypertension in whom – Ways to differentiate women destined to de-
there is no risk other than hypertension. This is evident velop preeclampsia from those who will not at a
from studies of women with mild gestational hyper- period during gestation when available inter-
tension in whom, as the components of the syndrome ventions will improve outcome.
of preeclampsia decrease (eg, no evidence of hyperuri- – Clarification if such markers or BP thresholds
cemia or an increase in cellular fibronectin), the likeli- can identify an increased risk of perinatal mor-
hood of adverse outcomes is reduced until it is difficult bidity in subsets of women
to differentiate their outcome from that of normoten-
– Clarification if uric acid level assessment will
sive women (52, 53). Thus, a target for research rec-
serve as a biomarker given its ease and minimal
ommended by the task force is to develop tests that
cost of its measurement.
can be performed on women with gestational hyper-
tension to predict the likelihood that they have or will • There is evidence that subsets of preeclampsia exist
proceed to preeclampsia or adverse outcome. characterized by gestational age onset, gestational
For many years, it has been evident that women age at delivery, the presence or absence of fetal
with preeclampsia have an increased risk of CV disease growth restriction, or the long-term risk of maternal
later in life. Recent epidemiological studies indicate CV disease. Additional research is needed to help
this to be an approximate twofold increase for all verify and characterize the subsets of the disease in a
women with a history of preeclampsia (54). However, manner that helps clarify morbidity and mortality
women with preeclampsia who give birth before 34 risks as well as specific management options.
• Additional evaluation is needed to show whether • Major perinatal morbidity with HELLP syndrome
the magnitude of 24-hour protein excretion discrim- occurring before 23–24 weeks of gestation has not
inates the ongoing risk of morbidity in preeclampsia, been improved with any current management
and, if so what the ideal cutoff needs to be. scheme used because delivery is usually mandated.
Work is needed to develop effective therapeutic in-
• Future research on more novel technologies, such
terventions to safely prolong pregnancy to viability
as plasma or urine metabolite profiles and circulat-
of the fetus without endangering maternal welfare.
ing microRNAs, may prove to not only be useful for
understanding the pathogenesis of the disease, but • Therapy to effectively treat patients with pre-
also in the development of novel therapies. eclampsia that fails to improve or resolve postpartum
using standard therapy requires more extensive
• Identify biophysical variables or biomarkers (or
investigation and standardization.
combinations) that distinguish women with mild
gestational hypertension who will not have adverse • A Clinical Trials Network for the performance of
outcomes with a negative predictive value suffi- preeclampsia-focused research should be consid-
cient to allow follow-up and management as a lowered for implementation.
risk patient.
Management of Preeclampsia, Eclampsia, and HELLP
• All of these recommended studies should focus not
Syndrome
only on clinical usefulness but how they directly
affect obstetrician’s management decisions, improve • More research should be performed to determine
health outcomes, and reduce costs to the health care the most appropriate antihypertensive treatment
system. for persistent postpartum hypertension.
• Randomized trials to determine optimum delivery

Therapy and Prevention of Preeclampsia, Eclampsia,
timing in women with mild gestational hyperten-
and HELLP Syndrome
sion and preeclampsia should be repeated in U.S.
• Research collaboration between investigators, the populations.
pharmaceutical industry, and governmental agen-
• Maternal mortality data should be assessed to bet-
cies should be encouraged to develop novel thera-
ter identify causes of death in hypertensive preg-
pies for the treatment of preeclampsia.
nant women.
• The role of potent corticosteroids to prevent pro-
• Some cases of eclampsia appear to be manifesta-
gression and accelerate recovery from HELLP syn-
tions of posterior reversible encephalopathy syn-
drome requires further study in a large randomized
drome. It should be determined whether or not
prospective clinical trial that is appropriately struc-
women with preeclampsia and milder cerebrovas-
tured to include only patients who do not require
cular symptoms (headache or visual disturbances)
corticosteroids for fetal indications (greater than
also have posterior reversible encephalopathy syn-
34 weeks of gestation).
drome.
• Research should be directed at determining the
• Identification of early posterior reversible encepha-
most appropriate antihypertensive treatment for
lopathy syndrome and prevention of its progression
persistent postpartum hypertension.
might prevent eclampsia. Studies are needed to
• The optimal use of diuretics in the postpartum determine if posterior reversible encephalopathy syn-
management of patients with preeclampsia, ec- drome can be detected without a magnetic resonance
lampsia, and HELLP syndrome requires study and imaging examination and whether any intervention
clarification to augment current management such as magnesium sulfate, steroids, diuretics, or oth-
schemes. er agents can be targeted to patients at greatest risk.
• The administration of potent corticosteroids appears • Management of eclampsia occurring before 34

