Controversias en Preeclampsia

OBSTETRICS AND GYNECOLOGY ADVANCES
CONTROVERSIES
IN PREECLAMPSIA

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or
by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no
expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No
liability is assumed for incidental or consequential damages in connection with or arising out of information
contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in
rendering legal, medical or any other professional services.
OBSTETRICS AND GYNECOLOGY
ADVANCES

Additional books in this series can be found on Novas website
under the Series tab.

Additional e-books in this series can be found on Novas website
under the e-book tab.

OBSTETRICS AND GYNECOLOGY ADVANCES

CONTROVERSIES
IN PREECLAMPSIA

EYAL SHEINER
AND
YARIV YOGEV
EDITORS

New York

Copyright 2014 by Nova Science Publishers, Inc.

All rights reserved. No part of this book may be reproduced, stored in a retrieval system or
transmitted in any form or by any means: electronic, electrostatic, magnetic, tape,
mechanical photocopying, recording or otherwise without the written permission of the
Publisher.

For permission to use material from this book please contact us:
Telephone 631-231-7269; Fax 631-231-8175
Web Site: http://www.novapublishers.com

NOTICE TO THE READER
The Publisher has taken reasonable care in the preparation of this book, but makes no
expressed or implied warranty of any kind and assumes no responsibility for any errors or
omissions. No liability is assumed for incidental or consequential damages in connection
with or arising out of information contained in this book. The Publisher shall not be liable
for any special, consequential, or exemplary damages resulting, in whole or in part, from
the readers use of, or reliance upon, this material. Any parts of this book based on
government reports are so indicated and copyright is claimed for those parts to the extent
applicable to compilations of such works.

Independent verification should be sought for any data, advice or recommendations
contained in this book. In addition, no responsibility is assumed by the publisher for any
injury and/or damage to persons or property arising from any methods, products,
instructions, ideas or otherwise contained in this publication.

This publication is designed to provide accurate and authoritative information with regard
to the subject matter covered herein. It is sold with the clear understanding that the
Publisher is not engaged in rendering legal or any other professional services. If legal or any
other expert assistance is required, the services of a competent person should be sought.
FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A
COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF
PUBLISHERS.

Additional color graphics may be available in the e-book version of this book.

Library of Congress Cataloging-in-Publication Data

Library of Congress Control Number: 2013956180

Published by Nova Science Publishers, Inc. New York

ISBN: (eBook)

Contents

Preface vii
Chapter I Epidemiology of Hypertensive Disorders
during Pregnancy 1
Asnat Walfisch, M.D.
Chapter II Differential Diagnosis for Preeclampsia 59
Liran Hiersch, M.D. and Yariv Yogev, M.D.
Chapter III Gestational Hypertension and Preeclampsia -
Is it the Same Disease? 71
Nir Melamed, M.D., M.Sc. and Yariv Yogev, M.D.
Chapter IV The Association between Maternal Obesity
and Hypertensive Disease in Pregnancy 85
Amir Aviram, M.D. and Yariv Yogev, M.D.
Chapter V The Association between Multifetal Gestation
and Hypertensive Disease in Pregnancy 99
Jakob Nowotny, M.D., Rania Okby, M.D.
and Eyal Sheiner, M.D., Ph.D.
Chapter VI Placental Modification of Its Secreted Peptides
as a Key to Immune Evasion and the Pathogenesis
of Preeclampsia 111
Philip Lowry, Ph.D.
Chapter VII The Role of Adipokines in Preeclampsia 127
Shali Mazaki-Tovi, M.D., Edi Vaisbuch, M.D.
and Roberto Romero, M.D., D.Med.Sci.
Contents vi
Chapter VIII Can We Predict Preeclampsia? 187
Irene Rebelo, M.D., Joo Bernardes, M.D.,
Eduardo Tejera, M.D. and Belmiro Patrcio, M.D.
Chapter IX Can We Prevent Preeclampsia?
Pharmacologic Prevention of Preeclampsia 211
Sara De Carolis, M.D., Elvira di Pasquo, M.D.,
Sergio Ferrazzani, M.D., Serafina Garofalo, M.D.,
Carmelinda Martino, M.D., Angela Botta, M.D.,
Silvi Salvi, M.D., Sascia Moresi, M.D.,
Gelsomina Del Sordo, M.D. and Antonio Lanzone, M.D.
Chapter X Can Calcium Prevent Preeclampsia? 223
Tamar Tzur, M.D. and Eyal Sheiner, M.D., Ph.D.
Chapter XI Hypertensive Disease of Pregnancy and Maternal
Morbidity and Mortality 237
Jamie O. Lo, M.D., John F. Mission, M.D.
and Aaron B. Caughey, M.D., Ph.D.
Chapter XII From Molecular Mechanisms to Treatment Options 261
Christos Iavazzo, M.D., M.Sc., Ph.D.
Chapter XIII Long-Term Consequences of Preeclampsia 281
Yoav Yinon, M.D.
About the Editors 301
Index 303

Preface

Hypertensive disorders complicate 5-10% of pregnancies and are a leading
cause of maternal and perinatal morbidity and mortality. This book serves to
highlight the increasing importance of hypertensive disorders in pregnancy
across the health care continuum. It provides a comprehensive, evidenced-
based and updated review of controversy aspects relating to preeclampsia and
other hypertensive complications in pregnancy. It starts with a broad overview
of preeclampsia including an extensive introduction explaining definitions and
epidemiology of the disease, and the differential diagnosis of preeclampsia.
Risk factors such as obesity and diabetes as well as multifetal gestations are
presented in separate chapters. Basic concepts dealing with the pathogenesis of
the disease are thoroughly covered including the role of adipokines in
preeclampsia. Specific attention is given to prediction and prevention of
preeclampsia. The book concludes with short and long term maternal outcome.
Written by international experts, this book is a valuable resource for a
broad spectrum of clinicians and healthcare professionals dealing with
maternal fetal medicine. Medical and nursing students as well as residents in
obstetrics and gynecology, and family practice will also benefit from it at any
stage of their training.

In: Controversies in Preeclampsia ISBN: 978-1-62948-825-7
Editors: Eyal Sheiner and Yariv Yogev 2014 Nova Science Publishers, Inc.

Chapter I

Epidemiology of Hypertensive
Disorders during Pregnancy

Asnat Walfisch, M.D.

Department of Obstetrics and Gynecology, Hillel Yaffe Medical Center,
Hadera, The "Technion" University Medical School,
Faculty of Health Sciences, Haifa, Israel

Introduction

Hypertensive disorders in pregnancy are a leading cause of maternal and
perinatal morbidity and mortality. This chapter will focus on the four major
disorders, their significance, related risks and the most widely accepted
management options.
The four major hypertensive disorders in pregnancy are: [1, 2]

1 Preeclampsia eclampsia
2 Gestational hypertension
3 Chronic hypertension
4 Preeclampsia superimposed on chronic hypertension

Corresponding author: Asnat Walfisch MD. Department of Obstetrics and Gynecology, Hillel
Yaffe Medical Center, Hadera. The "Technion" University Medical School, Faculty of
Health Sciences, Haifa, Israel. E-mail: asnatwalfisch@yahoo.com.
Asnat Walfisch 2
The diagnosis of a hypertensive disorder in a pregnant woman depends, in
part, upon the gestational age at presentation:
Preeclampsia is defined as the new onset of hypertension and proteinuria
after 20 weeks of gestation in a previously normotensive woman. It is
classified as mild or severe (table 1 and 2), and may be associated with other
symptoms and signs such as headache, edema, and visual disturbances. Rarely,
preeclampsia may develop before 20 weeks of gestation in patients with
antiphospholipid antibody (APLA) syndrome or in pregnancies with extensive
hydatidiform changes. Eclampsia is the development of a new onset
generalized convulsions and/ or coma in a woman whose condition also meets
the criteria for gestational hypertension or preeclampsia. The seizures should
not be attributable to another cause such as epilepsy. [3]
Gestational (transient) hypertension refers to elevated blood pressure first
detected after 20 weeks of gestation without co-existing proteinuria.
Chronic hypertension is defined as systolic pressure 140 mmHg and/or
diastolic pressure 90 mmHg that antedates pregnancy, is present before the
20
th
week of pregnancy, or persists longer than 12 weeks postpartum. [4]
Superimposed preeclampsia is worsening hypertension with new onset
proteinuria in a woman with chronic hypertension. Women with both
preexisting hypertension and proteinuria are considered preeclamptic if one of
the following occurs:
An exacerbation of blood pressure to the severe range (systolic 160
mmHg or diastolic 110 mmHg) after 20 weeks of gestation, especially if
accompanied by symptoms, increased liver enzymes, thrombocytopenia, or a
sudden increase in the proteinuria. Diagnoses may change over time: a patient
with gestational hypertension may develop a new onset proteinuria and be
considered preeclamptic, or have persistent blood pressure elevation
postpartum and be considered as chronically hypertensive.

Incidence and Significance

Hypertensive disorders complicate 10 to 20 % of pregnancies, depending
on the study population. Chronic hypertension complicates about 3 % of
pregnancies. [5] Gestational hypertension occurs in about 6% of pregnancies.
[5]
Preeclampsia occurs in up to 14% of all pregnancies worldwide, and about
5 - 8% in the United States. [1, 6-9]
Epidemiology of Hypertensive Disorders during Pregnancy 3
In a recently published systematic review evaluating the incidence of
hypertensive disorders of pregnancy, the overall estimates were lower, with
4.6% and 1.4% of all deliveries for preeclampsia and eclampsia respectively,
and a wide variation across regions. [10]
In high-risk groups, the rates of preeclampsia may even be higher.
Preeclampsia is mild in 75 percent of cases. [11] Ten percent of preeclampsia
occur before 34 weeks of gestation. Preeclampsia-eclampsia is one of three
most common causes of maternal mortality in the United States (thrombo-
embolic disease and hemorrhage are the other two causes) and the most
frequent cause of iatrogenic prematurity. [12] There is approximately one
maternal death due to preeclampsia-eclampsia per 100,000 live births. [13, 14]
Hypertensive disorders remain a leading cause of maternal death in developing
countries as well, accounting for more than a quarter in Latin America and the
Caribbean. [15]

Preeclampsia

Preeclampsia is defined as the new onset of hypertension and proteinuria
after 20 weeks of gestation in a previously normotensive woman. It is
classified as mild or severe (tables 1 and 2). It is a syndrome characterized by
heterogeneous clinical and laboratory findings. The clinical findings of
preeclampsia can manifest as either a maternal syndrome (hypertension,
proteinuria, various symptoms), or a fetal syndrome (growth restriction), or
both. [16]
Despite extensive research in this field, the cause of preeclampsia remains
unknown. During the past decade, numerous pathophysiologic abnormalities
have been suggested to explain the mechanisms leading to the development of
preeclampsia. Some of these mechanisms have included impaired trophoblast
differentiation and invasion, placental and endothelial dysfunction, immune
mal-adaptation to paternal antigens, and exaggerated systemic inflammatory
response. However, preeclampsia is a heterogeneous disorder, for which the
mechanisms can differ in women with various risk factors. In addition, the
diagnostic criteria for preeclampsia and its subtypes (mild, severe,
superimposed on chronic hypertension) have not been consistent among
published studies. As a result, research in this area has not resulted in
significant improvement in methods of prediction, markers for confirming the
diagnosis in various subtypes, prevention, or management of this disorder.
[17]
Asnat Walfisch 4
Prediction (See Also Chapter 8)

Many biomarkers and biophysical markers have been proposed to predict
or confirm the development of preeclampsia. These markers have included
serum placental growth factor (PLGF), soluble fms-like tyrosine kinase-1
receptor (sFLt-1), serum endoglin, placental protein-13, uterine artery Doppler
measurements, and urinary podocyte excretion.
Widmer et al. [18] performed a systematic review evaluating the potential
role of serum PLGF and sFLt-1 to be used for prediction of preeclampsia. The
authors demonstrated that third trimester increases in sFLt-1 and decreases in
PLGF levels are associated with preeclampsia, specifically in the severe
disease. However, evidence is insufficient to recommend these markers for use
as screening tests. This is due to the differences among the various studies
regarding gestational age at the time of the measurements, methods used for
analysis, population studies, and reporting of results. Another study [19]
evaluated serum levels of various angiogenic factors at various gestational
ages. This study demonstrated that circulating soluble endoglin levels
increased significantly beginning 23 months before the onset of
preeclampsia. The increased level of endoglin was usually accompanied by an
increased ratio of sFLt-1:PLGF. Other studies have demonstrated similar
findings. [20-22] However, despite the above literature on the association
between abnormal angiogenic factors and subsequent preeclampsia, none of
these studies provided adequate information that could be clinically useful for
the prediction of preeclampsia. There is still a need for prospective studies
with adequate sample sizes to address this question.
Placental protein-13 (PP-13) is produced in the placenta and is thought to
be involved in implantation and maternal vascular remodeling. Several studies
have shown that maternal screening with PP-13 levels in the first trimester
may be useful for prediction of preeclampsia. [17, 23]
An abnormal uterine artery Doppler velocimetry (high pulsatility index or
the presence of a notch) in the first and second trimester has been proposed
as a good screening test to predict preeclampsia. This test has been studied
alone and in combination with other prediction markers with good results. [24]
An abnormal umbilical artery Doppler measurement is another common
Doppler finding in women with established preeclampsia, particularly in those
leading to delivery before 34 weeks gestation. [25] Recent studies have
shown that although abnormal umbilical artery Doppler measurements are
very common in preeclampsia, such measurements had no prognostic value in
the management of these patients. [26]
Risk Factors

The main risk factors for the development of preeclampsia include:

1 Past obstetrical history of preeclampsia. A systematic review of
controlled studies reported that the relative risk of preeclampsia in
women with a history of the disorder compared to women with no
such history was 7.19 (95% CI 5.85-8.83). [27] In women who had
mild preeclampsia during their first pregnancy, the recurrence
incidence in a second pregnancy is up to 7 %, and women with early,
severe preeclampsia are at the greatest risk of recurrence (25 - 65%
percent). [28-30]
2 Co-morbidity (see also chapter 4). Diabetes mellitus pre-gestational,
also increases the risk of preeclampsia (RR 3.56, 95% CI 2.54-4.99).
[27] The reasons for this effect may be related to a variety of factors
such as underlying vascular disease, renal disease, and abnormal lipid
metabolism. [31] Preexisting hypertension, renal disease, obesity, and
collagen vascular disorders are also well-described risk factors.
3 First pregnancy. This important predisposing factor increases the risk
for developing preeclampsia with a relative risk of 2.91, (95% CI
1.28-6.61). [27] The reasons for this are unclear.
4 Positive family history and race. The relative risk is 2.9 (95% CI 1.70-
4.93). [27] This finding suggests a possible heritable character to the
disease, in some of the cases. [32, 33] The paternal contribution to
fetal genes may have a role in defective placentation and subsequent
preeclampsia. Both men and women who were the product of a
pregnancy complicated by preeclampsia are more likely to have a
child who was the product of a pregnancy complicated by
preeclampsia. [34] Of note, African American race is another
independent risk factor.
5 Thrombophilia: The antiphospholipid antibody (APLA) syndrome has
been associated with multiple pregnancy complications including
preeclampsia as well as fetal loss, and maternal thrombosis. [35]
Conflicting evidence exist in regards to association between
preeclampsia and hereditary thrombophilias.
6 Multiple gestation (see also chapter 5) increases the risk of
preeclampsia. For twin pregnancies the relative risk is 2.93, 95%
2.04-4.21. [27] The risk rises with the number of fetuses.
Asnat Walfisch 6
7 Advanced maternal age is an independent risk factor for preeclampsia
(maternal age > 40 RR 1.96, 95% CI 1.34-2.87). [27] This association
may reflect undiagnosed underlying chronic hypertension with
superimposed gestational hypertension. Very young women
(adolescents) may also be at increased risk but this fact is more
controversial [6]; and a systematic review did not demonstrate a
significant association. [27]
8 Laboratory markers: As mentioned above, a variety of laboratory tests
have been investigated as possible markers for prediction of
preeclampsia (e.g., AFP, hCG, uE3, inhibin A). Most have not been
shown to be sufficiently sensitive and specific to be clinically useful
as a screening test. Measurement of angiogenic factors (e.g., VEGF,
sFIt-1, PlGF, sEng) in blood or urine is a promising although
investigational approach for predicting preeclampsia.
9 Imaging markers: Uterine artery Doppler, although predictive, is not
considered sufficiently sensitive and specific to be clinically useful as
a screening test.

Other risk factors and their relationship to preeclampsia are unclear. An
association between urinary tract infection during pregnancy and development
of preeclampsia was shown (pooled odds ratio 1.57; 95% CI 1.45-1.70). [36]
An association between periodontal disease and preeclampsia is also suspected
(pooled odds ratio 1.76; 95% CI 1.43-2.18), but no association between
preeclampsia and other common infections is known. These possible
relationships require further investigation before drawing any conclusions
regarding causality. However, women who smoke cigarettes have a lower risk
of developing preeclampsia when compared with nonsmokers. [8]

Prevention (See Also Chapters 9, 10)

Many randomized trials and systematic reviews described the use of low
dose aspirin, calcium, and vitamin C+E to prevent or reduce the incidence or
severity of preeclampsia. Askie et al. [37] performed a meta-analysis of 31
randomized trials for prevention of preeclampsia using antiplatelet agents
(mainly low dose aspirin). Antiplatelet agents were associated with a small
reduction in the rate of preeclampsia, with a relative risk of 0.90 (95% CI,
0.850.97). The number of patients needed to be treated to prevent one case of
preeclampsia depended on the baseline risk in the study population.
Women with chronic hypertension had no reduction in the risk of
preeclampsia, with RR 0.97 (95% CI, 0.841.12). Therefore, at present, the
use of low dose aspirin to prevent preeclampsia should be individualized. In a
recent meta-analysis of trials that included only women with abnormal uterine
artery Doppler flow velocimetry who started low dose aspirin at or before 16
weeks of gestation, aspirin reduced the risk of preeclampsia (RR 0.6, 95% CI
0.40.8). [38] The benefits of calcium supplementation during pregnancy in
reducing the incidence of hypertensive disorders were also extensively
evaluated. An evidence-based review by the United States Food and Drug
Administration [39] concluded that the relationship between calcium and risk
of hypertension in pregnancy is inconsistent and inconclusive, and the
relationship between calcium and the risk of pregnancy-induced hypertension
and preeclampsia is highly unlikely. In contrast, a Cochrane review published
in 2010, evaluated the effects of calcium supplementation during pregnancy on
hypertensive disorders of pregnancy and related outcomes and concluded
differently. [40] The authors of this review concluded that calcium
supplementation halves the risk of pre-eclampsia, with the greatest effect
being in women with low baseline calcium intake and those at high risk for
development of preeclampsia. There is probably no benefit to routine calcium
supplementation for healthy, nulliparous women in whom baseline dietary
calcium intake is adequate. Unfortunately, the use of vitamin C (1000 mg/day)
plus vitamin E (400 IU/day) supplementation during pregnancy for the
prevention of preeclampsia did not prove beneficial. A systematic review [41]
of four published trials that included 4680 randomized pregnant women
concluded that combined vitamin C and E supplementation during pregnancy
does not reduce the risk of preeclampsia.
Interventions such as rest, exercise, reduced salt intake, garlic, marine oil,
antioxidants, progesterone, diuretics, and nitric oxide show insufficient
evidence to be recommended as preventive measurements for preeclampsia.
[42]

Clinical Manifestations

Clinical manifestations of preeclampsia develop long after placental
pathogenic changes. The gradual development of hypertension, proteinuria,
and edema in pregnancy is usually due to preeclampsia, particularly in a
primigravida.
Asnat Walfisch 8
Typically, these findings appear after 20 weeks of gestation and progress
until delivery. [1, 2] Nevertheless, in few cases symptoms begin earlier,
towards the end of the second trimester, [1] while others onset intra- or post-
partum. [2]
The occurrence of signs and symptoms of preeclampsia before 20 weeks
of gestation suggest an underlying molar pregnancy or the APLA syndrome.
Other possibilities (chromosomal aneuploidy in the fetus, drug use) should
also be considered. [43, 44]
The clinical features of preeclampsia are attributable to different maternal
responses to generalized endothelial dysfunction. Disturbed endothelial control
of vascular tone causes hypertension, increased vascular permeability results
in edema and proteinuria, and abnormal endothelial expression of pro-
coagulants leads to coagulopathy. These changes may also cause ischemia of
target organs (brain, liver, kidney, and placenta).
Furthermore, since poor perfusion is a major component of the disease
process, attempts to lower blood pressure may exacerbate organ dysfunction
even though the patient may become normotensive.

Hypertension

Hypertension in pregnancy is defined as the development of a systolic
blood pressure 140 mmHg or a diastolic blood pressure 90 mmHg after 20
weeks of gestation in a previously normotensive woman. [4] The blood
pressure must be measured with an appropriately sized cuff placed on the right
arm at the same level as the heart with the woman sitting for at least 10
minutes. Disappearance of the fifth Korotkoff sound indicates the diastolic
pressure. Two separate measures should be taken, six hours apart, for
establishing the diagnosis. Hypertension is usually the earliest clinical finding
of preeclampsia and is the most common clinical clue to the presence of
preeclampsia. In the past, an increase from baseline of the systolic or the
diastolic pressures was considered indicative of gestational hypertension, even
in the absence of hypertension. These criteria have been rejected because of
their low sensitivity (30%) and predictive values (30%), as well as lack of
association with adverse pregnancy outcome. [45, 46]
Importantly, before making a diagnosis of hypertension, the possibility of
"white coat hypertension" should be considered. This phenomenon is not
infrequent and if suspected may be diagnosed using a 24-hour ambulatory
blood pressure monitoring.
Pregnancy outcome in these cases is not different than normal pregnancies
except for a higher cesarean section rates, perhaps due to a wrong decision-
making processes based on the recorded high blood pressures. [47]
Nevertheless, a Cochrane review concluded there is insufficient information
on which to base a recommendation regarding the routine use of ambulatory
blood pressure monitoring for new onset hypertension in pregnant women.
[48]

Proteinuria

Proteinuria is defined as a total of 300 mg protein in a 24-hour urine
specimen (or persistent 1+ on urine dipstick at least twice, six hours apart).
Proteinuria must be present, in addition to hypertension, to make a diagnosis
of preeclampsia. Urinary protein excretion increases gradually, and is of
variable magnitude in preeclampsia, occasionally reaching the nephrotic range
(>5 g/day). This phenomenon is partially due to the impaired integrity of the
glomerular barrier (both size and charge selectivity) and impaired tubular
handling of filtered proteins (hypofiltration) leading to increased protein
excretion. [49, 50]
The protein-to-creatinine ratio may be calculated using a random urine
sample with a threshold of 0.14 to 0.19.

Cardiovascular System

Increased afterload may lead to decrements in left ventricular performance
although preeclampsia does not directly affect the myocardium. [51] After
clinical manifestations become apparent, there is a marked reduction in cardiac
output and increase in peripheral resistance. [51-53] Severe preeclampsia can
be associated with a highly variable hemodynamic profile. [54-58]
Edema is a common finding in normal pregnancy. Thus, the presence of
edema is no longer considered one of the diagnostic criteria for preeclampsia.
Nevertheless, a sudden and rapid weight gain or the occurrence of facial
edema warrants evaluation for other clinical manifestations of preeclampsia.
The intravascular volume is lower in preeclamptic pregnancies. The
reduced volume may be a consequence of vasoconstriction and not under-
filling of the arterial circulation. Thus, diuretics should be avoided in the
absence of pulmonary edema.
Asnat Walfisch 10
The etiology of pulmonary edema in preeclampsia, which occurs
particularly in the postpartum period, is multifactorial. Excessive elevations in
pulmonary vascular hydrostatic pressure (PCWP) compared to plasma oncotic
pressure, capillary leak, left heart failure, and iatrogenic volume overload may
be the explanations for this phenomenon in some cases. [59]

Renal Findings

The kidney is the organ most likely to manifest endothelial injury related
to preeclampsia. Glomerular filtration rate (GFR) decreases by 30 - 40% and
renal plasma flow decreases (to a lesser extent) when compared to pregnant
controls. GFR can be estimated using serum and urine creatinine together with
age and weight of the patient. The plasma creatinine concentration is generally
normal or only slightly elevated and renal failure is an unusual complication
that can occur in patients who develop severe disease. Hyperuricemia and
hypocalciuria also occur resulting from unclear mechanisms. [49, 60, 61] The
rise in serum uric acid concentration is thought to reflect renal ischemia that
induces increased proximal sodium and urate reabsorption. Other explanations
for hyperuricemia in preeclampsia include underlying metabolic syndrome,
tissue damage, oxidative stress, and inflammation. [62] The underlying renal
lesion of preeclampsia is a variant of thrombotic microangiopathy (TMA)
called Glomerular Endotheliosis. The histologic features of Glomerular
Endotheliosis include endothelial cell swelling and loss of fenestrations with
resulting occlusion of capillary lumens. [63] Fibrin deposition may also be
observed.

Liver

Vasospasm and precipitation of fibrin are typical of liver as well as kidney
involvement. [64] Other histologic findings observed in the liver of a
preeclamptic woman include: Periportal hemorrhage, ischemic lesions, and
microvesicular fat deposition. [65]
The clinical manifestations of liver involvement include right upper
quadrant or epigastric pain, elevated transaminases and, in the most severe
cases, subcapsular hemorrhage or hepatic rupture, which may be a part of
HELLP syndrome (Hemolysis, Elevated Liver function tests, Low Platelets
see below).
Hematologic System

Thrombocytopenia (due to formation of microthrombi) is the most
common coagulation abnormality observed in preeclampsia. [66] Unless there
are additional complications (abruption of the placenta or severe liver
involvement) the prothrombin time, partial thromboplastin time, and
fibrinogen concentration are not affected. Examination of a blood smear may
reveal schistocytes and helmet cells as evidence of microangiopathic
hemolysis. Hemolysis is associated with a low hematocrit, and elevation in the
serum lactate dehydrogenase concentration. The presence of both hemolysis
and hemoconcentration in preeclampsia may negate each other, resulting in a
normal hematocrit value.

Central Nervous System

Headache, blurred vision, scotomata, and, rarely, transient cortical
blindness may be signs of central nervous system involvement. Seizures in a
preeclamptic woman signify a change in diagnosis to eclampsia. Two percent
of severely preeclamptic women and 0.25%-0.5% of mildly preeclamptic
women will develop eclampsia. [11] Luckily, stroke, which is the most serious
complication of severe preeclampsia/eclampsia, is rare.
Histopathologic and imaging findings include: hemorrhage, petechiae,
vasculopathy, ischemic brain damage, microinfarcts, fibrinoid necrosis,
cerebral edema and ischemic/hemorrhagic changes in the posterior
hemispheres. [67-70]
Blindness related to retinal pathology (retinal artery or venous thrombosis,
retinal detachment, optic nerve damage, retinal artery spasm, and retinal
ischemia) may be permanent. [71]

Fetus and Uteroplacental Circulation

Chronic placental hypo-perfusion results in fetal growth restriction and
oligohydramnion. Severe preeclampsia results in 12% fetal growth restriction
and early onset preeclampsia in 23%. [72] Abruption of the placenta occurs in
less than 1 percent in women with mild preeclampsia, but has been reported in
3 percent of those with severe disease. [73]
Asnat Walfisch 12
Fetal or maternal complications may lead to iatrogenic preterm delivery,
while preeclampsia does not appear to accelerate fetal maturation, as once
believed. [74]

Diagnosis and Evaluation
(See Also Chapter 3)

Characteristic clinical features developing after 20 weeks of gestation in a
woman who was previously normotensive are the basis for diagnosis of
preeclampsia (Table 1).
Screening urine for proteinuria is an integral part of antepartum care
strategy to detect preeclampsia. Women with proteinuria on a dipstick should
undergo quantitative measurement of protein excretion (urine protein to
creatinine ratio or 24-hour urine protein excretion) as urinary protein dipstick
values do not correlate well with 24-hour urinary protein excretion values.
Severe disease is defined by the criteria in Table 2.
Preeclampsia should be suspected in any pregnant woman with new onset
hypertension even if proteinuria is absent.
In order to distinguish preeclampsia from other hypertensive disorders of
pregnancy, such as gestational hypertension and chronic hypertension, clinical
and laboratory findings are used. Nevertheless, frequently, signs and
symptoms of these disorders overlap (Table 3).
A variety of other disorders can present with symptoms or signs similar to
preeclampsia, eclampsia, and HELLP syndrome.

Table 1. Criteria for the diagnosis of preeclampsia

Criteria
1.
Systolic blood pressure 140 mmHg or diastolic blood pressure 90
mmHg
*

2. Proteinuria 300mg in a 24-hour urine specimen
**

*
In two measurements at least six hours apart, but no more than seven days.
Diastolic blood pressure is determined with patient sitting and based upon the fifth
Korotkoff sound.
**
A random +1 on urine dipstick is suggestive, but not diagnostic, of the presence of
this criterion.

Table 2. Criteria for the diagnosis of severe preeclampsia

The presence of preeclampsia
together with at least one of the
following:
Criteria
Severe hypertension:
Systolic blood pressure 160 mm Hg or
diastolic 110 mm Hg on two occasions at
least six hours apart.
Severe proteinuria: 5 grams in a 24 hours urine collection.
Symptoms of the central
nervous system:
Severe headache, blurred vision, scotomata,
altered mental status.
Symptoms of liver capsule
distention:
Right upper quadrant or epigastric pain.
Signs of hepatocellular injury:
Serum transaminase concentration at least
twice the upper normal limit.
Thrombocytopenia: < 100,000 platelets per mm3
Severe fetal growth restriction EFW 5
th
percentile
Oliguria < 0.5cc/Kg/hr or < 500 cc/24hr
Pulmonary edema
Demonstrated by chest X ray or by a
clinical evaluation
Cerebrovascular accident
Demonstrated using an imaging study or a
clinical evaluation

Although preeclampsia is the most common cause of hypertension,
coagulation abnormalities, liver abnormalities, and renal abnormalities in
pregnant women, the following conditions must be considered:
Acute fatty liver, thrombotic thrombocytopenic purpura/hemolytic uremic
syndrome (TTP/HUS), migraine, cerebral hemorrhage, gestational
thrombocytopenia and autoimmune thrombocytopenia, exacerbation of
systemic lupus erythematosus, cholestasis, hepatitis and pancreatitis.
The main goal is to support the diagnosis by excluding other disorders
characterized by hypertension and proteinuria.
Following the diagnosis of preeclampsia, the severity of the disease is
assessed. Mild preeclampsia includes those women who satisfy the criteria for
preeclampsia but do not have any features of a severe disease. Laboratory
evaluation helps to determine disease severity by characterizing end organ
involvement (Table 4). [4]
There are no data from randomized trials on which to base
recommendations for the optimal type and frequency of fetal monitoring.
Asnat Walfisch 14
Table 3. Differential diagnosis (DD) of common causes of hypertension
during pregnancy

Mild
preeclampsia
Severe
preclampsia
Chronic
hypertension
Gestational
hypertension
Onset
After 20 weeks
of gestation
After 20 weeks of
gestation
Before 20 weeks
of gestation
After 20 weeks
of gestation
Proteinuria
Present, increases
with time.
Present, increases
with time,
occasionally
reaching the
nephrotic range
Usually absent or
less than 1 g/day
in hypertensive
nephrosclerosis
Absent
Parity
More common in
primiparas
More common in
primiparas
Not more
common in
primiparas
Mildly more
common in
primiparas
Age
More common in
older (>40 years)
primigravidas
More common in
older (>40 years)
primigravidas
Older primi-and
multigravidas
More common in
older (>40 years)
primigravidas
Plasma uric
acid
concentration
Level rises to
above 5.5 mg/dL
(327 mmol/L)
Level rises to
above 5.5 mg/dL
(327 mmol/L)
Usually remains
below 5.5 mg/dL
(327 mmol/L)
Level rises to
above 5.5 mg/dL
(327 mmol/L)
Hematologic
changes
Usually normal
Often
accompanied by
thrombocytopenia,
and signs of
hemoconcentration
or hemolysis
Usually normal Usually normal
Liver function
tests
Usually normal Often abnormal Usually normal Usually normal
Resolution
Usually within
two to six weeks
postpartum (may
last 12 weeks)
Usually within two
to six weeks
postpartum (may
last 12 weeks)
Does not resolve
postpartum
Usually within
one week
postpartum (may
last 12 weeks)

It should however include serial assessments of: fetal movement counts,
fetal nonstress testing and assessment of amniotic fluid volume (biophysical
profile). Early fetal growth restriction may be the first manifestation of
preeclampsia or a sign of severe preeclampsia.
Therefore, a sonographic estimation of fetal weight should be performed
at the time of diagnosis of preeclampsia and then repeated periodically.
Doppler velocimetry is useful for assessing fetal status if fetal growth
restriction is present.

Table 4. Initial laboratory evaluation of preeclampsia

Test Purpose
Hematocrit / Hemoglobin Hemoconcentration, Hemolysis
Platelet count Thrombocytopenia
Quantification of protein
excretion
300 mg in 24 hours - mild disease
5gr in 24 hours severe disease
Serum creatinine
concentration
Elevation (1.2mg/dl) suggests severe disease
Serum ALT and AST
Elevation suggests hepatic dysfunction
indicative of severe disease
Serum lactate dehydrogenase
(LDH) concentration
Hemolysis
Peripheral blood smear
Red cell fragmentation (schistocytes or helmet
cells)
Serum uric acid concentration Elevation suggests the diagnosis
Coagulation function tests
Usually normal in the absence of
thrombocytopenia or liver dysfunction, and do
not need to be monitored routinely

Management

Delivery is the definitive treatment of preeclampsia, which in itself is a
completely reversible disease. As long as the patient remains undelivered,
there are increased risks of complications such as seizures, placental abruption,
HELLP syndrome, renal failure and cerebral hemorrhage. Although the fetus
is at increased risk of stillbirth and intrauterine growth restriction, delivery
may not always be beneficial. Conservative management may be pursued in
well-selected cases.
Once the diagnosis of preeclampsia is well established, subsequent
management will depend on the results of initial maternal and fetal assessment
and the gestational age. Safety of the mother and fetus is the main objective of
management. Specifically, the main goals of therapy are prevention of
convulsions and other complications as well as delivery of a surviving child.
The decision between delivery and continued pregnancy depends on
gestational age, fetal status, and severity of maternal condition at the time of
the initial assessment.
Asnat Walfisch 16
Fetal survival in preeclamptic pregnancies has improved during the last 2
decades because of more aggressive clinical management (early detection,
fetal monitoring, use of steroids, and timely delivery). [19]
Guidelines continue to recommend delivery if preeclampsia is diagnosed
at 37 completed weeks of gestation or later. [75] Women with mild
preeclampsia at term are induced if there are no contraindications to vaginal
birth, and an unfavorable cervix is not a reason to avoid labor induction. [76]
Delivery minimizes the risk of progression to severe disease and its
complications. Most experts advise delivery by no later than 40 weeks of
gestation for all preeclamptic women. [4, 75, 77, 78] Women with mild
disease remote from term can be managed expectantly to enable further fetal
growth and maturation.
Preeclamptic women are at risk of preterm delivery. Although it was once
thought that preeclampsia accelerated fetal lung maturation, respiratory
distress syndrome is not less common in preterm infants of preeclamptic
women [79] and antenatal corticosteroids to promote fetal lung maturity are
recommended before 34 weeks of gestation.
The indications for delivery for women with preeclampsia are the
following:

Fetal indications - Severe fetal growth restriction, oligohydramnios
and non-reassuring fetal status.
Maternal indications Term pregnancy (37w), HELLP syndrome,
deterioration in renal function, abruption of the placenta, persistent
severe headaches or visual changes, persistent severe epigastric pain,
nausea, or vomiting.

Severe preeclampsia (Table 2) is usually regarded as an indication for
delivery in order to minimize the risk of development of maternal and fetal
complications. Women who develop severe preeclampsia at or beyond 32- 34
weeks of gestation should be delivered. Delivery should be planned at an
institution with appropriate facilities for care of the preterm neonate.
Management of early onset (before 32-34 weeks of gestation) severe
preeclampsia is a challenge. Immediate delivery leads to high neonatal
mortality and morbidity rates, whereas, expectant management to increased
maternal mortality and morbidities and possible fetal death or asphyxial
damage. Sibai and Barton [80] conducted a review of published studies from
1990 to 2006 evaluating the risks and benefits of expectant management in
severe preeclamptic pregnancies.
It included two randomized trials and 11 observational studies. The
authors showed that expectant management is safe and improves neonatal
outcome in a selected group of patients with severe preeclampsia between 24
and 33 weeks of gestation. With close monitoring, expectantly managed
pregnancies complicated by severe preeclampsia can be extended by 5 to 19
days, on average, with good maternal and neonatal outcomes. [81]
For gestational age below 24 weeks, expectant management is associated
with high maternal morbidity and limited perinatal benefit. In cases of severe
preeclampsia and severe fetal growth restriction data to support this
management is limited and expectant management may increase stillbirth. [82]

Bed Rest

Although widely recommended, there are no large randomized trials
evaluating the risks and benefits of bed rest. A Cochrane review analyzed four
trials including 449 women. [83] Although one small trial suggested that bed
rest may be associated with reduced risk of severe hypertension and preterm
birth, at present, there is insufficient evidence to provide clear guidance.
Restrictive activity may be associated with an increased risk of thrombo-
embolic events and therefore, bed rest should not be recommended routinely
for hypertension in pregnancy.
Nevertheless, bed-rest in the lateral decubitus position augments utero-
placental blood flow, which can be of value if there is utero-placental
insufficiency. Thus, some rest in this position remains part of the routine
management of women with suspected utero-placental insufficiency (such as
those with fetal growth restriction).

Control of Hypertension

Although guidelines derived from systematic reviews are limited due to
lack of standardized clinical trials, many physicians withhold treatment unless
the systolic pressure is 160 mmHg or the diastolic pressure is 110 mmHg.
The higher the blood pressure, the higher the risk of cerebral hemorrhage. [1,
4, 84-86] There is, however, concern that lowering maternal blood pressure
may compromise placental perfusion and fetal well-being. [87-90] There is no
consensus as to the optimal blood pressure threshold for initiating therapy.
Asnat Walfisch 18
The only benefit of antihypertensive therapy in women with mild
hypertension is a reduced risk of developing severe hypertension. This is
considered insufficient to warrant exposing the fetus to the potential adverse
effects on its placental perfusion. The target blood pressures are usually
around 140 mm Hg systolic and 90 mm Hg diastolic.
Two clinical settings require consideration of antihypertensive therapy:

1 Acute management of severe hypertension, which may require
parenteral therapy.
2 Chronic blood pressure control in the selected cases of expectant
management of severe preeclampsia. [4, 91]

Acute Setting Parenteral Therapy

Labetalol - Labetalol has been shown to be effective and safe in
pregnancy, although data are limited. [91] Initially, 20 mg are administered
intravenously followed by 20 to 80 mg at 10 minute intervals and up to a
maximum cumulative dose of 300 mg. The fall in blood pressure begins within
5 to 10 minutes and lasts up to six hours. Constant infusion of 1 to 2 mg/min
can be used instead of intermittent therapy.
Hydralazine - Although used extensively in the setting of preeclampsia,
intravenous hydralazine is associated with significant maternal hypotension
when compared with other antihypertensive drugs. [89] Thus, hydralazine is
not recommended as a first-line drug for treatment of severe hypertension in
pregnant women, although evidence is not sufficient for making a definitive
conclusion. Initially, IV 5 mg is administered over two minutes; and,
depending upon the initial response, a 5 to 10 mg bolus is given after 20
minutes. The maximum bolus dose is 20 mg. The fall in blood pressure begins
within 10 to 30 minutes and lasts up to four hours.
Calcium channel blockers - Experience with nifedipine (30 mg) and
nicardipine in pregnancy is more limited than for labetalol and hydralazine.
[92-94] Administration of IV calcium channel blockers together with Mg So4
may lead to serious side effects such as pulmonary edema. Use of immediate
release sublingual nifedipine (10 mg) has been associated with an excessive
reduction in blood pressure leading to serious cardiovascular morbidity and is
discouraged. [95-97] Diazoxide - Although rarely necessary, this drug can be
used when adequate blood pressure control cannot be achieved with labetalol
or hydralazine. [1]
There is potential value to small doses of diazoxide (15 mg every three
minutes to a maximum dose of 300 mg) when compared to hydralazine in
terms of safety and effectiveness. [98]
Nitroprusside is contraindicated in late pregnancy due to possible fetal
cyanide poisoning. However, the drug may be considered as a last resort for
emergency control of refractory severe hypertension (0.5 to 10 mcg/kg/min).

Chronic Setting Oral Therapy

Occasionally, severe preeclamptic women are not delivered immediately.
Oral antihypertensive therapy is often indicated for these patients. Options for
oral antihypertensive therapy are the same as for women with chronic
hypertension (see below) and the blood pressure targets usually are 140 to 150
mm Hg systolic and 90 to 100 mm Hg diastolic.

Outcome

The major adverse outcomes associated with preeclampsia are:

Maternal (see also chapter 11): Central nervous system, hepatic, and
renal dysfunction (e.g., cerebral hemorrhage, hepatic rupture, renal
failure), and bleeding (related to thrombocytopenia, placental
abruption).
Fetal: Preterm delivery, fetal growth restriction, and perinatal death.

Factors that influence outcome include: Severity of the disease, gestational
age at onset and presence of coexisting conditions (e.g., multiple gestation,
diabetes mellitus, renal disease, thrombophilia, or preexisting hypertension).
[99]
With mild preeclampsia neonatal outcomes are generally good except for
a higher frequency of labor induction. [100] On the other hand, severe
preeclampsia is associated with increased rates of maternal liver and kidney
dysfunction, induced labor, cesarean delivery, preterm birth, fetal growth
restriction, and neonatal respiration difficulties. [94] The highest risk of
maternal and neonatal morbidity is in pregnancies complicated by early onset
severe preeclampsia.
Asnat Walfisch 20
Postpartum Course

Preeclampsia related hypertension usually resolves within a few weeks
and is almost always gone by 12 weeks postpartum. [101-103]
If hypertension persists beyond this period it should be evaluated and
treated as in any non-pregnant woman. However, evidence for an optimal
regimen is lacking. [104] If the hypertension is severe, antihypertensive agents
may be required temporarily postpartum. Oral antihypertensive medications
similar to those used in the non-pregnant population may be appropriate. Beta-
adrenergic blockers, calcium channel blockers, diuretics, and even angiotensin
converting enzyme (ACE) inhibitors are suitable choices for non-breastfeeding
mothers. The blood pressure should be monitored regularly to avoid
hypotension. Usually within 3 weeks the blood pressure returns to its baseline
values and therapy is stopped. In breastfeeding mothers calcium channel
blockers and beta-adrenergic blockers appear to be safe although both enter
breast milk. Labetalol and propranolol are preferred because these drugs are
not concentrated in breast milk. [4] ACE inhibitors and angiotensin receptor
antagonists should be avoided during lactation, and may be considered again
after lactation cessation. Diuretics may reduce the milk volume, but this does
not occur at doses 50 mg daily. [105]

Long Term Course (See Also Chapter 13)

Women with early onset severe preeclampsia are at greatest risk of
recurrence (25-65%) while in women who had mild preeclampsia during the
first pregnancy the incidence is much lower (5-7%). [28, 30, 106-108] Patients
with severe preeclampsia, particularly if occurring in the second trimester,
have a high risk for recurrent preeclampsia in subsequent pregnancies and for
chronic hypertension, perhaps due to irreversible vascular injury. [28, 30, 108]
Observational studies have shown that preeclampsia is a risk factor for
future development of cardiovascular disease. A systematic review evaluating
this risk has shown that compared with women with no history of the disease,
women with preeclampsia were at increased risk of the following:
hypertension (RR 3.70, 95% CI 2.70-5.05 at mean follow-up of 14 years),
ischemic heart disease (RR 2.16, 95% CI 1.86-2.52 at mean follow-up of 11.7
years), stroke (RR 1.81, 95% CI 1.45-2.27 at mean follow-up of 10.4 years),
and venous thrombo-embolism (RR 1.79, 95% CI 1.37-2.33 at mean follow-up
of 4.7 years). [109] In addition, the severity of preeclampsia is proportionally
related to the risk of future cardiac disease. [110, 111]
The reason for this observation may be the presence of unrecognized
latent hypertension, an inherited thrombophilia, or other genetic or
environmental factors predisposing to hypertension. Its been recently shown
that women with a history of hypertensive disorders in pregnancy have higher
levels of glucose, insulin, and unfavorable lipids compared with controls.
[112] Another explanation for these observations is that preeclampsia itself
may lead to permanent arterial changes leading to late cardiovascular disease.
[113]
There is now evidence that women with a history of preeclampsia are also
at an increased risk (two fold) for later diabetes mellitus. [114]
In contrast to high risk women (early onset preeclampsia, recurrent
preeclampsia, severe preeclampsia, or preeclampsia with onset as a multipara),
preeclampsia/eclampsia occurring late in gestation in primigravid women and
followed by a second normotensive pregnancy does not appear to be
associated with increased remote cardiovascular risk. [115]
A study from Israel reported an increased risk of cancer in women with a
history of preeclampsia (hazard ratio 1.27, 95% CI 1.03-1.57) with a median
follow-up of 29 years. [116] Site-specific increases were noted for cancer of
the stomach, lung or larynx, breast, and ovary. However, a systematic review
did not find any such association. [109] The discordant results may be
explained by several factors including differences in patient populations,
insufficient adjustment for confounders, differences in length of follow-up and
more.

HELLP Syndrome

HELLP syndrome (Hemolysis, Elevated Liver enzymes, Low Platelets)
probably represents a severe form of preeclampsia but this relationship
remains controversial. Both these entities are probably part of a disease
spectrum. Up to 20% of patients with HELLP syndrome do not have
hypertension or proteinuria. [117-119] Both severe preeclampsia and HELLP
syndrome may be associated with hepatic involvement including infarction,
hemorrhage, and rupture.
Most cases are diagnosed between 28 and 36 weeks of gestation with an
incidence of 1- 2 per 1000 pregnancies overall and 10 - 20% of women with
severe preeclampsia/eclampsia.
Asnat Walfisch 22
The disease may less often present postpartum (about a third of the cases)
[120] usually within 48 hours of delivery, but occasionally as long as seven
days postpartum. In these cases of postpartum HELLP syndrome, most
patients are not diagnosed with preeclampsia antepartum.
Risk factors for HELLP syndrome include personal or family history of
HELLP syndrome. Importantly, nulliparity is not a risk factor, as opposed to
preeclampsia. Recently, some genetic variants have been shown to be
associated with HELLP syndrome. [121]
Abdominal mid-epigastric or right upper quadrant pain and tenderness is
the most common clinical presentation although some patients are
asymptomatic. [120] The signs and symptoms by incidence according to
Weinstein and Sibai are as follows: [117, 122] Right upper quadrant or
epigastric pain (86-90%), nausea and/or vomiting (45-84%), headache (50%),
right upper quadrant tenderness on palpation (86%), diastolic blood pressure
above 110 mm Hg (67%), proteinuria - above 2+ on dipstick (85-96%), and
demonstrable edema (55-67%). Only in approximately 85 percent of cases
hypertensive proteinuria is present. [123] Serious maternal morbidity includes
disseminated intravascular coagulation (DIC), sub-capsular liver hematoma,
abruption of the placenta, acute renal failure, and pulmonary edema. [120]
The diagnosis of HELLP syndrome is based on the presence of specific
laboratory abnormalities in the blood count, smear, liver enzymes and LDH.
[123] No consensus exists regarding the degree of laboratory abnormality
diagnostic of HELLP syndrome. Nevertheless, the following criteria are
usually met: [120] Platelet count 100,000 cells / microL, serum AST 70
IU/L, serum LDH 600 IU/L or total bilirubin 1.2 mg/dL as well as blood
smear with signs of microangiopathic hemolytic anemia. If not all criteria are
met the diagnosis is referred to as partial HELLP. The diagnosis of HELLP
syndrome may sometimes be hard to differentiate from other diseases
complicating pregnancy such as: thrombotic thrombocytopenic purpura,
hemolytic-uremic syndrome, acute fatty liver of pregnancy, lupus flare,
idiopathic thrombocytopenic purpura, antiphospholipid syndrome,
gastroenteritis, hepatitis, appendicitis or gallbladder disease. [123]
The principal elements of management include stabilization of the patient,
assessment of the fetus and consideration of delivery. Delivery is the definitive
treatment for HELLP syndrome and indications for immediate delivery
include: [123]
Near term pregnancy (34w), abruption of the placenta, non-reassuring
fetal status or maternal multi-organ dysfunction including active deterioration
of the laboratory parameters.
If gestational age is less than 34 weeks, glucocorticoid course may be
administered assuming maternal and fetal status are reassuring. However,
attempts to delay delivery beyond 48 hours are not recommended. Few data
[124, 125] on expectant management of HELLP syndrome have shown the
following: Although maternal complications were uncommon with careful
maternal monitoring and laboratory abnormalities reversed in a subgroup of
patients, perinatal outcome was not improved. Thus, expectant management is
not recommended. [123]
As in preeclampsia, severe hypertension can usually be controlled using
labetalol, hydralazine, nifedipine or, in severe cases, with sodium
nitroprusside. [126] For convulsion prevention and treatment, IV magnesium
sulfate is administered.
Platelet transfusion is indicated only in the presence of significant
maternal bleeding or if the platelet count drops to < 20,000 cells/microL.
Dexamethazone was suggested by some to be associated with a more
rapid improvement in laboratory and clinical parameters. [127-130] However,
well-designed clinical trials did not support these findings. [131, 132]
Treatment with eculizumab, a targeted inhibitor of complement protein
C5, was reported to be used in a case of a woman with severe early HELLP
syndrome. The treatment was associated with marked clinical improvement
and normalization of lab parameters. [133]
The mode of delivery, as in severe preeclampsia, depends on gestational
age, cervical score, and maternal and fetal status. Following delivery,
laboratory values may initially worsen. Platelet count reaches its nadir usually
around 24-48 hours postpartum.
LDH concentration peak earlier. [134, 135] Maternal outcome following
HELLP syndrome is generally good; however, serious complications may
occur. The complications are interdependent: placental abruption may lead to
DIC, which may cause renal failure and pulmonary edema.
As for the fetus, 70% of cases lead to preterm delivery, and rates of intra
uterine growth retardation are high. [136] Perinatal mortality may reach 20%
and is closely related to gestational age, growth restriction and the presence of
placental abruption. [123]
Women with a history of HELLP syndrome are at a high risk of
developing preeclampsia in subsequent pregnancies. However, recurrent
HELLP or hepatic rupture is rare. [137-139]

Asnat Walfisch 24
Eclampsia

Eclampsia is defined as the development of generalized convulsions and/
or coma in a woman with gestational hypertension or preeclampsia. These
seizures should not be attributable to another coincidental neurologic disease.
[3] In general, eclampsia may develop anytime from 20
th
week of gestation to
the puerperium. Eclampsia prior to 20 weeks of gestation should raise the
possibility of an alternative diagnosis (see differential diagnosis below) or of
an underlying APLA (antiphospholipid antibody) syndrome or molar
pregnancy. APLA syndrome and molar pregnancies may lead to eclamptic
seizures before 20 weeks of gestation.
The seizures are one of several clinical manifestations of severe
preeclampsia and not the end result of preeclampsia. Thus, risk factors for
eclampsia are similar to those for preeclampsia. Approximately a half of the
cases develop before term pregnancy and a third at term, intra-partum or
within 48 hours of delivery. [140] Eclampsia occurring beyond 48 hours
postpartum is rare (see table 5). [141-143] The exact cause of eclamptic
seizures is not known. It may be related to cerebral overregulation and
vasospasm of cerebral arteries or to the loss of auto-regulation resulting in
hyper-perfusion, or to both. Both processes may be a result of high systemic
blood pressure. [144]

Incidence

Approximately 2% of severely preeclamptic women and 0.5% of mildly
preeclamptic women develop eclampsia. [11] The incidence of eclampsia
varies around the world with 5 cases per 10,000 live births in developed
countries versus 6 -100 cases per 10,000 live births in developing countries.
[140, 145, 146]

Table 5. Timing of eclampsia relative to gestational age [130, 195]

Gestational age Frequency (%)
Antepartum 38-55
Intrapartum 13-36
48 hours postpartum 5-39
>48 hours postpartum 5-17
Clinical Manifestations

Eclampsia is a clinical diagnosis. The generalized, tonic-clonic seizures
usually last 3-4 minutes and are self-limiting. Persistent headache, blurred
vision, photophobia, right upper quadrant or epigastric pain, and altered
mental status may occur before the seizure.
If the seizure is typical electroencephalographic or cerebral imaging
studies are not required. [147] Prolonged fetal bradycardia is common during
an eclamptic seizure, and does not necessarily require emergent cesarean
delivery. Fetal bradycardia is a result of maternal hypoxia and uterine hyper-
stimulation.
Stabilizing the mother by administration of oxygen, anticonvulsant and
antihypertensive drugs can help the fetus recover in-utero. However, the
possibility of placental abruption should be kept in mind mainly if the fetal
heart rate remains non-reassuring for more than 10 minutes despite
resuscitative efforts. [144]

Differential Diagnosis

Eclamptic seizures are indistinguishable from other generalized tonic-
clonic seizures. When convulsions occur during pregnancy, delivery, or the
preuperium, eclampsia is diagnosed until proven otherwise.
Other etiologies should be considered if seizures occur before 20 weeks of
gestation or in cases of focal neurologic deficits, prolonged coma, or atypical
eclampsia.
These include: epilepsy, intracranial hemorrhage or CVA (cerebrovascular
accident), space-occupying lesions of the CNS (central nervous system),
hypertensive encephalopathy, metabolic disorders, CNS infection (meningitis
or encephalitis) or vasculitis, thrombotic thrombocytopenic purpura (TTP) or
thrombophilia, drug abuse, post-dural puncture syndrome and finally
hyperventilation syndrome. [148]
Reversible posterior leukoencephalopathy syndrome (RPLS) is a common
clinical syndrome consisting of headaches, seizures, confusion, and visual
disturbances. It is accompanied with a characteristic neuroimaging picture. A
number of different causes may result in RPLS with similar findings on
neuroimaging. In a recently published series of 47 patients diagnosed with
eclampsia, 46 had RPLS on neuroimaging. [149]
Asnat Walfisch 26
Management

The definitive treatment of eclampsia is delivery to reduce the risk of
maternal morbidity and mortality. Immediate management issues include
prevention of hypoxia and acidosis, management of hypertension, control of
convulsion, prevention of recurrence, and delivery of the fetus and the
placenta.
During a seizure, airway maintenance and aspiration prevention are the
first step. The bedside rails should be raised to prevent fall and trauma.
Supplemental oxygen should be provided. Since 20% of deaths in eclampsia
are due to hypertensive CVAs, emergent antihypertensive therapy should be
instituted in hypertensive women. [150]
Options for treatment include labetalol or hydralazine. Pharmacologic
treatment of mild hypertension is not recommended, as neither maternal nor
fetal benefits have been demonstrated. [151] The initial convulsion is usually
short and treatment is primarily directed at prevention of recurrent convulsions
rather than control of the initial seizure. As many as ten percent of women will
experience another seizure if not treated. [152]
Regarding the mode of delivery, labor induction is a reasonable option for
women beyond 34 weeks of gestation or with a favorable cervix. Nevertheless,
long inductions should be avoided and the time frame should be pre-
determined. In a recent small trial in rural India that randomly assigned
eclamptic women to cesarean delivery or labor induction, there was no benefit
to the cesarean section group and three-quarters of women in the planned
vaginal delivery group delivered vaginally [153].

Anticonvulsant Therapy for Prevention
and Treatment of Eclampsia

Magnesium sulfate is the drug of choice for prevention of eclampsia and
of recurrent seizures. [154] Anticonvulsant therapy should be administered to
prevent seizures in women with severe preeclampsia or recurrent seizures in
eclamptic women. [9, 155] Anticonvulsant therapy may also be used for
prevention of seizures in women with mild preeclampsia, but its role in this
setting is controversial. [13, 156-159] The largest study performed on
preeclamptic women, enrolled over 10,000 women with preeclampsia.
The patients were randomly assigned to receive magnesium sulfate or
placebo. Therapy significantly reduced the risk of eclamptic convulsions (0.8
versus 1.9 percent, RR 0.42, 95% CI 0.29-0.60). However, to prevent one
convulsion, 63 women with severe preeclampsia or 109 women with mild
preeclampsia would need to be treated. [157]
Magnesium's mechanism of action as an anticonvulsant in preeclampsia is
not clearly understood. Some investigators attribute the anticonvulsant effect
of magnesium to blocked neuronal calcium influx through the glutamate
channel. [160] Magnesium is believed to block the N-methyl-D-aspartate
(NMDA) receptors in the central nervous system as implicated from rat
models. [161]
Other mechanisms may be related to vasodilatation of the cerebral vessels,
inhibition of platelet aggregation, protection of endothelial cells from damage
by free radicals and more. [162]
Therapy is generally initiated during labor, induction of labor, or prior to
planned delivery while administering corticosteroids. If the patient is
improving, therapy is discontinued 24 hours postpartum since the risk of
developing seizures drops.
The superiority of magnesium sulfate over phenytoin for prevention of
eclamptic seizures was illustrated in a randomized, controlled trial comparing
these two drugs. [154] Eclamptic seizures developed in 10 of 1089 women
assigned to phenytoin compared to none of 1049 women assigned to
magnesium sulfate. Maternal and neonatal outcomes were similar in both
groups. When compared to a lytic cocktail (a mixture of chlorpromazine,
promethazine and pethidine), a Cochrane review concluded that magnesium
sulfate is more effective and safe. [163]
An overview of randomized, controlled trials of magnesium sulfate
therapy compared to placebo or other anticonvulsants in severe preeclampsia
included 6343 patients. [156] Seizures rate was significantly lower with
magnesium sulfate therapy (RR 0.39, 95% CI 0.28-0.55).
Magnesium sulfates effectiveness for prevention of recurrent seizures in
women with eclampsia was clearly demonstrated in randomized controlled
trials. Its use can reduce the rate of recurrent seizures by one-half to two-thirds
(RR 0.44, 95% CI 0.32-0.51) and the rate of maternal death by one-third (RR
0.62, 95% CI 0.39-0.99). [11] Moreover it is cheaper, relatively easily
administered and less sedative than other anticonvulsant therapies.
The initial dose varies from 4 to 6 g intravenously over 15 minutes. [9]
This dose is safe even in the presence of renal insufficiency. The maintenance
dose is 2gper hour administered as a continuous intravenous infusion.
Asnat Walfisch 28
In women with myasthenia gravis, magnesium sulfate is contraindicated
since it can lead to a severe myasthenic crisis. Concurrence with calcium
channel blockers may produce hypotension. During the maintenance phase
monitoring of patellar reflex, respirations and urine output is imperative. A
serum concentration range of 4.8 to 8.4 mg/dL is recommended. [164]
Calcium gluconate (1 g intravenously) may be administered in cases of
magnesium toxicity. Magnesium toxicity is uncommon in general, especially
in women with good renal function. [165] Magnesium crosses the placneta
freely and maybe associated with reduced fetal heart rate variability. [166]
As mentioned above, the definitive treatment for eclampsia is delivery.
After maternal stabilization, the mode of delivery is considered. The
gestational age, cervical score and fetal condition and position are taken into
account. Cesarean delivery is a reasonable option, for women remote from
term with an unfavorable cervix, since less than one third will successfully
deliver vaginally. [152, 167, 168]

Outcome

Maternal mortality rates of 0 to 14 percent have been reported depending
on prenatal care, resource availability and gestational age. [140, 169, 170]
Perinatal mortality ranges from 9-23%. [140, 170] Complications occur in up
to 70 percent of women with eclampsia. These include: Premature delivery,
abruption of the placenta, perinatal death, acute renal failure, hepato-cellular
injury, intra-cerebral hemorrhage, cardio-respiratory arrest, postpartum
hemorrhage, coagulopathy and more. [156] Although most of these
complications resolve postpartum, cerebro-vascular damage may result in
permanent neurologic damage and is the most common cause of death. [171,
172] HELLP syndrome develops in up to 20 percent of eclamptic women.

Gestational Hypertension

Gestational hypertension is defined as systolic blood pressure 140
mmHg and/or a diastolic blood pressure 90 mmHg, in the absence of
proteinuria, in a previously normotensive pregnant woman at or after 20 weeks
of gestation. [78, 173] The onset of mild hypertension without proteinuria is
occasionally seen late in the third trimester.
Gestational hypertension is a diagnosis that may enclose three types of
patients: Transient hypertension of pregnancy- without progression to
preeclampsia, progression to preeclampsia and, lastly, women with previously
unrecognized chronic hypertension. Therefore, the diagnosis of gestational
hypertension should be used during pregnancy only in women who do not
meet criteria for preeclampsia or chronic hypertension. The final diagnosis is
verified twelve weeks postpartum after chronic hypertension has been ruled
out.
Some evidence suggests that gestational hypertension and preeclampsia
are actually the same entities which only vary in the disease stage. Others
argue that these are two different entities which carry different risk factors. For
example, first pregnancy is a strong risk factor for preeclampsia, but not for
gestational hypertension. [174] However, as many as 50 percent of women
with gestational hypertension go on to develop preeclampsia and the risk
correlates inversely with gestational age. [175, 176] The highest risk of
progression to preeclampsia is in women who develop gestational
hypertension before 30 weeks of gestation. [175-177]
Gestational hypertension has little adverse effect on the mother or fetus,
[1] unless hypertension is severe ( 160/110 mmHg). [100, 177] Pregnancy
outcome in mild gestational hypertension are generally favorable. [78, 100,
176-178] However, in cases of severe gestational hypertension the risk of
maternal and perinatal morbidity rises and is comparable to severe
preeclampsia rates. [78, 100, 174, 176-179] Morbidity includes: preterm
delivery, small for gestational age infants, and abruption of the placenta.
The hypertension typically resolves shortly postpartum, [4] but may recur
in subsequent pregnancies.
As mentioned above, gestational hypertension may not be benign in the
following two situations:

1 Remote from term May be related to the development of
preeclampsia and adverse neonatal outcome. [176]
2 Clinical features of severe disease Symptoms and signs of severe
disease (severe hypertension, persistent headache, visual changes,
growth restriction, oligohydramnios, epigastric or right upper
abdominal pain, thrombocytopenia, or liver function abnormalities).

In these two situations, women are at high risk of maternal and/or fetal
morbidity and should be managed as if they have preeclampsia. [100, 176,
179]
Asnat Walfisch 30
Maternal Evaluation

Primarily gestational hypertension should be distinguished from
preeclampsia (Table 3) and its severity must be determined. White coat
hypertension should also be excluded.
The presence or absence of proteinuria will determine whether the patient
is diagnosed with gestational hypertension or preeclampsia. Urine protein can
be quantified using a 24-hour urine collection or a urine protein-to-creatinine
ratio on a random urine sample. These methods are preferred over a simple
urine dipstick, which carries higher false negative and false positive rates.
Signs and symptoms of end organ damage should be ruled out by questioning,
physical examination and laboratory evaluation.
Twenty percent of women who develop eclampsia have no proteinuria,
[180] and 10 percent of women with other clinical or histological
manifestations of preeclampsia have no proteinuria. [181] Therefore close
follow-up of women with gestational hypertension is prudent.
Fetal well-being should be assessed with a biophysical profile including a
nonstress test. A sonographic estimation of fetal weight is obtained to exclude
growth restriction. Umbilical artery Doppler velocimetry is performed in cases
of growth restriction. [77]

Management and Prognosis

Due to the increased risk of developing preeclampsia and other
complications, patient counseling is important. Any symptoms suggestive of
severe disease should be reported. As in preeclampsia, antihypertensive agents
are not given unless hypertension is severe. Medical therapy of mild
hypertension does not improve neonatal outcome [16, 182] and may mask
severe disease. [77] There is no evidence from large randomized trials that any
maternal and fetal routine surveillance method decreases perinatal morbidity
or mortality. Mild gestational hypertension is usually diagnosed at or beyond
37 weeks of gestation and hence antenatal corticosteroids are rarely indicated.
[78] Delivery before 34 weeks occurs in as little as 1-5% of cases. [78] Since
some studies have reported that pregnancies complicated by gestational
hypertension are at increased risk of perinatal mortality and pregnancy
complications, [174, 183, 184] patients with mild gestational hypertension are
usually delivered no later than 40 weeks of gestation.
Induction at this point is recommended even in the presence of
unfavorable cervix. [76] The American College of Obstetricians and
Gynecologists (ACOG) recommend delivery at 37 to 39 completed weeks for
all women with any degree of gestational hypertension because of the risk of
progression to preeclampsia. [75]
The indications and choice of antihypertensive therapy in gestational
hypertension are the same as for women with preeclampsia. Severe
hypertension is treated medically to reduce the risk of stroke although there are
no data showing that these women are at increased risk of stroke. Women with
severe gestational hypertension are managed differently due to comparable
rates of pregnancy complications as with severe preeclampsia. In these cases,
maternal and fetal surveillance are more extensive and similar to that for
women with severe preeclampsia. Hypertension is treated with anti
hypertensive agents and delivery is considered.
During labor, the woman is monitored for development of proteinuria,
worsening hypertension, and symptoms of severe disease since preeclampsia
may develop intra-partum. Magnesium sulfate seizure prophylaxis is
administered if severe gestational hypertension or severe preeclampsia
develop.
Most women with gestational hypertension become normotensive soon
postpartum. [101] If the woman is still hypertensive by the 12th postpartum
week, she is diagnosed as chronically hypertensive (about 15% of cases).
[185] Gestational hypertension does not affect the endothelium, hence the
prompt resolution of the hypertension postpartum when compared with
preeclampsia (one week versus two weeks). [186] Gestational hypertension
tends to recur with subsequent pregnancies [184] and is associated with
hypertension later in life. [185, 187-189] A retrospective cohort study [188] of
over 3500 women who had gestational hypertension demonstrated a
significant association to hypertension later in life (adjusted odds ratio 2.47,
95% CI 1.74-3.51).

Chronic Hypertension

In pregnant women, chronic hypertension is defined as abnormally
elevated blood pressure (140/90 mmHg or greater) that is documented before
pregnancy. [190] Because of the physiologic decrease in blood pressure seen
in mid-pregnancy, chronic hypertensive patients may actually have pressures
in the normotensive range for a good portion of their pregnancy.
Asnat Walfisch 32
This will make the diagnosis difficult in those with scant prenatal care.
When pre-pregnancy blood pressure is unknown, the diagnosis is based on the
presence of hypertension before 20 weeks of gestation. Patients with mild
chronic hypertension are those with systolic blood pressures between 140-159
mmHg and diastolic pressures between 90-109 while those with a systolic
blood pressure 160 mmHg or a diastolic 110 mmHg are classified as
severe. This is a relatively common disorder occurring in 1-5% of pregnant
women. [190]
There are at least 120,000 pregnant women with chronic hypertension per
year in the United States, a rate expected to increase. [191] Essential
hypertension is responsible for 90% of chronic hypertension associated with
pregnancy. Causes of secondary hypertension include renal disease,
endocrinologic disorders, or collagen vascular disease. In chronic hypertension
elevated blood pressure is the cardinal pathophysiologic feature, whereas in
preeclampsia increased blood pressure is only a sign of the underlying
disorder. Thus, the impact of the two conditions on mother and fetus are
different, as is the management. The cost of managing chronic hypertension in
pregnancy is high, maternal and fetal related.

Adverse Pregnancy Outcome

Women with chronic hypertension are at increased risk of adverse
pregnancy outcome. [192] The most common complication is superimposed
preeclampsia, where the incidence is up to four-fold higher when compared to
the general obstetric population. [190, 193]
In addition, when evaluating the magnitude of fetal and maternal risk, in
this setting, a five-fold increase in low birth weight (RR 5.5, 95% CI 2.6-11.9),
a three-fold increase in perinatal mortality (OR 3.4, 95% CI 3.0-3.7), a two-
fold increase in abruption of the placenta (OR 2.1, 95% CI 1.1-3.9), and an
increased frequency of impaired fetal growth even in the absence of
superimposed preeclampsia have all been shown. [194, 195]
The absolute ranges of risk for adverse pregnancy outcome reported in
observational studies of women with mild and severe chronic hypertension are
high and include preterm birth, superimposed preeclampsia, fetal growth
restriction and abruption of the placenta (Table 6). [190]
Other potential problems are the known long-term risks of any
hypertensive disease and include: retinopathy, renal failure, heart failure,
hypertensive encephalopathy and cerebral hemorrhage. [196]
Table 6. Chronic hypertension Main adverse pregnancy outcome

Adverse Outcome Severe chronic HTN Mild chronic HTN
Preterm birth <37 weeks 62-70% 12-34%
Superimposed preeclampsia 50% 10-25%
Fetal growth restriction 31-40% 8-16%
Abruption of the placenta 5-10% 0.7-1.5%

Women with severe chronic hypertension and those with adverse
outcomes in previous pregnancies are at a higher risk of superimposed
preeclampsia, fetal growth restriction and abruption of the placenta. [191]
These women should therefore undergo thorough counseling about these risks
before conception and should be advised about the importance of adequate
blood pressure control before conception and early in pregnancy.
The treatment of chronic hypertension during pregnancy, despite these
risks, is controversial. Treatment holds limited beneficial effects; mainly
partial prevention of maternal morbidity which largely depend upon the
severity of the hypertensive disease.

Maternal Evaluation and Approach

The primary objective in the management of pregnancies complicated by
chronic hypertension is to reduce maternal risks and achieve optimal perinatal
survival. This objective can be achieved using an approach that includes pre-
conceptional evaluation and counseling, early antenatal care, frequent
antepartum visits to monitor both maternal and fetal well-being, timely
delivery with intensive intra-partum monitoring, and proper postpartum
management. For management and counseling purposes, women with chronic
hypertension should be categorized as having either low-risk or high-risk
hypertension in pregnancy. [190] Women are considered at low risk when they
have mild essential hypertension without any target organ involvement. All
other women should be considered to have high-risk chronic hypertension.
The initial evaluation of the hypertensive patient is beyond the scope of this
chapter. However secondary hypertension must always be considered in young
women, especially if white, non-obese and under 30 years of age with a
confirmed negative family history of hypertension. Women with chronic
hypertension who desire pregnancy should be encouraged to receive pre-
pregnancy care.
Asnat Walfisch 34
The cause and severity of the hypertension should be established. The
patient should cautiously and gradually be taken off anti-hypertensive drugs
with potential adverse effects on the fetus. Renal function and proteinuria
should be assessed.
Once conception has occurred, early prenatal care within an appropriate
setting is important. Frequent care is essential to optimize perinatal outcome in
these patients. During the initial visits, if not determined earlier, a detailed
evaluation of the etiology and severity of the chronic hypertension should be
made and careful attention given to co-morbidities and to the outcome of
previous pregnancies. Baseline laboratory tests recommended in pregnancy
include, at least, serum creatinine, blood urea nitrogen, glucose, and
electrolytes as well as urinalysis and urine culture. [85, 190]
These tests will effectively rule out many causes of previously
unrecognized secondary hypertension and will identify important co-
morbidities. Women who develop evidence of proteinuria on a urine dipstick
should have a quantitative test for urine protein. Patients with severe
hypertension or proteinuria should also have a retinal evaluation, chest x-ray,
EKG, antinuclear antibody testing, and, when indicated, serum complement
studies. An echocardiogram should be performed to evaluate cardiac function
in cases of long standing hypertension.
Patients with recurrent pregnancy loss or a history of thrombo-embolic
disease should be evaluated for APLA syndrome. Pregnancies in high-risk
hypertensive women with additional risk factors are associated with increased
maternal and perinatal complications. These pregnancies should be managed
in consultation with appropriate specialists. Close monitoring and multiple
hospitalizations may be necessary to control hypertension and associated
complications.

Indications for Treatment

There is no consensus on the best treatment approach for women with
mild chronic hypertension. Women with uncomplicated chronic hypertension
who are stable on medication may continue their therapy or have it tapered or
stopped during pregnancy as long as their blood pressure is monitored closely.
[4, 190]
Many times, acceptable blood pressures will be achieved during the
second trimester in the absence of the usual antihypertensive therapy due to
the physiological decrease in blood pressure at this time.
Mild Chronic Hypertension

Although a large number of trials were conducted focusing on the
potential benefits of antihypertensive therapy in pregnancy, these trials, even
with meta-analysis, lack sufficient power to detect modest treatment effects.
Mild essential hypertension is defined as systolic pressure of 140-159 or
diastolic pressure of 90- 109 mmHg.
Neither the fetus nor the patient appears to be at risk from mild
hypertensive disease.
Furthermore, controlled trials have not demonstrated any reduced risk of
preeclampsia or abruption, or any improvement in fetal or maternal outcome
when antihypertensive medications were given in this setting. [84, 89, 90, 195,
197, 198] The only demonstrated benefit, as concluded in two systematic
reviews, is the decreased incidence of severe hypertension. [90, 199] Up to 13
women would need to be treated to prevent one episode of severe
hypertension. [90]
Based on the available data, treatment is usually not initiated in pregnant
women with uncomplicated mild essential hypertension, especially in the first
trimester. If the patient is already on antihypertensive therapy and measured
blood pressures during early pregnancy are less than 120/80 mmHg,
discontinuation of therapy should strongly be considered. Nevertheless, signs
of hypertensive end-organ damage or persistent high blood pressures (systolic
pressures greater than 150 mmHg or diastolic pressures of over 100 mmHg)
should promote initiation of therapy.
These thresholds, although not necessarily in the severe range, allow a
non-emergent approach with oral drugs.
Specific subgroups of women with mild hypertension appear to be at
greater risk of fetal and maternal complications and may benefit from
antihypertensive therapy (Table 7). [190] Target blood pressures of around
140 / 90 mmHg are desirable.

Severe Chronic Hypertension

Severe hypertension is defined as blood pressure 160/100 mmHg. Even
in the absence of associated signs of early hypertensive encephalopathy,
severe hypertension should be treated to protect the mother from serious co -
morbidity, such as heart failure, renal failure or stroke.
Asnat Walfisch 36
Table 7. Suggested indications for therapy in mild chronic hypertension

1
Secondary hypertension (e.g., renal disease, collagen vascular disease,
coarctation of the aorta)
2 End-organ damage (e.g., retinopathy, ventricular dysfunction)
3 Maternal age over 40 years old
4 Microvascular disease
5 History of stroke
6 Previous perinatal loss
7 Diabetes
8 Dyslipidemia
9
Persistent high blood pressures of mild hypertensive disease (systolic
pressures 150 mmHg or diastolic pressures 95 mmHg)

Drug Therapy

All antihypertensive drugs cross the placenta. There are no data from large
well-designed randomized trials on which to base a recommendation for use of
one drug over another.
The pharmacologic approach to blood pressure control should be
individualized depending on the presence of other conditions, such as renal
disease, diabetes, and left ventricular dysfunction.
Usually, if maternal blood pressure is controlled with her own medications
prior to conception, it may be continued throughout the pregnancy and after
delivery, except for angiotensin-converting enzyme inhibitors, angiotensin
receptor blockers and atenolol. [190, 200]
If however the patient is not treated and an indication exists, treatment is
usually started with either labetalol or methyldopa. Calcium channel blockers
(long acting) may be added. These drugs have been extensively used during
pregnancy and are reasonably safe and effective. [1]

Methyldopa

This mild antihypertensive drug is one of the most widely used drugs in
pregnant women and is considered safe for the fetus. [1, 197, 201-204]
However, blood pressure goals may not be achieved, and the drug may have a
sedative effect.
Labetalol

Labetolol is the most widely used beta-adrenergic blocker in pregnancy.
Beta-adrenergic blockers are not associated with an increased risk of
congenital anomalies however their safety is somewhat controversial due to
few reports of preterm delivery, fetal growth restriction, and hypoglycemia.
[203] Labetalol has both alpha- and beta-adrenergic blocking activity, and may
preserve utero-placental blood flow better than other drugs in this class. Beta-
blockers are more effective in avoiding episodes of severe hypertension and
are better tolerated than methyldopa. [90, 204]

Calcium Channel Blockers

These agents appear to be safe for use in pregnancy according to
accumulating experience. [199] Long-acting nifedipine (30 to 90 mg once
daily as sustained release tablet, increase at 7 to 14 day intervals, maximum
dose 120 mg/day) has been used without major problems. [87, 205, 206]

Thiazide Diuretics

Although previously controversial, current recommendations suggest that
these agents can be continued as long as volume depletion is avoided. [1, 4,
202, 207, 208] Volume depletion is unlikely with chronic therapy, assuming
that drug dose and dietary sodium intake are constant, since fluid loss occurs
during the first two weeks of use. Angiotensin converting enzyme (ACE)
inhibitors and angiotensin II receptor blockers (ARBs) are fetopathic and are
contraindicated during pregnancy.

Antepartum Assessment

This assessment is directed toward early diagnosis of superimposed
preeclampsia and signs of placental insufficiency. Frequent prenatal visits are
recommended for monitoring maternal blood pressure, proteinuria, renal
function and fundal growth as well as periodic sonographic estimation of fetal
size and growth. [4, 190] Nevertheless, an uncomplicated pregnancy is
expected in over 85 % of hypertensive women. [1]
Asnat Walfisch 38
There is no consensus regarding the role of antepartum fetal assessment in
pregnancies complicated by mild maternal hypertension. Gestational age
should be determined to avoid uncertainty when fetal growth delay is
suspected. [190] In the absence of superimposed preeclampsia or fetal growth
restriction, the frequency of antepartum fetal assessment is controversial.
Nevertheless, many clinicians perform a nonstress test with amniotic fluid
index or biophysical profile weekly or twice per week in the later third
trimester.
In cases of utero-placental vasculopathy or intrauterine growth restriction,
close fetal surveillance is warranted. [85, 208] In these cases, serial
sonographic assessments of fetal growth are indicated as well as frequent
nonstress testing and/or biophysical profile examination. [4, 85, 208]

Delivery

Women with mild, uncomplicated chronic hypertension can be allowed to
go into spontaneous labor and deliver at term [85, 208] although the practice
of inducing labor at 39-40 weeks of gestation is common. Earlier delivery
should be considered for women with the following: severe hypertension,
superimposed preeclampsia, fetal growth restriction or other signs of placental
insufficiency, and in any other cases of suspected pregnancy complications.
The American College of Obstetricians and Gynecologists (ACOG)
recently suggested the following approach for women with chronic
hypertension: 38 to 39 6/7
ths
weeks of gestation for women not requiring
medication, 37 to 39 6/7
ths
weeks for women with hypertension controlled with
medication, and 36 to 37 6/7
ths
weeks for women with severe hypertension
difficult to control. [75]
Intrapartum management is directed at the avoidance of acute maternal
and fetal complications. Maternal blood pressure can be controlled with oral or
intravenous hydralazine or labetalol. Close attention must be given to the use
of intravenous fluids and to the noninvasive hemodynamic parameters. Fetuses
may be compromised by long-standing growth restriction and hypoxemia prior
to the onset of labor. Therefore, continuous fetal monitoring and fetal scalp pH
sampling, as needed, are important to assess the ability of the fetus to tolerate
labor.
Postpartum, high-risk patients should be monitored closely for at least 48
hours due to the risk of developing hypertensive encephalopathy, pulmonary
edema and renal failure.
Either oral or intravenous antihypertensive drugs can be used to control
severe hypertension. In some women, it is often necessary to switch to a new
agent such as an angiotensin-converting enzyme inhibitor, particularly in those
with pre-gestational diabetes mellitus and those with cardiomyopathy.
In patients with evidence of circulatory congestion or pulmonary edema,
diuretic therapy should be used. High-risk patients should be evaluated after
the postpartum period for cardiac or renal function change and for adjustment
of antihypertensive medication as stated above. Some patients may wish to
breast-feed their infants. As discussed previously, all antihypertensive drugs
are found in the breast milk, although drugs differ in the amount transferred to
the milk. [209] Long-term effect of maternal antihypertensive drugs on breast-
feeding infants is not known. Methyldopa appears to be safe since milk
concentrations are low. The use of methyldopa as a first-line oral therapy
appears to be a reasonable choice. Labetalol or propanolol are a better choice
than atenolol and metoprolol due to lower concentrations in breast milk. [209,
210] There is little information about the transfer of calcium channel blockers
to breast milk, but there are no apparent side effects. Diuretic agents may
induce a decrease in milk production. [209] Angiotensin-converting enzyme
inhibitors and angiotensin II receptor antagonists should be avoided because of
their effects on neonatal renal function.

Preeclampsia Superimposed
on Chronic Hypertension

Women with chronic hypertension should be monitored closely for early
detection of superimposed preeclampsia, the most frequent complication
associated with hypertension during pregnancy. Superimposed preeclampsia is
defined as worsening hypertension with new onset proteinuria in a woman
with chronic hypertension. Women with both preexisting hypertension and
proteinuria are considered preeclamptic if one of the following occurs:
An exacerbation of blood pressure to the severe range (systolic 160
mmHg or diastolic 110 mmHg) after 20 weeks of gestation, especially if
accompanied by symptoms or increased liver enzymes or thrombocytopenia,
or a sudden increase in the proteinuria.
However, current diagnostic criteria for hypertensive disorders of
pregnancy are not adequate in women who have preexisting hypertension or
proteinuria or both.
Asnat Walfisch 40
In these women, the definitions for superimposed preeclampsia are
arbitrary and lack reliable data to support their validity. [17] Many clinical,
biophysical, and biochemical markers have been proposed to either predict or
detect the development of superimposed preeclampsia. [18, 211-214] These
have included markers related to impaired trophoblast differentiation and
invasion, placental and endothelial dysfunction, coagulation and complement
activation, immune mal-adaptation to paternal antigens, and exaggerated
systemic inflammatory response. Some authors have suggested the diagnostic
usefulness of serum sFLt-1, soluble endoglin, and uric acid values in
differentiating women with preeclampsia from those with various other
hypertensive disorders of pregnancy. [17] However, major limitations
regarding the diagnostic criteria of preeclampsia used as well as sample size
make these studies insufficient.
Superimposed preeclampsia complicates approximately 5-50% of the
chronic hypertensive pregnancies, depending on whether the diagnosis of
preeclampsia was made simply on the basis of exacerbation of the
hypertension or if significant proteinuria was part of the definition. In patients
with risk factors, the incidence of superimposed preeclampsia is 25-50%.
Importantly, the incidence of superimposed preeclampsia (or placental
abruption) is not influenced by the use of antihypertensive medications. [215]
Decreased utero-placental perfusion can lead to worsening of the fetal growth
restriction. Spontaneous or intentional interruption of the pregnancy adds the
compounding complications of prematurity. Severe superimposed
preeclampsia developing after 28 weeks is an indication for delivery; prior to
28 weeks the pregnancy may be followed conservatively in a tertiary center
with daily evaluation of maternal and fetal condition, although this latter
approach remains controversial. [216, 217]