to benefit patients with cerebral edema. The poten- weeks of gestation requires further investigation to
tial role of any of these agents to benefit patients determine if delay of delivery for 24 –72 hours may
with eclampsia or patients developing cerebral significantly improve perinatal outcome without
edema or posterior reversible encephalopathy syn- adversely affecting maternal outcome.
drome deserves investigation.
• How often to evaluate patients in the postpartum Long Range Follow-Up of Women Who Have Had Pre-
period with severe forms of preeclampsia following eclampsia
hospital discharge remains unclear. Protocols to
• Studies are needed to determine the best immedi-
evaluate possible management schemes are desir-
ate and remote postpartum follow-up procedures
able to undertake so that best practices can be
in relation to the increased remote CV disease in
determined and implemented.
women who have had preeclampsia. The following
• Nifedipine use for BP control in the patient with questions need to be answered:
preeclampsia receiving magnesium sulfate requires – When and how often they should be evaluated?
further study to determine the limits of safety for
– What tests should be performed?
use of both drugs concurrently.
– Can risk be stratified with considerations in
• Persistent moderate hypertension several days into addition to early-onset, severe, recurrent pre-
the puerperium in patients with a severe form of eclampsia?
preeclampsia requires study as to which antihyper-
– Are there women with normal pregnancy out-
tensive agents are best to administer and how best
comes with increased risk of CV disease who can
to monitor and assess their effectiveness.
be identified by assessments of metabolic and
• A subset of patients with HELLP syndrome present vascular changes during pregnancy?
with evidence of renal compromise early in the
• More research on fetal programming of CV diseases
course of the disease. The factors leading to this
(in utero influences on the development of CV
and the optimal management of the adversely
issues later in life) is needed.
affected kidneys in these patients requires further
investigation. • Studies of the psychologic effect of preeclampsia
are needed.
• The role of umbilical artery Doppler velocimetry
and its effect on perinatal morbidity and mortality
Chronic Hypertension
in the complicated pregnancies without IUGR,
including pregnancies complicated by hyperten- • Current data regarding teratogenicity of drugs that
sion, diabetes, and other disorders associated with decrease angiotensin production or their actions
placental abnormalities requires further investi- have been questioned. This combined with the
gation. problem of stopping therapy in some women with
hypertensive preeclampsia, dictates more research
Mechanistic Clinical Research to determine the effects of renin angiotensin sys-
tem inhibitors during early pregnancy on fetal out-
• Research is needed to identify the mechanisms that comes.
account for the increased risk of CV disease in wom-
en with a medical history of preeclampsia. • More clinical evidence is needed to guide the man-
agement of hypertension during pregnancy. Specif-
• Research on the molecular mechanisms involved in ically, it is not known whether lowering moderate
the regulation of proangiogenic and antiangiogenic chronic hypertension (greater than 150 mm Hg sys-
factors is needed. tolic and 95 mm Hg diastolic; less than 160 mm Hg
• Research on the mechanisms whereby obesity systolic and 110 mm Hg diastolic) confers either
affects placentation is warranted. maternal or fetal risk or benefit during pregnancy.
Clinical trials should evaluate specific BP targets,
• Research on the mechanisms whereby chronic using specific antihypertensive agents, and evaluat-
hypertension increases the risk of developing pre- ing meaningful clinical outcomes such as preterm
eclampsia is needed. birth, IUGR, and severe maternal disease, including
• Further studies of the renal abnormalities in preeclampsia and HELLP syndrome.
eclampsia are warranted to better explain the basis
for the decreased glomerular filtration rate and Education
strategies to reverse the renal pathology and • Evaluation of the effect of prenatal education for
decreasing glomerular filtration rate. women with low literacy on pregnancy outcomes is
needed.
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Hypertension in Pregnancy