References

[1] Cunningham, F. G., Lindheimer, M. D. Hypertension in pregnancy. N.
Engl. J. Med. 1992; 326:927.
[2] Sibai, B. M. Pitfalls in diagnosis and management of preeclampsia. Am.
J. Obstet. Gynecol. 1988; 159:1.
[3] American College of Obstetricians and Gynecologists. Hypertension in
Pregnancy. ACOG. Technical Bulletin #219. American College of
obstetricians and Gynecologists, Washington, DC, 1996.
[4] Working group report on high blood pressure in pregnancy. National
Institutes of Health, Washington, DC 2000.
[5] Lain, K. Y., Roberts, J. M. Contemporary concepts of the pathogenesis
and management of preeclampsia. JAMA 2002; 287:3183.
[6] Saftlas, A. F., Olson, D. R., Franks, A. L., et al. Epidemiology of
preeclampsia and eclampsia in the United States, 1979-1986. Am. J.
Obstet. Gynecol. 1990; 163:460.
[7] Maternal mortality--United States, 1982-1996. MMWR Morb. Mortal.
Wkly. Rep. 1998; 47:705.
[8] Sibai, B. M., Gordon, T., Thom, E., et al. Risk factors for preeclampsia
in healthy nulliparous women: a prospective multicenter study. The
National Institute of Child Health and Human Development Network of
Maternal-Fetal Medicine Units. Am. J. Obstet. Gynecol. 1995; 172:642.
[9] ACOG practice bulletin. Diagnosis and management of preeclampsia
and eclampsia. Number 33, January 2002. Obstet. Gynecol. 2002; 99:
159.
[10] Abalos, E., Cuesta, C., Grosso, A. L., Chou, D., Say, L. Global and
regional estimates of preeclampsia and eclampsia: a systematic review.
Eur. J. Obstet. Gynecol. Reprod. Biol. 2013 Jun. 6.
[11] Sibai, B. M. Magnesium sulfate prophylaxis in preeclampsia: Lessons
learned from recent trials. Am. J. Obstet. Gynecol. 2004; 190:1520.
[12] www.cdc.gov. (accessed October 18, 2006).
[13] Livingston, J. C., Livingston, L. W., Ramsey, R., et al. Magnesium
sulfate in women with mild preeclampsia: a randomized controlled trial.
[14] MacKay, A. P., Berg, C. J., Atrash, H. K. Pregnancy-related mortality
from preeclampsia and eclampsia. Obstet. Gynecol. 2001; 97:533.
[15] Khan, K. S., Wojdyla, D., Say, L., et al. WHO analysis of causes of
maternal death: a systematic review. Lancet 2006; 367:10661074.
[16] Sibai, B., Dekker, G., Kupfermic, M. Preeclampsia. Lancet 2005; 365:
785799.
[17] Sibai, B. Hypertensive disorders of pregnancy: the United States
perspective. Curr. Opin. Ob. Gyn. 2008, 20:102106.
[18] Widmer, M., Villar, J., Benigni, A., et al. Mapping the theory of
preeclampsia and the role of angiogenic factors: A systemic review.
Obstet. Gynecol. 2007;109:168180.
[19] Levine, R. J., Lam, C., Qian, C., et al. Soluble endoglin and other
circulating angiogenic factors in preeclampsia. N. Engl. J. Med. 2006;
355:9921005.
Asnat Walfisch 42
[20] Vatlen, L. J., Eskild, A., Nilsen, T. I. L., et al. Changes in circulating
level of angiogenic factors from the first to second trimester as
predictors of preeclampsia. Am. J. Obstet. Gynecol. 2007; 196:239.e1
239.e6.
[21] Smith, G. C. S., Crossley, J. A., Aitken, D. A., et al. Circulating
angiogenic factors in early pregnancy and the risk of preeclampsia,
intrauterine growth restriction, spontaneous preterm birth, and stillbirth.
Obstet. Gynecol. 2007; 109:13161324.
[22] Rana, S., Karumanchi, A., Levine, R. J., et al. Sequential changes in
antiangiogenic factors in early pregnancy and risk of developing
preeclampsia. Hypertension 2007; 50:137142.
[23] Chafetz, I., Kuhnreich, I., Sanner, M., et al. First-trimester placental
protein 13 screening for preeclampsia and intrauterine growth
restriction. Am. J. Obstet. Gynecol. 2007; 197:35.e135.e7.
[24] Papageorghiou, A. T., Leslie, K. Uterine artery Doppler in the prediction
of adverse pregnancy outcome. Curr. Opin. Obstet. Gynecol. 2007; 19:
103109.
[25] Li, H., Gudnason, H., Olofsson, P., et al. Increased uterine artery
vascular impedance is related to adverse outcome of pregnancy but is
present in only one-third of late third- trimester preeclamptic women.
Ultrasound Obstet. Gynecol. 2005; 25:459463.
[26] Geerts, I., Odendaal, H. J. Severe early onset preeclampsia: prognostic
value of ultrasound and Doppler assessment. J. Perinatol. 2007; 27:335
342.
[27] Duckitt, K., Harrington, D. Risk factors for pre-eclampsia at antenatal
booking: systematic review of controlled studies. BMJ 2005; 330:565.
[28] Sibai, B. M., El-Nazer, A., Gonzalez-Ruiz, A. Severe preeclampsia-
eclampsia in young primigravid women: Subsequent pregnancy outcome
and remote prognosis. Am. J. Obstet. Gynecol. 1986; 155:1011.
[29] Van Rijn, B. B., Hoeks, L. B., Bots, M. L., et al. Outcomes of
subsequent pregnancy after first pregnancy with early-onset
preeclampsia. Am. J. Obstet. Gynecol. 2006; 195:723.
[30] Sibai, B. M., Mercer, B., Sarinoglu, C. Severe preeclampsia in the
second trimester: Recurrence risk and long-term prognosis. Am. J.
[31] Dekker, G. A., Sibai, B. M. Etiology and pathogenesis of preeclampsia:
current concepts. Am. J. Obstet. Gynecol. 1998; 179:1359.
[32] Dawson, L. M., Parfrey, P. S., Hefferton, D., et al. Familial risk of
preeclampsia in newfoundland: a population-based study. J. Am. Soc.
Nephrol. 2002; 13:1901.
[33] Nilsson, E., Salonen Ros, H., Cnattingius, S., Lichtenstein, P. The
importance of genetic and environmental effects for pre-eclampsia and
gestational hypertension: a family study. BJOG 2004; 111:200.
[34] Esplin, M. S., Fausett, M. B., Fraser, A., Kerber, R., Mineau, G.,
Carrillo, J., Varner, M. W. Paternal and maternal components of the
predisposition to preeclampsia. N. Engl. J. Med. 2001 22; 344(12):867-
72.
[35] Stella, C. L., How, H. Y., Sibai, B. M. Thrombophilia and adverse
maternal-perinatal outcome: controversies in screening and
management. Am. J. Perinatol. 2006; 23:499.
[36] Conde-Agudelo, A., Villar, J., Lindheimer, M. Maternal infection and
risk of preeclampsia: systematic review and metaanalysis. Am. J. Obstet.
Gynecol. 2008; 198:7.
[37] Askie, L. M., Duley, L., Henderson-Smart, D. J., Stewart, L. A., On
behalf of the PARIS Collaborative Group. Antiplatelet agents for
prevention of preeclampsia: a meta-analysis of individual patient data.
Lancet 2007; 369:17911798.
[38] Villa, P. M., Kajantie, E., Rikknen, K., et al. Aspirin in the prevention
of pre-eclampsia in high-risk women: a randomised placebo-controlled
PREDO Trial and a meta-analysis of randomised trials. BJOG 2013;
120:64.
[39] Trumbo, P. R., Ellwood, K. C. Supplemental calcium and risk reduction
of hypertension, pregnancy-induced hypertension, and preeclampsia: An
evidence-based review by the US Food and Drug Administration. Nutr.
Rev. 2007; 65:7887.
[40] Hofmeyr, G. J., Lawrie, T. A., Atallah, . N., Duley, L. Calcium
supplementation during pregnancy for preventing hypertensive disorders
and related problems. Cochrane Database of Systematic Reviews 2010,
Issue 8. Art. No.: CD001059. DOI:10.1002/14651858.CD001059.pub3.
[41] Polyzos, N. P., Mauri, D., Tsappi, M., et al. Combined Vitamin C and E
supplementation during pregnancy for preeclampsia prevention: A
systematic review. Obstet. Gynecol. Survey 2007; 62:202206.
[42] Kasawara, K. T., do Nascimento, S. L., Costa, M. L., et al. Exercise and
physical activity in the prevention of pre-eclampsia: systematic review.
Acta Obstet. Gynecol. Scand. 2012; 91:1147.
Asnat Walfisch 44
[43] Towers, C. V., Pircon, R. A., Nageotte, M. P., et al. Cocaine intoxication
presenting as preeclampsia and eclampsia. Obstet. Gynecol. 1993; 81:
545.
[44] Broekhuizen, F. F., Elejalde, R., Hamilton, P. R. Early-onset
preeclampsia, triploidy and fetal hydrops. J. Reprod. Med. 1983; 28:223.
[45] Villar, M. A., Sibai, B. M. Clinical significance of elevated mean arterial
blood pressure in second trimester and threshold increase in systolic or
diastolic blood pressure during third trimester [see comments]. Am. J.
[46] Levine, R. J., Ewell, M. G., Hauth, J. C., et al. Should the definition of
preeclampsia include a rise in diastolic blood pressure of < 15 mm Hg to
a level <90 mm Hg in association with proteinuria? Am. J. Obstet.
Gynecol. 2000; 183:787.
[47] Bellomo, G., Narducci, P. L., Rondoni, F., et al. Prognostic value of 24-
hour blood pressure in pregnancy. JAMA 1999; 282:1447.
[48] Bergel, E., Carroli, G., Althabe, F. Ambulatory versus conventional
methods for monitoring blood pressure during pregnancy (Cochrane
Review). Cochrane Database Syst. Rev. 2002;CD001231.
[49] Moran, P., Lindheimer, M. D., Davison, J. M. The renal response to
preeclampsia. Semin. Nephrol. 2004; 24:588.
[50] Moran, P., Baylis, P. H., Lindheimer, M. D., Davison, J. M. Glomerular
ultrafiltration in normal and preeclamptic pregnancy. J. Am. Soc.
Nephrol. 2003; 14:648.
[51] Lang, R. M., Pridjian, G., Feldman, T., et al. Left ventricular mechanics
in preeclampsia. Am. Heart J. 1991; 121:1768.
[52] Bosio, P. M., McKenna, P. J., Conroy, R., O'Herlihy, C. Maternal
central hemodynamics in hypertensive disorders of pregnancy. Obstet.
Gynecol. 1999; 94:978.
[53] Visser, W., Wallenburg, H. C. Central hemodynamic observations in
untreated preeclamptic patients. Hypertension 1991; 17:1072.
[54] Hankins, G. D., Wendel, G. D. Jr, Cunningham, F. G., Leveno, K. J.
Longitudinal evaluation of hemodynamic changes in eclampsia. Am. J.
[55] Cotton, D. B., Lee, W., Huhta, J. C., Dorman, K. F. Hemodynamic
profile of severe pregnancy-induced hypertension. Am. J. Obstet.
Gynecol. 1988; 158:523.
[56] Phelan, J. P., Yurth, D. A. Severe preeclampsia. I. Peripartum
hemodynamic observations. Am. J. Obstet. Gynecol. 1982; 144:17.
[57] Clark, S. L., Greenspoon, J. S., Aldahl, D., Phelan, J. P. Severe
preeclampsia with persistent oliguria: management of hemodynamic
subsets. Am. J. Obstet. Gynecol. 1986; 154:490.
[58] Mabie, W. C., Ratts, T. E., Sibai, B. M. The central hemodynamics of
severe preeclampsia. Am. J. Obstet. Gynecol. 1989; 161:1443.
[59] Benedetti, T. J., Kates, R., Williams, V. Hemodynamic observations in
severe preeclampsia complicated by pulmonary edema. Am. J. Obstet.
Gynecol. 1985; 152:330.
[60] Taufield, P. A., Ales, K. L., Resnick, L. M., et al. Hypocalciuria in
preeclampsia. N. Engl. J. Med. 1987; 316:715.
[61] August, P., Marcaccio, B., Gertner, J. M., et al. Abnormal 1,25
dihydroxyvitamin D metabolism in preeclampsia. Am. J. Obstet.
Gynecol. 1992; 166:1295.
[62] Powers, R. W., Bodnar, L. M., Ness, R. B., et al. Uric acid
concentrations in early pregnancy among preeclamptic women with
gestational hyperuricemia at delivery. Am. J. Obstet. Gynecol. 2006;
194: 160.
[63] Stillman, I. E., Karumanchi, S. A. The glomerular injury of
preeclampsia. J. Am. Soc. Nephrol. 2007; 18:2281.
[64] Arias, F., Mancilla-Jimenez, R. Hepatic fibrinogen deposits in pre-
eclampsia. Immunofluorescent evidence. N. Engl. J. Med. 1976; 295:
578.
[65] Minakami, H., Oka, N., Sato, T., et al. Preeclampsia: a microvesicular
fat disease of the liver?. Am. J. Obstet. Gynecol. 1988; 159:1043.
[66] Stubbs, T. M., Lazarchick, J., Van Dorsten, J. P., et al. Evidence of
accelerated platelet production and consumption in nonthrombo-
cytopenic preeclampsia. Am. J. Obstet. Gynecol. 1986; 155: 263.
[67] Sheehan, H. L., Lynch, J. B. Pathology of toxaemia of pregnancy.
Churchill and Livingstone, London 1973.
[68] Richards, A., Graham, D., Bullock, R. Clinicopathological study of
neurological complications due to hypertensive disorders of pregnancy.
J. Neurol. Neurosurg. Psychiatry 1988; 51:416.
[69] Drislane, F. W., Wang, A. M. Multifocal cerebral hemorrhage in
eclampsia and severe pre-eclampsia. J. Neurol. 1997; 244:194.
[70] Morriss, M. C., Twickler, D. M., Hatab, M. R., et al. Cerebral blood
flow and cranial magnetic resonance imaging in eclampsia and severe
preeclampsia. Obstet. Gynecol. 1997; 89:561.
Asnat Walfisch 46
[71] Carpenter, F., Kava, H. L., Plotkin, D. The development of total
blindness as a complication of pregnancy. Am. J. Obstet. Gynecol. 1953;
66: 641.
[72] Odegard, R. A., Vatten, L. J., Nilsen, S. T., et al. Preeclampsia and fetal
growth. Obstet. Gynecol. 2000; 96:950.
[73] Sibai, B. M., Mercer, B. M., Schiff, E., Friedman, S. A. Aggressive
versus expectant management of severe preeclampsia at 28-32 weeks'
gestation: A randomized controlled trial. Am. J. Obstet. Gynecol. 1994;
171: 818.
[74] Friedman, S. A., Schiff, E., Kao, L., Sibai, B. M. Neonatal outcome after
preterm delivery for preeclampsia. Am. J. Obstet. Gynecol. 1995;172:
1785.
[75] American College of Obstetricians and Gynecologists. ACOG
committee opinion no. 560: Medically indicated late-preterm and early-
term deliveries. Obstet. Gynecol. 2013; 121:908.
[76] Tajik, P., van der Tuuk, K., Koopmans, C. M., et al. Should cervical
favourability play a role in the decision for labour induction in
gestational hypertension or mild pre-eclampsia at term? An exploratory
analysis of the HYPITAT trial. BJOG 2012; 119:1123.
[77] Nicholson, J. M., Kellar, L. C., Kellar, G. M. The impact of the
interaction between increasing gestational age and obstetrical risk on
birth outcomes: evidence of a varying optimal time of delivery. J.
Perinatol., 2006; 26:392.
[78] Sibai, B. M. Diagnosis and management of gestational hypertension and
[79] Chang, E. Y., Menard, M. K., Vermillion, S. T., et al. The association
between hyaline membrane disease and preeclampsia. Am. J. Obstet.
Gynecol. 2004; 191:1414.
[80] Sibai, B. M., Barton, J. R. Expectant management of severe
preeclampsia remote from term: patient selection, treatment, and
delivery indications. Am. J. Obstet. Gynecol. 2007; 196:514.e1514.e9.
[81] Norwitz, E. R., Edmund, F., Funai, E. F. Expectant management of
severe preeclampsia. UPTODATE January 3, 2008.
[82] Haddad, B., Kayem, G., Deis, S., Sibai, B. M. Are perinatal and
maternal outcomes different during expectant management of severe
preeclampsia in the presence of intrauterine growth restriction? Am. J.
Obstet. Gynecol. 2007; 196:237.e1237.e5.
[83] Meher, S., Abalos, E., Carroli, G., Meher, S. Bed rest with or without
hospitalisation for hypertension during pregnancy. Cochrane Database
Syst. Rev. 2005; :CD003514.
[84] Remuzzi, G., Ruggenenti, P. Prevention and treatment of pregnancy-
associated hypertension: What have we learned in the last 10 years? Am.
J. Kidney Dis. 1991; 18:285.
[85] American College of Obstetricians and Gynecologists. Chronic
hypertension in pregnancy. ACOG practice bulletin #29. American
College of Obstetricians and Gynecologists, Washington, DC 2001.
[86] Martin, J. N. Jr, Thigpen, B. D., Moore, R. C., et al. Stroke and severe
preeclampsia and eclampsia: a paradigm shift focusing on systolic blood
pressure. Obstet. Gynecol. 2005; 105:246.
[87] Sibai, B. M., Barton, J. R., Akl, S., et al. A randomized prospective
comparison of nifedipine and bed rest versus bed rest alone in the
management of preeclampsia remote from term. Am. J. Obstet. Gynecol.
1992; 167:879.
[88] Von Dadelszen, P., Magee, L. A. Fall in mean arterial pressure and fetal
growth restriction in pregnancy hypertension: an updated metaregression
analysis. J. Obstet. Gynaecol. Can. 2002; 24:941.
[89] Magee, L. A., Ornstein, M. P., von Dadelszen, P. Fortnightly review:
management of hypertension in pregnancy. BMJ 1999; 318:1332.
[90] Abalos, E., Duley, L., Steyn, D. W., Henderson-Smart, D. J.
Antihypertensive drug therapy for mild to moderate hypertension during
pregnancy (Cochrane Review). Cochrane Database Syst. Rev. 2007: CD
002252.
[91] Duley, L., Henderson-Smart, D. J., Meher, S. Drugs for treatment of
very high blood pressure during pregnancy. Cochrane Database Syst.
Rev. 2006;3:CD001449.
[92] Hanff, L. M., Vulto, A. G., Bartels, P. A., et al. Intravenous use of the
calcium-channel blocker nicardipine as second-line treatment in severe,
early-onset pre-eclamptic patients. J. Hypertens. 2005; 23:2319.
[93] Elatrous, S., Nouira, S., Ouanes Besbes, L., et al. Short-term treatment
of severe hypertension of pregnancy: prospective comparison of
nicardipine and labetalol. Intensive Care Med. 2002; 28:1281.
[94] Jannet, D., Carbonne, B., Sebban, E., Milliez, J. Nicardipine versus
metoprolol in the treatment of hypertension during pregnancy: a
randomized comparative trial. Obstet. Gynecol. 1994; 84:354.
Asnat Walfisch 48
[95] O'Mailia, J. J., Sander, G. E., Giles, T. D. Nifedipine-associated
myocardial ischemia or infarction in the treatment of hypertensive
urgencies. Ann. Intern. Med. 1987; 107:185.
[96] Grossman, E., Messerli, F. H., Grodzicki, T., Kowey, P. Should a
moratorium be placed on sublingual nifedipine capsules given for
hypertensive emergencies and pseudoemergencies?. JAMA 1996; 276:
1328.
[97] Impey, L. Severe hypotension and fetal distress following sublingual
administration of nifedipine to a patient with severe pregnancy induced
hypertension at 33 weeks. Br. J. Obstet. Gynaecol. 1993; 100:959.
[98] Hennessy, A., Thornton, C. E., Makris, A., et al. A randomised
comparison of hydralazine and mini-bolus diazoxide for hypertensive
emergencies in pregnancy: The PIVOT trial. Aust. N. Z. J. Obstet.
Gynaecol. 2007; 47:279.
[99] Heard, A. R., Dekker, G. A., Chan, A., et al. Hypertension during
pregnancy in South Australia, Part 1: Pregnancy outcomes. Aust. N. Z. J.
Obstet. Gynaecol. 2004; 44:404.
[100] Hauth, J. C., Ewell, M. G., Levine, R. J., et al. Pregnancy outcomes in
healthy nulliparas who developed hypertension. Calcium for
Preeclampsia Prevention Study Group. Obstet. Gynecol. 2000; 95:24.
[101] Ferrazzani, S., De Carolis, S., Pomini, F., et al. The duration of
hypertension in the puerperium of preeclamptic women: relationship
with renal impairment and week of delivery. Am. J. Obstet. Gynecol.
1994; 171:506.
[102] Podymow, T., August, P. Postpartum course of gestational hypertension
and preeclampsia. Hypertension in pregnancy 20006; 25:210.
[103] Sibai, B. M. Etiology and management of postpartum hypertension-
preeclampsia. Am. J. Obstet. Gynecol. 2012; 206:470.
[104] Magee, L., von Dadelszen, P. Prevention and treatment of postpartum
hypertension. Cochrane Database Syst. Rev. 2013; 4:CD004351.
[105] http://toxnet.nlm.nih.gov/cgi-bin/sis/search/f?./temp/~0BtRSx:1
(accessed November 2, 2007).
[106] Campbell, D. M., MacGillivray, I. Preeclampsia in second pregnancy.
Br. J. Obstet. Gynaecol. 1985; 92:131.
[107] Xiong, X., Fraser, W. D., Demianczuk, N. N. History of abortion,
preterm, term birth, and risk of preeclampsia: A population-based study.
Am. J. Obstet. Gynecol. 2002; 187:1013.
[108] Sibai, B. M., Sarinoglu, C., Mercer, B. M. Eclampsia. VII. Pregnancy
outcome after eclampsia and long-term prognosis. Am. J. Obstet.
Gynecol. 1992; 166:1757.
[109] Bellamy, L., Casas, J. P., Hingorani, A. D., Williams, D. J. Pre-
eclampsia and risk of cardiovascular disease and cancer in later life:
systematic review and meta-analysis. BMJ 2007; 335:974.
[110] Fraser, A., Nelson, S. M., Macdonald-Wallis, C., et al. Associations of
pregnancy complications with calculated cardiovascular disease risk and
cardiovascular risk factors in middle age: the Avon Longitudinal Study
of Parents and Children. Circulation 2012; 125:1367.
[111] Hermes, W., Franx, A., van Pampus, M. G., et al. Cardiovascular risk
factors in women who had hypertensive disorders late in pregnancy: a
cohort study. Am. J. Obstet. Gynecol. 2013; 208:474.e1.
[112] Hermes, W., Ket, J. C., van Pampus, M. G., et al. Biochemical
cardiovascular risk factors after hypertensive pregnancy disorders: a
systematic review and meta-analysis. Obstet. Gynecol. Surv. 2012; 67:
793.
[113] Bytautiene, E., Bulayeva, N., Bhat, G., et al. Long-term alterations in
maternal plasma proteome after sFlt1-induced preeclampsia in mice. Am.
J. Obstet. Gynecol. 2013; 208:388.e1.
[114] Feig, D. S., Shah, B. R., Lipscombe, L. L., et al. Preeclampsia as a risk
factor for diabetes: a population-based cohort study. PLoS Med. 2013;
10: e1001425.
[115] Chesley, L. C., Annitto, J. E., Cosgrove, R. A. The remote prognosis of
eclamptic women: Sixth periodic report. Am. J. Obstet. Gynecol. 1976;
124: 446.
[116] Paltiel, O., Friedlander, Y., Tiram, E., et al. Cancer after pre-eclampsia:
follow up of the Jerusalem perinatal study cohort. BMJ 2004; 328:919.
[117] Sibai, B. M., Taslimi, M. M., el-Nazer, A., et al. Maternal-perinatal
outcome associated with the syndrome of hemolysis, elevated liver
enzymes, and low platelets in severe preeclampsia-eclampsia. Am. J.
[118] Reubinoff, B. E., Schenker, J. G. HELLP syndrome a syndrome of
hemolysis, elevated liver enzymes, and low platelet count
complicating pre-eclampsia-eclampsia. Int. J. Gynaecol. Obstet. 1991;
36: 95.
[119] Sibai, B. M. The HELLP syndrome (hemolysis, elevated liver enzymes,
and low platelets): Much ado about nothing? Am. J. Obstet. Gynecol.
1990; 162:311.
Asnat Walfisch 50
[120] Sibai, B. M., Ramadan, M. K., Usta, I., et al. Maternal morbidity and
mortality in 442 pregnancies with hemolysis, elevated liver enzymes,
and low platelets (HELLP syndrome). Am. J. Obstet. Gynecol. 1993;
169: 1000.
[121] Abildgaard, U., Heimdal, K. Pathogenesis of the syndrome of hemolysis,
elevated liver enzymes, and low platelet count (HELLP): a review. Eur.
J. Obstet. Gynecol. Reprod. Biol. 2013; 166:117.
[122] Weinstein, L. Preeclampsia/Eclampsia with hemolysis, elevated liver
enzymes, and thrombocytopenia. Obstet. Gynecol. 1985;66:657-60.
[123] Sibai, B. M. Diagnosis, controversies, and management of the syndrome
of hemolysis, elevated liver enzymes, and low platelet count. Obstet.
Gynecol. 2004; 103:981.
[124] Visser, W., Wallenburg, H. C. Temporising management of severe pre-
eclampsia with and without the HELLP syndrome. Br. J. Obstet.
Gynaecol. 1995; 102:111.
[125] Van Pampus, M. G., Wolf, H., Westenberg, S. M., et al. Maternal and
perinatal outcome after expectant management of the HELLP syndrome
compared with pre-eclampsia without HELLP syndrome. Eur. J. Obstet.
Gynecol. Reprod. Biol. 1998; 76:31.
[126] Stone, J. H. HELLP syndrome: Hemolysis, elevated liver enzymes, and
low platelets. JAMA 1998; 280:559.
[127] O'Brien, J. M., Shumate, S. A., Satchwell, S. L., et al. Maternal benefit
of corticosteroid therapy in patients with HELLP (hemolysis, elevated
liver enzymes, and low platelet count) syndrome: impact on the rate of
regional anesthesia. Am. J. Obstet. Gynecol. 2002; 186:475.
[128] Matchaba, P., Moodley, J. Corticosteroids for HELLP syndrome in
pregnancy. Cochrane Database Syst. Rev. 2004; :CD002076.
[129] Isler, C. M., Barrilleaux, P. S., Magann, E. F., et al. A prospective,
randomized trial comparing the efficacy of dexamethasone and
betamethasone for the treatment of antepartum HELLP (hemolysis,
elevated liver enzymes, and low platelet count) syndrome. Am. J. Obstet.
Gynecol. 2001; 184:1332.
[130] Martin, J. N. Jr, Thigpen, B. D., Rose, C. H., Cushman, J. Maternal
benefit of high-dose intravenous corticosteroid therapy for HELLP
syndrome. Am. J. Obstet. Gynecol. 2003; 189:830.
[131] Fonseca, J. E., Mendez, F., Catano, C., Arias, F. Dexamethasone
treatment does not improve the outcome of women with HELLP
syndrome: a double-blind, placebo-controlled, randomized clinical trial.
[132] Katz, L., de Amorim, M. M., Figueiroa, J. N., Pinto, E., Silva, J. L.
Postpartum dexamethasone for women with hemolysis, elevated liver
enzymes, and low platelets (HELLP) syndrome: a double-blind, placebo-
controlled, randomized clinical trial. Am. J. Obstet. Gynecol. 2008; 198:
283.
[133] Burwick, R. M., Feinberg, B. B. Eculizumab for the treatment of
preeclampsia/HELLP syndrome. Placenta 2013; 34:201.
[134] Martin, J. N. Jr, Blake, P. G., Perry, K. G. Jr, et al. The natural history of
HELLP syndrome: Patterns of disease progression and regression. Am. J.
[135] Hupuczi, P., Nagy, B., Sziller, I., et al. Characteristic laboratory changes
in pregnancies complicated by HELLP syndrome. Hypertens. Pregnancy
2007; 26:389.
[136] Sibai, B. M., Spinnato, J. A., Watson, D. L., et al. Pregnancy outcome in
303 cases with severe preeclampsia. Obstet. Gynecol. 1984; 64:319.
[137] Greenstein, D., Henderson, J., Boyer, T. Liver hemorrhage: Recurrent
episodes during pregnancy complicated by preeclampsia.
Gastroenterology 1994; 106:1668.
[138] Sibai, B. M., Ramadan, M. K., Chari, R. S., Friedman, S. A. Pregnancies
complicated by HELLP syndrome (hemolysis, elevated liver enzymes,
and low platelets): Subsequent pregnancy outcome and long-term
prognosis. Am. J. Obstet. Gynecol. 1995; 172:125.
[139] Wust, M. D., Bolte, A. C., de Vries, J. I., et al. Pregnancy outcome after
previous pregnancy complicated by hepatic rupture. Hypertens.
Pregnancy 2004; 23:29.
[140] Douglas, K. A., Redman, C. W. Eclampsia in the United Kingdom. BMJ
1994; 309:1395.
[141] Lubarsky, S. L., Barton, J. R., Friedman, S. A., et al. Late postpartum
eclampsia revisited. Obstet. Gynecol. 1994; 83:502.
[142] Miles, J. F. Jr, Martin, J. N. Jr, Blake, P. G., et al. Postpartum eclampsia:
a recurring perinatal dilemma. Obstet. Gynecol. 1990; 76:328.
[143] Chames, M. C., Livingston, J. C., Ivester, T. S., Barton, J. R. Late
postpartum eclampsia: A preventable disease? Am. J. Obstet. Gynecol.
2002; 186:1174.
[144] Morriss, M. C., Twickler, D. M., Hatab, M. R., et al. Cerebral blood
flow and cranial magnetic resonance imaging in eclampsia and severe
[145] Tuffnell, D. J., Jankowicz, D., Lindow, S. W., et al. Outcomes of severe
pre-eclampsia/eclampsia in Yorkshire 1999/2003. BJOG 2005; 112:875.
Asnat Walfisch 52
[146] Geographic variation in the incidence of hypertension in pregnancy.
World Health Organization International Collaborative Study of
Hypertensive Disorders of Pregnancy. Am. J. Obstet. Gynecol. 1988;
158: 80.
[147] Dahmus, M. A., Barton, J. R., Sibai, B. M. Cerebral imaging in
eclampsia: Magnetic resonance imaging versus computed tomography.
[148] Cunningham, F. G., Grant, N. F., Leveno, K. J., et al. (eds):
Hypertensive disorders in pregnancy. In: Williams Obstetrics, 21
st
ed.
New York, McGraw-Hill, 2001, pp. 567-618.
[149] Brewer, J., Owens, M. Y., Wallace, K., et al. Posterior reversible
encephalopathy syndrome in 46 of 47 patients with eclampsia. Am. J.
Obstet. Gynecol. 2013; 208:468.e1.
[150] Lindenstrom, E., Boysen, G., Nyboe, J. Influence of systolic and
diastolic blood pressure on stroke risk: a prospective observational
study. Am. J. Epidemiol. 1995; 142:1279.
[151] Norwitz, E. R. Eclampsia. UPTODATE May 2008.
[152] Pritchard, J. A., Cunningham, F. G., Pritchard, S. A. The Parkland
Memorial Hospital protocol for treatment of eclampsia: evaluation of
245 cases. Am. J. Obstet. Gynecol. 1984; 148:951.
[153] Seal, S. L., Ghosh, D., Kamilya, G., et al. Does route of delivery affect
maternal and perinatal outcome in women with eclampsia? A
randomized controlled pilot study. Am. J. Obstet. Gynecol. 2012; 206:
484.e1.
[154] Lucas, M. J., Leveno, K. J., Cunningham, F. G. A comparison of
magnesium sulfate with phenytoin for the prevention of eclamspia. N.
Engl. J. Med. 1995; 333:201.
[155] Roberts, J. M., Villar, J., Arulkumaran, S. Preventing and treating
eclamptic seizures. BMJ 2002; 325:609.
[156] Hall, D. R., Odendaal, H. J., Smith, M. Is the prophylactic
administration of magnesium sulphate in women with pre-eclampsia
indicated prior to labour?. BJOG 2000; 107:903.
[157] Altman, D., Carroli, G., Duley, L., Farrell, B., Moodley, J., Neilson, J.,
Smith, D.; Magpie Trial Collaboration Group. Do women with pre-
eclampsia, and their babies, benefit from magnesium sulphate? The
Magpie Trial: a randomized placebo-controlled trial. Lancet 2002; 359:
1877.
[158] Alexander, J. M., McIntire, D. D., Leveno, K. J., Cunningham, F. G.
Selective magnesium sulfate prophylaxis for the prevention of eclampsia
in women with gestational hypertension. Obstet. Gynecol. 2006; 108:
826.
[159] Witlin, A. G., Friedman, S. A., Sibai, B. M. The effect of magnesium
sulfate therapy on the duration of labor in women with mild
preeclampsia at term: a randomized, double-blind, placebo-controlled
trial. Am. J. Obstet. Gynecol. 1997; 176:623.
[160] Lipton, S. A., Rosenberg, P. A.: Excitatory amino acids as a final
common pathway for neurologic disorders. N. Engl. J. Med. 1994; 330:
613.
[161] Hallak, M., Hotca, J. W., Evans, J. B. Magnesium sulfate affects the N-
methyl-D-aspartate receptor binding in maternal rat brain. Am. J. Obstet.
Gynecol. 1998;178:S112.
[162] Roberts, J. M. Magnesium for preeclampsia and eclampsia. N. Engl. J.
Med. 1995; 333:250.
[163] Duley, L., Gulmezoglu, A. M. Magnesium sulphate versus lytic cocktail
for eclampsia. Cochrane Database Syst. Rev. 2001; :CD002960.
[164] Sibai, B. M., Lipshitz, J., Anderson, G. D., Dilts, P. V. Jr. Reassessment
of intravenous MgSO4 therapy in preeclampsia-eclampsia. Obstet.
Gynecol. 1981; 57:199.
[165] Smith, J. M., Lowe, R. F., Fullerton, J., et al. An integrative review of
the side effects related to the use of magnesium sulfate for pre-eclampsia
and eclampsia management. BMC Pregnancy Childbirth 2013; 13:34.
[166] Duffy, C. R., Odibo, A. O., Roehl, K. A., et al. Effect of magnesium
sulfate on fetal heart rate patterns in the second stage of labor. Obstet.
Gynecol. 2012; 119:1129.
[167] Alexander, J. M., Bloom, S. L., McIntire, D. D., Leveno, K. J. Severe
preeclampsia and the very low birth weight infant: is induction of labor
harmful? Obstet. Gynecol. 1999; 93:485.
[168] Nassar, A. H., Adra, A. M., Chakhtoura, N., et al. Severe preeclampsia
remote from term: labor induction or elective cesarean delivery? Am. J.
[169] Sibai, B. M., McCubbin, J. H., Anderson, G. D., et al. Eclampsia. I.
Observations from 67 recent cases. Obstet. Gynecol. 1981; 58:609.
[170] Lpez-Llera, M. Main clinical types and subtypes of eclampsia. Am. J.
[171] Sibai, B. M., Spinnato, J. A., Watson, D. L., et al. Eclampsia. IV.
Neurological findings and future outcome. Am. J. Obstet. Gynecol. 1985;
152:184.
Asnat Walfisch 54
[172] Okanloma, K. A., Moodley, J. Neurological complications associated
with the pre-eclampsia/eclampsia syndrome. Int. J. Gynaecol. Obstet.
2000; 71:223.
[173] Report of the National High Blood Pressure Education Program
Working Group on High Blood Pressure in Pregnancy. Am. J. Obstet.
Gynecol. 2000;183:S1.
[174] Villar, J., Carroli, G., Wojdyla, D., et al. Preeclampsia, gestational
hypertension and intrauterine growth restriction, related or independent
conditions?. Am. J. Obstet. Gynecol. 2006; 194:921.
[175] Saudan, P., Brown, M. A., Buddle, M. L., Jones, M. Does gestational
hypertension become pre-eclampsia? Br. J. Obstet. Gynaecol 1998; 105:
1177.
[176] Barton, J. R., O'brien, J. M., Bergauer, N. K., Jacques, D. L., et al. Mild
gestational hypertension remote from term: progression and outcome.
[177] Buchbinder, A., Sibai, B. M., Caritis, S., et al. Adverse perinatal
outcomes are significantly higher in severe gestational hypertension than
in mild preeclampsia. Am. J. Obstet. Gynecol. 2002; 186:66.
[178] Hnat, M. D., Sibai, B. M., Caritis, S., et al. Perinatal outcome in women
with recurrent preeclampsia compared with women who develop
preeclampsia as nulliparas. Am. J. Obstet. Gynecol. 2002; 186:422.
[179] Knuist, M., Bonsel, G. J., Zondervan, H. A., Treffers, P. E.
Intensification of fetal and maternal surveillance in pregnant women
with hypertensive disorders. Int. J. Gynaecol. Obstet. 1998; 61:127.
[180] Chesley, L. C.: Hypertensive Disorders in Pregnancy, Appleton Century
Crofts, New York 1978.
[181] Fisher, K. A., Luger, A., Spargo, B. H., Lindheimer, M. D. Hypertension
in pregnancy: Clinical-pathological correlations and late prognosis.
Medicine (Baltimore) 1981; 60:267.
[182] Sibai, B. M., Eclampsia, V. I. Maternal-perinatal outcome in 254
consecutive cases. Am. J. Obstet. Gynecol. 1990; 163:1049.
[183] Magee, L. A., von Dadelszen, P., Bohun, C. M., et al. Serious perinatal
complications of non-proteinuric hypertension: an international,
multicentre, retrospective cohort study. J. Obstet. Gynaecol. Can. 2003;
25: 372.
[184] Steer, P. J., Little, M. P., Kold-Jensen, T., et al. Maternal blood pressure
in pregnancy, birth weight, and perinatal mortality in first births:
prospective study. BMJ 2004; 329:1312.
[185] Reiter, L., Brown, M. A., Whitworth, J. A. Hypertension in pregnancy:
The incidence of underlying renal disease and essential hypertension.
Am. J. Kidney Dis. 1994; 24:883.
[186] Magloire, L., Funai, E. F. Gestational hypertension. UPTODATE June
2007.
[187] Hjartardottir, S., Leifsson, B. G., Geirsson, R. T., Steinthorsdottir, V.
Recurrence of hypertensive disorder in second pregnancy. Am. J. Obstet.
Gynecol. 2006; 194:916.
[188] Wilson, B. J., Watson, M. S., Prescott, G. J., Sunderland, S., et al.
Hypertensive diseases of pregnancy and risk of hypertension and stroke
in later life: results from cohort study. BMJ 2003; 326:845.
[189] Mnnist, T., Mendola, P., Vrsmki, M., et al. Elevated blood
pressure in pregnancy and subsequent chronic disease risk. Circulation
2013; 127:681.
[190] Sibai, B. M. Chronic hypertension in pregnancy. Obstet. Gynecol. 2002;
100: 369-377.
[191] Sibai, B. M. Caring for women with hypertension in pregnancy. JAMA
2007;298:1566.
[192] Orbach, H., Matok, I., Gorodischer, R., et al. Hypertension and
antihypertensive drugs in pregnancy and perinatal outcomes. Am. J.
Obstet. Gynecol. 2013; 208:301.e1.
[193] Powrie, R. O. A 30-year-old woman with chronic hypertension trying to
conceive. JAMA 2007; 298:1548.
[194] Ferrer, R. L., Sibai, B. M., Mulrow, C. D., et al. Management of mild
chronic hypertension during pregnancy: a review. Obstet. Gynecol.
2000; 96:849.
[195] Mulrow, C. D., et al. Management of chronic hypertension in pregnancy.
Agency for Healthcare Research and Quality, August 2000. Evidence
report/Technology assessment 14. AHRQ publication 00-E011.
[196] Gilbert, W. M., Young, A. L., Danielsen, B. Pregnancy outcomes in
women with chronic hypertension. J. Reprod. Med. 2007; 52:1046.
[197] Redman, C. W. Controlled trials of antihypertensive drugs in pregnancy.
Am. J. Kidney Dis. 1991; 17:149.
[198] Sibai, B. M., Mabie, W. C., Shamsa, F., et al. A comparison of no
medication versus methyldopa or labetalol in chronic hypertension
during pregnancy. Am. J. Obstet. Gynecol. 1990; 162:960.
[199] Magee, L. A., Duley, L. Oral beta-blockers for mild to moderate
hypertension during pregnancy. Cochrane Database Syst. Rev. 2003: CD
002863.
Asnat Walfisch 56
[200] Umans, J. G., Lindheimer, M. D. Antihypertensive treatment. In:
Lindheimer, M. D., Roberts, J. M., Cunningham, F. G., eds. Chesleys
Hypertensive Disorders in Pregnancy. 2
nd
ed. Norwalk, CT: Appleton
and Lange; 1998:581-604.
[201] Cockburn, J., Moar, V. A., Ounsted, M., Redman, C. W. Final report of
study on hypertension during pregnancy: the effects of specific treatment
on the growth and development of the children. Lancet 1982; 1:647.
[202] Ferris, T. F. Hypertension in pregnancy. The Kidney 1990; 23: Number
1.
[203] Montan, S., Ingemarsson, I., Marsal, K., Sjberg, N. O. Randomised
controlled trial of atenolol and pindolol in human pregnancy: Effects on
fetal hemodynamics. BMJ 1992; 304:946.
[204] Lydakis, C., Lip, G. Y., Beevers, M., Beevers, D. G. Atenolol and fetal
growth in pregnancies complicated by hypertension. Am. J. Hypertens.
1999; 12:541.
[205] Fenakel, K., Fenakel, G., Appelman, Z., et al. Nifedipine in the
treatment of severe preeclampsia. Obstet. Gynecol. 1991; 77:331.
[206] Smith, P., Anthony, J., Johanson, R. Nifedipine in pregnancy. BJOG
2000; 107:299.
[207] Collins, R., Yusuf, S., Peto, R. Overview of randomised trials of
diuretics in pregnancy. Br. Med. J. (Clin. Res. Ed.) 1985; 290:17.
[208] American College of Obstetricians and Gynecologists. ACOG Practice
Bulletin No. 125: Chronic hypertension in pregnancy. Obstet. Gynecol.
2012; 119:396.
[209] Briggs, G. G., Freeman, R. K., Yaffee, S. J. Drugs in pregnancy and
lactation: A reference guide to fetal and neonatal risk. 5
th
ed. Baltimore:
Williams and Wilkins, 1998.
[210] White, W. B. Management of hypertension during lactation.
Hypertension 1984;6: 297300.
[211] Sibai, B. M. Biomarker for hypertension-preeclampsia: are we close yet?
Am. J. Obstet. Gynecol. 2007;197(1):1-2.
[212] Conde-Agudelo, A., Villar, J., Linheimer, M. World Health
Organization systemic review of screening tests for preeclampsia.
Obstet. Gynecol. 2004;104(6): 1367-1391.
[213] Nicolaides, K. H., Bindra, R., Twian, O. M., et al. A novel approach to
first-trimester screening for early preeclampsia combining serum PP-13
and Doppler ultrasound. Ultrasound Obstet. Gynecol. 2006;27(1):13-17.
[214] Espinoza, J., Romero, R., Nien, J. K., et al. Identification of patients at
risk for early onset and/or severe preeclampsia with the use of uterine
artery Doppler velocimetry and placental growth factor. Am. J. Obstet.
Gynecol. 2007;196:326.e1- 326.e13.
[215] Sibai, B. M. Chronic hypertension in pregnancy. Clin. Perinatol. 1991;
18:833-44.
[216] Sibai, B. M., Akl, S., Fairlie, F., Moretti, M. A protocol for managing
severe preeclampsia in the second trimester. Am. J. Obstet. Gynecol.
1990; 163:733-8.
[217] Sibai, B. M. Diagnosis, prevention, and management of eclampsia.


Chapter II

Differential Diagnosis
for Preeclampsia

Liran Hiersch, M.D. and Yariv Yogev, M.D.

Helen Schneider Hospital for Women, Rabin Medical Center,
Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv University,
Tel Aviv, Israel

Introduction

Mild hypertension and proteinuria with no laboratory abnormalities in
term pregnancy is usually related to preeclampsia. However, in more severe
cases especially when other features not commonly described in preeclampsia
are present, other disorders should be taken into consideration since
misdiagnosis and treatment delay is often associated with an increased rate of
maternal and perinatal adverse outcome.
The diagnostic challenge is even greater since many of the disorders in the
differential diagnosis of preeclampsia are not infrequently superimposed by
preeclampsia as well. In the following chapter a description of the main
disorders which could mimic severe preeclampsia would be given with a

Corresponding author: Yariv Yogev, MD, Department of Obstetrics and Gynecology, Helen
Schneider Hospital for Women, Rabin Medical Center, Petah Tiqwa 49100, Israel. Tel:
+972-3-9377680; E-mail: yarivyogev@hotmail.com.
Liran Hiersch and Yariv Yogev 60
consideration regarding the features that could help in reaching the correct
diagnosis.

Acute Fatty Liver of Pregnancy

Acute fatty liver of pregnancy (AFLP) is rare but potentially one of the
most fatal complications of pregnancy. The incidence of AFLP ranges from 1
in 10,000 to 1 in 15,000 deliveries [1-3] and it is more common in nulliparous
and in multiple gestations [1, 2, 4, 5]. The clinical symptoms usually begins
during the third trimester [2, 5, 6], although it may be presented initially only
in the post-partum period [4, 6]. The most common complaints are persistent
nausea and vomiting, hypertension and abdominal pain with more than 90% of
women having at least 1 of these findings or combinations thereof [2]. Patients
with AFLP are ill-appearing with accompanying jaundice. Some will have low
grade fever which is absent in preeclampsia.
The hallmark of AFLP is markedly elevated liver enzymes such as AST,
ALT, alkaline phosphatases and hyperbilirubinemia usually exceeding 5 mg/
dL. The platelets count is initially normal but thrombocytopenia could be
present [1, 7]. Coagulation studies, especially in severe cases, are consistent
with disseminated intravascular coagulopathy (DIC) [2, 4-6, 8] due to a
reduced production of clotting factors, as opposed to DIC seen in severe
preeclampsia which is related to abnormal consumption [9].
Imaging modalities such as liver ultrasonography (US), computed
tomography (CT) or magnetic resonance imaging (MRI) could be used,
although none of them could exclude the diagnosis of AFLP sufficiently [10,
11]. The gold standard for confirming the diagnosis is liver biopsy revealing
swollen, pale hepatocytes with central nuclei [12]. However, it is rarely used
and the diagnosis is usually made based on clinical and laboratory findings [1,
4-6]. AFLP is associated with an increased rate of maternal and neonatal
morbidity and mortality [1, 2, 4, 6, 13]. The higher rate of maternal mortality
reported in the past declined in recent reports to less than 10%, although
maternal morbidity rate including hypoglycemia, sepsis, pancreatitis, DIC and
renal failure remains relatively high [2, 8, 11, 14, 15]. Perinatal mortality rate
is declining in recent reports to approximately 10% with high morbidity rate
primarily due to prematurity [2, 14, 16]. In general, after establishing the
diagnosis and maternal stabilization, prompt delivery is the ultimate treatment
since no spontaneous resolution of AFLP without delivery was reported. Most
patients will show signs of recovery 2-3 days following delivery with close
Differential Diagnosis for Preeclampsia 61
monitoring of vital signs and laboratory studies needed until then. Treatment
of AFLP by plasma exchange (PE) is safe and effective, and timely application
of PE in the early phase of the disease can effectively halt and reverse the
progression of AFLP [17, 18].
Nevertheless, in rare cases a progression to fulminant hepatic failure with
the requirement of liver transplantation could occur [12].
Distinguishing AFLP from HELLP syndrome can be challenging as up to
50% of women with AFLP have concomitant preeclampsia [4, 19]. However,
several features could be helpful in the common scenario of overlapping
clinical features. Since AFLP affects the synthetic function of the liver,
hypoglycemia is a frequent complication. Moreover, hyperbilirubinemia and
hypofibrinogemia are more prominent in AFLP than in HELLP syndrome
[20]. Profoundly decreased antithrombin levels also suggest AFLP [7, 20].

Thrombotic Thrombocytopenic Purpura

Thrombotic thrombocytopenic purpura (TTP) is an extremely rare
condition occurring during pregnancy or in the post-partum period with
incidence of less than 1 in 100,000 pregnancies [21]. Pregnancy induced TTP
was observed to occur at early third trimester, while post-partum TTP usually
follows term pregnancies [21]. The classic pentad of TTP consists of
thrombocytopenia, microangiopathic hemolytic anemia, neurologic
abnormalities, renal dysfunction and fever although it is rarely seen in its
complete form [22]. Anemia and thrombocytopenia are usually present and in
a severe form [22-24]. Other symptoms and sign include abdominal pain,
nausea or gastrointestinal bleeding and/or hematuria.
Besides severe anemia and thrombocytopenia, marked elevated levels of
serum lactate hydrogenase (LDH) is usually present with blood smear
revealing schistocytes [22, 23, 25].
The underlying pathological disturbance involves systemic or intrarenal
aggregation of platelets within the arterioles and capillaries in association with
endothelial cell injury. Large multimers of von Willebrand factor (VWF) are
found in maternal serum, which originate from the endothelial cells, but also
can be produced by platelets. In acquired TTP, the activity of A VWF-cleaving
metalloprotease (ADAMTS13) activity is markedly reduced (<5% of normal)
which subsequently cause an adhesion and aggregation of platelets in the
microcirculation [1, 22-24, 26].
The treatment of TTP during pregnancy is similar to non-pregnant women
and is based mainly on plasma exchange. Its widespread use has decreased the
mortality rate from 90% to about 10% [27, 28]. Second line therapy for
refractory cases includes vincristine, rituximab and splenectomy which have
been described during pregnancy with favorable outcome [20, 29].
There is also a decline in the rate of neonatal mortality from 80% [30] to
less 50% in recent reports with prematurity as the main effector of neonatal
outcome [1, 31].
It is of most importance to distinguish TTP from PET/HELLP since delay
in plasma exchange in TTP could result in higher rates of maternal morbidity
and mortality, whereas delivery is the optimal treatment for PET/HELLP.
Several laboratory studies could assist in that differentiation.
Although the activity of ADAMTS13 is reduced in patients with HELLP
syndrome compared to those with normal pregnancies, it is still in the normal
range and can be used to distinguish between TTP and HELLP syndrome [32,
33]. In addition, a high LDH to AST ratio (>22) was also suggested to support
the diagnosis of TTP [34]. The absence of coagulation abnormalities and
normal levels of transaminases are also suggestive of TTP [20, 35].

Hemolytic Uremic Syndrome

Hemolytic uremic syndrome (HUS), like TTP, is a rare microangiopathic
disorder [1]. Most of pregnancy related cases of HUS occur during the
postpartum period [36-38]. HUS is primarily a disease of infancy and early
childhood. In its classic form, it is preceded by a prodrome of Escherichia coli-
mediated bloody mucoid diarrhea.
Typical HUS is commonly related to an infection by shiga-toxin
producing E. coli. Stool cultures may detect this bacteria or its toxin, and
PCRs can detect the shiga-toxin virulence genes. Atypical cases of HUS are
mainly related to abnormalities of the alternative complement pathway and
mutations of H, I, or B factors [39].
The microvascular injury in HUS affects mainly the kidney with a
resultant edema, hypertension, microscopic hematuria and proteinuria and
frequent deterioration to end stage renal disease [1, 39]. Other laboratory
findings are similar to those observed in TTP, but in a less severe form. As in
TTP, plasma exchange is considered the treatment of choice, though it is less
effective and many will eventually require dialysis.
For the atypical form of HUS, the humanized monoclonal antibody
Eculizumab was reported to be effective, although the experience in pregnancy
is limited [40-42].

Systemic Lupus Erythematous
Exacerbation

Systemic lupus erythematous (SLE) is a systemic autoimmune disease that
primarily affects women of childbearing age [1, 43]. This chronic disease is
distinguished by its multi-organ involvement, characteristic inflammatory
lesions of the skin, joints, serous membranes, central nervous system (CNS)
and most importantly, the kidney. Its clinical course is often one of disease
flares followed by variable periods of remission [44]. Reports of the effect of
pregnancy on SLE activity are mixed, with some studies reporting a two- to
three-fold increased risk of flare, whereas others indicate no increased risk
[45-47]. Risk factors for a SLE flare include active disease within 6 months
before conception, a history of multiple flares, and discontinuation of
hydroxychloroquine [46]. Pregnancy in a woman with SLE is associated with
an increased risk of adverse maternal and fetal outcomes such as preterm
delivery (38-54%), intrauterine growth restriction (11-29%) fetal loss (4-19%)
and the coexistence of preeclampsia (7-15%) [46, 48-51].
Pregnant women with lupus nephritis could present with hypertension,
proteinuria and thrombocytopenia, especially in an acute flare. Although
similar features are present in preeclampsia and coexistence could occur, some
features could be used to help differentiation the two conditions. Serum uric
acid >5.5 mg/dl, a urine calcium level of <195 mg/day, and rising liver
enzyme levels should raise the concern for preeclampsia, whereas a rise in
dsDNA antibody titer, low or dropping complement levels, active urinary
sediment and an increased lupus activity in other organs indicate an acute flare
[44].
Management of SLE flares during pregnancy should be individualized and
consider the effect on both mother and fetus. Non-steroidal anti-inflammatory
drugs (NSAIDS) should be avoided in the second or third trimester for their
potential adverse effect on fetal cardiac, renal and gastrointestinal systems
[52]. Hydroxychloroquine (HCQ) is typically used to treat the arthritis and
skin manifestation of SLE and its safety profile and ability to decrease flares
has led to the recommendation to continue its use throughout pregnancy,
especially in women using it prior to conception [44, 53]. When symptoms
cannot be adequately controlled using HCQ alone or in combination with
acetaminophen, glucocorticoids can be used [54]. Cyclosporine and the more
potent agent Tacrolimus are considered effective in controlling for lupus
nephritis during pregnancy with safe fetal profile [55-57].
Antiphospholipid antibodies (APLA) are present in 5% of the general
population and in almost 40% of patients with SLE [58-60].
It is associated with increased rate of adverse pregnancy outcome such as
fetal loss and maternal thromboembolic events [61]. Since thrombocytopenia
is seen in 40-50% and hemolytic anemia in approximately 20% of these cases
it could be mistaken for other thrombotic microangiopathies or HELLP
syndrome [62].

Table. Features of disorder mimicking severe preeclampsia

Parameter
HELLP
Syndrome
AFLP TTP/HUS
SLE
Exacerbation
Hypertension 60-80% 20-40%
20-75% (more
common in HUS)
60-80%
Proteinuria
300mg/day
90% 30% w/ Hematuria
w/ Hematuria
or cellular cast
Fever Absent 20-40% 40-60% common
Thrombocytopenia
20,000-
100,000
>50,000 <20,000 20,000-95,000
Hemolytic anemia >50% Rare Usually present
15-25%
Usually w/
APLA
Elevated
transaminase
Usually
Markedly, w/ direct
hyperbilirubinemia
Mild, Indirect
hyperbilirubinemia
Mild w/ APLA
Other / Unique
features
- >20
weeks of
gestation
-Hypoglycemia
-ill appearing w/
Jaundice
-ADAMTS13 <5%
(TTP)
-LDH/AST >22
-Rising anti
dsDNA Ab
titers
-Complement
>25% drop
HELLP, Hemolysis, elevated liver enzymes, low platelets; AFLP, Acute fatty liver of
pregnancy; TTP/HUS, Thrombotic thrombocytopenic purpura/ Hemolytic uremic
syndrome; SLE, Systemic lupus erythematous; APLA, Antiphospholipid
antibodies; ADAMTS13, A disintegerin and metalloproteinase with thrombo-
spondin type-1 motif; LDH, Lactate dehydrogenase; AST, Aspartate Amino-
transferase; dsDNA ab, Double stranded deoxyribonucleic acid antibodies.

In less than 1% of women with APLA an entity of catastrophic
antiphospholipid antibody syndrome (CAPS) could occur. It is characterized
by an acute thrombotic microangiopathy affecting the small vessels of at least
three organ systems [44]. The kidneys, lungs and brain are the most commonly
affected organs and the specific pregnancy-related manifestations of CAPS
include placental thrombosis, myometrial thrombotic angiopathy and pelvic
vein thrombosis [63].
Almost 50% of cases of CAPS occurring during pregnancy or in the post-
partum period were reported in patients with SLE [64]. Unfortunately, CAPS
related maternal and perinatal morbidity is high with almost 50% maternal
mortality [62].

Conclusion

The above mentioned disorders can occur during pregnancy or in the
postpartum period. Therefore, these entities should be kept in mind when
facing a patient with unusual presentation of preeclampsia or when other
symptoms, signs and laboratory abnormalities are present. Despite the rare
incidence compared to preeclampsia, they are associated with high rate of
devastating maternal and perinatal outcome, especially when treatment is
delayed. Often a multidisciplinary approach is required for optimal results.

References

[1] Sibai, B. M. Imitators of severe pre-eclampsia. Semin. Perinatol. 2009;
33: 196-205.
[2] Nelson, D. B., Yost, N. P., Cunningham, F. G. Acute fatty liver of
pregnancy: clinical outcomes and expected duration of recovery. Am. J.
Obstet. Gynecol. 2013 Jul. 13. [Epub. ahead of print].
[3] Barber, M. A., Eguiluz, I., Martn, A., Plasencia, W., Valle, L., Garca, J.
A. Acute fatty liver of pregnancy: analysis of five consecutive cases
from a tertiary centre. J. Obstet. Gynaecol. 2010; 30:241-3.
[4] Fesenmeier, M. F., Coppage, K. H., Lambers, D. S., Barton, J. R., Sibai,
B. M. Acute fatty liver of pregnancy in 3 tertiary care centers. Am. J.
Obstet. Gynecol. 2005; 192:1416-9.
[5] Vigil-DeGracia, P., Lavergne, J. A. Acute fatty liver of pregnancy. Int. J.
Gynaecol. Obstet. 2001; 72:193-5.
[6] Usta, I. M., Barton, J. R., Amon, E. A., Gonzalez, A., Sibai, B. M. Acute
fatty liver of pregnancy: an experience in the diagnosis and management
of fourteen cases. Am. J. Obstet. Gynecol. 1994; 171:1342-7.
[7] Castro, M. A., Fassett, M. J., Reynolds, T. B., Shaw, K. J., Goodwin, T.
M. Reversible peripartum liver failure: a new perspective on the
diagnosis, treatment, and cause of acute fatty liver of pregnancy, based
on 28 consecutive cases. Am. J. Obstet. Gynecol. 1999; 181:389-95.
[8] Zhou, G., Zhang, X., Ge, S. Retrospective Analysis of Acute Fatty Liver
of Pregnancy: Twenty-Eight Cases and Discussion of Anesthesia.
Gynecol. Obstet. Invest. 2013 Jun. 20. [Epub. ahead of print].
[9] Sibai, B. M. Diagnosis, controversies, and management of the syndrome
of hemolysis, elevated liver enzymes, and low platelet count. Obstet.
Gynecol. 2004; 103:981-91.
[10] Castro, M. A., Ouzounian, J. G., Colletti, P. M., Shaw, K. J., Stein, S.
M., Goodwin, T. M. Radiologic studies in acute fatty liver of pregnancy.
A review of the literature and 19 new cases. J. Reprod. Med. 1996; 41:
839-43.
[11] Wei, Q., Zhang, L., Liu, X. Clinical diagnosis and treatment of acute
fatty liver of pregnancy: a literature review and 11 new cases. J. Obstet.
Gynaecol. Res. 2010; 36:751-6.
[12] Knox, T. A., Olans, L. B. Liver disease in pregnancy. N. Engl. J. Med.
1996; 335:569-76.
[13] Vigil-de Gracia, P., Montufar-Rueda, C. Acute fatty liver of pregnancy:
diagnosis, treatment, and outcome based on 35 consecutive cases. J.
Matern. Fetal Neonatal. Med. 2011; 24:1143-6.
[14] Knight, M., Nelson-Piercy, C., Kurinczuk, J. J., Spark, P., Brocklehurst,
P.; UK Obstetric Surveillance System. A prospective national study of
acute fatty liver of pregnancy in the UK. Gut 2008; 57:951-6.
[15] Dekker, R. R., Schutte, J. M., Stekelenburg, J., Zwart, J. J., van
Roosmalen, J. Maternal mortality and severe maternal morbidity from
acute fatty liver of pregnancy in the Netherlands. Eur. J. Obstet.
Gynecol. Reprod. Biol. 2011; 157:27-31.
[16] Yang, Z., Yamada, J., Zhao, Y., Strauss, A. W., Ibdah, J. A. Prospective
screening for pediatric mitochondrial trifunctional protein defects in
pregnancies complicated by liver disease. JAMA 2002; 288:2163-6.
[17] Jin, F., Cao, M., Bai, Y., Zhang, Y., Yang, Y., Zhang, B. Therapeutic
effects of plasma exchange for the treatment of 39 patients with acute
fatty liver of pregnancy. Discov. Med. 2012; 13:369-73.
[18] Chu, Y. F., Meng, M., Zeng, J., Zhou, H. Y., Jiang, J. J., Ren, H. S.,
Zhang, J. C., et al. Effectiveness of combining plasma exchange with
continuous hemodiafiltration on acute Fatty liver of pregnancy
complicated by multiple organ dysfunction. Artif. Organs 2012; 36:530-
4.
[19] Pereira, S. P., O'Donohue, J., Wendon, J., Williams, R. Maternal and
perinatal outcome in severe pregnancy-related liver disease. Hepatology
1997; 26:1258-62.
[20] Ganesan, C., Maynard, S. E. Acute kidney injury in pregnancy: the
thrombotic microangiopathies. J. Nephrol. 2011; 24:554-63.
[21] Martin, J. N. Jr, Bailey, A. P., Rehberg, J. F., Owens, M. T., Keiser, S.
D., May, W. L. Thrombotic thrombocytopenic purpura in 166
pregnancies: 1955-2006. Am. J. Obstet. Gynecol. 2008; 199:98-104.
[22] George, J. N., Terrell, D. R., Swisher, K. K., Vesely, S. K. Lessons
learned from the Oklahoma thrombotic thrombocytopenic purpura-
hemolytic uremic syndrome registry. J. Clin. Apher. 2008; 23:129-37.
[23] Moak, J. L. Thrombotic microangiopathies. N. Engl. J. Med. 2002; 347:
589-600.
[24] George, J. N. Clinical practice. Thrombotic thrombocytopenic purpura.
N. Engl. J. Med. 2006; 354:1927-35.
[25] Egerman, R. S., Witlin, A. G., Friedman, S. A., Sibai, B. M. Thrombotic
thrombocytopenic purpura and hemolytic uremic syndrome in
pregnancy: review of 11 cases. Am. J. Obstet. Gynecol. 1996; 175:950-6.
[26] Gerth, J., Schleussner, E., Kentouche, K., Busch, M., Seifert, M., Wolf,
G. Pregnancy-associated thrombotic thrombocytopenic purpura.
Thromb. Haemost. 2009; 101:248-51.
[27] Martin, J. N. Jr, Bailey, A. P., Rehberg, J. F., Owens, M. T., Keiser, S.
D., May, W. L. Thrombotic thrombocytopenic purpura in 166
pregnancies: 1955-2006. Am. J. Obstet. Gynecol. 2008; 199:98-104.
[28] George, J. N. The thrombotic thrombocytopenic purpura and hemolytic
uremic syndromes: evaluation, management, and long-term outcomes
experience of the Oklahoma TTP-HUS Registry, 1989-2007. Kidney Int.
Suppl. 2009; 112:S52-4.
[29] Dashe, J. S., Ramin, S. M., Cunningham, F. G. The long-term
consequences of thrombotic microangiopathy (thrombotic thrombocyto-
penic purpura and hemolytic uremic syndrome) in pregnancy. Obstet.
Gynecol. 1998; 91:662-8.
[30] Weiner, C. P. Thrombotic microangiopathy in pregnancy and the
postpartum period. Semin. Hematol. 1987; 24:119-29.
[31] He, Y., Chen, Y., Zhao, Y., Zhang, Y., Yang, W. Clinical study on five
cases of thrombotic thrombocytopenic purpura complicating pregnancy.
Aust. N. Z. J. Obstet. Gynaecol. 2010; 50:519-22.
[32] Lattuada, A., Rossi, E., Calzarossa, C., Candolfi, R., Mannucci, P. M.
Mild to moderate reduction of a von Willebrand factor cleaving protease
(ADAMTS-13) in pregnant women with HELLP microangiopathic
syndrome. Haematologica 2003; 88:1029-34.
[33] Hulstein, J. J., van Runnard Heimel, P. J., Franx, A., Lenting, P. J.,
Bruinse, H. W., Silence, K., et al. Acute activation of the endothelium
results in increased levels of active von Willebrand factor in hemolysis,
elevated liver enzymes and low platelets (HELLP) syndrome. J. Thromb.
Haemost. 2006; 4:2569-75.
[34] Keiser, S. D., Boyd, K. W., Rehberg, J. F., Elkins, S., Owens, M. Y.,
Sunesara, I., et al. A high LDH to AST ratio helps to differentiate
pregnancy-associated thrombotic thrombocytopenic purpura (TTP) from
HELLP syndrome. J. Matern. Fetal. Neonatal. Med. 2012; 25:1059-63.
[35] Stella, C. L., Dacus, J., Guzman, E., Dhillon, P., Coppage, K., How, H.,
et al. The diagnostic dilemma of thrombotic thrombocytopenic purpura/
hemolytic uremic syndrome in the obstetric triage and emergency
department: lessons from 4 tertiary hospitals. Am. J. Obstet. Gynecol.
2009; 200:381.e1-6.
[36] Hebisch, G., Bernasconi, M. T., Gmuer, J., Huch, A., Stallmach, T.
Pregnancy-associated recurrent hemolytic uremic syndrome with fetal
thrombotic vasculopathy in the placenta. Am. J. Obstet. Gynecol. 2001;
185: 1265-6.
[37] Pajor, A., Hintalan, A., Bakos, L., Lintner, F. Postpartum hemolytic
uremic syndrome following placental abruption. Eur. J. Obstet. Gynecol.
Reprod. Biol. 1993; 49:201-4.
[38] Fakhouri, F., Roumenina, L., Provot, F., Salle, M., Caillard, S., Couzi,
L., et al. Pregnancy-associated hemolytic uremic syndrome revisited in
the era of complement gene mutations. J. Am. Soc. Nephrol. 2010; 21:
859-67.
[39] Flandrois, M., Bessire, A., Vieira-Roth, S., Vergnaud, M., Frmeaux-
Bacchi, V., Eckart, P. Hemolytic and uremic syndrome and maternal-
fetal Escherichia coli K1 infection. Arch. Pediatr. 2011; 18:283-6.
[40] Ardissino, G., Wally Ossola, M., Maria Baffero, G., Rigotti, A., Cugno,
M. Eculizumab for atypical hemolytic uremic syndrome in pregnancy.
Obstet. Gynecol. 2013; 122:487-9.
[41] Zschiedrich, S., Prager, E. P., Kuehn, E. W. Successful treatment of the
postpartum atypical hemolytic uremic syndrome with eculizumab. Ann.
Intern. Med. 2013; 159:76.
[42] Legendre, C. M., Licht, C., Muus, P., Greenbaum, L. A., Babu, S.,
Bedrosian, C., et al. Terminal complement inhibitor eculizumab in
atypical hemolytic-uremic syndrome. N. Engl. J. Med. 2013; 368:2169-
81.
[43] Corts-Hernndez, J., Ordi-Ros, J., Paredes, F., Casellas, M., Castillo,
F., Vilardell-Tarres, M. Clinical predictors of fetal and maternal
outcome in systemic lupus erythematosus: a prospective study of 103
pregnancies. Rheumatology 2002; 41:643-50.
[44] Stojan, G., Baer, A. N. Flares of systemic lupus erythematosus during
pregnancy and the puerperium: prevention, diagnosis and management.
Expert Rev. Clin. Immunol. 2012; 8:439-53.
[45] Zen, M., Ghirardello, A., Iaccarino, L., Tonon, M., Campana, C.,
Arienti, S., Rampudda, M., Canova, M., Doria, A. Hormones, immune
response, and pregnancy in healthy women and SLE patients. Swiss
Med. Wkly. 2010; 140:187-201.
[46] Clowse, M. E. Lupus activity in pregnancy. Rheum. Dis. Clin. North Am.
2007; 33:237-52.
[47] Lockshin, M. D. Pregnancy does not cause systemic lupus
erythematosus to worsen. Arthritis Rheum. 1989; 32:665-70.
[48] Ostensen, M., Clowse, M. Pathogenesis of pregnancy complications in
systemic lupus erythematosus. Curr. Opin. Rheumatol. 2013; 25:591-6.
[49] Madazli, R., Yuksel, M. A., Oncul, M., Imamoglu, M., Yilmaz, H.
Obstetric outcomes and prognostic factors of lupus pregnancies. Arch.
Gynecol. Obstet. 2013 Jun. 27. [Epub. ahead of print].
[50] Chakravarty, E. F., Coln, I., Langen, E. S., Nix, D. A., El-Sayed, Y. Y.,
Genovese, M. C., et al. Factors that predict prematurity and
preeclampsia in pregnancies that are complicated by systemic lupus
erythematosus. Am. J. Obstet. Gynecol. 2005; 192:1897-904.
[51] Smyth, A., Oliveira, G. H., Lahr, B. D., Bailey, K. R., Norby, S. M.,
Garovic, V. D. A systematic review and meta-analysis of pregnancy
outcomes in patients with systemic lupus erythematosus and lupus
nephritis. Clin. J. Am. Soc. Nephrol. 2010; 5:2060-8.
[52] stensen, M., Khamashta, M., Lockshin, M., Parke, A., Brucato, A.,
Carp, H., et al. Anti-inflammatory and immunosuppressive drugs and
reproduction. Arthritis Res. Ther. 2006; 8:209.
[53] Levy, R. A., Vilela, V. S., Cataldo, M. J., Ramos, R. C., Duarte, J. L.,
Tura, B. R., et al. Hydroxychloroquine (HCQ) in lupus pregnancy:
double-blind and placebo-controlled study. Lupus 2001; 10:401-4.
[54] Petri, M. Pregnancy in SLE. Baillieres Clin. Rheumatol. 1998; 12:449-
76.
[55] Szeto, C. C., Kwan, B. C., Lai, F. M., Tam, L. S., Li, E. K., Chow, K.
M., et al. Tacrolimus for the treatment of systemic lupus erythematosus
with pure class V nephritis. Rheumatology 2008; 47:1678-81.
[56] Alsuwaida, A. Successful management of systemic lupus erythematosus
nephritis flare-up during pregnancy with tacrolimus. Mod. Rheumatol.
2011; 21:73-5.
[57] Bar, J., Stahl, B., Hod, M., Wittenberg, C., Pardo, J., Merlob, P. Is
immunosuppression therapy in renal allograft recipients teratogenic? A
single-center experience. Am. J. Med. Genet. A 2003; 116:31-6.
[58] Tincani, A., Bompane, D., Danieli, E., Doria, A. Pregnancy, lupus and
antiphospholipid syndrome (Hughes syndrome). Lupus 2006; 15:156-60.
[59] Hanly, J. G. Antiphospholipid syndrome: an overview. CMAJ 2003;
168: 1675-82.
[60] Marchetti, T., Cohen, M., de Moerloose, P. Obstetrical antiphospholipid
syndrome: from the pathogenesis to the clinical and therapeutic
implications. Clin. Dev. Immunol. 2013; 2013:159124.
[61] Abou-Nassar, K., Carrier, M., Ramsay, T., Rodger, M. A. The
association between antiphospholipid antibodies and placenta mediated
complications: a systematic review and meta-analysis. Thromb. Res.
2011; 128:77-85.
[62] Levine, J. S., Branch, D. W., Rauch, J. The antiphospholipid syndrome.
N. Engl. J. Med. 2002; 346:752-63.
[63] Gmez-Puerta, J. A., Espinosa, G., Cervera, R. Catastrophic
antiphospholipid syndrome: diagnosis and management in pregnancy.
Clin. Lab. Med. 2013; 33:391-400.
[64] Gmez-Puerta, J. A., Cervera, R., Espinosa, G., Asherson, R. A., Garca-
Carrasco, M., da Costa, I. P., et al. Catastrophic antiphospholipid
syndrome during pregnancy and puerperium: maternal and fetal
characteristics of 15 cases. Ann. Rheum. Dis. 2007; 66:740-6.
[65] George, J. N. How I treat patients with thrombotic thrombocytopenic
purpura: 2010. Blood 2010; 116:4060-9.

Chapter III

and Preeclampsia -
Is it the Same Disease?

Nir Melamed, M.D., M.Sc. and Yariv Yogev, M.D.
Department of Obstetrics and Gynecology, Rabin Medical Center,
Beilinson Campus, Petah Tiqwa, and Sackler Faculty of Medicine,
Tel Aviv University, Tel Aviv, Israel

Background

Gestational hypertension (GHTN) is defined as a persistent blood pressure
(BP) measurements above 140/90 on at least two occasions at least 6 hours
apart in the absence of proteinuria, first detected beyond 20 weeks of gestation
[1]. According to the current nomenclature, GHTN should be considered as a
temporary diagnosis (Figure 1) [1]. In cases in which there is evidence of
proteinuria later in pregnancy, the final diagnosis is preeclampsia (PET).
Otherwise, the final diagnosis is determined based on reevaluation of BP at
around 3 months post partum - in cases in which hypertension (HTN) resolves,
which is the common scenario [2], the final diagnosis is transient HTN of
pregnancy (Figure 1). Persistence of GHTN for more than 3 months post
partum is consistent with the diagnosis of chronic hypertension (CHTN). Thus,
the term GHTN (in contrast to the term pregnancy induced hypertension (PIH)
used in the previous terminology) merely describes the condition of HTN
Nir Melamed and Yariv Yogev 72
during pregnancy without committing as to whether the HTN is secondary to
pregnancy or actually represents undetected CHTN [1].

GHTN, gestational hypertension; PET, preeclampsia; HTN, hypertension; BP blood
pressure.
Figure 1. Gestational hypertension as a temporary diagnosis.
Interestingly, despite the fact that GHTN is the most common form of
hypertensive complications of pregnancy [3, 4], most research efforts have
been directed at PET and the amount of data available regarding GHTN are
much more limited than that available for PET.
In addition, there are also concerns with respect to the quality of data
available on GHTN. In many of the available studies, a proportion of the
women considered to have GHTN might actually had an undiagnosed CHTN
since most of these studies did not provide information on BP levels in early
pregnancy or at 3 months postpartum.
Similarly, another proportion of these women may actually represent
undiagnosed PET since many of the studies excluded proteinuria by spot urine
dipstick which have been shown to have relatively limited sensitivity for the
detection of proteinuria [5-7].
Still, despite the limitations described above, there are several questions of
interest with respect to GHTN. One of the long-standing controversies is
whether GHTN is an independent clinical entity or whether it is simply a pre-
PET condition. Another practical question relates to the risk of progression to
PET in women diagnosed with GHTN.
Gestational Hypertension and Preeclampsia - Is it the Same Disease? 73
Finally, it remains unclear whether GHTN by itself is associated with
adverse pregnancy outcome. The current chapter will summarize the most up
to date information with respect to these questions.

Is Gest HTN an Independent Clinical
Entity or Simply a Pre-PET Condition?

One of the long-standing controversies with respect to GHTN and PET
relates to whether GHTN and PET are two independent different clinical
entities or whether GHTN is simply a mild form of PET or a pre-PET
condition. One approach to address this question is through comparison of the
epidemiological, pathologic, pathogenetic and pathophysiologic characteristics
of these two disorders.

Epidemiologic Characteristics of GHTN and PET

Several studies compared the risk factors for GHTN and PET. In a large
population based study from Sweden, it was found that while some factors
were associated with the two conditions, other factors such as multiple
gestations and diabetes were associated only with PET but not with GHTN [8].
Villar et al. [9], in a secondary analysis of the WHO Antenatal Care Trial
involving almost 40,000 women, reported similar findings. While factors such
as primiparity and maternal respiratory disease were associated only with PET,
other factors such as antepartum hemorrhage and a history of large for
gestational age (LGA) newborn were associated only with GHTN.
Other studies reported differences in the risk of recurrence of each of these
disorders in subsequent pregnancies.
Overall, the risk of recurrence of a hypertensive complication in
subsequent pregnancy in women who were diagnosed with GHTN is their
previous pregnancy appears to be considerably higher than for women who
were diagnosed with PET in their previous pregnancy (20-47% vs. 5-10%,
respectively) [10, 11].
In addition, in a large retrospective study, it was also found that women
with GHTN in their previous pregnancy were more likely to experience
GHTN than PET in their subsequent pregnancy (26% vs. 6%), while women
who were diagnosed with PET in their previous pregnancy had a similar risk
of recurrence for either PET or GHTN in their subsequent pregnancy (6%)
[12].
Overall it appears that although some of the epidemiologic characteristics
of GHTN and PET are similar, there is also evidence that each of these
disorders has distinct epidemiologic features.

Pathologic Characteristics of GHTN and PET

Data on the pathologic characteristics of the placenta in pregnancies
complicated by GHTN is scarce. In a relatively recent study, Correa et al. [13]
compared the pathologic findings in placentas from women with PET and
GHTN. Although some of the pathologic features were similar between the
two groups, placentas from women with PET were characterized by a higher
number of syncytial knots in as well as differences in the size and distribution
of fibrin deposits compared with placentas of women with GHTN.

Pathogenetic Characteristics of GHTN and PET

There is evidence suggesting that there are differences in the pathogenesis
of PET and GHTN. Noori et al. [14], in a recent prospective study, compared
the degree of endothelial dysfunction and levels of angiogenic markers
between women with GHTN and women with PET. The authors followed 159
women from 10 weeks of gestation up to 3 months postpartum. Flow mediated
dilatation (FMD, a sonographic measure of vascular or endothelial function)
was abnormal only in the PET group, while the results in the GHTN group
were similar to that of normal controls. Similarly, the levels of the angiogenic
markers sFLT1 and endoglin were elevated only in pregnancies complicated
by PET while the levels in the GHTN group were not different from those
observed in control pregnancies [14]. These findings suggest that endothelial
dysfunction and increased levels of angiogenic markers are characteristics that
are specific for PET but not for GHTN.
The level of endothelial microparticles has been found to be elevated in
women with PET, reflecting endothelial cell damage. In a prospective study of
110 pregnant women the levels of endothelial microparticles were compared
between women with GTHN vs. PET [15]. The authors found that endothelial
microparticle levels were significantly higher only in women with PET while
the levels in women with GHTN were not significant from that observed in
control pregnancies.
Khalil et al. compare the effect of treatment with methyldopa on the levels
of angiogenic markers in women with GHTN and PET [16]. The authors
found that methyldopa was associated with a significant fall (50%) in sFlt1
and sEng only in women with PET but not in women with GHTN. The authors
concluded that these findings support the concept of a fundamental difference
in the pathogenesis of GHTN and PET.
In another recent study, Sandrim et al. [17] found differences in vascular
endothelial growth factor (VEGF) polymorphism between women with GHTN
and women in PET, raising the possibility of differences in the genetic
predisposition/basis for PET and GHTN.

Pathophysiologic Characteristics of GHTN and PET

Finally, there are also data suggesting difference in the pathophysiology of
each of the two disorders. In a study that compared platelets activity in women
with PET and GHTN it was found that the sensitivity of platelets to
prostaglandin E1 (PGE1) was decreased only in women with PET, while the
sensitivity in women with GHTN was similar to that of controls, suggesting
that platelets activation is again a characteristic specific to PET [18]. There are
also well known observations with respect to other pathophysiologic changes
such as maternal blood volume which have been shown to be decreased only
in women with PET but in pregnancies complicated by GHTN [19]. In
summary, it appears that there are significant differences between PET and
GHTN with respect to the epidemiological, pathologic, pathogenetic and
pathophysiologic characteristics of these two disorders. Overall, these
differences provide support to the hypothesis that GHTN and PET are two
distinct entities. Nevertheless, some pregnant women who initially present
with isolated HTN do go on and progress to PET as reflected by the new onset
of proteinuria or laboratory evidence for the HELLP syndrome. How do these
two apparently conflicting observations be explained? One possible
explanation is that the women who present with isolated HTN in pregnancy
are actually a heterogeneous group so that some of these women represent
simply an early or initial stage of PET prior to the development of overt
proteinuria, while others have GHTN of pregnancy which appears to be a
distinct disorder with different characteristics than those of PET (Figure 2).
This conception is supported by a recent study [20] in which the levels of the
angiogenic markers were compared between three groups of patients: women
with GHTN, women who initially presented with isolated HTN but later on
progressed to PET, and women who were diagnosed with PET at the time of
presentation. It was found the sFlt/PlGF ratio and sEng levels at the time of
presentation were similar for the two latter groups (i.e., those with a final
diagnosis of PET, irrespective whether proteinuria was present at the time of
presentation), while the levels of the angiogenic markers were significantly
lower for those women with a final diagnosis of GHTN.

GHTN, gestational hypertension; PET, preeclampsia.
Data are derived from the publication by Saudan et al. [Saudan BJOG 1998].
Figure 2. The relationship between gestational age at presentation with GHTN and the
risk and lag time for progression to PET.
Such an explanation raises several interesting questions with respect to
this group of women who present with isolated hypertension in pregnancy,
including: 1) what is the relative proportion of the GHTN and early PET
subgroups out of the overall group of women who present with isolated HTN?,
or, in other words, what is that risk for women who initially presents with
isolated HTN in pregnancy to go on and progress to PET later in pregnancy?
2) Is it possible to distinguish between these two subgroup?, or, in other
words, is it possible to identify those women who present with isolated HTN
that are more likely to progress to PET than to have GHTN? 3) In those
women in whom isolated HTN represents an early stage of PET = what is the
lag time prior to progression to PET?

What Is the Risk of Progression to PET?

Saudan et al. assessed the risk of progression from GHTN to PET
included 528 women who initially presented with mild GHTN [21]. The
overall rate of progression to PET among this group of women was 17%.
In addition, it was found that the risk of progression was inversely related
to gestational age at the time of presentation with GHTN, so that that risk of
progression among women who were diagnosed with GHTN prior to 34 weeks
was as high as 36-42% while that risk was considerably lower when GHTN
was diagnosed after 34 weeks of gestation (7-20%) [21].
In another study that addressed the same question, the overall risk of
progression to PET among 748 women who presented with mild GHTN at 24-
35 gestational weeks was 46%, of whom 10% progressed to severe PET [22].
In concordance with the previous study described above, these authors also
found that the risk of progression was considerably higher when GHTN was
diagnosed prior to 34 weeks of gestation. The differences in the overall risk of
progression to PET between these this study and the one described above
(46% vs. 17%) is probably the result of the different distribution of the
gestational age at the time of presentation with GHTN between these two
studies.

Can Women with GHTN Who Are at Risk of Progression to PET
Be Identified?

Several studies have tried to identify risk factors for progression to PET
among women who initially presented with GHTN. As described above, the
most important factor associated with progression to PET is earlier gestational
age at the time of presentation with GHTN [21, 22].
In a more recent study of 75 women with GHTN [23] the authors
investigated the association between the risk of progression to PET and factors
such as markers of insulin resistance (leptin and adiponectin), the levels of
placental hormones (bHCG, estrogen and progesterone) and the BP values on
24-hour ambulatory monitoring. It was found that in addition to an earlier
gestational age at presentation, the only other factor that predicted progression
to PET was a higher systolic BP on 24-hour ambulatory monitoring [23].
In another recent prospective study of 206 women with GHTN [24] the
overall rate of progression to PET was 45%. It was found the uric acid levels
at the time of presentation were strongly associated with the risk of
progression to PET so that each increase of 1 mg/dL in uric acid levels was
associated with a 7-fold increase in the risk of progression to PET. Using ROC
analysis, the optimal uric acid level cutoff for the prediction of progression to
PET was 5.2 mg/dL which was associated with a sensitivity of 87.7% and a
specificity of 93.3% [24].
Finally, in another study of 65 women who presented with GHTN at 24-
26 weeks of gestational age [25], the authors found that an abnormal uterine
artery Doppler (using a cutoff of RI >0.57) was associated with a positive- and
a negative-predictive values of 80% and 90%, respectively, for the progression
to PET.

What Is the Lag Time between Presentation with GHTN and
Progression to PET?

In the study of Saudan et al. described above [21], it was found that of the
528 women who initially presented with mild GHTN, those women who
eventually progressed to PET did so within a mean lag period of 1 to 5 weeks
from the time of presentation. In addition, the authors found that this lag
period was inversely related to gestational age at diagnosis. Thus, of the
women who presented with GHTN prior to 32 weeks of gestation, almost 40%
progressed to PET with a median lag period of about 33 days. Of the women
who presented with GHTN between 32 and 35 weeks of gestation, 25%
progressed to PET with median lag period of about 12 days. Finally, of the
women who presented with GHTN at 36 weeks of gestation and beyond, about
10% progressed to PET with a median lag time of 6 days.
In summary, the overall risk of progression to PET among women who
present with isolated HTN in pregnancy range from 10% to 50% and is mainly
related to the gestational age at the time of presentation with isolated HTN
(Figure 2). Thus, while the risk of progression to PET among women who
present at 36 weeks of gestation or beyond is only around 10% [21], the risk is
higher than 40% among women who present prior to 34 weeks of gestation
[2].
In addition, there are several factors that may be used to distinguish
women who are at risk of progression to PET (and the isolated HTN in their
case probably represents early stage of PET) from those who probably have
GHTN and are thus less likely to develop PET later in pregnancy. Some of
these factors include earlier gestational age, higher BP values, higher uric acid
levels, and abnormal uterine artery Doppler at the time of presentation (Figure
2).
Finally, it appears that those women with isolated HTN who will
eventually progress to PET do so within a lag period of 1-5 weeks, and this lag
period is inversely related to gestational age at the time of presentation (Figure
2).

Does GHTN Affect Pregnancy Outcome?

There is considerable amount of data showing that women with PET,
either those who presented with PET or those who initially presented with
isolated HTN and later on progressed to PET, are at increased risk for adverse
pregnancy outcome [26]. However, whether women with GHTN who do not
progress to PET are also at such an increased risk is unclear.
In a large multicenter study involving 2413 nulliparous women [27], the
outcome of pregnancies complicated by either PET or GHTN was compared to
that of uncomplicated pregnancies. Overall, the rate of perinatal complications
including prematurity, low birth weight, fetal growth restriction, placental
abruption and perinatal mortality was higher only in the PET group, while the
rate of these complications in the GHTN group was similar to that observed in
uncomplicated pregnancies. Similarly, in another recent retrospective study of
nulliparous women with GHTN or mild PET [28], the rate of fetal growth
restriction, placental abruption and low 5-minutes Apgar score were higher
only in the mild PET group but not in the GHTN group.
Other studies investigated whether the risk of adverse pregnancy outcome
in pregnancies complicated by GHTN is related to the severity of HTN. In a
secondary analysis of a large randomized controlled trial on the use of calcium
in the prevention of PET [4], the authors compared the outcome of women
with mild vs. severe HTN. While the outcome of women in the mild HTN was
similar to that of uncomplicated pregnancies, women with severe HTN had a
significantly higher rate of severe complications including placental abruption,
fetal growth restriction, neonatal morbidity, and maternal renal dysfunction.
With that respect it is unclear whether there is a certain threshold of HTN
above which the risk of adverse pregnancy outcome increases or whether there
is a continuous relationship between the severity of HTN and the risk of
pregnancy complications. A large multicenter study from the UK [29] assessed
the relationship between the diastolic BP as a continuous variable and outcome
measures such as birth weight and perinatal mortality in otherwise
uncomplicated pregnancies, so that women with known chronic HTN or PET
were excluded. The authors identified a continuous decrease in birthweight
and a continuous increase in perinatal mortality in cases in which the diastolic
BP was over 90, and these changes when even more pronounced in cases of
severe GHTN (diastolic BP exceeded 110).
In summary, there is evidence that GHTN is associated with an increased
risk of pregnancy complications in a manner that is related to the severity of
GHTN in a continuous manner.

GHTN, gestational hypertension; PET, preeclampsia; HTN, hypertension.
Figure 3. Women with isolated HTN represent a heterogeneous group.

Conclusion

In summary, current evidence suggest that GHTN and PET are distinct
conditions with different clinical characteristics. Thus, it appears that patients
who present with isolated HTN in pregnancy form a heterogeneous groups of
women.
While most of these cases represent GHTN, in about 10-50% of these
cases the isolated HTN represents an early stage of PET putting these women
at risk of progressing to overt PET later in pregnancy. The proportion of the
women in the latter group who are at risk of progression to PET is higher in
cases with lower gestational age at diagnosis, elevated uric acid levels, higher
systolic BP at presentation, and abnormal Uterine artery Doppler. Those who
eventually progress to PET do so within a period of 1-5 weeks from the time
of diagnosis with isolated HTN and this lag period is inversely related to
gestational age at the time of diagnosis with GHTN.
Finally, it appears that even those women who have GHTN and to not
progress to PET are at an increased risk for pregnancy complications, and that
this risk is related to the severity of GHTN in a continuous manner.
The practical implications of these findings are that women who present
with isolated HTN in pregnancy should be monitored closely for the presence
of severe HTN and progression to PET, especially if the diagnosis of GHTN
was made prior to 34 weeks of gestation or in the presence of elevated uric
acid levels, high BP values or abnormal uterine artery Doppler. Still, it should
be emphasized that in practice, most cases of GTHN are relatively mild and
are usually diagnosed at term, so that the risk of PET and adverse pregnancy
outcome is relatively low.