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HYPE RTE N SION

HYPE RTE N SION IN PREGNANCY

Library of Congress Cataloging-in-Publication Data

Copyright 2013 by the American College of Obstetricians and Gynecologists,

Task Force on Hypertension in Pregnancy v

Chapter 1: Classification of Hypertensive Disorders 13

Chapter 2: Establishing the Diagnosis of Preeclampsia and Eclampsia 17

Chapter 3: Prediction of Preeclampsia 21

Chapter 4: Prevention of Preeclampsia 27

Dietary Salt Intake 29

Chapter 5: Management of Preeclampsia and HELLP Syndrome 31

Chapter 6: Management of Women With Prior Preeclampsia 47

Chapter 7: Chronic Hypertension in Pregnancy and Superimposed Preeclampsia 51

Chapter 8: Later-Life Cardiovascular Disease in Women With Prior Preeclampsia 71

Chapter 9: Patient Education 73

Chapter 10: State of the Science and Research Recommendations 79

James M. Roberts, MD, Chair Maurice Druzin, MD

John R. Barton, MD Arun Jeyabalan, MD, MS

S. Ananth Karumanchi, MD Catherine Y. Spong, MD

Conflict of Interest Disclosures

American Academy of Physician Assistants

BOX E-1. Severe Features of Preeclampsia (Any of these findings) ^

• Thrombocytopenia (platelet count less than 100,000/microliter)

TABLE E-1. Diagnostic Criteria for Preeclampsia ^

• If evidence of fetal growth restriction is found in

– preterm premature rupture of membranes Quality of evidence: High

Women with a medical history of preeclampsia should

and inflammation, and secondary mediators that

TABLE 2-1. Diagnostic Criteria for Preeclampsia ^

Pressure Education Program Working Group (2).

Prediction of Preeclampsia Using

various populations (9–12). A recent Cochrane sys-

*Meta-analysis of more than 30,000 women in randomized Quality of evidence: High

Maternal and Fetal Findings

• 37 0/7 weeks or more of gestation

• Less than 37 0/7 weeks of gestation

• 37 0/7 weeks or more of gestation Yes

risks associated with expectant management include

Magnesium Sulfate Prophylaxis Antihypertensive Drugs to Treat Severe

• Observe in labor and delivery for first 24–48 hours

Contraindications to continued expectant management

Are there additional expectant complications?

• Achievement of 34 0/7 weeks of gestation

FIGURE 5-2. Management of severe preeclampsia at less than 34 weeks of gestation. ^

with HELLP syndrome. Because a significant fetal

Placement of a catheter in a central vein for deter- Postpartum Hypertension and

TASK FORCE RECOMMENDATIONS

• For women in whom gestational hypertension, pre-

be performed for at least 72 hours postpartum and Quality of evidence: Low

BOX 6-1. Evaluation and Management of Women at Risk of Preeclampsia Recurrence ^

as outlined by the Seventh Report of the Joint National

systolic BP is 140 mm Hg or higher or the diastolic BP

TABLE 7-2. Common Oral Antihypertensive Agents in Pregnancy ^

Quality of evidence: Moderate Clinicians should recognize that there is often

regarding expectant management beyond the 48 hours

BOX 8-1.  valuation for Risk Factors ^

BOX 9-1.  ey Components of Effective Health Communication and Patient Education ^

• Do not assume a patient’s literacy level or understanding based on her appearance.

BOX 9-2.  hunk-and-Check ^

Why should you care?

• Thrombocytopenia (platelet count less than 100,000/microliter)

BOX 8-1. valuation for Risk Factors ^

BOX 9-1. ey Components of Effective Health Communication and Patient Education ^

BOX 9-2. hunk-and-Check ^

BOX 9-3. ost Commonly Reported Barriers to Providing Preeclampsia Education ^