References

Working Group on High Blood Pressure in Pregnancy. Am. J. Obstet.
Gynecol. 2000;183:S1-S22.
[2] Reiter, L., Brown, M. A., Whitworth, J. A. Hypertension in pregnancy:
the incidence of underlying renal disease and essential hypertension. Am.
J. Kidney Dis. 1994;24:883-7.
[3] Walker, J. J. Pre-eclampsia. Lancet 2000;356:1260-5.
[4] Hauth, J. C., Ewell, M. G., Levine, R. J., et al. Pregnancy outcomes in
healthy nulliparas who developed hypertension. Calcium for
Preeclampsia Prevention Study Group. Obstet. Gynecol. 2000;95:24-8.
[5] Morris, R. K., Riley, R. D., Doug, M., Deeks, J. J., Kilby, M. D.
Diagnostic accuracy of spot urinary protein and albumin to creatinine
ratios for detection of significant proteinuria or adverse pregnancy
outcome in patients with suspected pre-eclampsia: systematic review and
meta-analysis. BMJ 2012;345:e4342.
[6] Gangaram, R., Ojwang, P. J., Moodley, J., Maharaj, D. The accuracy of
urine dipsticks as a screening test for proteinuria in hypertensive
disorders of pregnancy. Hypertens. Pregnancy 2005;24:117-23.
[7] Gangaram, R., Naicker, M., Moodley, J. Accuracy of the spot urinary
microalbumin:creatinine ratio and visual dipsticks in hypertensive
pregnant women. Eur. J. Obstet. Gynecol. Reprod. Biol. 2009;144:146-
8.
[8] Ros, H. S., Cnattingius, S., Lipworth, L. Comparison of risk factors for
preeclampsia and gestational hypertension in a population-based cohort
study. Am. J. Epidemiol. 1998;147:1062-70.
[9] Villar, J., Carroli, G., Wojdyla, D., et al. Preeclampsia, gestational
hypertension and intrauterine growth restriction, related or independent
conditions? Am. J. Obstet. Gynecol. 2006;194:921-31.
[10] Hargood, J. L., Brown, M. A. Pregnancy-induced hypertension:
recurrence rate in second pregnancies. Med. J. Aust. 1991;154:376-7.
[11] Dukler, D., Porath, A., Bashiri, A., Erez, O., Mazor, M. Remote
prognosis of primiparous women with preeclampsia. Eur. J. Obstet.
Gynecol. Reprod. Biol. 2001;96:69-74.
[12] Brown, M. A., Mackenzie, C., Dunsmuir, W., et al. Can we predict
recurrence of pre-eclampsia or gestational hypertension? BJOG 2007;
114:984-93.
[13] Correa, R. R., Gilio, D. B., Cavellani, C. L., et al. Placental
morphometrical and histopathology changes in the different clinical
presentations of hypertensive syndromes in pregnancy. Arch. Gynecol.
Obstet. 2008;277:201-6.
[14] Noori, M., Donald, A. E., Angelakopoulou, A., Hingorani, A. D.,
Williams, D. J. Prospective study of placental angiogenic factors and
maternal vascular function before and after preeclampsia and gestational
hypertension. Circulation 2010;122:478-87.
[15] Gonzalez-Quintero, V. H., Smarkusky, L. P., Jimenez, J. J., et al.
Elevated plasma endothelial microparticles: preeclampsia versus
gestational hypertension. Am. J. Obstet. Gynecol. 2004;191:1418-24.
[16] Khalil, A., Muttukrishna, S., Harrington, K., Jauniaux, E. Effect of
antihypertensive therapy with alpha methyldopa on levels of angiogenic
factors in pregnancies with hypertensive disorders. PLoS One 2008;3: e
2766.
[17] Sandrim, V. C., Palei, A. C., Cavalli, R. C., et al. Vascular endothelial
growth factor genotypes and haplotypes are associated with pre-
eclampsia but not with gestational hypertension. Mol. Hum. Reprod.
2009; 15:115-20.
[18] Torres, P. J., Escolar, G., Palacio, M., Gratacos, E., Alonso, P. L.,
Ordinas, A. Platelet sensitivity to prostaglandin E1 inhibition is reduced
in pre-eclampsia but not in nonproteinuric gestational hypertension. Br.
J. Obstet. Gynaecol. 1996;103:19-24.
[19] Silver, H. M., Seebeck, M., Carlson, R. Comparison of total blood
volume in normal, preeclamptic, and nonproteinuric gestational
hypertensive pregnancy by simultaneous measurement of red blood cell
and plasma volumes. Am. J. Obstet. Gynecol. 1998;179:87-93.
[20] Hirashima, C., Ohkuchi, A., Takahashi, K., et al. Gestational
hypertension as a subclinical preeclampsia in view of serum levels of
angiogenesis-related factors. Hypertens. Res. 2011;34:212-7.
hypertension become pre-eclampsia? Br. J. Obstet. Gynaecol. 1998;105:
1177-84.
[22] Barton, J. R., O'Brien, J. M., Bergauer, N. K., Jacques, D. L., Sibai, B.
M. Mild gestational hypertension remote from term: progression and
outcome. Am. J. Obstet. Gynecol. 2001;184:979-83.
[23] Davis, G. K., Mackenzie, C., Brown, M. A., et al. Predicting
transformation from gestational hypertension to preeclampsia in clinical
practice: a possible role for 24 hour ambulatory blood pressure
monitoring. Hypertens. Pregnancy 2007;26:77-87.
[24] Bellomo, G., Venanzi, S., Saronio, P., Verdura, C., Narducci, P. L.
Prognostic significance of serum uric acid in women with gestational
hypertension. Hypertension 2011;58:704-8.
[25] Florio, P., D'Aniello, G., Sabatini, L., et al. Factor II: C activity and
uterine artery Doppler evaluation to improve the early prediction of pre-
eclampsia on women with gestational hypertension. J. Hypertens. 2005;
23:141-6.
[26] Sibai, B. M., Spinnato, J. A., Watson, D. L., Hill, G. A., Anderson, G. D.
Pregnancy outcome in 303 cases with severe preeclampsia. Obstet.
Gynecol. 1984;64:319-25.
with hypertensive disorders. Int. J. Gynaecol. Obstet. 1998;61:127-33.
[28] Cruz, M. O., Gao, W., Hibbard, J. U. Obstetrical and perinatal outcomes
among women with gestational hypertension, mild preeclampsia, and
mild chronic hypertension. Am. J. Obstet. Gynecol. 2011;205:260 e1-9.
[29] Steer, P. J., Little, M. P., Kold-Jensen, T., Chapple, J., Elliott, P.
Maternal blood pressure in pregnancy, birth weight, and perinatal
mortality in first births: prospective study. BMJ 2004;329:1312.


Chapter IV

The Association between
Maternal Obesity and
Hypertensive Disease
in Pregnancy

Amir Aviram, M.D. and Yariv Yogev, M.D.

Helen Schneider Hospital for Women, Rabin Medical Center,
Petach Tikva, and Sackler Faculty of Medicine, Tel Aviv
University, Tel Aviv, Israel

Introduction

Hypertensive disorders comprise a spectrum of medical conditions that
ranges from mild pre-pregnancy blood pressure elevation, through gestational
transient hypertension, HELLP (Hemolysis, elevated liver enzymes, low
platelets) syndrome, preeclampsia and eclampsia. These disorders are the most
common medical disorders encountered during pregnancy, with estimated
overall incidence of 6-8% - of those approximately 70% are gestational
hypertension and preeclampsia [1]. Gestational hypertension is defined as

Corresponding author: Yariv Yogev, M. D., Department of Obstetrics and Gynecology, Helen
Schneider Hospital for Women, Rabin Medical Center, Petah Tiqwa 49100, Israel. Tel:
+972-3-9377680; E-mail: yarivyogev@hotmail.com.
Amir Aviram and Yariv Yogev 86
systolic blood pressure (BP) exceeding or equal to 140 mmHg and/or diastolic
BP exceeding or equal to 90 mmHg, on two separate measurements conducted
at least six hours apart. An essential part of the definition is the timing of
onset; gestational hypertension can be defines as such only after 20 weeks of
gestation in an otherwise normotensive parturient. Gestational hypertension is
the most common hypertensive disorder in pregnancy, with incidence up to
17% in nulliparous women and approximately up to 4 % in multiparous
women [2-4]. It may progress to pre-eclampsia in up to 50% of cases, with
increased risk as gestational age at diagnosis decline [5].
Pre-eclampsia is defined as gestational hypertension in the presence of
proteinuria (more than 300 mg of protein in a 24-hours urine collection
specimen). Pre-eclampsia is considered severe if systolic BP160 mmHg and
or diastolic BP110 mmHg, if proteinuria exceeds 5 grams per 24-hours urine
collection, or in the presence of symptoms such as headache, visual
disturbance or abdominal discomfort, as well as the development of HELLP
syndrome or other signs of multiorgan involvement. It's incidence may be as
high as 7% in nulliparous women [2, 3].
Obesity has long been recognized as a global health concern, may it be
among adults, adolescents or children, of both sexes. World Health
organization's (WHO) reports convey alarming figures regarding this
phenomena, with up to 1.6 billion overweight adults and 400 million obese
adults in 2005 [6]. WHO and the National Institute for Health (NIH) define
overweight as a Body Mass Index (BMI) of 25 to 29.9 kg/m
2
and obesity as
BMI 30 kg/m
2
or greater. Obesity is also sub-categorized into three sub-
groups: Class I (BMI 30-34.9 kg/m
2
), Class II (BMI 35-39.9 kg/m
2
) and Class
III (BMI 40 kg/m
2
or greater) [6].
Current predictions assess that by the year 2015, 2.3 billion adults will be
overweight and 700 million obese. Results from the United States National
Health and Nutrition Examination Survey (NHANES) indicate that 66.3% of
adults in the United States are either overweight or obese, with half of them in
the latter category.
As obesity becomes ever growing concern, the number of women in
reproductive age who are overweight or obese increases, and the incidence of
obesity among pregnant women is now estimated between 18.5 and 38.3
percent [7].
Maternal overweight is now a known risk factor which affects the vast
continuum of pregnancy, from conception, via pregnancy risks of the first
trimester such as abortions, through later complications (gestational diabetes,
hypertensive disorders, respiratory complications and thromboembolic events)
The Association between Maternal Obesity and Hypertensive Disease ... 87
and finally, delivery itself with higher risk of intrapartum complications and
cesarean deliveries [7-9].

Obesity and Hypertension

Weight gain at large and obesity particularly, are risk factors for
hypertension [10], and account for up to 28% of chronic hypertension cases
among women [11], with relative risk of 1.7 and 5.2 for women gaining 5 to
10 kg and 25.0 kg, respectively [12].
The main and leading theory depicts the intriguing connection of insulin
resistance and hypertension. Insulin resistance, which tends to increase among
the overweight and obese, leads to impaired glucose intolerance, which in turn,
leads to hyperinsulinemia.
Even though the exact mechanism is poorly understood, some hypotheses
were developed trying to explain how hyperinsulinemia cause hypertension,
including theories concerned with endothelial dysfunction, over-expression of
receptors for angiotensin, increased reabsorption of sodium in the kidney and
more [13-15].

Pathogenesis of Gestational
Hypertension and Preeclampsia

It is unclear whether gestational hypertension and preeclampsia are the
same disease in different stages, or different diseases that share some common
phenotypes. On the one hand, parturients with gestational hypertension may
progress towards preeclampsia, while on the other hand, several characteristics
of these disorders are quite different. For example, the risk of recurrence is
higher for gestational hypertension than preeclampsia [16, 17], and while
primiparity is a known risk factor for preeclampsia, it is not so for gestational
hypertension [18].
Moreover, patients with gestational hypertension who progress to
preeclampsia are different from those with gestational hypertension who do
not develop preeclampsia; the risk for developing preeclampsia as gestational
age at the diagnosis of gestational hypertension declines, with up to 5-fold the
risk for women developing gestational hypertension at or prior to 30 weeks of
gestation compared with women at or above 36 weeks of gestation [19, 20].
Additionally, the levels of sFlt-1 (discussed later in this chapter) are
significantly higher in women developing preeclampsia [21].
The exact mechanism involved in the development of preeclampsia is
unclear, but the key factor involved is abnormal placentation.
In pregnancies complicated with preeclampsia, the cytotrophoblast cells
invade the decidual segment, but not the myometrial segment, of the spiral
arteries (as opposed to pregnancies not complicated with preeclampsia) [22,
23], thus not permitting the natural transformation of these vessels to large
capacitance and low resistance vessels. This abnormal remodeling of the spiral
arteries leads to adverse pregnancy outcomes including preeclampsia. In one
theory, the abnormal remodeling results in placental ischemia which causes
endothelial cell dysfunction [24]. Furthermore, vascular-related disorders such
as hypertension and diabetes, and low-oxygen environment such as high
altitudes, are known risk factors for preeclampsia, thus reinforcing the
correlation between placental hypoxemia and preeclampsia [25, 26].
The clinical manifestations of preeclampsia, which are thought to be the
consequence of placental ischemia, are mediated through placental factors
migrating into maternal circulation. Soluble fms-like tyrosine kinase 1 (sFlt-1)
is produced by the placenta and binds to the receptor of VEGF (Vascular
endothelial growth factor) and to (PLGF). When it's production increases, as in
cases of preeclampsia, the levels of PLGF and VEGF decreases, causing
endothelial cell dysfunction [27] and it was already established the sFlt-1
levels correlate with disease severity [28, 29].
The etiology of preeclampsia was also studied from immunological
perspective and it seems that maternal exposure to paternal antigens may
correlate with preeclampsia. As with organ transplant, the differences
regarding the major histocompatability complex genes (human leukocyte
antigens or HLA) may causes rejection. Extravillous trophoblast cells from
combined maternal-paternal origin exhibit HLA antigens, and natural killer
cells exhibit receptors that recognize these antigens, the encounter between
these cells may have an effect on placentation [24].
Additional theories were suggested, explaining preeclampsia from
different point of views such as genetic imprinting, nutritional aspects,
inflammation reaction and cardiovascular maladaptation, but they are beyond
the scope of these discussion.

Pathogenesis of Obesity and Pregnancy
Hypertensive Disorders

As suggested above, the relationship between obesity, hyperinsulinemia
and hypertension has already been recognized.
Insulin resistance and hyperinsulinemia may be the basic common ground
of elevated blood pressure and diabetes mellitus. A pregnant patient may
develop metabolic syndrome prior to, during or after the pregnancy, with some
of the elements existing prior to conception, while other follow during
gestation itself. As such, obesity along with hypertensive disorders and
gestational diabetes mellitus (GDM) are central attributes of the metabolic
syndrome that may occur whilst pregnant.
Other than insulin resistance, endothelial activation and low grade
inflammation play an integral role in preeclampsia-eclampsia, obesity and
gestational diabetes. Insulin resistance with secondary hyperinsulinemia is
suspected to be the link between hypertension and diabetes. The hypertensive
effect of hyperinsulinemia is postulated to be due to weight gain, extra cellular
fluid volume expansion due to renal sodium retention probably resultant of
increased sympathetic activity due to insulin [30]. Several studies have
suggested that gestational hypertension, but not preeclampsia is associated
with insulin resistance [31, 32], while others have illustrated that the
association is true for the entire spectrum of hypertensive disorders [33-37].
This is not uniformly accepted as there are studies who do not concur with
these findings. Still, the majority of studied supports the role of insulin
resistance in the pathogenesis of the hypertensive disorders in pregnancy
from gestational hypertension, to preeclampsia and eclampsia, as is the case
for non pregnancy essential hypertension.
Caruso et al. [31] examined 16 women with hypertension during the third
trimester with a euglycemic-hyperinsulinemic clamp. Women with gestational
hypertension demonstrated a 40% reduction in the steady state insulin
sensitivity index compared with the control subjects; moreover, this reduction
did not occur with preeclampsia. These findings suggest that insulin resistance
contributes to late pregnancy gestational hypertension and not to preeclampsia.
In another cohort of 320 normal weight women [32], without GDM or any
history of hypertension or thyroid disease, insulin and C-peptide were
measured at the time of the routine GCT (Glucose Challenge Test).
The data showed that fasting C-peptide and glucose-stimulated C-peptide
concentrations (which served as surrogate markers for insulin resistance), are
significantly associated with the later development of gestational hypertension
(OR 1.7, 95% CI 1.12.7 and OR 3.8, 95% CI 1.59.6, respectively). This
association suggests that insulin resistance, is closely related to gestational
hypertension. In contrast, Kajaa et al. [33] reported that preeclampsia is a state
of increased insulin resistance, and it persists for at least 3 months after
pregnancy.
They measured insulin sensitivity using the minimal model technique in
22 preeclamptic women versus 16 healthy controls and demonstrated that
insulin sensitivity was 37% lower in preeclamptic women. Similar results were
obtained in another study, where 572 normotensive pregnant women, were
followed for fasting plasma glucose and insulin concentrations. Women who
subsequently developed gestational hypertension or preeclampsia had higher
levels of insulin resistance (OR 3.13, 95% CI .41-6.94) [34]. Wolf et al. [35] in
a prospective case-control cohort study examined first trimester sex hormone
binding globulin levels (which are inhibited by insulin and serve as surrogate
marker of insulin resistance) and second trimester GCT values, among 45
women diagnosed with either preeclampsia or eclampsia versus 90
normotensive controls. Women who developed preeclampsia were found to
have lower sex hormone binding globulin levels (302130 vs. 396186 nmol/
l) and higher GCT values (122.425.2 vs. 111.623.4 mg/dl). Sex hormone
binding globulin association with preeclampsia reached statistical significance
only among women with BMI>25 kg/m
2
, suggesting an obesity-related
threshold effect and an overall association between insulin resistance and
preeclampsia.
Additionally, among non-diabetic gravid women, mid-pregnancy
postprandial glycemia has been noted to be positively associated with odds of
subsequent gestational hypertension and preeclampsia. A retrospective case-
control study of 97 women with new-onset hypertension in late pregnancy and
77 normotensive control gravidas demonstrated after adjustment for BMI and
baseline systolic and diastolic blood pressures, that GCT values were
significantly higher among those developing hypertension [36]. The Toronto
Tri-Hospital Project cohort study has found similar correlation between
preeclampsia and OGTT values, in 3836 women. Postprandial glucose but not
fasting glucose values showed an association with the probability for
subsequent preeclampsia, with the most significant being the 2 hour value
[37].

Obesity and Pregnancy Hypertensive
Disorders in Singleton Pregnancies

One of the largest studies portraying the relationship between obesity and
gestational hypertensive disorders was conducted by Sebire et al. [38], who
performed a retrospective analysis of 287,213 singleton pregnancies, of whom
27.5% were overweight (BMI 25-29.9 kg/m
2
) and 11% obese (BMI 30 kg/m
2

and above). They found that compared with women with normal BMI,
overweight in pregnancy was significantly associated with preeclampsia (OR
1.44, 99% CI 1.3-1.6), as was obesity (OR 2.1, 95% CI 1.9-2.5).
Sibai et al. [39] in their prospective analysis have shown the pre-
pregnancy obesity is the second most important contributor for the
development of preeclampsia, and calculated that the risk for preeclampsia
increases at weight about 20% above desired weight. In another report,
BMI>35 kg/m
2
was found to have an odds ratio of 3.2 for the development of
preeclampsia compared with BMI<20 kg/m
2
[40]. Sattar et al. [41] aimed to
assess whether waist circumference at the first antenatal visit predicts risk of
developing hypertension later in pregnancy. They assessed 1142 women and
found the median waist circumference, as a surrogate measure of obesity, was
higher among patients with gestational hypertension or preeclampsia.
A large prospective multicenter trial [42] assessed parturients by
overweight categories, with BMI<30 kg/m
2
as controls, and BMI 30-34.9
kg/m
2
and BMI>35 kg/m
2
as study groups. Overall 16,102 participants were
included, of whom 1,473 obese (BMI 30-34.9 kg/m
2
), and 877 morbidly obese
(BMI>35 kg/m
2
) patients. Obesity and morbid obesity were statistically
significant associated with gestational hypertension (OR 2.5 and 3.2) and
preeclampsia (OR 1.6 and 3.3). Baeten et al. [43] conducted a population-
based cohort study with 96,801 cases. They found that the rate of most
outcomes increased with increasing body mass index category. Compared with
lean women, both overweight and obese women had a significantly increased
risk for preeclampsia an eclampsia.
Cedergren [44] evaluated prospectively 3480 morbidly obese women
(BMI>40 kg/m
2
) and compared pregnancy outcome with women with BMI
35.1-40 kg/m
2
and women with BMI 19.8-26 kg/m
2
. Morbid obesity during
pregnancy posed almost 5-fold risk for preeclampsia (aOR 4.8, 95% CI 4.0-
5.7). Kumari [45] found similar results, with hypertensive disorders present in
28.9% among parturients with BMI >40 kg/m
2
compared with 2.9% among
normal BMI parturients. Other reports demonstrated similar trends [46, 47],
with a dose-respond-like manner, i.e., as BMI rises, so is the risk for
hypertensive disorders.
And finally, O'Brien et al. [48] in their meta-analysis of 1.4 million
women, calculated that the risk of preeclampsia doubled for each 5-7 kg/m
2

rise in pre-pregnancy BMI, and that the relation persisted in after exclusion of
women with chronic hypertension, diabetes mellitus or multiple gestations, or
after adjustment for other confounders.

Obesity and Pregnancy Hypertensive
Disorders in Multiple Gestations

As with singleton gestations, obesity was also found to be an independent
risk factor for hypertensive disorders in multiple gestations. Fox et al. [49]
compared pregnancy outcomes in twin pregnancies based on maternal pre-
pregnancy BMI using an historical cohort of 514 patients. Pre-pregnancy
obesity (BMI>30 kg/m
2
) was associated with gestational hypertension (34.1%
versus 17.9%, p=0.011) and preeclampsia (27.3% versus 14.4%, p=0.028).
The same researchers found that pre-pregnancy obesity and an adjustable OR
of 2.4 (95% CI 1.1-5.2) for preeclampsia [50]. In contrast, Suzuki and Igarashi
[51] found no such correlation between obesity an hypertensive disorders in
twin gestations, though their study group was quite small (45 cases).

Treatment and Prevention

Devader et al. [52] studying normal pre-pregnancy BMI women compared
those gaining 25-35 lb with women gaining less than 25 lb during pregnancy.
He found lower odds for preeclampsia (aOR 0.56, 95% CI 0.49-0.64) and
higher odds for small for gestational age infants (aOR 2.14, 95% CI 2.01-
2.27). Similarly, Kiel et al. [53], using the same birth registry, reported that
overweight and obese women gaining less than the recommended 15 lb (only
31%) were at a significantly lower risk for preeclampsia. Thangaratinam et al.
[54] in their meta-analysis of 44 trials and 7278 women evaluated 3 types of
interventions during pregnancy diet, physical activity, or both. They found
that interventions were associated with a decreased risk for preeclampsia (OR
0.74. 95% CI 0.60-0.92), with dietary intervention achieving the best result.
As for operative intervention, it was shown that bariatric surgery poses no
risk for adverse perinatal outcomes [55-57], apart from a slightly elevated risk
for small-for-gestational age infant [58]. On the other hand, bariatric surgery
prior to pregnancy may significantly improve pregnancy outcome. Weintraub
et al. [59] performed a retrospective study of women delivering after bariatric
surgery (n = 507), and compared them with women delivering before bariatric
surgery (n = 301). They found that the incidence of hypertensive disorders was
significantly reduced after bariatric surgery (23.6% vs. 11.2%; P<0.001) and
that bariatric surgery was independently associated with a reduction in
hypertensive disorders (OR 0.38, 95% CI 0.25-0.59; P<0.001).
The same group later compared pregnancies outcomes of women prior to
bariatric surgery with pregnancies outcomes of the same women after bariatric
surgery [60]. They found a significant reduction in the incidence of
hypertensive disorders (31.9% versus 16.6%; P = .004) with OR of 0.4 (95%
CI 0.2-0.8).

Conclusion

Obesity increases the risk for gestational hypertensive disorders. The
primary mechanism probably responsible for this relationship is increased
insulin resistance leading to hyperinsulinemia. This relationship was
established in retrospective as well as prospective trials, and obesity proved to
be an independent risk factor for gestational hypertension as well as for
preeclampsia. It seems that the same is true for multiple gestations even
though the current data are limited. Interventions to reduce the impact of
obesity on hypertension include pre-pregnancy weight reduction, gestational
weight gain limitations with physical activity and dietary changes, and pre-
pregnancy bariatric surgery.

References

[1] Sibai, B. M. Diagnosis and management of gestational hypertension and
preeclampsia. Obstet. Gynecol. 2003;102(1):181-92.
[2] Hauth, J. C., Ewell, M. G., Levine, R. L., Esterlitz, J. R., Sibai, B. M.,
Curet, L. B. Pregnancy outcomes in healthy nulliparas women who
subsequently developed hypertension. Obstet. Gynecol. 2000;95:248.
with hypertensive disorders. Int. J. Gynecol. Obstet. 1998;61:127.
[4] Buchbinder, A., Sibai, B. M., Caritis, S., Macpherson, C., Hauth, J.,
Lindheimer, M. D. Adverse perinatal outcomes are significantly higher
in severe gestational hypertension than in mild preeclampsia. Am. J.
Obstet. Gynecol. 2002;186:6671.
[5] Hnat, M. D., Sibai, B. M., Caritis, S., Hauth, J., Lindheimer, M. D.,
MacPherson, C. Perinatal outcome in women with recurrent
preeclampsia compared with women who develop preeclampsia as
nulliparas. Am. J. Obstet. Gynecol. 2002; 186:4226.
[6] World health Organization. Obesity: Preventing and managing the
global epidemic. Geneva (Switzerland): World health Organization;
2000. WHO technical report series 894.
[7] Yogev, Y., Catalano, P. M. Pregnancy and Obesity. Obstet. Gynecol.
Clin. N. Am., 2009;36:285-300.
[8] Reece, A. E. Perspectives on obesity, pregnancy and birth outcomes in
the United States: the scope of the problem. Am. J. Obstet. Gynecol.
2008; 198(1):23-7.
[9] Langer, O. Management of obesity in GDM: old habits die hard. J.
Matern. Fetal Neonatal. Med. 2008; 21(3):165-71.
[10] Tu, W., Eckert, G. J., DiMeglio, L. A., Yu, Z., Jung, J., Pratt, J. H.
Intensified effect of adiposity on blood pressure in overweight and obese
children. Hypertension 2011; 58:818.
[11] Wilson, P. W., D'Agostino, R. B., Sullivan, L., Parise, H., Kannel, W. B.
Overweight and obesity as determinants of cardiovascular risk: the
Framingham experience. Arch. Intern. Med. 2002; 162:1867.
[12] Huang, Z., Willett, W. C., Manson, J. E., Rosner, B., Stampfer, M. J., et
al. Body weight, weight change, and risk for hypertension in women.
Ann. Intern. Med. 1998; 128:81.
[13] Rocchini, A. P., Katch, V., Kveselis, D., Moorehead, C., Martin, M., et
al. Insulin and renal sodium retention in obese adolescents. Hypertension
1989; 14:367.
[14] Steinberg, H. O., Chaker, H., Leaming, R., Johnson, A., Brechtel, G.,
Baron, A. D. Obesity/insulin resistance is associated with endothelial
dysfunction. Implications for the syndrome of insulin resistance. J. Clin.
Invest. 1996; 97:2601.
[15] Kincaid-Smith, P. Hypothesis: obesity and the insulin resistance
syndrome play a major role in end-stage renal failure attributed to
hypertension and labelled 'hypertensive nephrosclerosis'. J. Hypertens.
2004; 22:1051.
[16] Hjartardottir, S., Leifsson, B. G., Geirsson, R. T., Steinthorsdottir, V.
Recurrence of hypertensive disorder in second pregnancy. Am. J. Obstet.
Gynecol. 2006; 194:916.
[17] Brown, M. A., Mackenzie, C., Dunsmuir, W., Roberts, L., Ikin, K., et al.
Can we predict recurrence of pre-eclampsia or gestational hypertension?
BJOG 2007; 114:984.
[18] Villar, J., Carroli, G., Wojdyla, D., Abalos, E., Giordano, D., et al.;
World Health Organization Antenatal Care Trial Research Group.
Preeclampsia, gestational hypertension and intrauterine growth
restriction, related or independent conditions? Am. J. Obstet. Gynecol.
2006; 194:921.
hypertension become pre-eclampsia? Br. J. Obstet. Gynaecol. 1998; 105:
1177.
[20] Barton, J. R., O'brien, J. M., Bergauer, N. K., Jacques, D. L., Sibai, B.
M. Mild gestational hypertension remote from term: progression and
outcome. Am. J. Obstet. Gynecol. 2001; 184:979.
[21] Noori, M., Donald, A. E., Angelakopoulou, A., Hingorani, A. D.,
Williams, D. J. Prospective study of placental angiogenic factors and
maternal vascular function before and after preeclampsia and gestational
hypertension. Circulation 2010; 122:478.
[22] Roberts, J. M., Redman, C. W. Pre-eclampsia: more than pregnancy-
induced hypertension. Lancet 1993; 341:1447.
[23] Meekins, J. W., Pijnenborg, R., Hanssens, M., McFadyen, I. R., van
Asshe, A. A study of placental bed spiral arteries and trophoblast
invasion in normal and severe pre-eclamptic pregnancies. Br. J. Obstet.
Gynaecol. 1994; 101:669.
[24] Dekker, G. A., Sibai, B. M. Etiology and pathogenesis of preeclampsia:
current concepts. Am. J. Obstet. Gynecol. 1998; 179(5):1359-75.
[25] Dekker, G. A. Risk factors for preeclampsia. Clin. Obstet. Gynecol.
1999; 42:422.
[26] Palmer, S. K., Moore, L. G., Young, D., Cregger, B., Berman, J. C.,
Zamudio, S. Altered blood pressure course during normal pregnancy and
increased preeclampsia at high altitude (3100 meters) in Colorado. Am.
J. Obstet. Gynecol. 1999; 180:1161.
[27] Sibai, B. M.: Discussion. Evidence supporting a role for blockade of the
vascular endothelial growth factor system in the pathophysiology of
preeclampsia. Am. J.
[28] Chaiworapongsa, T., Romero, R., Espinoza, J., Bujold, E., Mee Kim, Y.,
et al. Evidence supporting a role for blockade of the vascular endothelial
growth factor system in the pathophysiology of preeclampsia. Am. J.
[29] Levine, R. J., Maynard, S. E., Qian, C., Lim, K. H., England, L. J., et al.
Circulating angiogenic factors and the risk of preeclampsia. N. Engl. J.
Med. 2004; 350:672.
[30] Howard, G., O'Leary, D. H., Zaccaro, D., Haffner, S., Rewers, M., et al.
Insulin sensitivity and atherosclerosis. Circulation. 1996:15; 93(10):
1809-17.
[31] Caruso, A., Ferrazzani, S., De Carolis, S., Lucchese, A., Lanzone, A., et
al. Gestational hypertension but not pre-eclampsia is associated with
insulin resistance syndrome characteristics. Hum. Reprod. 1999; 14(1):
219-23.
[32] Yasuhi, I., Hogan, J. W., Canick, J., Sosa, M. B., Carpenter, M. W.
Midpregnancy serum C-peptide concentration and subsequent
pregnancy-induced hypertension. Diabetes Care. 2001:24(4):743-7.
[33] Kaaja, R., Laivuori, H., Laakso, M., Tikkanen, M. J., Ylikorkala, O.
Evidence of a state of increased insulin resistance in preeclampsia.
Metabolism. 1999; 48 (7): 892-6.
[34] Sierra-Laguado, J., Garca, R. G., Celedn, J., Arenas-Mantilla, M.,
Pradilla, L. P., et al. Determination of insulin resistance using the
homeostatic model assessment (HOMA) and its relation with the risk of
developing pregnancy-induced hypertension. Am. J. Hypertens. 2007; 20
(4):437-42.
[35] Wolf, M., Sandler, L., Munoz, K., Hsu, K., Ecker, J. L., Thadhani, R.
First trimester insulin resistance and subsequent preeclampsia: a
prospective study. Clin. Endocrinol. Metab. 2002:87(4):1563-8.
[36] Solomon, C. G., Graves, S. W., Green, M. F., Seely, E. W. Glucose
intolerance as a predictor of hypertension in pregnancy. Hypertension.
1994; 23(6 Pt 1):717-21.
[37] Sermer, M., Naylor, C. D., Gare, D. J., Kensole, A. B., Ritchie, J. W., et
al. Impact of increasing carbohydrate intolerance on maternal-fetal
outcomes in 3637 women without gestational diabetes: The Toronto
Trihospital Gestational Project: Am. J. Obstet. Gynecol. 1995:173:146-
56.
[38] Sebire, N. J., Jolly, M., Harris, J. P., Wadsworth, J., Joffe, M., et al.
Maternal obesity and pregnancy outcome: a study of 287,213
pregnancies in London. Int. J. Obes. Relat. Metab. Disord. 2001 Aug.;25
(8):1175-82.
[39] Sibai, B. M., Gordon, T., Thom, E., Caritis, S. N., Klebanoff, M., et al.
Risk factors for preeclampsia in healthy nulliparous women: a
prospective multicenter study. The National Institute of Child Health and
Human Development Network of Maternal-Fetal Medicine Units. Am. J.
Obstet. Gynecol. 1995;172: 642-8.
[40] Sibai, B. M., Ewell, M., Levine, R. J., Klebanoff, M. A., Esterlitz, J., et
al. Risk factors associated with preeclampsia in healthy nulliparous
women. The Calcium for Preeclampsia Prevention (CPEP) Study Group.
Am. J. Obstet. Gynecol. 1997;177:1003-10.
[41] Sattar, N., Clark, P., Holmes, A., Lean, M. E., Walker, I., Greer, I. A.
Antenatal waist circumference and hypertension risk. Obstet. Gynecol.
2001; 97:268-71.
[42] Weiss, J. L., Malone, F. D., Emig, D., Ball, R. H., Nyberg, D. A., et al.
FASTER Research Consortium. Obesity, obstetric complications and
cesarean delivery rate--a population-based screening study. Am. J.
Obstet. Gynecol. 2004; 190(4):1091-7.
[43] Baeten, J. M., Bukusi, E. A., Lambe, M. pregnancy complications and
outcomes among Overweight and Obese Nulliparous Women. Am. J.
Public Health. 2001; 91:436-40.
[44] Cedergren, M. I. Maternal morbid obesity and the risk of adverse
pregnancy outcome. Obstet. Gynecol. 2004; 103(2):219-24.
[45] Kumari, A. S. Pregnancy outcome in women with morbid obesity. Int. J.
Gynaecol. Obstet. 2001; 73(2):101-7.
[46] Bianco, A. T., Smilen, S. W., Davis, Y., Lopez, S., Lapinski, R.,
Lockwood, C. J. Pregnancy outcome and weight gain recommendations
for the morbidly obese woman. Obstet. Gynecol. 1998; 91(1):97-102.
[47] Schrauwers, C., Dekker, G. Maternal and perinatal outcome in obese
pregnant patients. J. Matern. Fetal Neonatal. Med. 2009;22(3):218-26.
[48] O'Brien, T. E., Ray, J. G., Chan, W. S. Maternal body mass index and
the risk of preeclampsia: a systematic overview. Epidemiology. 2003
May;14(3):368-74.
[49] Fox, N. S., Roman, A. S., Saltzman, D. H., Klauser, C. K., Rebarber, A.
Obesity and adverse pregnancy outcomes in twin pregnancies. J.
Matern. Fetal Neonatal. Med. 2013 Jul. 23. [Epub. ahead of print].
[50] Fox, N. S., Roman, A. S., Saltzman, D. H., Hourizadeh, T., Hastings, J.,
Rebarber, A. Risk Factors for Preeclampsia in Twin Pregnancies. Am. J.
Perinatol. 2013 Apr. 16. [Epub. ahead of print].
[51] Suzuki, S., Igarashi, M. Risk factors for preeclampsia in Japanese twin
pregnancies: comparison with those in singleton pregnancies. Arch.
Gynecol. Obstet. 2009;280(3):389-93.
[52] DeVader, S. R., Neeley, H. L., Myles, T. D., Leet, T. L. Evaluation of
gestational weight gain guidelines for women with normal prepregnancy
body mass index. Obstet. Gynecol. 2007; 110: 74551.
[53] Kiel, D. W., Dodson, E. A., Artal, R., Boehmer, T. K., Leet, T. L.
Gestational weight gain and pregnancy outcomes in obese women: how
much is enough? Obstet. Gynecol. 2007; 110: 7528.
[54] Thangaratinam, S., Rogozinska, E., Jolly, K., Glinkowski, S.,
Roseboom, T., et al. Effects of interventions in pregnancy on maternal
weight and obstetric outcomes: meta-analysis of randomised evidence.
BMJ. 2012;16:344:e2088.
[55] Sheiner, E., Levy, A., Silverberg, D., Menes, T. S., Levy, I., et al.
Pregnancy after bariatric surgery is not associated with adverse perinatal
outcome. Am. J. Obstet. Gynecol. 2004;190(5):1335-40.
[56] Sheiner, E., Menes, T. S., Silverberg, D., Abramowicz, J. S., Levy, I., et
al. Pregnancy outcome of patients with gestational diabetes mellitus
following bariatric surgery. Am. J. Obstet. Gynecol. 2006;194(2):431-5.
[57] Josefsson, A., Bladh, M., Wirhn, A. B., Sydsj, G. Risk for congenital
malformations in offspring of women who have undergone bariatric
surgery. A national cohort. BJOG. 2013 Aug. 9. [Epub. ahead of print].
[58] Kjr, M. M., Lauenborg, J., Breum, B. M., Nilas, L. The risk of adverse
pregnancy outcome after bariatric surgery: a nationwide register-based
matched cohort study. Am. J. Obstet. Gynecol. 2013;208(6):464.e1-5.
[59] Weintraub, A. Y., Levy, A., Levi, I., Mazor, M., Wiznitzer, A., Sheiner,
E. Effect of bariatric surgery on pregnancy outcome. Int. J. Gynaecol.
Obstet. 2008;103(3):246-51.
[60] Aricha-Tamir, B., Weintraub, A. Y., Levi, I., Sheiner, E. Downsizing
pregnancy complications: a study of paired pregnancy outcomes before
and after bariatric surgery. Surg. Obes. Relat. Dis. 2012;8(4):434-9.


Chapter V

The Association between
Multifetal Gestation and
Hypertensive Disease
in Pregnancy

J akob Nowotny, M.D., Rania Okby, M.D.
and Eyal Sheiner, M.D., Ph.D.

Department of Obstetrics and Gynecology,
Soroka University Medical Center, Faculty of Health Sciences,
Ben Gurion University of the Negev, Beer-Sheva, Israel

Introduction

The incidence of multifetal gestation in general and twin pregnancy in
particular has risen in the last decades. In the United States, between 1980 and
2006, the rate of twin births climbed 101% [1]. Twin births accounted for 3.3
% of all live births in 2009 [2]. The two major reasons for this increase were
the use of assisted reproductive techniques (ART) and older maternal age at
childbirth [2]. Approximately 1% of infants born in the Unites States in 2006
were conceived with the use of ART and these ART-assisted births accounted
for 18% of all multiple births [1].

Corresponding author: Eyal Sheiner MD, PhD, Email: sheiner@bgu.ac.il

Jakob Nowotny, Rania Okby and Eyal Sheiner 100
Multiple pregnancies are associated with higher maternal morbidity
including miscarriage, anemia, hypertensive disorders, postpartum
hemorrhage, cesarean section and postpartum illness [2, 3]. Multiple
pregnancies are also associated with higher fetal-neonatal morbidity and
mortality including stillbirth, malformation, preterm birth and intra-uterine
growth restriction (IUGR) [2, 3]. This is in addition to certain conditions
which are unique to twin pregnancies, i.e., twinto-twin transfusion syndrome
(TTTS), twin anemiapolycythemia sequence (TAPS), selective intrauterine
growth restriction and twin reversed arterial perfusion sequence (TRAP).

Epidemiology

Rates for gestational hypertension and preeclampsia in twin pregnancies
have been shown to be significantly higher than rates in singleton gestations
[1-4]. Twin pregnancies have a 21% incidence of pregnancy-induced
hypertensive disorders, while their singleton counterparts had only a 13%
incidence [5], with a later onset as compared to twin pregnancies [4].
Preeclampsia rates in women with twin gestations are anywhere between 2-4
times higher than in singleton pregnancies, especially in primigravid women
[3, 4, 6]. The risk of a nulliparous twin pregnancy is documented as up to 14
times greater than that of a nulliparous singleton pregnancy [7]. The risk of
developing preeclampsia in twin pregnancies has been documented to be as
high as 35% [6].
There have been multiple studies attempting to determine whether risk
factors for the development of preeclampsia in twin pregnancies are similar to
those in singleton pregnancies [8-10]. Some of the risk factors classically
associated with singleton preeclampsia, i.e advanced maternal age, increased
BMI, and a history of preeclampsia or infertility, are not seen to be risk factors
in twin gestations [11, 12], while Coonrod et al. found no significant
differences in the risk factors between twin and singleton pregnancies in a
population based cohort study [7]. A recent large case-control study by Fox et
al. [9] showed that on univariable analysis, the risk factors associated with
preeclampsia in twin pregnancies are egg donation, nonwhite race, nulliparity,
prepregnancy obesity, and gestational diabetes mellitus, while Lucovnik et al.
found high prepregnancy BMI to pose an especially high risk for the
development of preeclampsia in twin gestation [10]. Furthermore, on
multivariable analysis, egg donation and prepregnancy obesity were found to
be independent risk factors [9, 10]. The worldwide obesity epidemic and the
The Association between Multifetal Gestation ... 101
increase in use of ARTs are both likely to contribute to an increase in the rate
of preeclampsia in women with twin pregnancy.
Another recent study showed that a larger proportion of women with
dichorionic twins developed preeclampsia (specifically, mild preeclampsia), as
compared to those with monochorionic twins [13].
Aside from the higher rate of preeclampsia in twin pregnancies,
preeclampsia in twin pregnancies has been shown to occur earlier and to be
more severe [3, 4, 6, 14]. Long and Oats [6] demonstrated that 70% of
preeclampsia patients with twin pregnancies were diagnosed before 37 weeks
as compared to only 24% in singleton pregnancies. Also, preeclampsia was
found to be of the severe type in 45% of cases in twin pregnancies as
compared to 21% in singleton preeclamptic pregnancies.
Epidemiological differences between twin and singleton pregnancy
preeclampsia have fueled researchers to explore the pathophysiology
differences that may be involved.

Pathophysiology

Current understanding of singleton pregnancy preeclampsia pathogenesis
involves incomplete trophoblast invasion of maternal spiral arteries that leads
to a cascade of relative ischemia and oxidative stress on the placental tissue.
This unfavorable placental state subsequently leads to the release of such
mediators as soluble fms-like tyrosine kinase 1 (sFlt1) into the maternal
circulation causing an intravascular systemic response which eventually leads
to increased vascular reactivity and the clinical manifestations of preeclampsia
[15].
Bdolah et al. [16] investigated two hypotheses for the pathogenesis of
preeclampsia in twin pregnancies. The first suggests that the placenta produces
more sFlt1 per unit of placenta due to relative hypoxia and the second suggests
that the mere existence of more trophoblastic placental tissue increases the net
production of sFlt1, resulting in a high serum concentration. Based on the
study results, the researchers propose that the latter hypothesis is more likely
due to the fact that placental weights in twin pregnancies were correlated very
well with serum sFlt1 levels.
Soluble fms-like tyrosine kinase 1 (sFlt1) and soluble endoglin (sEng)
have been shown to be anti-angiogenic molecules which act by antagonizing
such proangiogenic molecules as vascular endothelial growth factor (VEGF)
and placental growth factor (PlGF) [17, 18]. Clinically, a rising ratio in
sFlt1:PlGF in addition to high levels of soluble endoglin levels both herald the
onset of preeclampsia [19, 20]. sFlt1 in particular has been suggested to be a
key player in the pathogenesis of preeclampsia.
sENG and sFLT1 levels were significantly increased in twin pregnancies,
while adiponectin did not show an increase as compared to singleton
pregnancies suggesting an increased pro inflammatory state and increased
oxidative stress early on in twin pregnancies [21].
The basis for the immunogenic pathophysiology theory of preeclampsia is
the recognition of fetal and trophoblastic tissue as foreign tissue by the
mothers immune system. Monozygous pregnancies should then be at a lower
risk than dizygous gestations. Maxwell et al. as well as Savvidou et al. did not
demonstrate zygosity or chorionicity to affect the rate of preeclampsia in twin
gestations [22]. Sparks et al. in a larger retrospective cohort study, however,
recently found that women with dichorionic (DC) twins were more likely to
develop preeclampsia, and specifically mild preeclampsia, compared to those
with monochorionic (MC) twins. The researchers proposed that the
pathological mechanism between DC and MC twin pregnancies may differ
[13].
Another pathophysiological discrepancy between singleton and twin
pregnancy preeclampsia comes from the immunological theory of
preeclampsia. In this theory, T helper (Th) 2 cells have been suspected to be
protective against Th1 cells which are associated with inflammation, poor
placentation, and endothelial dysfunction. The Th 1/Th2 ratio in preeclampsia
patients with twin gestations has been significantly lower than singleton
pregnancy preeclampsia patients [23, 24].
For singleton pregnancies, uterine artery Doppler at 22-24 weeks
identifies women at higher risk for the development of subsequent
complications of placental insufficiency [25]. Unlike in singleton pregnancies,
uterine artery Doppler abnormalities indicating placental vascular pathology
(diastolic notch, increased pulsatility index) are generally not seen in twin
pregnancies associated with normal fetal growth [26]. While an increased
pulsatility index with notching was the best predictor of preeclampsia and
intrauterine growth restriction among low-risk patients with singleton
pregnancies, these abnormal uterine waveforms are not a good predictor in
twin pregnancies, as resistance index values are lower and show a different
slope. Twin pregnancies may present with gestational hypertension and
preeclampsia despite normal uterine artery velocity waveforms [27]. Such
factors as reduced resistance and pulsatility indices in uterine arteries of
normal twin pregnancies have limited the clinical prediction of hypertensive
disorders via ultrasound [27, 28]. and have lead to attempts to find more
appropriate uterine artery reference ranges for identifying high-risk women
[29]. Furthermore, this may indicate that the pathophysiology of preeclampsia
in twin pregnancies is unrelated to uteroplacental insufficiency [28].
Shinagawa et al. proposed the presence of different mechanisms for the
pathogenesis of preeclampsia between twin and singleton gestations based on
their observation of increased endothelin-1 levels but no difference in
adenosine or vascular resistance in the uterine arteries between preeclamptic
twin and singleton gestations [30].
Women who conceive multiple gestations via ART were twice as likely to
develop preeclampsia than women who conceive spontaneously [31]. As early
as the first trimester, twin pregnancies conceived using ART had a higher level
of sFlt1 than twin pregnancies conceived spontaneously, while sEng remained
unchanged [32]. The increase in sFlt1 and its anti-angiogenic properties
causing a vascular response may be crucial in the pathophysiology of
preeclampsia and its higher incidence in twin pregnancies.
The link between multifetal pregnancy and increased rate of preeclampsia
is strengthened by the increase in severe preeclampsia in triplet as compared to
twin pregnancies (22.6% vs. 5.7%) [33], and the retrospective comparison of
preeclampsia incidence in triplet reductions. The incidence of preeclampsia in
twins remaining after a reduction and in non-reduced twins was lower than in
non-reduced triplets (14% and 23% vs. 30%) [34]. The case report of the
resolution of preeclampsia after the intrauterine death of one of the HLA-
identical twins and its recurrence upon growth of the placenta of the remaining
twin later in pregnancy, lend validity to preeclampsia as a dose-dependent
phenomenon dependent on placental tissue for its pathogenicity [35].
A genetic basis for preeclampsia has been proposed, but the mode of
inheritance has not been established. A polygenetic mode of inheritance was
proposed by Trogstad et al. based on the observation that the recurrence risk of
preeclampsia is lower when the first pregnancy was a twin and not a singleton
pregnancy [36].

Maternal Outcomes

It is well-known that maternal and perinatal complications are more
frequent in twin when compared to singleton pregnancies [37]. Maternal
mortality is higher as compared to singleton eclamptic women and is highest
with male fetuses, while perinatal and maternal mortality were lower when
cesarean sections were performed [38].
When compared to singletons, preeclampsia develops earlier in twin
pregnancies [11]. The cesarean delivery rate is more common in twins with
preeclampsia compared to singletons with preeclampsia, with a relative risk of
1.78 as reported by Sibai et al. (2000) [3]. In addition, women carrying twins
are at a 4-fold increase rate of development of hemolysis, elevated liver
enzymes, low platelet (HELLP) syndrome as compared with a singleton [11].
However, other studies did not show this association [7].
Lucovnik et al. (2012) had shown that such placental complications as
placenta previa, placental abruption or adherent placenta were more common
in twin pregnancies complicated by preeclampsia compared to twins without
preeclampsia (OR 1.73, 95% CI 1.04-2.58) [10].
Suzuki et al. showed no significant differences in IVF-related risks in
elderly primiparousdichorionic twin pregnancies conceived by IVF as
compared to those conceived spontaneously, aside from an increased rate of
elective Cesarean sections in the IVF group [11]. Marchand et al. investigated
the different types of ART in singleton pregnancies and found no significant
differences in rates of hypertension, preeclampsia, HELLP syndrome and
intrauterine fetal demise between spontaneous pregnancy, in-vitro fertilization,
intra cytoplasmic injection, and other modes of simple assisted reproductive
technology. They did describe a significantly lower rate of gestational diabetes
in ICSI vs. the other three groups [39].
Recently, our group has investigated whether twin delivery with and
without preeclampsia poses a risk for subsequent maternal long-term
cardiovascular morbidity. Kaplan-Meier survival curve was used to estimate
cumulative incidence of cardiovascular hospitalizations during a long-term
follow-up period (1988-2012). Women with twins complicated by
preeclampsia were at a significant risk for long-term cardiovascular morbidity
in a follow-up period of more than a decade (Figures; unpublished data).

Fetal and Neonatal Outcomes

Fetuses and newborns of women with preeclampsia are at increased risk
for such neonatal complications as preterm delivery, small-for-gestational-age
and increased risk for being admitted in neonatal intensive care unit [6].
Preeclampsia in twin gestations was associated with higher rates of such
adverse neonatal outcomes as abruptio placenta, than in singleton pregnancies
[3].

(a)

(b)
Figure 1. Kaplan-Meier survival curve showing survival analysis (a) and cumulative
hazard (b) of long term cardiovascular hospitalizations in women with twins with and
without preeclampsia.
Table 1. Maternal and neonatal complications in multiple pregnancies
compare to singletons

Maternal
complications:

HELLP syndrome
Cesarean delivery
Placental complications (placenta previa, placental
abruption or adherent placenta)
Maternal long-term cardiovascular morbidity
Maternal mortality
Neonatal
complications:

Preterm birth
Small for gestational age
Admission in neonatal intensive care unit

It was observed that the rate of adverse neonatal outcomes was more
common in severe preeclampsia than in mild preeclampsia [40].
In conclusion, obstetricians should be aware of the increased risk for
preeclampsia, which may be developed earlier and in a more severe form than
in singletons, with an increased risk for maternal and neonatal complications.
It is recommended to have more frequent screening for gestational
hypertensive disorders in twin pregnancies for early detection aimed at
decreasing adverse maternal and neonatal outcomes.

References

[1] Ros, H.S., S. Cnattingius, and L. Lipworth, Comparison of risk factors
for preeclampsia and gestational hypertension in a population-based
cohort study. Am. J. Epidemiol., 1998. 147(11): p. 1062-70.
[2] Leszczynska-Gorzelak, B., G. Szymczyk, and J.J. Oleszczuk, [Twin
pregnancy and preeclampsia]. Ginekol. Pol., 2000. 71(11): p. 1422-8.
[3] Sibai, B.M., et al., Hypertensive disorders in twin versus singleton
gestations. National Institute of Child Health and Human Development
Network of Maternal-Fetal Medicine Units. Am. J. Obstet. Gynecol.,
2000. 182(4): p. 938-42.
[4] Krotz, S., et al., Hypertensive disease in twin pregnancies: a review.
Twin Res., 2002. 5(1): p. 8-14.
[5] Santema, J.G., I. Koppelaar, and H.C. Wallenburg, Hypertensive
disorders in twin pregnancy. Eur. J. Obstet. Gynecol. Reprod. Biol.,
1995. 58(1): p. 9-13.
[6] Long, P.A. and J.N. Oats, Preeclampsia in twin pregnancy--severity and
pathogenesis. Aust. N. Z. J. Obstet. Gynaecol., 1987. 27(1): p. 1-5.
[7] Coonrod, D.V., et al., Risk factors for preeclampsia in twin pregnancies:
a population-based cohort study. Obstet. Gynecol., 1995. 85(5 Pt 1): p.
645-50.
[8] Erez, O., et al., Preeclampsia in twin gestations: association with IVF
treatments, parity and. J. Matern. Fetal. Neonatal. Med., 2006. 19(3): p.
141-6.
[9] Fox, N.S., et al., Risk Factors for Preeclampsia in Twin Pregnancies.
Am. J. Perinatol., 2013.
[10] Lucovnik, M., et al., Risk factors for preeclampsia in twin pregnancies: a
population-based matched case-control study. J. Perinat. Med., 2012.
40(4): p. 379-82.
[11] Suzuki, S. and M. Igarashi, Risk factors for preeclampsia in Japanese
twin pregnancies: comparison with those in singleton pregnancies. Arch.
Gynecol. Obstet., 2009. 280(3): p. 389-93.
[12] Fox, N.S., et al., Outcomes of multiple gestations with advanced
maternal age. J. Matern. Fetal. Neonatal. Med., 2009. 22(7): p. 593-6.
[13] Sparks, T.N., et al., Does risk of preeclampsia differ by twin
chorionicity? J. Matern. Fetal. Neonatal. Med., 2013.
[14] ACOG Practice Bulletin #56: Multiple gestation: complicated twin,
triplet, and. Obstet. Gynecol., 2004. 104(4): p. 869-83.
[15] Steegers, E.A., et al., Pre-eclampsia. Lancet, 2010. 376(9741): p. 631-
44.
[16] Bdolah, Y., et al., Twin pregnancy and the risk of preeclampsia: bigger
placenta or relative. Am. J. Obstet. Gynecol., 2008. 198(4): p. 428.e1-6.
[17] Maynard, S.E., et al., Excess placental soluble fms-like tyrosine kinase 1
(sFlt1) may contribute to. J. Clin. Invest., 2003. 111(5): p. 649-58.
[18] Venkatesha, S., et al., Soluble endoglin contributes to the pathogenesis
of preeclampsia. Nat. Med., 2006. 12(6): p. 642-9.
[19] Levine, R.J., et al., Soluble endoglin and other circulating antiangiogenic
factors in preeclampsia. N. Engl. J. Med., 2006. 355(10): p. 992-1005.
[20] Levine, R.J., et al., Circulating angiogenic factors and the risk of
preeclampsia. N. Engl. J. Med., 2004. 350(7): p. 672-83.
[21] Wang, C.N., et al., Early anti-angiogenic proteins expression in amniotic
fluid of twin fetuses. Twin Res. Hum. Genet., 2011. 14(5): p. 452-6.
[22] Maxwell, C.V., et al., Relationship of twin zygosity and risk of
preeclampsia. Am. J. Obstet. Gynecol., 2001. 185(4): p. 819-21.
[23] Suzuki, S. and N. Ouchi, T helper 1/t helper 2 cell immunity in
preeclamptic twin pregnancy. J. Nippon. Med. Sch., 2007. 74(6): p. 434-
6.
[24] Saito, S. and M. Sakai, Th1/Th2 balance in preeclampsia. J. Reprod.
Immunol., 2003. 59(2): p. 161-73.
[25] Palma-Dias, R.S., et al., Screening for placental insufficiency by
transvaginal uterine artery Doppler at. Fetal. Diagn. Ther., 2008. 24(4):
p. 462-9.
[26] Rana, S., et al., Angiogenic factors and the risk of adverse outcomes in
women with suspected. Circulation, 2012. 125(7): p. 911-9.
[27] Rizzo, G., D. Arduini, and C. Romanini, Uterine artery Doppler velocity
waveforms in twin pregnancies. Obstet. Gynecol., 1993. 82(6): p. 978-
83.
[28] Geipel, A., et al., Doppler assessment of the uterine circulation in the
second trimester in twin. Ultrasound Obstet. Gynecol., 2002. 20(6): p.
541-5.
[29] Geipel, A., et al., Reference ranges for Doppler assessment of uterine
artery resistance and. Ultrasound Obstet. Gynecol., 2011. 37(6): p. 663-
7.
[30] Shinagawa, T., et al., Maternal plasma adenosine and endothelin-1 levels
in twin gestation complicated by preeclampsia. Arch. Gynecol. Obstet.,
2002. 267(2): p. 72-5.
[31] Lynch, A., et al., Preeclampsia in multiple gestation: the role of assisted
reproductive technologies. Obstet. Gynecol., 2002. 99(3): p. 445-51.
[32] Sanchez, O., et al., First trimester serum angiogenic/anti-angiogenic
status in twin pregnancies. Hum. Reprod., 2012. 27(2): p. 358-65.
[33] Mastrobattista, J.M., et al., The rate of severe preeclampsia is increased
in triplet as compared to twin gestations. Am. J. Perinatol., 1997. 14(5):
p. 263-5.
[34] Smith-Levitin, M., et al., Selective reduction of multifetal pregnancies to
twins improves outcome over nonreduced triplet gestations. Am. J.
Obstet. Gynecol., 1996. 175(4 Pt 1): p. 878-82.
[35] Bschierl, F. and E. Beinder, Temporary resolution of preeclamptic
symptoms after intrauterine death of one twin. Hypertens Pregnancy,
2005. 24(3): p. 313-7.
[36] Trogstad, L., et al., Recurrence risk of preeclampsia in twin and
singleton pregnancies. Am. J. Med. Genet. A, 2004. 126A(1): p. 41-5.
[37] Rao, A., S. Sairam, and H. Shehata, Obstetric complications of twin
pregnancies. Best Pract. Res. Clin. Obstet. Gynaecol., 2004. 18(4): p.
557-76.
[38] Lopez-Llera, M., E. De la Luna Olsen, and J. Niz Ramos, Eclampsia in
twin pregnancy. J. Reprod. Med., 1989. 34(10): p. 802-6.
[39] Marchand, E., et al., [Is there more complications with pregnancies from
the assisted reproductive technology than spontaneous pregnancies? A
retrospective study over 6 years]. J. Gynecol. Obstet. Biol. Reprod.,
(Paris), 2011. 40(6): p. 522-8.
[40] Blickstein, I., H. Ben-Hur, and R. Borenstein, Perinatal outcome of twin
pregnancies complicated with preeclampsia. Am. J. Perinatol., 1992.
9(4): p. 258-60.


Chapter VI

Placental Modification of Its
Secreted Peptides as a Key
to Immune Evasion and the
Pathogenesis of Preeclampsia

Philip Lowry, Ph.D.

University of Reading, Reading, Berkshire, United Kingdom

Introduction

This chapter will describe the sequence of observations that kindled
interest in the bioactive peptides that may cause the symptoms of
preeclampsia: first, the placental origin of melanotropin activity; then the
interaction between corticotropin releasing factor and its binding protein; and
latterly a tachykinin that was subsequently found to be post-translationally
modified specifically in the placenta by phosphocholine, a group normally
used by parasites to alter certain proteins, with the effect of inhibiting immune
surveillance and rejection. This pathway may finally have led to an
understanding of the identity of the elusive placental factor that, whilst acting
to compensate for the poor implantation of the placenta, causes the many
symptoms seen in the mother during preeclampsia.

Email: p.j.lowry@reading.ac.uk
Philip Lowry 112
The immunological and physiological problems facing the survival of the
feto-placental unit during pregnancy are very complex. The fact that a
pregnancy goes to term with a healthy baby sometimes inside a not too
healthy mother it is quite a remarkable mystery. It is clear that it is mainly
the placenta and not the baby (and certainly not the mother) that orchestrates
pregnancy as, when a fetus is not present (hydatiform mole), the placenta (in
this case undifferentiated) will go to term, and in some cases can cause
pathologies such as preeclampsia [1].
The first problem facing the developing embryo is to become implanted
into the uterine wall; then, as the trophoblast develops in the case of human
pregnancy, the placenta starts to invade the wall of the myometrium without
triggering the mothers immune system to reject the placenta. It is often
forgotten that the placenta is in effect an allograft: in normal pregnancy it
shares only half the genes of the mother, and in the case of a surrogacy it is a
xenograft sharing none of its genes with the mother. Thus, as the placenta
invades the uterine wall, it should elicit an immune response causing it to be
rejected; yet, in most cases, normal pregnancy ensues. The fact that the health
of the mother can also be compromised for the benefit of the feto-placental
unit also implies that this is behaving as a parasite or pathogen.
As there is no neural connection between the placenta and the mother, the
only means by which the placenta can send the appropriate messages
necessary to control the mothers metabolism is to secrete hormones at the
placento-myometrial boundary, where they can diffuse into the mothers
blood. The classical placental protein hormones include chorionic
gonadotropin and placental lactogen and are benign, but there are many cases
of pregnancy in which endocrine pathologies such as diabetes and thyroid
disease ensue, and others such as preeclampsia in which a number of diverse
life-threatening symptoms are involved.

Evolution of The Concept That
a Neuropeptide may be Involved
in Preeclampsia

In his early career the author began investigating the peptide hormones of
the hypothalamic-pituitary-adrenal axis, discovering the C-terminal fragment
of ACTH (corticotrophin-like intermediate peptide, CLIP) in the intermediate
lobe (pars intermedia) of the pituitary gland [2] and in tumors associated with
Placental Modification of Its Secreted Peptides ... 113
the ectopic ACTH syndrome [3]. This led to the concept of tissue-specific
processing of ACTH in different parts of the pituitary gland and in tumors [4].
In those non-human mammalian species that have a distinct pars intermedia in
their pituitary gland, ACTH is processed to CLIP and the melanotropins such
as alpha-melanotropin (-MSH), which is post-translationally modified by
acetylation at its N terminal and is amidated at its C terminal. However, the
adult human pituitary does not contain pars intermedia tissue, and thus does
not process ACTH to the level of the melanotropins and CLIP. In the
mammalian brain, where -MSH seems to have a clear function in eating
behavior, the question of whether the molecule is acetylated or not has not
been resolved.
Relevant to this area of research was a paper published by McGuiness in
1963, which suggested that melanotropic activity (bioassayed in intact frogs)
was elevated in the blood of pregnant women and reached very high
concentrations in preeclampsia, suggesting that the placenta secreted a
melanotropin [5].
In an attempt to investigate placental melanotropin and remove any
possible artifact in an intact frog in vivo bioassay, the author used an in vitro
frog skin bioassay instead, but was unable to detect any melanotropic activity
in extracts of blood taken from mothers suffering from preeclampsia
(unpublished observations). It was concluded that McGuiness results may
have been attributable to factors in the blood samples that would stimulate the
intact frog to release melanotropin from its own pituitary gland. A sensitive in
vitro rat pituitary cell bioassay system was then developed to investigate the
hypothalamic releasing factor(s) that were responsible for the release of
peptides derived from ACTH and MSH from the pituitary gland. It revealed
that vasopressin and the 41-residue peptide corticotropin releasing factor
(CRF) synergized in their activity at the pituitary corticotroph in releasing
ACTH [6].
The use of blood samples in such a system proved difficult, therefore a
specific two-site immunometric assay was developed which was sensitive
and robust enough to measure the CRF peptide directly in human blood,
enabling the in-depth study of CRF in samples taken from pregnant women.
Application of this assay led to the observation that the placenta was indeed
capable of secreting the same CRF, normally found in the brain and
hypothalamus, into the circulation of both the mother and fetus, to reach
concentrations in the third trimester that mimicked those found in the
hypothalamic portal blood in stressed animals [7]. Interestingly, the CRF was
significantly increased in pregnant women suffering from pregnancy-induced
Philip Lowry 114
hypertension and pre-term labor [8, 9]. Paradoxically, neither corticotropin nor
cortisol is increased in the mothers blood in pregnancy, suggesting that
placental CRF is not in a biologically active form. Further work led to the
purification [10] and cloning [11] of the material responsible: a unique high-
affinity plasma binding protein (CRF-BP) secreted by the human liver that was
present in the blood in sufficient concentrations to be capable of neutralizing
the biological activity of CRF in the peripheral circulation of both mother and
fetus. This provided an explanation for the protection of both maternal and
fetal pituitary glands from the effects of placental CRF throughout most of
pregnancy, although it came no closer to revealing the identity of the factor in
the blood of women suffering from preeclampsia that McGuiness had noted to
cause the release of melanotropin in the intact frog in vivo bioassay.
Additionally It was also observed that the increasing circulating
concentrations of CRF near term coincided with a reduction in the
concentration of circulating CRF-BP, and it was concluded that this occurred
by specific clearance of the complex [12]. During pregnancy this results in
equimolar concentrations of the two components (CRF and CRF-BP) being
reached three weeks before term [9], and hence any further increase in
placental CRF would circulate in the unbound active form at this time. This
accelerated increase in biological CRF activity in blood towards term would
allow it to have a peripheral action in the final moments of parturition, most
probably stimulating the release of pituitary ACTH in both mother and fetus
and giving rise to the pre-partum increase in cortisol.

Placental Neurokinin B

It is generally recognized that preeclampsia is due to poor implantation of
the placenta [13] resulting in increasing concentrations of a placental factor or
factors being secreted in an attempt to correct the associated ischemia and
improve the transfer of nutrients and gases. When the needs of the placenta
remain unmet because of the compromised implantation, these factor(s) might
then be secreted in increasing amounts and thus be responsible for the life-
threatening symptoms in the mother seen in this condition.
During the early 1990s, the authors group had begun to establish gene-
mining techniques; these proved to be applicable to the search for genes
expressed in samples of human placentas from pregnancies terminated
between 9 and 13 weeks. One interesting neuropeptide gene that was highly
expressed at this time when many natural abortions take place was that of
neurokinin B [14], a member of the tachykinin family which in humans
includes substance P, neurokinin A and the more recently described
endokinins [15]. Using a commercial antiserum in a classical
radioimmunoassay and extracting each plasma sample on a Sepak cartridge to
remove interfering proteins, it was found that NKB-like material in the blood
of pregnant women reached nanomolar concentrations in preeclampsia [14].
The primary site of action of NKB (via its preferred receptor, NK3R) would
appear to be to increase the heart rate [16] and simultaneously contract the
portal [17] and mesenteric blood vessels [18], leading to an increase in blood
pressure [14]. This would result in more blood being available for other tissues
particularly to satisfy the need of the placenta by way of increased perfusion
of the uterus [19]. NKB has also been found to dilate placental blood vessels
[20]. Unlike the many substances reported to be raised in preeclampsia, NKB
uniquely, in progressively stimulating the other NK receptors (NK1R and
NK2R) as its concentration rises, could be responsible for many of the
symptoms observed in preeclampsia, such as cerebral accident [21], platelet
pathology [22], edema of the liver and lungs [23] and oxidative stress [24]. As
the physiological actions of NKB on blood flow suggested it could be the
factor expressed to correct the effects of poor implantation in which case it
would be unusually elevated in early pregnancy its measurement may be
able to identify women who would later develop preeclampsia.
In order to make available a user-friendly assay, antibodies were raised to
several fragments of the NKB and its precursor (pro-NKB) and these were
then used in a variety of specific two-site immunometric assays to detect the
relevant placental peptides. Among the observations made were:

1. Placental concentrations of the various pro-NKB peptides were very
low and placental extracts contained more partially processed material
than fully processed products. There was also evidence for precursor
NKB peptides in blood.
2. The original radioimmunoassay using the commercial antiserum
seemed to cross react in a similar fashion with both placental and
brain NKB. However, the specific two-site immunometric assay
which required that the two immunoglobulins react with their
respective epitopes (NKB(1-5) and NKB(6-10)) reacted with brain
NKB as expected, but hardly detected the placental form at all.
3. Placental NKB consistently eluted ahead of brain NKB on gel
filtration, suggesting that it was slightly larger (ca +30%).

Philip Lowry 116
These observations led to the conclusion that placental NKB was different
from the brain form.
The normal processing of NKB (a 10mer) would be via a 13mer
intermediate, NKB-Gly-Lys-Arg, and it was therefore initially suspected that
this could be the form secreted by the placenta, to be subjected to
carboxypeptidase action at the point of secretion, with the resulting C-terminal
glycine converted to the biologically active amide form in the mothers
periphery. Concentrations of NKB in the human placenta are very low, but to
test this hypothesis sufficient material was isolated from a healthy placenta
donated by a pregnant member of the group who was delivered by cesarean
section for breech presentation, two weeks before term. The limited purified
material gave weak signals on TOF mass spectrometry at 1580 and 1596
Daltons approximately 28 Daltons larger than NKB-Gly-Lys-Arg and its
methionine sulphoxide homologue form, respectively.
One modification that fits with a mass difference of 28 Daltons is
dimethylation. When tested, the placental NKB partially cross reacted with an
anti-dimethyl-lysine antibody, suggesting that placental NKB was NKB-Gly-
(dimethyl)Lys-Arg. However: the synthetic dimethylated 13mer peptide did
not cross react in the original NKB radioimmunoassay; the dimethyl-lysine
residue could not be removed by treatment with carboxypeptidase B; the
synthetic peptide was biologically inactive in vivo; and antibodies raised
against C-terminal fragments containing the dimethylated tripeptide extension
did not cross react with placental NKB (unpublished observations).
Several attempts at purification of placental NKB and submission to TOF-
TOF fragmentation mass spectral analysis did not reveal any identifiable Y or
B ions that would support its identity as NKB-Gly-(dimethyl)Lys-Arg; the
only strong signals that were obtained were at 104 and 184 Daltons. Neither of
these masses is consistent with that of any amino acid; however, they are
consistent with choline and phosphocholine (PC), respectively. There were
also some small peaks present in the mass spectrometric fragmentation
suggestive of the presence of glycerol and a coordinated alkene. Given that the
placenta is full of membranous tissue, the mass ions of choline and
phosphocholine (and the presence of glycerol), these results could merely have
represented contamination of the purified placental NKB with phosphatidyl
choline an important and abundant component of all membranes.
Alternatively, choline bears three methyl groups, and could have been the
moiety that cross-reacted in the earlier anti-dimethyl-lysine antibody
experiment.
Three publications, however, offered some support for PC being
physically present on placental NKB accounting for the mass difference on
TOF mass spectroscopy and suggested some interesting potential properties
for the group. The first property comes from a mass spectrometric study of the
effect of PC coupled directly to the tachykinin, substance P [25]. Not only did
PC attenuate the mass signal of the parent peptide twenty-fold, it also resulted
in atypical fragmentation with very poor signals apart from those of choline
and phosphocholine very reminiscent of the results obtained with placental
NKB! The second is the existence of a phosphocholine transferase [26] that is
highly expressed in the placenta and testis (the two immune-privileged
peripheral tissues) and is located at the endoplasmic reticulum [27], suggesting
it may be involved in the post-translational modification of secretory
peptides/proteins in these tissues. The third is the identification of certain PC-
modified proteins secreted by filarial nematodes, which aid survival of these
parasites by attenuating the hosts immune surveillance system. These
secretory proteins have phosphocholine attached via complex N-linked
polysaccharide post-translational modifications; however, it is the PC group
per se that carries the immunosuppressive properties: when chemically
attached to bovine serum albumin, this group endows the PC-derivatized
albumin with the same spectrum of immune bioactivity as the nematode PC-
proteins [28, 29]. Thus, it was possible that PC was attached to placental NKB
(and other placental peptide/proteins), and endows them with similar
immunosuppressive activity [30].
The exact structure of the post-translational moiety requires advances in
mass spectrometry and synthetic chemistry, but one which fits all the
observations is a variant of platelet activating factor, in which the acetyl group
is replaced by NKB via the Asp
4
acid side-chain [31].
As pregnancy is the only condition in which NKB immunoreactivity is
found in the peripheral circulation and the preferred receptor for NKB, NK3R,
is also located mainly in vascular beds outside neural tissue, it can now be
concluded that phosphocholinated NKB should be considered as the natural
agonist of the NK3 receptor. It is interesting to note that most NK3 receptor
studies have used a peptide analogue called senktide [32], rather than the brain
form of NKB, which is a rather poor agonist. Senktide is a synthetic N-
terminally truncated NKB peptide analogue in which the Asp
4
residue (the
same residue that is phosphocholinated in placental NKB) has been modified
chemically with a succinyl group.
Philip Lowry 118
Other Placental Neuropeptide Precursors
are Phosphocholinated

The use of an anti-phosphocholine immunoglobulin in combination with
antibodies to other placental neuropeptides in a series of two-site assays
revealed that NKB was not unique in being phosphocholinated;
phosphocholination seems to be the rule rather than the exception, and may
have opened up a new era of placental endocrinology. Other placental
neuropeptides may well undergo the same modification; the studies described
are a reflection of the antisera available in the authors laboratory, which
included those raised to pro-opiomelanocortin, activin, hemokinin, endokinin
A and CRF. In the case of activin and CRF, it was concluded that the
phosphocholination was not present on the fully processed biologically active
products, but is present on their respective precursors [30].
It is important to note here that, for the rat studies, des-Arg-hemokinin
was used as standard and for raising antibodies, ignoring the erroneous
proposal in the original paper reporting the gene sequence that its precursor
would be processed in the same way as that of substance P [33]. The reason
why substance P keeps the extra arginine residue at its N terminal (unlike
other characterized tachykinins) is simply resistance to trypsin-like cleavage of
the peptide bond formed between this arginine and the imino group of the
adjacent proline residue (CLIP also has Arg-Pro- at its N terminal [2]); this is
not the case with pro-hemokinin, in which processing would occur after this
arginine. It is thus not very surprising that a recent study using antibodies to
substance P that cross reacted fully with Arg-hemokinin failed to detect any
immunoreactivity in a cell line expressing the hemokinin gene [34].
It is perhaps relevant here to mention that the equivalent arginine residue
position in pro-endokinin (also known as human pro-hemokinin) is substituted
by threonine, thus removing the only processing site on the N-terminal
upstream side of the tachykinin 10mer sequence. This would lead to the
naturally processed endokinin A having a long N-terminal extension. Indeed, it
was possible to detect this extended peptide in human placental extracts with a
two-site immunometric assay, and the same study showed that a synthetic
construct of the extended peptide had full NK1 receptor activity [14]. The
elution position of the major peak of immunoreactive rat adrenal hemokinin on
gel filtration suggested that it was also N-terminally extended (unpublished
observations). Endokinin A has also been detected immunologically in
platelets and appears to take part in thrombus formation [35]. It is interesting
to note that the potential excessive secretion of human placental endokinin,
unlike NKB, would not cause hypertension in the mother but modified with
platelet activating factor along with its strong activity at NK1 receptors may
be responsible for many of the symptoms seen in the HELLP syndrome.
Despite earlier conclusions that the rat placenta does not synthesize pro-
CRF [36], it was found that this is not the case; indeed, closer examination of
rat placental CRF precursor peptides led to the conclusion that, unlike the
human placenta, in the rat placenta there is little processing to the 41-residue
CRF, phosphocholine groups being attached to the N-terminal upstream part in
the non-CRF region of the precursor. In this region of the rat precursor, there
are also two consensus tripeptide motifs for glycosylation. From careful
examination of the data, it can be concluded that there appears to be more than
one phosphocholine group attached in this upstream region and that, in the
secreted material in the rat placenta, this modification was complete. This was
not the case for post-translational modification with the polysaccharide
moieties, in which there was evidence for none, one and two such groups in
the final secreted products [30].

What Conclusions Can We Draw from These Observations?

Apart from inhibiting the biological activity of human placental CRF
bioactivity during pregnancy, another function for CRF-BP has still to be
found. Conversely, the rat placenta seems to be able to avoid fully processing
pro-CRF, at least at the time point studied (19 days). There are two possible
explanations for this difference:

(i) There is a sudden change to increased placental processing at the final
stages of rat pregnancy, which results in an increasing amount of CRF
biological activity. In human pregnancy this is the outcome of
increasing concentrations of CRF causing a reduction in available
CRF-BP.
(ii) The need for phosphocholinated pro-CRF peptides reaching the
mothers circulation is the overriding biological function and the lack
of processing in the rat and presence of the CRF-BP in the human are
just different ways in which these two species prevent the expression
of harmful CRF biological activity in the early stages of pregnancy.
As the other neuropeptide precursors examined were also
phosphocholinated they would also help to satisfy this need, and it
Philip Lowry 120
may well be that many other placental peptides and proteins that have
been observed in the mother's blood during pregnancy are also
phosphocholinated. We cannot speculate at this stage as to the effect
this would have on their respective normal biological (or
immunological) activity, but given the fact that chemical
phosphocholination of serum albumin and ovalbumin imparts immune
attenuating properties, it is quite feasible that this modification would
convert all these other secreted placental proteins into potential
immune suppressing proteins.

The original finding of phosphocholination as a post-translational
modification on ES-62 (a glycoprotein secreted by certain filarial nematodes)
providing protection against immune surveillance by the host [28, 29] has
relevance to the situation found in many infections in which the invader
highjacks the hosts systems for the benefit of its own survival. The mode of
immunomodulation by PC-modified proteins is even more subtle in the case of
survival of the infecting placenta in the pregnant host, as they would
promote a Th2-type rather than a Th1-type response. Indeed, nematode
infection has been found to promote allograft survival through the induction of
type 2 immunity and inhibition of allospecific cytotoxic T-lymphocyte activity
[37].

What are the Possible Implications for
This Post-Translational Modification?

1. If PC-NKB is released in early pregnancy from poorly implanted
placentas, its measurement could identify women destined to develop
preeclampsia.
2. Treatment with a PC-NKB-like drug in early pregnancy could help
women who experience recurrent miscarriage due to an over active
immune system.
3. ES-62 has been shown to inhibit chemically induced arthritis in mice
[38]. If the maternal remission from rheumatoid arthritis often seen
during human pregnancy is due to the effects of circulating placental
PC-peptides and proteins, long-acting PC-modified peptide-like
compounds could become natural therapeutic drugs for treatment of
this disease.
4. The candidate enzyme CTP:phosphocholine cytidylyltransferase
highly expressed in the placenta, is also expressed in some tumor cell
lines [27]. If these tumors are also using phosphocholination to evade
immune surveillance, drugs that inhibit this enzyme could expose
these types of tumor to the immune system, leading to their regression
and involution.
5. Human stem cells engineered to phosphocholinate certain proteins
that would impart immunoresistance could provide a universal
transplant which, like a surrogate embryo, would be accepted by all
recipients irrespective of genetic background, thus negating the need
for immunosuppressive drugs.

In conclusion, it is amusing to reflect that concepts such as post-
translational modification and tissue-specific processing that dominated a
scientists early career would come back to haunt him many years later and
feature in the most difficult and elusive endocrine puzzle he encountered. It
would have been interesting to see if placental NKB would indeed darken the
skin of intact frogs, but difficulties in purifying enough material from
placentas and in chemical synthesis of NKB with the novel post-translational
moiety attached, and animal license issues, have prevented this experiment.
There are many more important questions that remain to be answered, but the
one concept that is certain is that the placenta is a parasitic endocrine organ
par excellence.

References

[1] Page EW. The relation between hydatid moles, relative ischemia of the
gravid uterus, and the placental origin of eclampsia. American Journal of
Obstetrics and Gynecology, 1939; 37: 291-293.
[2] Scott AP, Ratcliffe JC, Rees LH, Landon J, Bennett HPJ, Lowry PJ,
McMartin C. A new pituitary peptide. Nature New Biology, 1973; 224:
65-67.
[3] Ratcliffe JG, Scott AP, Bennett HPJ, Lowry PJ, McMartin C, Strong JA,
Wallabaum PR. Production of a corticotrophin-like intermediate lobe
peptide and of corticotrophin by a bronchial carcinoid tumour. Clinical
Endocinology, 1973; 2: 51-55.
Philip Lowry 122
[4] Lowry PJ, Silman RE, Hope J, Scott AP. Structure and biosynthesis of
peptides related to corticotrophins and beta-melanotrophins. Annals of
the New York Academy of Sciences, 1977; 297: 49-62.
[5] McGuinness BW. Melanocyte-stimulating hormone: a clinical and
laboratory study. Annals of the New York Academy of Sciences, 1963;
100: 640-657.
[6] Gillies GE, Linton EA, Lowry PJ. The corticotrophin releasing activity
of the new CRF is potentiated several-fold by vasopressin. Nature, 1982;
299: 355-357.
[7] Campbell EA, Linton EA, Wolfe CD, Scraggs PR, Jones MT, Lowry PJ.
Plasma corticotropin-releasing hormone concentrations during
pregnancy and parturition. Journal of Clinical Endocrinology and
Metabolism, 1987; 64: 1054-1059.
[8] Wolfe CDA, Patel SP, Linton EA, Campbell EA, Anderson J, Dornhorst
A, Lowry PJ, Jones MT. Plasma corticotrophin-releasing factor (CRF) in
abnormal pregnancy. British Journal of Obstetrics and Gynaecology,
1988; 95: 997-1002.
[9] McLean M, Bisits A, Davies J, Woods R, Lowry PJ, Smith R. A
placental clock controlling the length of human pregnancy. Nature
Medicine, 1995; 1: 460-463.
[10] Behan DP, Linton EA, Lowry PJ. The isolation of the plasma
corticotrophin releasing factor binding protein. Journal of
Endocrinology, 1989; 122: 23-31.
[11] Potter E, Behan DP, Fischer WH, Linton EA, Lowry PJ, Vale WW.
Cloning and characterization of the cDNAs for human and rat
corticotropin releasing factor-binding proteins. Nature, 1991; 349: 423-
426.
[12] Woods RJ, Grossman A, Saphier P, Kennedy K, Ur E, Behan D, Potter
E, Vale W, Lowry PJ. Association of h-CRH to its binding protein in
blood may trigger clearance of the complex. Journal of Clinical
Endocrinology and Metabolism, 1994; 78: 73-76.
[13] Pijnenborg R, Dixon G, Robertson WB, Brosens I. Trophoblastic
invasion of human decidua from 8 to 18 weeks of pregnancy. Placenta,
1980; 1: 3-19.
[14] Page NM, Woods RJ, Gardiner SM, Lomthaisong K, Gladwell RT,
Butlin DJ, Manyonda IT, Lowry PJ. Excessive placental secretion of
neurokinin B during the third trimester causes pre-eclampsia. Nature,
2000; 405: 797-800.
[15] Page NM, Bell NJ, Gardiner SM, Manyonda IT, Brayley KJ, Strange
PG, Lowry PJ. Characterisation of the endokinins: human tachykinins
with cardiovascular activity. Proceedings of the National Academy of
Sciences, 2003; 100: 6245-6250.
[16] Thompson GW, Hoover DB, Ardell JL, Armour JA. Canine intrinsic
cardiac neurons involved in cardiac regulation possess NK1, NK2 and
NK3 receptors. American Journal of Physiology, 1998; 44: 1683-1689.
[17] Mastrangelo D, Mathison R, Huggel HJ, Dion S, DOrleans-Juste P,
Rhaleb NE, Drapeau G, Rovero P, Regoli D. The rat isolated portal vein:
a preparation sensitive to neurokinins, particularly neurokinin B.
European Journal of Pharmacology, 1987; 134; 321-326.
[18] DOrleans-Juste P, Claing A, Telemaque S, Warner TD, Regoli D.
Neurokinins produce selective venoconstriction via NK-3 receptors in
the rat mesenteric vascular bed. European Journal of Pharmacology,
1991; 204: 329-334.
[19] Page NM, Lowry PJ. Is pre-eclampsia simply a response to the side
effects of a placental tachykinin? Journal of Endocrinology, 2000; 167:
355-361.
[20] Brownbill P, Bell NJ, Woods RJ, Lowry PJ, Page NM, Sibley CP.
Neurokinin B is a paracrine vasodilator in the human fetal placental
circulation. Journal of Clinical Endocrinology and Metabolism, 2003;
88: 2164-2170.
[21] Jansen I, Alafaci C, McCulloch J, Uddman R, Edvinsson L. Tachykinins
(substance P, neurokinin A, neuropeptide K, and neurokinin B) in the
cerebral circulation: vasomotor responses in vitro and in situ. Journal of
Cerebral Blood Flow and Metabolism, 1991; 11: 567-575.
[22] Graham GJ, Stevens JM, Page NM, Grant AD, Brain SD, Lowry PJ,
Gibbins JM. Tachykinins regulate the function of platelets. Blood, 2004;
104: 1058-1065.
[23] Grant AD, Akhtar R, Gerard NP, Brain SD. Neurokinin B induces
oedema formation in mouse lung via tachykinin receptor-independent
mechanisms. Journal of Physiology, 2002; 543: 1007-1014.
[24] Sawicki G, Dakour, J; Morrish, DW. Functional proteomics of
neurokinin B in the placenta indicates a novel role in regulating
cytotrophoblast antioxidant defences. Proteomics, 2003; 3: 2044-2051.
[25] Grabitzki J, Sauerland V, Geyer R, Lochnit G. Identification of
phophorylcholine substituted peptides by their characteristic mass
spectrometric fragmentation. European Journal of Mass Spectrometry,
2005; 11: 335-344.
Philip Lowry 124
[26] Lykidis A, Murti KG, Jackowski S. Cloning and characterization of a
second human CTP:Phosphocholine Cytidylyltransferase. The Journal of
Biological Chemistry, 1998; 273: 14022-14029.
[27] Lykidis A, Baburina I, Jackowski S. Distribution of
CTP:Phosphocholine cytidylyltransferase (CCT) isoforms. The Journal
of Biological Chemistry, 1999; 274: 26992-27001.
[28] Harnett W, Harnett MM. Inhibition of murine B cell proliferation and
down-regulation of protein kinase C levels by a phosphocholine-
containing filarial excretory production. Journal of Immunology, 1993;
151: 4829-4837.
[29] Harnett W, Harnett MM, Byron O. Structural/functional aspects of ES-
62- a secreted immunomodulatory phosphorylcholine containing filarial
nematode glycoprotein. Current Protein & Peptide Science, 2003; 4: 59-
72.
[30] Lovell TM, Woods RJ, Butlin DJ, Brayley KJ, Manyonda IT, Jarvis J,
Howell S, Lowry PJ. Identification of a novel mammalian post-
translational modification, phosphocholine, on placental secretory
polypeptides. Journal of Molecular Endocrinology, 2007; 39: 189-198.
[31] Lowry P. 1-0-Alkenyl-sn-glyceryl-3-phosphorylcholine may be a novel
post-translational modification used by the placenta. Biopolymers, 2011;
96: 189-192.
[32] Wormser U, Laufer R, Hart Y, Chorev M, Gilon C, Selinger Z. Highly
selective agonists for substance P receptor subtypes. The EMBO
Journal, 1986; 5: 2805-2808.
[33] Zhang Y, Lu L, Furlonger C, Wu GE, Paige CJ. Hemokinin is a
hematopoietic-specific tachykinin that regulates B lymphopoiesis.
Nature Immunology, 2000; 1: 392-397.
[34] Nelson DA, Bost KL. Quantification of hemokinin-1 peptide production
and secretion from mouse B cells. Cellular Immunology, 2005; 237:
115-122.
[35] Jones S, Tucker KL, Sage T, Kaiser WJ, Barrett NE, Lowry PJ, Zimmer
A, Hunt SP, Emerson M, Gibbins JM. Peripheral tachykinins and the
neurokinin receptor NK1 are required for platelet thrombus formation.
Blood, 2008; 111: 605-612.
[36] Robinson BG, Arbister JL, Emanuel RL, Majzoub JA. Species specific
placental corticotrophin releasing hormone messenger RNA and peptide
expression. Molecular and Cellular Endocrinology, 1989; 62: 337-341.
[37] Liwski R, Zhou J, McAlister V, Lee TD. Prolongation of allograft
survival by Nippostrongylus brasiliensis is associated with decreased
allospecific cytotoxic T lymphocyte activity and development of T
cytotoxic cell type 2 cells. Transplantation, 2000; 69: 1912-1922.
[38] McInnes IB, Leung BP, Harnett M, Gracie JA, Liew FY, Harnett W. A
novel therapeutic approach targeting articular inflammation using the
filarial nematode-derived phosphorylcholine-containing glycoprotein
ES-62. Journal of Immunology, 2003; 171: 2127-2133.


Chapter VII

The Role of Adipokines
in Preeclampsia

Shali Mazaki-Tovi, M.D.
*1
, Edi Vaisbuch, M.D.
2
and Roberto Romero, M.D., D.Med.Sci.
3

1
Sheba Medical Center, Tel-Hashomer, Israel
2
Kaplan Medical Center, Rehovot, Israel
3
Perinatology Research Branch, NICHD/NIH/ DHHS,
Hutzel Womens Hospital, Detroit, MI, US

Introduction

Adipokines - A New Culprit in Insulin Resistance and Related
Metabolic Complications

Adipose tissue has emerged as a powerful endocrine organ [1-13] that can
exert autocrine, paracrine and endocrine effects by the production and

*
E-mail: smazaki@med.wayne.edu
E-mail: evaisbuch@med.wayne.edu
Correspondence: Roberto Romero, MD, D(Med)Sci, Perinatology Research Branch,

NICHD/NIH/ DHHS, Hutzel Womens Hospital, Box No. 4, 3990 John R, Detroit, MI
48201 US, Telephone (313) 993-2700, Fax: (313) 993-2694, E-mail: romeror@mail.nih.gov
Shali Mazaki-Tovi, Edi Vaisbuch and Roberto Romero 128
secretion of bioactive mediators from adipocytes and other adipose-tissue
cells, collectively termed adipokines. The adipokines family includes
structurally and functionally diverse proteins including: tumor necrosis factor
(TNF)- [3,14-17] and interleukin (IL)-6 [18-23], monocyte chemoattractant
protein-1, [24;25] plasminogen activator inhibitor-1, [26-28] angiotensinogen,
[29, 30] vascular endothelial growth factor, [31, 32[ leptin, [33-39]
adiponectin, [40-44] resistin, [45-49] visfatin50 and retinol binding protein [4.
51-54].
Adipocytokines have been implicated in the pathophysiology of common
metabolic complications such as insulin resistance, [1, 55-62] obesity, [63-67]
and the metabolic syndrome. [62, 68-74] In addition to their well-established
role in glucose and lipid metabolism, adipokines are mediators of the immune
response and they have been implicated in inflammatory disorders such as
asthma, [75-77] inflammatory bowel disease, [78-80] rheumatoid arthritis, [81,
82] and multiple sclerosis. [83, 84] Furthermore, several adipocytokines such
as resistin [85-88] and visfatin [89-91] have an immunoregulatory effect on
the innate immune response while others, like leptin and adiponectin, have
been shown to regulate both the innate [92-95] and the adaptive immune
pathways. [96, 97]
Leptin and adiponectin were chosen as the subject of this chapter since
they are considered classical adipokines. The term classical is used to
emphasize that adipose tissue, specifically the adipocyte, is the major (in the
case of adiponectin, the exclusive) source of these highly active molecules.

Leptin - The First Adipocyte Derived Hormone to be
Discovered

Leptin, a 167amino acid is the product of the human leptin gene and it
was first describe by the group of Friedman in 1994. [39] This 16 kDa protein
is a pleiotropic adipokine that has been implicated in a vast array of
physiologic and pathologic conditions including: energy homeostasis, glucose
metabolism, innate and adaptive immune response, appetite, neuroendocrine
function, bone metabolism, insulin resistance, obesity, cardiovascular disease
and reproductive fitness. [98, 99]
Leptin exerts its effect by binding to a cell-surface specific receptor. There
are several leptin receptors, and all are thought to be the product of an
alternative splicing of a single Lepr gene. Nevertheless, there are evidence to
The Role of Adipokines in Preeclampsia 129
suggest that despite the multiple isoforms of leptin receptor, this adipokine
mediates its effect through a single isoform (LepRb). [100]
Leptin is secreted mainly by white adipose tissue, nevertheless leptin is
not tissue-specific and several tissues and cells have been demonstrated to
secrete this adipokine including the human placenta. [101] During pregnancy,
the placenta contributes a substantial amount of leptin to both maternal and
fetal circulation as suggested by a dramatic decrease in circulating
concentrations of this adipokine within a few day after delivery both in
mothers [102] and neonates. [103] Despite the dramatic decline in postpartum
circulating neonatal leptin concentration, it has been proposed that only 5% of
placental leptin production is secreted to fetal circulation whereas the other
95% are delivered into the maternal compartment.

Adiponectin- The Missing Link between Adiposity
and Metabolic Complications?

Adiponectin, identified independently by four groups, [44, 104-106] is the
most abundant gene (AMP1) product of adipose tissue. It circulates at
relatively high concentrations [40, 63, 66, 104, 107, 108] and accounts for
0.01% of the total plasma proteins. The plasma concentrations of adiponectin
are paradoxically lower in obese than in non-obese individuals. [40, 104] In
addition, weight reduction is associated with an increase in plasma adiponectin
concentration, [64, 66] suggesting that adipose tissue exerts a negative
feedback on adiponectin production and/or secretion. Adiponectin plays an
important role in the pathophysiology of insulin resistance and diabetes, [109-
116] atherosclerosis, [70-72, 117, 118] hypertension, [73, 119, 120]
dislipidemia [121
-
123] and angiogenesis. [124, 125]
Adiponectin circulates in human plasma in distinct forms including: 1.
low-molecular-weight (LMW) trimers; 2. medium-molecular-weight (MMW)
hexamers; and 3. high-molecular-weight (HMW) oligomers (12 to 18
subunits).[40, 44, 126-132] The importance of this observation stems from the
fact that these adiponectin multimers can exert distinct biological effects,
[127-134] activate different single transduction pathways [127, 132] and may
have different affinity to the adiponectin receptors. [135] In particular, the
adiponectin sensitivity index (S
A
), [131] which is the ratio of HMW to total
adiponectin, was reported to be a more sensitive marker of the biological
activity of adiponectin. [128, 128, 129, 131, 133, 134, 136-155] Indeed, S
A
has
a better correlation with insulin resistance [128, 129, 131, 134, 136-140],
obesity, [141-144] cardiovascular diseases [128, 133, 145, 146] and other
impaired metabolic states [147-155] than total adiponectin.
The structural diversity of adiponectin multimers has been proposed to be
associated with its pleiotropic effect. Structurally, adiponectin belongs to the
complement 1q family, which is known to form characteristic multimers. [156-
158] This adipokine undergoes post-translational modification [159, 160]
within the adipocytes into the multimeric forms, including: LMW trimers,
MMW hexamers, and HMW oligomers. [44, 106, 126, 127, 130, 132, 161]
The multimeric forms do not interchange with each other after secretion,
neither in-vivo nor in vitro. [130] It has been suggested that the various
adiponectin isoforms have distinct biological activities: 1) in vitro, HMW and
MMW adiponectin have pro-inflammatory properties such as induction of IL-
6 from human monocyte and activation of nuclear factor (NF)-B, [132, 162-
164] whereas LMW adiponectin inhibits the release of IL-6 (pro-inflammatory
cytokine), [154, 165] and increase the secretion of IL-10(anti-inflammatory
cytokine). [165] In addition, only HMW adiponectin has been shown to
suppress apoptosis of endothelial cells; [133] 2) MMW and HMW
adiponectincan activate NF-B, while LMW adiponectin activates AMP-
activated protein kinase (AMPK) in skeletal muscle. [132] These findings
represent a novel paradigm in which the multimerization state of a hormone
can regulate a specific signaling; 3) administration of HMW, but not LMW,
adiponectin multimers to adiponectin knock-out mice results in a dose-
depended reduction in serum glucose concentrations; [131] 4) mutations in the
collagen domain are associated with Type-2 diabetes mellitus (DM) and
extremely low concentrations of HMW adiponectin; [111, 127, 166] 5) the
plasma HMW/Total adiponecin ratio has a better correlation with insulin
resistance indices than total adiponectin concentrations and the HMW/Total
adiponecin ratio was lower in patients with diabetes compared to non-diabetic
subjects; [131, 133, 136, 138, 140, 151] and 6) weight reduction and treatment
with insulin sensitizing drugs (e.g. thiazolidineone) preferentially elevates the
HMW adiponectin compared to the other two isoforms [131, 133;134] or to
total adiponectin concentration. [143, 144, 146] In addition, refeeding of
patients with anorexia nervosa was associated with a decrease in HMW
adiponectin concentrations. [152, 167]

What is Preeclampsia?

Preeclampsia, one of the great obstetrical syndromes [168, 169], affects
approximately 5% of pregnancies and is a major cause of both maternal and
neonatal death worldwide. [170-178] Consistent with its syndromic nature,
preeclampsia has been associated with an anti-angiogenic state, [179-213]
endothelial cell dysfunction, [214-223] an exaggerated intravascular pro-
inflammatory response [213, 224-232] and a predominantly T helper (Th1)-
biased immune response. [233-244] In addition, preeclampsia has been
associated with metabolic complications such as obesity, insulin resistance and
dyslipidemia. This is of special importance, since the rising prevalence of
metabolic complications is glaringly evident in women of reproductive age
who are increasingly plagued by obesity [245-247] and because these
metabolic alterations can be subjected to therapeutic manipulation by lifestyle
modifications, medications or surgery.
This syndrome is characterized by new-onset hypertension and proteinuria
after 20 weeks of gestation, and may result in maternal multi-organ damage
affecting the kidneys, liver and the central nervous system. This multisystem
disorder is unique to human pregnancy and results from multiple causes. Term
preeclampsia comprises the majority (75%) of the cases among healthy
nulliparous women and is often mild, resulting mainly in maternal
consequences. In contrast, early-onset preeclampsia (necessitating delivery
before 34 weeks of gestation) is mainly a disease of multiparous women, has a
more severe clinical presentation and is often associated with the life-
threatening HELLP syndrome, [248-257, 257-260].

What is the Rationale to Investigate the Role of Adipokines
in Patients with Preeclampsia?

The discovery of adipokines evoked a rapidly growing interest in
elucidating their putative role in complications of pregnancy. The rationale
underlying the study of these active molecules in preeclampsia of pregnancy
rests on two major observations: the first is the strong association between
obesity and preeclampsia in large epidemiological studies and the second is
the role played by adipokines in metabolic derangements that predisposes
pregnant women to develop these complications (e.g. insulin resistance, lipid
metabolism, endothelial cell dysfunction).
A growing body of evidence strongly supports the association between
preeclampsia and common metabolic complications: 1) obesity is an
independent risk factor for preeclampsia. [173, 245, 261-272] Indeed, obese
pregnant women have a 2 to 4-fold higher prevalence of preeclampsia [273,
274] and a meta-analysis concerning the association between maternal BMI
and preeclampsia showed that the risk for preeclampsia doubled with each 57
kg/m
2
increase in BMI; [275] 2) patients with insulin resistance are more
likely to develop preeclampsia; [276-287] 3) preeclampsia is also associated
with hypertriglyceridemia, [288, 289] hypercholesterolemia, [290] increased
concentrations of free fatty acids [291] and reduced high density lipoprotein
(HDL) concentrations; [288] 4) women who had preeclampsia have an
increased risk for metabolic syndrome-related morbidity [292-295] and
mortality [296-298] later in life. Despite the compelling evidence for the
association between obesity-related complications and preeclampsia, the
mechanism by which excess adipose tissue exerts its deleterious effect and
predisposes pregnant women to develop preeclampsia remains unknown; and
5) an exaggerated inflammatory response is one of the characteristics of
preeclampsia and systemic inflammation is one of the hallmarks of obesity.
[299]

Maternal Circulating Leptin
and Adiponectin in Normal Pregnancy

Maternal Circulating Leptin in Normal Pregnancy

Soon after the discovery of leptin in 1994, [39] this hormone was detected
in the maternal circulation. [300, 301] Hardie et al. [302] were among the first
to conduct a longitudinal study of maternal circulating leptin in normal
pregnant women. Samples were obtained during 5, 7, 9 and 11 weeks of
gestation, and once a month starting on the 4
th
month of pregnancy (n=5).
Leptin concentrations were elevated throughout gestation compared to the
non-pregnant state (P < 0.05), and peaked during the second trimester (P <
0.05). Post-partum maternal circulating leptin concentrations decreased
significantly compared to concentration during pregnancy.
Highman et al. [303] determine maternal circulating leptin in 10 women
before pregnancy, during the first trimester pregnancy (12 to 14 weeks), and in
the third trimester (34 to 36 weeks). There was a 66% increase in maternal
leptin concentrations between pre-pregnancy and the third trimester (25.4
19.9 ng/mL vs. 38.4 27.3 ng/mL, P = 0.003). Concomitantly, total body fat
depot increased by 9%. [304] Interestingly, first trimester maternal leptin
circulating concentrations(37.5 26.2 ng/mL) were also significantly higher
than in the pre-pregnancy period, suggesting that the increase in maternal
leptin is independent of fat accrual (at least during the first trimester). Nuamah
et al. [305] determined total and free leptin in 5 pregnant women in each
trimester (8-12, 28-32 and 35-37 weeks of gestation). The authors reported
similar patterns of alteration in circulating leptin concentrations (i.e., high
concentrations in the second trimester). However, free leptin concentrations
remained largely unchanged during the course of the pregnancy. The
investigators proposed that the combination of constant concentrations of free
leptin despite the increase in total leptin during pregnancy results from
increased leptin binding capacity in pregnant women. This, in turn, may
contribute to leptin resistance during pregnancy and the metabolic
consequences of this condition such as increase fat accumulation and insulin
resistance.
An additional line of investigation is the association between maternal
circulating leptin concentrations and insulin resistance in normal gestation.
McLachlan et al. [57] conducted a study in which 19 healthy pregnant women
underwent intravenous glucose tolerance tests in the third trimester of
pregnancy (mean gestational age 34.0 0.3 weeks) and 4 months postpartum.
The investigators determined insulin sensitivity, insulin secretion, as well as
maternal circulating concentrations of leptin, adiponectin, TNF, and CRP.
Leptin was the only adipokine that was correlated with insulin sensitivity
index during the third trimester. In addition leptin and CRP were correlated
with maternal body mass index (BMI) during pregnancy. Of note, postpartum
leptin was associated with insulin sensitivity index, fasting insulin, high-
density lipoprotein (HDL) and triglycerides concentrations, as well as with
maternal BMI and percentage of body fat. [57]
Mastorakos at el. [306] conducted a longitudinal study that included 80
Caucasian, non-obese, normal pregnant women. During each trimester of
pregnancy (1012, 2426, and 3436 weeks of gestation) the participants
underwent anthropometric measurements, blood sampling, and a 75-g oral
glucose tolerance test. Homeostasis mathematical model assessment (HOMA-
R), insulin sensitivity index, and indices of -cell secretion were calculated for
each visit. Leptin was positively correlated with insulin resistance (r = 0.54, P
< 0.05), -cell insulin secretion (r = 0.56, P < 0.05), and maternal weight (r =
0.71, P < 0.05) during early pregnancy.

Table 1. Maternal circulating leptin in pregnant women with and without preeclampsia

First Author Control (n) Study (n) Trimester at
Sampling
GA at
Sampling
Adiponectin
Concentrations
Comment
Sattar [381] 12 9 2
nd
and 3
rd
2639 No difference
Mise [353] 93 32 3
rd
2941 Higher in PE Higher in severe than mild PE
McCarthy [335] 24 24 3
rd
38.2 0.4 Higher in PE
Williams [356] 192 38 2
nd
15-22 Higher in PE Higher in women destined to
develop PE
Laivuori [357] 16 22 3
rd
29-39 Higher in PE
Teppa [358] 18 18 3
rd
Anim-Nyame [349] 13 19 2
nd
and 3
rd
16-38 Higher in PE Higher in women destined to
develop PE
Martnez-Abundis
[382]
32 26 3
rd
36.23.9 No difference No difference between severe
and mild PE
Vitoratos [354] 17 18 3
rd
28-34 Higher in PE
Laml [380] 36 36 3
rd
40.1 1.2 Lower in PE
Bartha [359] 27 25 3
rd
Clausen [351] 71 71 2
nd
18 Lower in PE
Chappell [350] 17 21 2
nd
18-24 Higher in PE
Gursoy [360] 21 21 3
rd
NA Higher in PE
Kafulafula [361] 92 68 3
rd
34.9 5.1 Higher in PE Only black African parturients
Chan [383] 100 20 2
nd
18.3 1.8 No difference
Salomon [352] 60 30 1
st
7-13 No difference
Atamer [362] 40 96 3
rd
30.53.4 Higher in PE No difference between severe
and mild PE
Celik [384] 23 16 3
rd
36.70.3 No difference
Ning [363] 487 55 1
st
13 Higher in PE Higher in women destined to
develop PE

Sampling
GA at
Sampling
Adiponectin
Concentrations
Comment
Kocyigit [364] 20 53 3
rd
NA Higher in PE
Naruse [365] 40 15 3
rd
28-40 Higher in PE
Koyigit [366] 30 40 3
rd
NA Higher in PE
Baksu [385] 30 50 3
rd
NA No difference
Haugen [367] 23 15 3
rd
33-38 Higher in PE
Hendler [386] 22 77 3
rd
36-40 No difference No difference between severe
and mild PE
Lu [371] 42 38 3
rd
29-41 Higher in PE
Masuyama [368] 30 30 3
rd
Ouyang [369] 20 53 3
rd
37.80.7 Higher in PE Higher in severe than mild PE
Savvidou [370] 44 13 2
nd
and 3
rd
2333 Higher in PE
Nakatsukasa [372] 34 34 3
rd
Herse [373] 30 32 3
rd
Adali [374] 22 50 3
rd
NA Higher in PE
Masuyama [375] 38 38 3
rd
37.2 1.8 Higher in PE High in late-onset and in early-
onset PE
Samolis [376] 53 37 1
st
13 Higher in PE Higher in women destined to
develop PE
Stepan [377] 37 37 2
nd
and 3
rd
23.8-39.8 Higher in PE
Dalamaga [387] 262 106 3
rd
Molvarec [378] 60 60 3
rd
36-39 Higher in PE
Masuyama [379] 56 56 3
rd
36.41.0 Higher in PE

The precise physiological role of leptin in human gestation has not been
fully elucidated. Specifically, it is not clear what is the importance of the
dramatic increase in maternal circulating leptin concentration. It has been
proposed that the increase in maternal leptin concentrations aims at enhancing
the mobilization of maternal fat depot to increase the transplacental lipids
influx. [307] Additional effects of leptin include stimulation of hCG, [308]
proinflammatory cytokines (i.e., IL-1, IL-6, and TNF) [309] and
prostaglandings (PGE2, PGF
2
) [309] from the placenta. It is important to
mention in that context that compelling evidence suggests a role for leptin in
fetal growth and development. [103, 310-320] Nevertheless, this line of
investigation is beyond the scope of this chapter.

Maternal Circulating Adiponectin in Normal Pregnancy

Metabolic adaptations to pregnancy include insulin resistance, [321-328]
hyperlipidemia, [329-332] and increased weight and fat accrual. [333-337]
These alterations are considered components of the metabolic syndrome, [338]
although physiological alterations during pregnancy do not meet the threshold
values for the definition of this condition. Importantly, adiponectin has been
implicated in the pathophysiology of all these metabolic complications. [1, 56,
58, 62, 63, 66-70, 72, 73] In addition, adiponectin has profound insulin-
sensitizing properties and exerts its beneficiary effects on both carbohydrates
and lipids metabolism. Collectively, these findings have made adiponectin an
attractive candidate to regulate metabolic changes during pregnancy.
Fuglsang et al. [339] have conducted a longitudinal study in which blood
samples were obtained from 11 pregnant women in early first trimester (>7
weeks of gestation), early and late second trimester (17 to 26 weeks) and in the
third trimester (>35 weeks of gestation). Blood samples were also obtained on
the 5
th
and the 8
th
postpartum week. Seventeen non-pregnant women were
included in the control group. The investigators reported that while maternal
circulating adiponectin did not differ significantly between pregnant women in
the first trimester and non-pregnant women, maternal adiponectin
concentration changed significantly as a function of gestational age.
Specifically, maternal adiponectin concentration were higher in early second
trimester (12.62.0 mg/L) than in the first (11.41.9 mg/L), late second
(11.41.7 mg/L), third trimester (9.71.6 mg/L) and the postpartum period
(9.11.7 mg/L). The investigators also reported that serum adiponectin
concentration were negatively correlated with maternal BMI, but only from
week 18 onwards. [339] High maternal circulating adiponectin concentration
during pregnancy in lean pregnant women has been confirmed in larger, cross-
sectional studies. [340;341]
In a longitudinal study of 10 lean women Catalano et al.
1
determined both
circulating maternal adiponectin and mRNA expression of adiponectin in
adipose tissue. Blood samples and adipose tissue biopsies were obtained
before conception, in the first (1214 weeks) and third (3436 weeks)
trimesters. The investigators reported that adiponectin concentrations were
lower in the third trimester than in the pre-pregnancy period (9.91.4 vs.
13.51.8 g/mL, P < 0.004). Concomitant decrease in adiponectin mRNA
expression was observed in the adipose tissue samples (2.5-fold decrease). Of
note, consistent with the negative correlation between adiposity and circulating
adiponectin concentrations reported in non-pregnant individuals, maternal fat
mass increased by 25% during the study period.
We [342] have conducted a across-sectional study in which maternal
adiponectin concentrations were determine in normal weight (BMI<25 kg/m
2
)
vs. overweight/obese (BMI25 kg/m
2
) pregnant women. Similarly to a non-
pregnant state we reported that the median plasma adiponectin concentration
in overweight/obese women was significantly lower than that of women with
normal weight (7.37 g/mL, range: 2.76-22.38 vs. 8.87 g/mL, range: 2.77-
25.03; P < 0.05). Plasma adiponectin concentrations were significantly lower
in overweight/obese women than in women of normal weight between 11-14
weeks (7.9 g/mL, 2.7-16.4 vs. 10.2 g/mL, 4.6-22.1; P < 0.003), 19-22
weeks 96.5 g/mL, 4.1-18.7 vs. 9.0 g/mL, 4.2-17.9; P < 0.001], 23-26 weeks
(6.7 g/mL, 3.9-16.5 vs. 8.6 g/mL, 3.8-19.4; P < 0.01] and after 37 weeks
(7.2 g/mL, 2.8-19.2 vs. 8.6 g/mL, 3.3-17.4; P < 0.002). Interestingly,
plasma adiponectin concentrations of women with normal weight, but not
overweight/obese pregnant women had a significant negative correlation with
gestational age (r = -0.14; P = 0.004).
A compelling body of evidence to supports an important role for
adiponectin multimers and their relative distribution in the regulation of
adiponectin biological actions. Thus, our group has conducted a cross-
sectional study in which circulating maternal concentrations of total, HMW,
MMW and LMW adiponectin were determined in three groups: 1) normal
pregnant women of normal body mass index (BMI) (n=466); 2)
overweight/obese pregnant women (BMI 25; n=257); and 3) non-pregnant
women of normal weight (n=40). [342] Comparisons between pregnant and
non-pregnant women revealed that the median maternal concentration of
HMW adiponectin was significantly higher in pregnant women than in non-
pregnant women (3.5 g/mL vs. 2.8 g/mL; P = 0.01). Likewise, pregnant
women had a higher median HMW/Total adiponectin ratio than non-pregnant
women (0.56 vs. 0.46; P < 0.01). In contrast, the median maternal plasma
concentration of LMW adiponectin was lower in pregnant than non-pregnant
women 1.2 ng/mL vs. 1.8 g/mL; P < 0.01).
Normal weight and overweight/obese pregnant women differ in their total
and relative distribution of adiponectin multimers. The median maternal
plasma concentration of total adiponectin was higher in normal weight than
overweight/obese women between 11-14 weeks of gestation (6.5 g/mL vs.
5.8 g/mL; P = 0.02), 19-22 weeks of gestation (6.6 g/mL vs. 5.8 g/mL; P =
0.01) and between 31-34 weeks of gestation (7.3 g/mL vs. 5.0 g/mL; P =
0.01). [342]
The median maternal plasma concentration of HMW adiponectin was
higher in normal weight than overweight/obese women between 11-14 weeks
of gestation (3.9 vs. 2.7; P < 0.01), 19-22 weeks of gestation (3.6 g/mL vs.
2.7 g/mL; P < 0.01), 31-34 weeks of gestation (4.0 g/mL vs. 2.6 g/mL; P =
0.01) and at term (3.9 g/mL vs. 2.9 g/mL; P = 0.01). The median maternal
HMW/Total adiponectin ratio was higher in normal weight than in
overweight/obese women between 11-14 weeks of gestation (0.58. vs. 0.51; P
< 0.01) and between 19-22 weeks of gestation (0.57 vs. 0.52; P = 0.03). [342]
These finding are of special importance since the regulation of the biological
effect of adiponectin is mediated, in part, by the relative abundance of
adiponectin isoforms. Finally, our group has constructed nomograms for total
adiponectin, HNW, MMW, and LMW adiponectin multimers in normal
weight and overweight/obese pregnant women. [342]
Predictably, maternal circulating adiponectin concentrations were
correlated with insulin resistance indices. Lpez-Bermejo et al. [56] conducted
a cross-sectional study of normal pregnant women at term (n=51). Maternal
serum glucose, insulin, glycosylated haemaglobin, and adiponectin were
determined and insulin resistance was calculated using the homeostasis model
of assessment for insulin resistance (HOMA-IR). In multiple regression
analyses, HOMA-IR, maternal BMI at delivery and systolic blood pressure
were independent predictors of adiponectin concentration (explaining 15, 8
and 7% of adiponectin variance, respectively). [56] Catalano et al. [1] have
calculated insulin sensitivity using the glucose clamp technique and were able
to demonstrate a significant negative correlation between the alterations in
maternal plasma adiponectin concentrations and both fasting insulin
concentrations (r = 0.66, P < 0.0001). Furthermore, the investigators
concluded that decreased insulin regulation of glucose utilization, rather than
endogenous hepatic glucose, accounts for the association between adiponectin
and insulin sensitivity.
There is an on-going debate regarding the role of the placenta as a
potential source for maternal circulating adiponectin and evidence for [343,
344] and against [103, 345, 346] placental production of this adipokine has
been reported. Despite this controversy, it is safe to assume that adipose tissue
is the main, if not the sole, source of maternal circulating adiponectin. Thus,
alterations in maternal plasma/serum concentrations of this adipokine strongly
support a regulatory role for adipose tissue in the adaptation to normal
pregnancy.

Maternal Circulating Leptin
and Preeclampsia

Longitudinal Studies and Maternal Circulating Leptin
Concentrations in Early Gestation and Subsequent
Development of Preeclampsia

Williams et al. [347] have conducted a nested case-control study that
included 38 women with preeclampsia and 192 normotensive pregnant
women. Blood samples were obtained between 15 and 22 weeks of gestations,
before any clinical signs or symptoms of preeclampsia were apparent. There
was a disparity in maternal serum leptin concentrations in the second trimester
between normal weight and overweight/obese women. While among normal
weight pregnant women, those with preeclampsia had a significantly higher
leptin concentration than normotensive women (20.5 10.9 ng/mL vs. 13.6
6.8 ng/mL, P = 0.005, a 33% increase), such difference was not detected
among overweight/obese pregnant women with and without preeclampsia
(22.3 7.5 ng/mL vs. 27.8 12.1 ng/mL, respectively; P = 0.084). [348]
These results were adjusted for pre-pregnancy maternal BMI, fetal gender,
parity, as well as ethnic origin.
Anim-Nyame et al. [349] have conducted a longitudinal study in which
included 7 normal pregnant women and 8 patients who subsequently
developed preeclampsia. Blood samples were obtained at 16, 20, 24, 28, 32, 36
and 38 weeks gestation. The investigators reported that circulating maternal
leptin in women destined to develop preeclampsia were significantly higher
starting after 20 weeks of gestation. An opposite pattern in maternal plasma
leptin concentrations has been observed after 32 weeks between the two
groups: while in normal pregnant women there was a decrease, patients who
were destined to develop preeclampsia had a significant increase in circulating
leptin. The elevated maternal plasma leptin concentration in patients with
preeclampsia were paralleled with the clinical presentation of the disease.
[349]
Similar findings were reported by Chappell et al. [350] who conducted a
prospective case-control study, in which leptin, placenta growth factor, and
plasminogen activator inhibitor were measured repeatedly during pregnancy in
21 women who later developed preeclampsia and 17 normal pregnant women.
The serum leptin concentration was significantly higher in the preeclampsia
group than in the control (74%; 95% CI, 21%-135%).
In contrast to the abovementioned reports, Clausen et al. [351] reported
lower maternal concentrations of leptin at 18 weeks of gestation in 71 pregnant
women subsequently developed preeclampsia compared to 71 controls
matched for age, parity and first trimester body mass index. Similar findings
were reported by Salomon et al. [352]

Maternal Circulating Adiponectin in Second and Third
Trimester in Patients with Preeclampsia

Maternal serum leptin concentrations in pregnant women with and without
preeclampsia have been thoroughly investigated. The overwhelm majority of
the studies have reported higher concentrations of leptin patients with
preeclampsia than in normotensive, healthy controls. [349, 350, 353-379] Only
two studies reported lower concentrations of leptin in preeclampmtic patients
[351, 380] and a few failed to find a significant difference between the two
groups. [352, 381-387]
Mise et al. [353] were the first to report higher concentrations of maternal
leptin in patients with preeclampsia (n=32) compared to control (n=93).
Similar finding has been reported in subsequent case-control studies of
pregnant women in the third trimester with and without preeclamsia. [354,
355, 357-362, 364-369, 371-375] These finding were also corroborated in a
more recent publications by Molvarec [378] and byMasuyama et al. [379]
Further support the association between maternal hyperleptinemia and
preeclampsia comes for several studies in which leptin levels in the severe PE
group were significantly higher than those in the mild PE group. Mise et al.
[353] reported that plasma leptin levels in the severe preeclampsia group
(101.5 14.9 ng/mL, n=18) was significantly higher compared to patients with
mild preeclampsia (38.2 4.8 ng/mL, n = 14, p<0.0001). Ouyang et al. [29]
determined maternal leptin concentrations in 3 groups: 1. normotensive
pregnant women; 2. patients with mild preeclampsia (n=32); and women with
severe preeclampsia (n=21). The plasma levels of leptin were: 12.35 6.01,
19.59 4.41 and 27.35 3.36, respectively. Compared to normotensive
pregnant women, patients with mild preeclampsia had higher concentrations of
leptin (p<0.05) and those with severe preeclampsia had higher concentrations
of leptin and those diagnoded with mild preeclampsia (p<0.01).

Genetic Association Studies Concerning Leptin
and Preeclampsia

Muy-Rivera et al. [388] were among the first to report an association
between polymorphism in leptin gene and preeclampsia. Genotype for the
tetranucleotide repeat (TTTC)(n), polymorphism in the 3 -flanking region of
the leptin gene was determined in 40 preeclampsia cases and 39 controls using
PCR. Alleles of the polymorphism were characterized by size distributions
[short repeats (class I); and long repeats (class II)]. The I/II genotype was
associated with a 3.8-fold increased risk of preeclampsia (OR=3.8; 95 % CI
0.8-18.0); and the II/II genotype was not observed among our cases (0 % vs.
33 % p<0.001). These finding suggests a relations between functional variants
in the leptin gene and the risk for preeclampsia.
Sugathadasa et al. [389] investigate 2548 G/A polymorphism of LEP
gene in 62 patients with and 63 pregnant women without preeclampsia. The
authors reported that the frequency of the AA genotype was significantly
higher in the preeclampsia groups compared to controls (p < 0.001). The A
allele conferred a relative risk of 1.67 for the disease (p < 0.0001).
Using a different approach, Rig et al. [390] evaluated the LEPR gene
polymorphisms Lys109Arg (A109G) and Gln223Arg (A223G) in severely
preeclamptic women. In a case-control study, they analyzed blood samples
from patients with severe preeclampsia (n=124) and healthy control (n=107).
Pregnant women with the LEPR 223G allele (223A/G or 223G/G genotype)
had almost double the risk of developing severe preeclampsia compared with
patients with the 223A/A genotype (adjusted OR = 1.92, 95% CI: 1.07-3.41).
Haplotype estimation of A109G and A223G polymorphisms of the LEPR gene
revealed that the G-A haplotype versus other pooled haplotypes was
significantly less common in the preeclamptic group (p < 0.01), while the G-G
haplotype versus others was overrepresented among patients with severe
preeclamptic patients (p < 0.01), compared with controls..
It is not entirely clear why preeclampsia is associated with increased
maternal circulating leptin. One possible explanation is increased secretion by
the placenta. [307] As the increase in maternal circulating leptin precedes the
clinical manifestations of preeclampsia, enhanced excretion by the kidneys
seems unlikely. Similarly, the effect of high leptin in maternal circulation and
the potential contribution to the pathophysiology of preeclampsia remain
elusive.

Maternal Circulating Adiponectin
in Preeclampsia

Alterations in adiponectin concentrations have been implicated in insulin
resistance, [109-116], atherosclerosis and endothelial cell dysfunction, [70, 72,
117, 118] and hypertension [73, 119, 120, which are known risk factors for
preeclampsia. Nevertheless, in contrast to the consensus in the literature
concerning the association between high maternal circulating leptin
concentrations and preeclampsia, the evidence regarding maternal adiponectin
concentrations in the presence of preeclampsia is inconsistent: higher,[365,
367, 371, 372, 375, 377, 379, 386, 391-398] lower, [344, 368, 369, 373, 399-
403] and similar adiponectin concentrations [370, 387, 404, 405] have been
reported in patients with preeclampsia compared to normal pregnant women
(Table 2).

Maternal Circulating Adiponectin Concentrations in the First
Trimester and Subsequent Development of Preeclampsia

D'Anna et al. [399] have conducted a nested case-control study in which
maternal blood samples were obtained between 9 to 13 weeks of gestation.
The study included a control group (n=82) and women who subsequently
developed preeclampsia (n=34) or gestational hypertension (n=48). When
patients destined to develop either preeclampsia or gestational hypertension
were pooled together, the median adiponectin concentration was significantly
lower in these patients than in the control group (7.6 vs. 13.0 g/mL; P <
0.001). Importantly, a comparison between the two hypertensive subgroups

Table 2. Maternal circulating adiponectin in pregnant women with and without preeclampsia

Sampling
GA at
Sampling
Adiponectin
Concentrations
Comment
Ramsay [391] 30 15 3
rd
35-36 Higher in PE
Naruse [365] 40 15 3
rd
28-40 Higher in PE
Kajantie [392] 15 22 3
rd
29-39 Higher in PE
D'Anna [399] 82 48 1
st
9-13 Lower in PE Low in patient destined to
develop PE
Haugen [467] 23 15 3
rd
33-38 Higher in PE
Hendler [386] 22 77 3
rd
36-40 Higher in PE High in mild and severe PE
Suwaki [393] 27 27 3
rd
37-40 Higher in PE
Takemura [394] 14 14 3
rd
35.0 4.0 Higher in PE Selective increase in HMW in
PE
Lu [371] 42 38 3
rd
29-41 Higher in PE
D'Anna [400] 36 36 1
st
9-13 Lower in PE Low in late-onset than early-
onset PE
O'Sullivan [404] 10 12 3
rd
36 No difference
Cortelazzi [401] 33 9 2
nd
and 3
rd
2037 Lower in PE
Masuyama [368] 30 30 3
rd
Ichida [344] 81 27 3
rd
NA Lower in PE
Ouyang [369] 20 53 3
rd
37.80.7 Lower in PE Low in severe than mild PE
Nien [395]

150 59 3
rd
32 3.6 Higher in PE All patient had severe PE
Savvidou [370] 44 13 2
nd
and 3
rd
2333 No difference
Fasshauer [396] 20 16 3
rd
28.5 6.7 Higher in PE High HMW in PE
Nakatsukasa
[372]
34 34 3
rd

Table 2. (Continued)

Sampling
GA at
Sampling
Adiponectin
Concentrations
Comment
Herse [374] 30 32 3
rd
Mazaki-Tovi
[402]
225 111 3
rd
29.3-38.9 Lower in PE High HMW and LMW in PE
Masuyama [375] 38 38 3
rd
37.2 1.8 Higher in PE High in late but not in early-
onset PE
Mori [403] 17 15 3
rd
NA Lower in PE
Liu [397] 28 20 3
rd
Nanda [398] 300 90 1
st
11-13 Higher in PE High in patient destined to
develop PE
Stepan [377] 37 37 2
nd
and 3
rd
Dalamaga [387] 262 106 3
rd
Valds [405] 35 10 1
st
11-14 No difference
Masuyama [379] 56 56 3
rd
36.41.0 Higher in PE

revealed that the median maternal plasma adiponectin was significantly lower
in patients destined to develop preeclampsia than in women who subsequently
had gestational hypertension (6.6 vs. 9.3 g/mL; P = .01). When maternal
plasma adiponectin cut-off of 6.4 g/mL was used (mean value of lower
quartile of distribution among control patients), 25% of gestational
hypertension patients and 47% of patients with preeclampsia had plasma
adiponectin concentration below than value compared with 7% in the control
group (P < .001 for both comparisons). [399] In another study from this group
[400] in which first-trimester plasma adiponectin mean levels were determined
in pregnant women with (n=36) and without (n=36) preeclampsia, adiponectin
concentrations were significantly lower in patients with preeclampsia than that
in the control group (8.4 +/- 3.3 versus 14.8 +/- 4.6 microgram/ml; P < 0.001).
In addition, first-trimester plasma adiponectin mean concentrations in the late-
onset subgroup were significantly lower compared with the concentrations in
early-onset subgroup (6.2 +/- 1.4 microgram/ml versus 11.1 +/- 3.2
microgram/ml; P < 0.001). The authors proposed that the differences between
first-trimester adiponectin concentrations in patients with early- versus late-
onset pre-eclampsia might suggest a different pathogenesis.
In a large case control study Nanda et al. [398] determined maternal serum
adiponectin, at 11-13 weeks in 90 patients who subsequently developed
preeclampsia (60 late- and early preeclampsia) and in 300 normal controls. In
contrast to the reports by D'Anna et al. [399, 400] adiponectin multiple of the
median was increased in early but not in late preeclampsia (1.32 and 1.05 vs.
1.02). In addition, maternal serum adiponectin did not improve the
performance of screening for preeclampsia provided by a combination of the
maternal factors (i.e., uterine artery PI and serum PAPP-A). The authors
concluded that maternal serum adiponectin levels at 11-13 weeks are increased
in women that develop early preeclampsia by a mechanism unrelated to
impaired placentation. In a smaller study by Valds et al. [405] there were no
significant differences in first-trimester (11-14 weeks of gestation) maternal
adiponectin levels between normal pregnant women and those who were
destined to develop preeclampsia (mean adiponectin 8 ng/ml vs. 6.8 ng/ml,
respectively).

Maternal Circulating Adiponectin in Second and Third
Trimester in Patients with Preeclampsia

Ramsay et al. [391] were the first to report the concentrations of
adiponectin in patients with preeclampsia (n=15) and controls (n=30). Third
trimester (35-36 weeks of gestation) maternal serum adiponectin
concentrations were significantly higher in patients with preeclampsia (21.6
8.18 g/mL vs. 14.7 7.06 g/mL; P = 0.01). The authors described this
finding as paradoxical since obesity and insulin resistance, which are
strongly associated with low circulating adiponectin, are well-established risk
factors for preeclampsia. The investigators propose several explanations for
this finding including exaggerated adipocyte lipolysis, counter-response aim at
enhancing fat utilization and attenuating endothelial damage and decreased
excretion by the kidney.
Cortelazzi et al. [401] were the first to report lower concentrations of
adiponectin in patient with preeclampsia compared with normotensive
pregnant women. The authors reported that while similar in normal pregnant
women and nonpregnant controls, maternal adiponectin concentrations were
significantly lower in women with PE (20-37 weeks; 5.0 +/- 0.7 vs. 9.5 +/- 0.7
mg/l; P = 0.008) than those found in normal women matched for gestational
age.

Adiponectin Multimers in Preeclampsia

Takemura et al. [394] conducted a case-control study including pregnant
women with (n=14) and without preeclampsia (n=14) at term. The authors
reported that serum concentrations of the HMW form of adiponectin were
significantly increased in women with preeclampsia, whereas the MMW and
LMW forms are comparable in patients with preeclampsia compared to normal
pregnant women. Similarly, Fasshauer et al. [396] reported higher maternal
serum HMW adiponectin concentrations in patients with preeclampsia (n=16)
compared to lean normal pregnant women (n=20).
Our group
402
has conducted a cross-sectional study to determine whether
preeclampsia is associated with changes in circulating adiponectin multimers.
The study population included women with: 1) normal pregnancy (n=225) and
2) patients with preeclampsia (n=111). The median maternal serum
concentration of total adiponectin was lower in patients with preeclampsia
than in those with a normal pregnancy (5.0 g/mL vs. 6.4 g/mL; P < 0.001,
Figure 2). Patients with preeclampsia had a lower median serum
concentrations of HMW (2.3 g/mL vs. 3.6 g/mL; P < 0.001, Figure 2) and
LMW adiponectin (1.0 g/mL vs. 1.3 g/mL; P = 0.01, Figure 1) than those
with a normal pregnancy. The median maternal serum concentration of MMW
adiponectin did not differ between patients with preeclampsia and women with
a normal pregnancy (1.3 g/mL vs. 1.4 g/mL; P = 0.7, Figure 1).[402]

Figure 1. Comparison of the median serum total, HMW, MMW and LMW adiponectin
concentrations between pregnant women with normal pregnancies and those with
preeclampsia. The median maternal serum concentration of total adiponectin was
lower in patients with preeclampsia than in those with a normal pregnancy. Similarly,
patients with preeclampsia had lower serum concentrations of HMW and LMW
adiponectin than those with a normal pregnancy. The median maternal serum
concentration of MMW adiponectin did not differ between patients with preeclampsia
and those with a normal pregnancy.
Reproduced with permission from Mazaki-Tovi et al. J Perinat Med. 2009;37(4):349-
63 [402].
Differences among the two groups were not only in the absolute
concentrations of adiponectin multimers but also in their relative abundance.
The median maternal HMW/Total adiponectin ratio was lower in patients with
preeclampsia than in those with a normal pregnancy (0.46 vs. 0.55; P < 0.001,
Figure 2). In contrast, patients with preeclampsia had a higher median
MMW/Total adiponectin ratio (0.29 vs. 0.22; P < 0.001, Figure 2) as well as a
higher LMW/Total adiponectin ratio (0.25 vs. 0.21; P = 0.009, Figure 2) than

Normal pregnancy
(n = 225)
p = 0.012
p < 0.001
0
2,500
5,000
7,500
10,000
12,500
15,000
17,500
20,000
22,500
M
a
t
e
r
n
a
l

s
e
r
u
m

a
d
i
p
o
n
e
c
t
i
n

c
o
n
c
e
n
t
r
a
t
i
o
n

(
n
g
/
m
L
)
Preeclampsia
(n = 111)
Total Adiponectin
HMW Adiponectin
MMW Adiponectin
LMW Adiponectin
p < 0.001
those with a normal pregnancy. [402] Of note, the various adiponectin
isoforms can not interchange with each other after secretion. [130] Thus, the
altered regulation of adiponectin multimeric complexes occurs in the
adipocytes. Collectively, these results suggest that altered function of adipose
tissue is a feature of preeclampsia.

Figure 2. Comparison of HMW/Total adiponectin MMW/Total adiponectin and
LMW/Total adiponectin ratio between pregnant women with normal pregnancies and
those with preeclampsia The median maternal HMW/Total adiponectin ratio was lower
in patients with preeclampsia than in those with a normal pregnancy. In contrast,
patients with preeclampsia had a higher median MMW/Total adiponectin ratio as well
as a higher LMW/Total adiponectin ratio than those with a normal pregnancy.
Reproduced with permission from Mazaki-Tovi et al. J Perinat Med. 2009;37(4):349-
63 [401].

Evidence from Genetic Association Studies

An additional line of evidence for the relationship between adiponectin
and preeclampsia comes from genetic association studies. Saarela et al. [406]
determined the genotype for two single nucleotide polymorphisms (SNPs),
SNP45 in exon 2 and SNP276 in intron 2, in the adiponectin gene in 133
Finnish women with preeclampsia and 245 normotensive controls. In addition,
the authors conducted analysis of the pair of loci haplotype to examine the
estimated haplotype frequencies of these SNPs among the two study groups.
The authors reported that the TT genotype vs. the pooled G genotypes in
SNP276 was associated with protection against preeclampsia (odds ratio 0.27,
95% CI 0.09-0.80).
Bienertov-Vask et al. [407] conducted a case-control study comprised a
total of 123 pre-eclamptic women and 150 healthy controls (Czech Caucasian
population). Participants were genotyped for a common polymorphism of the
adiponectin (APM1) gene: APM1 T94G (exon 2) polymorphisms using
polymerase chain reaction. This polymorphism was significantly associated
with a low birth weight in pre-eclamptic pregnancies, with mothers carrying
the T-allele having an almost three-fold increase in the likelihood of giving
birth to a child with a low birth weight for its gestational age (odds ratio, 2.7;
95% confidence interval, 0.18-5.9; P=0.004). The authors concluded that while
APM1 T94G polymorphism do not seem to be major genetic determinants of
susceptibility to pre-eclampsia it may be associated in controlling the birth
weight in this subset population.
Youpeng et al. [408] determined exon 2 SNP +45T/G (rs2241766)
genotype and intron 2 SNP +276G/T genotype (rs1501299) and their allele
distributions in 188 Han Chinese pregnant women (81 normal-term, 20 mild
and 87 severe preeclampsia). There found no no significant differences among
the three groups in genotype distribution or allele frequencies of either SNP.
However, systolic pressure and 24-h urinary protein were lower in TT
homozygotes than those in TG+GG patients at SNP +45T/G in the severe
preeclamptic group. In addition, blood pressure, serum adiponectin level and
24-h urinary protein were lower in GG homozygotes than those in TG+TT
patients at SNP +276G/T in the severe preeclamptic group. The risk of severe
blood pressure (defined as 160/110 mm Hg) and of high serum adiponectin in
T-allele carriers at +276G/T in the severe preeclamptic group were 5.3 and 5.8
times higher, respectively, compared with GG patients. The author concluded
that adiponectin +45T/G and +276G/T polymorphisms are associated with
important clinical manifestations of preeclampsia and that polymorphism
+276G/T is associated with serum adiponectin level.

Summary

Despite the pandemic proportions of obesity in young women, the
mechanism by which adipose tissue exerts its deleterious effect on gestation is
not clear. Characterization of the role played by adipokines in normal gestation
and preeclampsia may improve prediction and diagnosis of this common and
potentially fatal complication of pregnancy. Adiponectin and leptin have been
implicated in the pathophysiology of endothelial cell dysfunction, insulin
resistance, inflammation, and anti-angiogenesis, all well recognized features of
preeclampsia. Alterations in the relative distribution of these adipokines may
reflect altered regulation of adipose tissue level. A large body of evidence
strongly suggests that dysregulation of maternal adiponectin and leptin
concentrations are associated with preeclampsia and can provide a mechanistic
molecular basis for the association between metabolic impairments, altered
inflammatory response and preeclampsia. Finally, the implicit promise of
adipokines research is that the discovery of novel adipokines and new
mechanisms of disease will identify adipokines as a target for pharmacological
intervention aim at preventing preeclampsia or attenuating its sequelae on the
mother, fetus and neonate.

References

[1] Catalano PM, Hoegh M, Minium J, Huston-Presley L, Bernard S,
Kalhan S et al. Adiponectin in human pregnancy: implications for
regulation of glucose and lipid metabolism. Diabetologia 2006;49:1677-
85.
[2] Gimeno RE, Klaman LD. Adipose tissue as an active endocrine organ:
recent advances. Curr.Opin.Pharmacol. 2005;5:122-28.
[3] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of
tumor necrosis factor-alpha: direct role in obesity-linked insulin
resistance. Science 1993;259:87-91.
[4] Hotamisligil GS. Inflammation and metabolic disorders. Nature
2006;444:860-67.
[5] Hutley L, Prins JB. Fat as an endocrine organ: relationship to the
metabolic syndrome. Am.J.Med.Sci. 2005;330:280-89.
[6] Kahn BB, Flier JS. Obesity and insulin resistance. J.Clin.Invest
2000;106:473-81.
[7] Kahn SE, Hull RL, Utzschneider KM. Mechanisms linking obesity to
insulin resistance and type 2 diabetes. Nature 2006;444:840-46.
[8] Matsuzawa Y, Funahashi T, Nakamura T. Molecular mechanism of
metabolic syndrome X: contribution of adipocytokines adipocyte-
derived bioactive substances. Ann.N.Y.Acad.Sci. 1999;892:146-54.
[9] Montague CT, O'Rahilly S. The perils of portliness: causes and
consequences of visceral adiposity. Diabetes 2000;49:883-88.
[10] Spiegelman BM, Flier JS. Obesity and the regulation of energy balance.
Cell 2001;104:531-43.
[11] Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue,
inflammation and immunity. Nat.Rev.Immunol. 2006;6:772-83.
[12] Trayhurn P. Endocrine and signalling role of adipose tissue: new
perspectives on fat. Acta Physiol Scand. 2005;184:285-93.
[13] Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes.
J.Clin.Invest 2005;115:1111-19.
[14] Hotamisligil GS, Arner P, Caro JF, Atkinson RL, Spiegelman BM.
Increased adipose tissue expression of tumor necrosis factor-alpha in
human obesity and insulin resistance. J.Clin.Invest 1995;95:2409-15.
[15] Kern PA, Saghizadeh M, Ong JM, Bosch RJ, Deem R, Simsolo RB. The
expression of tumor necrosis factor in human adipose tissue. Regulation
by obesity, weight loss, and relationship to lipoprotein lipase.
J.Clin.Invest 1995;95:2111-19.
[16] Montague CT, Prins JB, Sanders L, Zhang J, Sewter CP, Digby J et al.
Depot-related gene expression in human subcutaneous and omental
adipocytes. Diabetes 1998;47:1384-91.
[17] Uysal KT, Wiesbrock SM, Marino MW, Hotamisligil GS. Protection
from obesity-induced insulin resistance in mice lacking TNF-alpha
function. Nature 1997;389:610-14.
[18] Coppack SW. Pro-inflammatory cytokines and adipose tissue.
Proc.Nutr.Soc. 2001;60:349-56.
[19] Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous
adipose tissues of obese subjects release interleukin-6: depot difference
and regulation by glucocorticoid. J.Clin.Endocrinol.Metab 1998;83:847-
50.
[20] Mohamed-Ali V, Goodrick S, Rawesh A, Katz DR, Miles JM, Yudkin
JS et al. Subcutaneous adipose tissue releases interleukin-6, but not
tumor necrosis factor-alpha, in vivo. J.Clin.Endocrinol.Metab
1997;82:4196-200.
[21] Purohit A, Ghilchik MW, Duncan L, Wang DY, Singh A, Walker MM
et al. Aromatase activity and interleukin-6 production by normal and
malignant breast tissues. J.Clin.Endocrinol.Metab 1995;80:3052-58.
[22] Vidal H. Gene expression in visceral and subcutaneous adipose tissues.
Ann.Med. 2001;33:547-55.
[23] Wang B, Jenkins JR, Trayhurn P. Expression and secretion of
inflammation-related adipokines by human adipocytes differentiated in
culture: integrated response to TNF-alpha. Am.J.Physiol
Endocrinol.Metab 2005;288:E731-E740.
[24] Sartipy P, Loskutoff DJ. Monocyte chemoattractant protein 1 in obesity
and insulin resistance. Proc.Natl.Acad.Sci.U.S.A 2003;100:7265-70.
[25] Mazurek T, Zhang L, Zalewski A, Mannion JD, Diehl JT, Arafat H et al.
Human epicardial adipose tissue is a source of inflammatory mediators.
Circulation 2003;108:2460-66.
[26] Alessi MC, Peiretti F, Morange P, Henry M, Nalbone G, Juhan-Vague I.
Production of plasminogen activator inhibitor 1 by human adipose
tissue: possible link between visceral fat accumulation and vascular
disease. Diabetes 1997;46:860-67.
[27] Eriksson P, Reynisdottir S, Lonnqvist F, Stemme V, Hamsten A, Arner
P. Adipose tissue secretion of plasminogen activator inhibitor-1 in non-
obese and obese individuals. Diabetologia 1998;41:65-71.
[28] Shimomura I, Funahashi T, Takahashi M, Maeda K, Kotani K,
Nakamura T et al. Enhanced expression of PAI-1 in visceral fat: possible
contributor to vascular disease in obesity. Nat.Med. 1996;2:800-03.
[29] Jones BH, Standridge MK, Taylor JW, Moustaid N. Angiotensinogen
gene expression in adipose tissue: analysis of obese models and
hormonal and nutritional control. Am.J.Physiol 1997;273:R236-R242.
[30] Karlsson C, Lindell K, Ottosson M, Sjostrom L, Carlsson B, Carlsson
LM. Human adipose tissue expresses angiotensinogen and enzymes
required for its conversion to angiotensin II. J.Clin.Endocrinol.Metab
1998;83:3925-29.
[31] Claffey KP, Wilkison WO, Spiegelman BM. Vascular endothelial
growth factor. Regulation by cell differentiation and activated second
messenger pathways. J.Biol.Chem. 1992;267:16317-22.
[32] Fain JN, Madan AK, Hiler ML, Cheema P, Bahouth SW. Comparison of
the release of adipokines by adipose tissue, adipose tissue matrix, and
adipocytes from visceral and subcutaneous abdominal adipose tissues of
obese humans. Endocrinology 2004;145:2273-82.
[33] Farooqi IS, Keogh JM, Kamath S, Jones S, Gibson WT, Trussell R et al.
Partial leptin deficiency and human adiposity. Nature 2001;414:34-35.
[34] Friedman JM, Halaas JL. Leptin and the regulation of body weight in
mammals. Nature 1998;395:763-70.
[35] Fruhbeck G, Jebb SA, Prentice AM. Leptin: physiology and
pathophysiology. Clin.Physiol 1998;18:399-419.
[36] Hamilton BS, Paglia D, Kwan AY, Deitel M. Increased obese mRNA
expression in omental fat cells from massively obese humans. Nat.Med.
1995;1:953-56.
[37] Lonnqvist F, Arner P, Nordfors L, Schalling M. Overexpression of the
obese (ob) gene in adipose tissue of human obese subjects. Nat.Med.
1995;1:950-53.
[38] MacDougald OA, Hwang CS, Fan H, Lane MD. Regulated expression of
the obese gene product (leptin) in white adipose tissue and 3T3-L1
adipocytes. Proc.Natl.Acad.Sci.U.S.A 1995;92:9034-37.
[39] Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM.
Positional cloning of the mouse obese gene and its human homologue.
Nature 1994;372:425-32.
[40] Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J et al.
Paradoxical decrease of an adipose-specific protein, adiponectin, in
obesity. Biochem.Biophys.Res.Commun. 1999;257:79-83.
[41] Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptors.
Endocr.Rev. 2005;26:439-51.
[42] Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K.
Adiponectin and adiponectin receptors in insulin resistance, diabetes,
and the metabolic syndrome. J.Clin.Invest 2006;116:1784-92.
[43] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y,
Matsubara K. cDNA cloning and expression of a novel adipose specific
collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).
Biochem.Biophys.Res.Commun. 1996;221:286-89.
[44] Scherer PE, Williams S, Fogliano M, Baldini G, Lodish HF. A novel
serum protein similar to C1q, produced exclusively in adipocytes.
J.Biol.Chem. 1995;270:26746-49.
[45] Banerjee RR, Rangwala SM, Shapiro JS, Rich AS, Rhoades B, Qi Y et
al. Regulation of fasted blood glucose by resistin. Science
2004;303:1195-98.
[46] Holcomb IN, Kabakoff RC, Chan B, Baker TW, Gurney A, Henzel W et
al. FIZZ1, a novel cysteine-rich secreted protein associated with
pulmonary inflammation, defines a new gene family. EMBO J.
2000;19:4046-55.
[47] Kim KH, Lee K, Moon YS, Sul HS. A cysteine-rich adipose tissue-
specific secretory factor inhibits adipocyte differentiation. J.Biol.Chem.
2001;276:11252-56.
[48] Kusminski CM, McTernan PG, Kumar S. Role of resistin in obesity,
insulin resistance and Type II diabetes. Clin.Sci.(Lond) 2005;109:243-
56.
[49] Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM et
al. The hormone resistin links obesity to diabetes. Nature 2001;409:307-
12.
[50] Haider DG, Schaller G, Kapiotis S, Maier C, Luger A, Wolzt M. The
release of the adipocytokine visfatin is regulated by glucose and insulin.
Diabetologia 2006;49:1909-14.
[51] Graham TE, Yang Q, Bluher M, Hammarstedt A, Ciaraldi TP, Henry RR
et al. Retinol-binding protein 4 and insulin resistance in lean, obese, and
diabetic subjects. N.Engl.J Med 2006;354:2552-63.
[52] Muoio DM, Newgard CB. Metabolism: A is for adipokine. Nature
2005;436:337-38.
[53] Polonsky KS. Retinol-binding protein 4, insulin resistance, and type 2
diabetes. N.Engl.J Med 2006;354:2596-98.
[54] Yang Q, Graham TE, Mody N, Preitner F, Peroni OD, Zabolotny JM et
al. Serum retinol binding protein 4 contributes to insulin resistance in
obesity and type 2 diabetes. Nature 2005;436:356-62.
[55] Kirwan JP, Hauguel-De MS, Lepercq J, Challier JC, Huston-Presley L,
Friedman JE et al. TNF-alpha is a predictor of insulin resistance in
human pregnancy. Diabetes 2002;51:2207-13.
[56] Lopez-Bermejo A, Fernandez-Real JM, Garrido E, Rovira R, Brichs R,
Genaro P et al. Maternal soluble tumour necrosis factor receptor type 2
(sTNFR2) and adiponectin are both related to blood pressure during
gestation and infant's birthweight. Clin.Endocrinol.(Oxf) 2004;61:544-
52.
[57] McLachlan KA, O'Neal D, Jenkins A, Alford FP. Do adiponectin,
TNFalpha, leptin and CRP relate to insulin resistance in pregnancy?
Studies in women with and without gestational diabetes, during and after
pregnancy. Diabetes Metab Res.Rev. 2006;22:131-38.
[58] Retnakaran R, Hanley AJ, Raif N, Connelly PW, Sermer M, Zinman B.
Reduced adiponectin concentration in women with gestational diabetes:
a potential factor in progression to type 2 diabetes. Diabetes Care
2004;27:799-800.
[59] Silha JV, Krsek M, Skrha JV, Sucharda P, Nyomba BL, Murphy LJ.
Plasma resistin, adiponectin and leptin levels in lean and obese subjects:
correlations with insulin resistance. Eur.J.Endocrinol. 2003;149:331-35.
[60] Steppan CM, Lazar MA. Resistin and obesity-associated insulin
resistance. Trends Endocrinol.Metab 2002;13:18-23.
[61] Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles
of pathogenesis and therapy. Lancet 2005;365:1333-46.
[62] Farvid MS, Ng TW, Chan DC, Barrett PH, Watts GF. Association of
adiponectin and resistin with adipose tissue compartments, insulin
resistance and dyslipidaemia. Diabetes Obes.Metab 2005;7:406-13.
[63] Ahima RS, Flier JS. Adipose tissue as an endocrine organ. Trends
Endocrinol.Metab 2000;11:327-32.
[64] Esposito K, Pontillo A, Di Palo C, Giugliano G, Masella M, Marfella R
et al. Effect of weight loss and lifestyle changes on vascular
inflammatory markers in obese women: a randomized trial. JAMA
2003;289:1799-804.
[65] Klok MD, Jakobsdottir S, Drent ML. The role of leptin and ghrelin in
the regulation of food intake and body weight in humans: a review.
Obes.Rev. 2007;8:21-34.
[66] Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL et
al. Weight reduction increases plasma levels of an adipose-derived anti-
inflammatory protein, adiponectin. J.Clin.Endocrinol.Metab
2001;86:3815-19.
[67] Frayn KN. Obesity and metabolic disease: is adipose tissue the culprit?
Proc.Nutr.Soc. 2005;64:7-13.
[68] Gable DR, Hurel SJ, Humphries SE. Adiponectin and its gene variants
as risk factors for insulin resistance, the metabolic syndrome and
cardiovascular disease. Atherosclerosis 2006;188:231-44.
[69] Matsuzawa Y, Funahashi T, Kihara S, Shimomura I. Adiponectin and
metabolic syndrome. Arterioscler.Thromb.Vasc.Biol. 2004;24:29-33.
[70] Okamoto Y, Arita Y, Nishida M, Muraguchi M, Ouchi N, Takahashi M
et al. An adipocyte-derived plasma protein, adiponectin, adheres to
injured vascular walls. Horm.Metab Res. 2000;32:47-50.
[71] Okamoto Y, Kihara S, Ouchi N, Nishida M, Arita Y, Kumada M et al.
Adiponectin reduces atherosclerosis in apolipoprotein E-deficient mice.
Circulation 2002;106:2767-70.
[72] Ouchi N, Kihara S, Arita Y, Nishida M, Matsuyama A, Okamoto Y et al.
Adipocyte-derived plasma protein, adiponectin, suppresses lipid
accumulation and class A scavenger receptor expression in human
monocyte-derived macrophages. Circulation 2001;103:1057-63.
[73] Ouchi N, Ohishi M, Kihara S, Funahashi T, Nakamura T, Nagaretani H
et al. Association of hypoadiponectinemia with impaired vasoreactivity.
Hypertension 2003;42:231-34.
[74] Unger RH. Hyperleptinemia: protecting the heart from lipid overload.
[75] Gurkan F, Atamer Y, Ece A, Kocyigit Y, Tuzun H, Mete N. Serum
leptin levels in asthmatic children treated with an inhaled corticosteroid.
Ann.Allergy Asthma Immunol. 2004;93:277-80.
[76] Guler N, Kirerleri E, Ones U, Tamay Z, Salmayenli N, Darendeliler F.
Leptin: does it have any role in childhood asthma? J.Allergy
Clin.Immunol. 2004;114:254-59.
[77] Shore SA, Schwartzman IN, Mellema MS, Flynt L, Imrich A, Johnston
RA. Effect of leptin on allergic airway responses in mice. J.Allergy
Clin.Immunol. 2005;115:103-09.
[78] Barbier M, Vidal H, Desreumaux P, Dubuquoy L, Bourreille A,
Colombel JF et al. Overexpression of leptin mRNA in mesenteric
adipose tissue in inflammatory bowel diseases. Gastroenterol.Clin.Biol.
2003;27:987-91.
[79] Siegmund B, Sennello JA, Lehr HA, Batra A, Fedke I, Zeitz M et al.
Development of intestinal inflammation in double IL-10- and leptin-
deficient mice. J.Leukoc.Biol. 2004;76:782-86.
[80] Tuzun A, Uygun A, Yesilova Z, Ozel AM, Erdil A, Yaman H et al.
Leptin levels in the acute stage of ulcerative colitis.
J.Gastroenterol.Hepatol. 2004;19:429-32.
[81] Schaffler A, Ehling A, Neumann E, Herfarth H, Tarner I, Scholmerich J
et al. Adipocytokines in synovial fluid. JAMA 2003;290:1709-10.
[82] Bernotiene E, Palmer G, Talabot-Ayer D, Szalay-Quinodoz I, Aubert
ML, Gabay C. Delayed resolution of acute inflammation during
zymosan-induced arthritis in leptin-deficient mice. Arthritis Res.Ther.
2004;6:R256-R263.
[83] Matarese G, Sanna V, Di GA, Lord GM, Howard JK, Bloom SR et al.
Leptin potentiates experimental autoimmune encephalomyelitis in SJL
female mice and confers susceptibility to males. Eur.J.Immunol.
2001;31:1324-32.
[84] Batocchi AP, Rotondi M, Caggiula M, Frisullo G, Odoardi F, Nociti V
et al. Leptin as a marker of multiple sclerosis activity in patients treated
with interferon-beta. J.Neuroimmunol. 2003;139:150-54.
[85] Kusanovic JP, Romero R, Mazaki-Tovi S, Chaiworapongsa T, Mittal P,
Gotsch F et al. Resistin in amniotic fluid and its association with intra-
amniotic infection and inflammation. J Matern Fetal Neonatal Med
2008;21:902-16.
[86] Verma S, Li SH, Wang CH, Fedak PW, Li RK, Weisel RD et al. Resistin
promotes endothelial cell activation: further evidence of adipokine-
endothelial interaction. Circulation 2003;108:736-40.
[87] Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an
adipokine with potent proinflammatory properties. J.Immunol.
2005;174:5789-95.
[88] Silswal N, Singh AK, Aruna B, Mukhopadhyay S, Ghosh S, Ehtesham
NZ. Human resistin stimulates the pro-inflammatory cytokines TNF-
alpha and IL-12 in macrophages by NF-kappaB-dependent pathway.
[89] Jia SH, Li Y, Parodo J, Kapus A, Fan L, Rotstein OD et al. Pre-B cell
colony-enhancing factor inhibits neutrophil apoptosis in experimental
inflammation and clinical sepsis. J.Clin.Invest 2004;113:1318-27.
[90] Ognjanovic S, Bryant-Greenwood GD. Pre-B-cell colony-enhancing
factor, a novel cytokine of human fetal membranes.
Am.J.Obstet.Gynecol. 2002;187:1051-58.
[91] Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Gotsch F, Mittal P et
al. Visfatin/Pre-B cell colony-enhancing factor in amniotic fluid in
normal pregnancy, spontaneous labor at term, preterm labor and prelabor
rupture of membranes: an association with subclinical intrauterine
infection in preterm parturition. J Perinat.Med 2008;36:485-96.
[92] Gainsford T, Willson TA, Metcalf D, Handman E, McFarlane C, Ng A
et al. Leptin can induce proliferation, differentiation, and functional
activation of hemopoietic cells. Proc.Natl.Acad.Sci.U.S.A
1996;93:14564-68.
[93] Tian Z, Sun R, Wei H, Gao B. Impaired natural killer (NK) cell activity
in leptin receptor deficient mice: leptin as a critical regulator in NK cell
development and activation. Biochem.Biophys.Res.Commun.
2002;298:297-302.
[94] Matarese G, Moschos S, Mantzoros CS. Leptin in immunology.
J.Immunol. 2005;174:3137-42.
[95] Zhao T, Hou M, Xia M, Wang Q, Zhu H, Xiao Y et al. Globular
adiponectin decreases leptin-induced tumor necrosis factor-alpha
expression by murine macrophages: involvement of cAMP-PKA and
MAPK pathways. Cell Immunol. 2005;238:19-30.
[96] Lord GM, Matarese G, Howard JK, Baker RJ, Bloom SR, Lechler RI.
Leptin modulates the T-cell immune response and reverses starvation-
induced immunosuppression. Nature 1998;394:897-901.
[97] Howard JK, Lord GM, Matarese G, Vendetti S, Ghatei MA, Ritter MA
et al. Leptin protects mice from starvation-induced lymphoid atrophy
and increases thymic cellularity in ob/ob mice. J.Clin.Invest
1999;104:1051-59.
[98] Kelesidis T, Kelesidis I, Chou S, Mantzoros CS. Narrative review: the
role of leptin in human physiology: emerging clinical applications.
Ann.Intern.Med 2010;152:93-100.
[99] Patel SB, Reams GP, Spear RM, Freeman RH, Villarreal D. Leptin:
linking obesity, the metabolic syndrome, and cardiovascular disease.
Curr.Hypertens.Rep. 2008;10:131-37.
[100] Villanueva EC, Myers MG, Jr. Leptin receptor signaling and the
regulation of mammalian physiology. Int.J Obes.(Lond) 2008;32 Suppl
7:S8-12.
[101] Masuzaki H, Ogawa Y, Sagawa N, Hosoda K, Matsumoto T, Mise H et
al. Nonadipose tissue production of leptin: leptin as a novel placenta-
derived hormone in humans. Nat.Med 1997;3:1029-33.
[102] Sivan E, Whittaker PG, Sinha D, Homko CJ, Lin M, Reece EA et al.
Leptin in human pregnancy: the relationship with gestational hormones.
Am.J Obstet.Gynecol. 1998;179:1128-32.
[103] Sivan E, Mazaki-Tovi S, Pariente C, Efraty Y, Schiff E, Hemi R et al.
Adiponectin in human cord blood: relation to fetal birth weight and
gender. J.Clin.Endocrinol.Metab 2003;88:5656-60.
[104] Hu E, Liang P, Spiegelman BM. AdipoQ is a novel adipose-specific
gene dysregulated in obesity. J.Biol.Chem. 1996;271:10697-703.
[105] Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y,
Matsubara K. cDNA cloning and expression of a novel adipose specific
collagen-like factor, apM1 (AdiPose Most abundant Gene transcript 1).
[106] Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and
characterization of GBP28, a novel gelatin-binding protein purified from
human plasma. J.Biochem.(Tokyo) 1996;120:803-12.
[107] Kershaw EE, Flier JS. Adipose tissue as an endocrine organ.
J.Clin.Endocrinol.Metab 2004;89:2548-56.
[108] Yokota T, Oritani K, Takahashi I, Ishikawa J, Matsuyama A, Ouchi N et
al. Adiponectin, a new member of the family of soluble defense
collagens, negatively regulates the growth of myelomonocytic
progenitors and the functions of macrophages. Blood 2000;96:1723-32.
[109] Berg AH, Combs TP, Du X, Brownlee M, Scherer PE. The adipocyte-
secreted protein Acrp30 enhances hepatic insulin action. Nat.Med.
2001;7:947-53.
[110] Fruebis J, Tsao TS, Javorschi S, Ebbets-Reed D, Erickson MR, Yen FT
et al. Proteolytic cleavage product of 30-kDa adipocyte complement-
related protein increases fatty acid oxidation in muscle and causes
weight loss in mice. Proc.Natl.Acad.Sci.U.S.A 2001;98:2005-10.
[111] Hara K, Boutin P, Mori Y, Tobe K, Dina C, Yasuda K et al. Genetic
variation in the gene encoding adiponectin is associated with an
increased risk of type 2 diabetes in the Japanese population. Diabetes
2002;51:536-40.
[112] Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y et
al. Plasma concentrations of a novel, adipose-specific protein,
adiponectin, in type 2 diabetic patients. Arterioscler.Thromb.Vasc.Biol.
2000;20:1595-99.
[113] Kissebah AH, Sonnenberg GE, Myklebust J, Goldstein M, Broman K,
James RG et al. Quantitative trait loci on chromosomes 3 and 17
influence phenotypes of the metabolic syndrome.
Proc.Natl.Acad.Sci.U.S.A 2000;97:14478-83.
[114] Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE et
al. Hypoadiponectinemia in obesity and type 2 diabetes: close
association with insulin resistance and hyperinsulinemia. J.Clin.
Endocrinol.Metab 2001;86:1930-35.
[115] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K et al.
The fat-derived hormone adiponectin reverses insulin resistance
associated with both lipoatrophy and obesity. Nat.Med. 2001;7:941-46.
[116] Zacharova J, Chiasson JL, Laakso M. The common polymorphisms
(single nucleotide polymorphism [SNP] +45 and SNP +276) of the
adiponectin gene predict the conversion from impaired glucose tolerance
to type 2 diabetes: the STOP-NIDDM trial. Diabetes 2005;54:893-99.
[117] Ouchi N, Kihara S, Arita Y, Maeda K, Kuriyama H, Okamoto Y et al.
Novel modulator for endothelial adhesion molecules: adipocyte-derived
plasma protein adiponectin. Circulation 1999;100:2473-76.
[118] Ouchi N, Kihara S, Arita Y, Okamoto Y, Maeda K, Kuriyama H et al.
Adiponectin, an adipocyte-derived plasma protein, inhibits endothelial
NF-kappaB signaling through a cAMP-dependent pathway. Circulation
2000;102:1296-301.
[119] Kazumi T, Kawaguchi A, Sakai K, Hirano T, Yoshino G. Young men
with high-normal blood pressure have lower serum adiponectin, smaller
LDL size, and higher elevated heart rate than those with optimal blood
pressure. Diabetes Care 2002;25:971-76.
[120] Iwashima Y, Katsuya T, Ishikawa K, Ouchi N, Ohishi M, Sugimoto K et
al. Hypoadiponectinemia is an independent risk factor for hypertension.
[121] Matsushita K, Yatsuya H, Tamakoshi K, Wada K, Otsuka R, Takefuji S
et al. Comparison of circulating adiponectin and proinflammatory
markers regarding their association with metabolic syndrome in
Japanese men. Arterioscler.Thromb.Vasc.Biol. 2006;26:871-76.
[122] Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin
concentrations in women with dyslipidemia. J.Clin.Endocrinol.Metab
2002;87:2764-69.
[123] Despres JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic
risk factors in overweight patients with dyslipidemia. N.Engl.J.Med.
2005;353:2121-34.
[124] Ouchi N, Kobayashi H, Kihara S, Kumada M, Sato K, Inoue T et al.
Adiponectin stimulates angiogenesis by promoting cross-talk between
AMP-activated protein kinase and Akt signaling in endothelial cells.
J.Biol.Chem. 2004;279:1304-09.
[125] Shibata R, Ouchi N, Kihara S, Sato K, Funahashi T, Walsh K.
Adiponectin stimulates angiogenesis in response to tissue ischemia
through stimulation of amp-activated protein kinase signaling.
J.Biol.Chem. 2004;279:28670-74.
[126] Tsao TS, Murrey HE, Hug C, Lee DH, Lodish HF. Oligomerization
state-dependent activation of NF-kappa B signaling pathway by
adipocyte complement-related protein of 30 kDa (Acrp30). J.Biol.Chem.
2002;277:29359-62.
[127] Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S et al. Impaired
multimerization of human adiponectin mutants associated with diabetes.
Molecular structure and multimer formation of adiponectin.
J.Biol.Chem. 2003;278:40352-63.
[128] Aso Y, Yamamoto R, Wakabayashi S, Uchida T, Takayanagi K,
Takebayashi K et al. Comparison of serum high-molecular weight
(HMW) adiponectin with total adiponectin concentrations in type 2
diabetic patients with coronary artery disease using a novel enzyme-
linked immunosorbent assay to detect HMW adiponectin. Diabetes
2006;55:1954-60.
[129] Bobbert T, Rochlitz H, Wegewitz U, Akpulat S, Mai K, Weickert MO et
al. Changes of adiponectin oligomer composition by moderate weight
reduction. Diabetes 2005;54:2712-19.
[130] Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T et al.
Structure-function studies of the adipocyte-secreted hormone
Acrp30/adiponectin. Implications fpr metabolic regulation and
bioactivity. J.Biol.Chem. 2003;278:9073-85.
[131] Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP
et al. Complex distribution, not absolute amount of adiponectin,
correlates with thiazolidinedione-mediated improvement in insulin
sensitivity. J.Biol.Chem. 2004;279:12152-62.
[132] Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB et al.
Role of disulfide bonds in Acrp30/adiponectin structure and signaling
specificity. Different oligomers activate different signal transduction
pathways. J.Biol.Chem. 2003;278:50810-17.
[133] Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y et al.
Selective suppression of endothelial cell apoptosis by the high molecular
weight form of adiponectin. Circ.Res. 2004;94:e27-e31.
[134] Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C et al.
Mechanisms of early insulin-sensitizing effects of thiazolidinediones in
type 2 diabetes. Diabetes 2004;53:1621-29.
[135] Yamauchi T, Kamon J, Ito Y, Tsuchida A, Yokomizo T, Kita S et al.
Cloning of adiponectin receptors that mediate antidiabetic metabolic
effects. Nature 2003;423:762-69.
[136] Katsuki A, Suematsu M, Gabazza EC, Murashima S, Nakatani K,
Togashi K et al. Decreased high-molecular weight adiponectin-to-total
adiponectin ratio in sera is associated with insulin resistance in Japanese
metabolically obese, normal-weight men with normal glucose tolerance.
Diabetes Care 2006;29:2327-28.
[137] Abbasi F, Chang SA, Chu JW, Ciaraldi TP, Lamendola C, McLaughlin
T et al. Improvements in insulin resistance with weight loss, in contrast
to rosiglitazone, are not associated with changes in plasma adiponectin
or adiponectin multimeric complexes. Am.J.Physiol Regul.Integr.Comp
Physiol 2006;290:R139-R144.
[138] Basu R, Pajvani UB, Rizza RA, Scherer PE. Selective downregulation of
the high molecular weight form of adiponectin in hyperinsulinemia and
in type 2 diabetes: differential regulation from nondiabetic subjects.
Diabetes 2007;56:2174-77.
[139] Komaba H, Igaki N, Goto S, Yokota K, Doi H, Takemoto T et al.
Increased serum high-molecular-weight complex of adiponectin in type
2 diabetic patients with impaired renal function. Am.J.Nephrol.
2006;26:476-82.
[140] Nakashima R, Kamei N, Yamane K, Nakanishi S, Nakashima A, Kohno
N. Decreased total and high molecular weight adiponectin are
independent risk factors for the development of type 2 diabetes in
Japanese-Americans. J.Clin.Endocrinol.Metab 2006;91:3873-77.
[141] Araki S, Dobashi K, Kubo K, Asayama K, Shirahata A. High molecular
weight, rather than total, adiponectin levels better reflect metabolic
abnormalities associated with childhood obesity.
[142] Engl J, Bobbert T, Ciardi C, Laimer M, Tatarczyk T, Kaser S et al.
Effects of pronounced weight loss on adiponectin oligomer composition
and metabolic parameters. Obesity.(Silver.Spring) 2007;15:1172-78.
[143] Salani B, Briatore L, Andraghetti G, Adami GF, Maggi D, Cordera R.
High-molecular weight adiponectin isoforms increase after
biliopancreatic diversion in obese subjects. Obesity.(Silver.Spring)
2006;14:1511-14.
[144] Swarbrick MM, ustrheim-Smith IT, Stanhope KL, Van L, Ali MR,
Wolfe BM et al. Circulating concentrations of high-molecular-weight
adiponectin are increased following Roux-en-Y gastric bypass surgery.
Diabetologia 2006;49:2552-58.
[145] Inoue T, Kotooka N, Morooka T, Komoda H, Uchida T, Aso Y et al.
High molecular weight adiponectin as a predictor of long-term clinical
outcome in patients with coronary artery disease. Am.J.Cardiol.
2007;100:569-74.
[146] Oki K, Koide J, Nakanishi S, Nakashima R, Yamane K. Fenofibrate
increases high molecular weight adiponectin in subjects with
hypertriglyceridemia. Endocr.J. 2007;54:431-35.
[147] Aroda V, Ciaraldi TP, Chang SA, Dahan MH, Chang RJ, Henry RR.
Circulating and cellular adiponectin in polycystic ovary syndrome:
relationship to glucose tolerance and insulin action. Fertil.Steril. 2007.
[148] Bluher M, Brennan AM, Kelesidis T, Kratzsch J, Fasshauer M, Kralisch
S et al. Total and high-molecular weight adiponectin in relation to
metabolic variables at baseline and in response to an exercise treatment
program: comparative evaluation of three assays. Diabetes Care
2007;30:280-85.
[149] Fisher FF, Trujillo ME, Hanif W, Barnett AH, McTernan PG, Scherer
PE et al. Serum high molecular weight complex of adiponectin
correlates better with glucose tolerance than total serum adiponectin in
Indo-Asian males. Diabetologia 2005;48:1084-87.
[150] Glintborg D, Frystyk J, Hojlund K, Andersen KK, Henriksen JE,
Hermann AP et al. Total and high molecular weight (HMW) adiponectin
levels and measures of glucose and lipid metabolism following
pioglitazone treatment in a randomized placebo-controlled study in
polycystic ovary syndrome. Clin.Endocrinol.(Oxf) 2007.
[151] Hara K, Horikoshi M, Yamauchi T, Yago H, Miyazaki O, Ebinuma H et
al. Measurement of the high-molecular weight form of adiponectin in
plasma is useful for the prediction of insulin resistance and metabolic
syndrome. Diabetes Care 2006;29:1357-62.
[152] Modan-Moses D, Stein D, Pariente C, Yaroslavsky A, Ram A, Faigin M
et al. Modulation of adiponectin and leptin during refeeding of female
anorexia nervosa patients. J.Clin.Endocrinol.Metab 2007;92:1843-47.
[153] O'Leary VB, Jorett AE, Marchetti CM, Gonzalez F, Phillips SA, Ciaraldi
TP et al. Enhanced adiponectin multimer ratio and skeletal muscle
adiponectin receptor expression following exercise training and diet in
older insulin-resistant adults. Am.J.Physiol Endocrinol.Metab
2007;293:E421-E427.
[154] Schober F, Neumeier M, Weigert J, Wurm S, Wanninger J, Schaffler A
et al. Low molecular weight adiponectin negatively correlates with the
waist circumference and monocytic IL-6 release. Biochem.Biophys.
Res.Commun. 2007;361:968-73.
[155] Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T et al.
Peroxisome proliferator-activated receptor (PPAR)alpha activation
increases adiponectin receptors and reduces obesity-related
inflammation in adipose tissue: comparison of activation of PPARalpha,
PPARgamma, and their combination. Diabetes 2005;54:3358-70.
[156] Crouch E, Persson A, Chang D, Heuser J. Molecular structure of
pulmonary surfactant protein D (SP-D). J.Biol.Chem. 1994;269:17311-
19.
[157] McCormack FX, Pattanajitvilai S, Stewart J, Possmayer F, Inchley K,
Voelker DR. The Cys6 intermolecular disulfide bond and the collagen-
like region of rat SP-A play critical roles in interactions with alveolar
type II cells and surfactant lipids. J.Biol.Chem. 1997;272:27971-79.
[158] Wong GW, Wang J, Hug C, Tsao TS, Lodish HF. A family of
Acrp30/adiponectin structural and functional paralogs. Proc. Natl. Acad.
Sci. U.S.A 2004;101:10302-07.
[159] Wang Y, Xu A, Knight C, Xu LY, Cooper GJ. Hydroxylation and
glycosylation of the four conserved lysine residues in the collagenous
domain of adiponectin. Potential role in the modulation of its insulin-
sensitizing activity. J.Biol.Chem. 2002;277:19521-29.
[160] Wang Y, Lam KS, Chan L, Chan KW, Lam JB, Lam MC et al. Post-
translational modifications of the four conserved lysine residues within
the collagenous domain of adiponectin are required for the formation of
its high molecular weight oligomeric complex. J.Biol.Chem.
2006;281:16391-400.
[161] Phillips SA, Ciaraldi TP, Kong AP, Bandukwala R, Aroda V, Carter L et
al. Modulation of circulating and adipose tissue adiponectin levels by
antidiabetic therapy. Diabetes 2003;52:667-74.
[162] Abke S, Neumeier M, Weigert J, Wehrwein G, Eggenhofer E, Schaffler
A et al. Adiponectin-induced secretion of interleukin-6 (IL-6), monocyte
chemotactic protein-1 (MCP-1, CCL2) and interleukin-8 (IL-8, CXCL8)
is impaired in monocytes from patients with type I diabetes.
Cardiovasc.Diabetol. 2006;5:17.
[163] Rovin BH, Song H. Chemokine induction by the adipocyte-derived
cytokine adiponectin. Clin.Immunol. 2006;120:99-105.
[164] Haugen F, Drevon CA. Activation of nuclear factor-kappaB by high
molecular weight and globular adiponectin. Endocrinology
2007;148:5478-86.
[165] Neumeier M, Weigert J, Schaffler A, Wehrwein G, Muller-Ladner U,
Scholmerich J et al. Different effects of adiponectin isoforms in human
monocytic cells. J.Leukoc.Biol. 2006;79:803-08.
[166] Tasanen K, Eble JA, Aumailley M, Schumann H, Baetge J, Tu H et al.
Collagen XVII is destabilized by a glycine substitution mutation in the
cell adhesion domain Col15. J.Biol.Chem. 2000;275:3093-99.
[167] Iwahashi H, Funahashi T, Kurokawa N, Sayama K, Fukuda E, Okita K
et al. Plasma adiponectin levels in women with anorexia nervosa.
Horm.Metab Res. 2003;35:537-40.
[168] Romero R. Prenatal medicine: the child is the father of the man. Prenatal
and Neonatal Medicine 1996;1:8-11.
[169] Di Renzo GC. The great obstetrical syndromes. J Matern.Fetal Neonatal
Med 2009;22:633-35.
[170] Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia:
current concepts. Am.J.Obstet.Gynecol. 1998;179:1359-75.
[171] Lindheimer MD. Hypertension in pregnancy. Hypertension
1993;22:127-37.
[172] MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from
preeclampsia and eclampsia. Obstet.Gynecol. 2001;97:533-38.
[173] Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D et
al. Risk factors for preeclampsia in healthy nulliparous women: a
Human Development Network of Maternal-Fetal Medicine Units.
[174] Newman MG, Robichaux AG, Stedman CM, Jaekle RK, Fontenot MT,
Dotson T et al. Perinatal outcomes in preeclampsia that is complicated
by massive proteinuria. Am.J.Obstet.Gynecol. 2003;188:264-68.
[175] Seely EW. Hypertension in pregnancy: a potential window into long-
term cardiovascular risk in women. J.Clin.Endocrinol.Metab
1999;84:1858-61.
[176] WHO. The World Health Report 2005: Make every mother and child
count. Geneva: 2005.
[177] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet
2005;365:785-99.
[178] Maynard S, Epstein FH, Karumanchi SA. Preeclampsia and angiogenic
imbalance. Annu.Rev.Med 2008;59:61-78.
[179] Aggarwal PK, Jain V, Sakhuja V, Karumanchi SA, Jha V. Low urinary
placental growth factor is a marker of pre-eclampsia. Kidney Int.
2006;69:621-24.
[180] Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee KY,
Goncalves LF et al. Evidence supporting a role for blockade of the
vascular endothelial growth factor system in the pathophysiology of
preeclampsia. Young Investigator Award. Am.J Obstet Gynecol.
2004;190:1541-47.
[181] Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J
et al. Plasma soluble vascular endothelial growth factor receptor-1
concentration is elevated prior to the clinical diagnosis of pre-eclampsia.
J Matern.Fetal Neonatal Med. 2005;17:3-18.
[182] Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos
E. Placental angiogenic growth factors and uterine artery Doppler
findings for characterization of different subsets in preeclampsia and in
isolated intrauterine growth restriction. Am.J.Obstet.Gynecol.
2006;195:201-07.
[183] Espinoza, J., Nien, J. K., Kusanovic, J. P., Goncalves, L. F., Medina, L.
H., Gomez, R., and Romero, R. The combined use of uterine artery
Doppler and maternal plasma placental growth factor concentrations
identifies patients at risk for early onset and/or severe preeclampsia.
Ultrasound Obstet Gynecol 28(4), 387-388. 2006. Ref Type: Abstract
[184] Espinoza J, Romero R, Nien JK, Kusanovic JP, Richani K, Gomez R et
al. A role of the anti-angiogenic factor sVEGFR-1 in the 'mirror
syndrome' (Ballantyne's syndrome). J.Matern.Fetal Neonatal Med.
2006;19:607-13.
[185] Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T et al.
Elevated serum soluble vascular endothelial growth factor receptor 1
(sVEGFR-1) levels in women with preeclampsia. J
Clin.Endocrinol.Metab 2003;88:2348-51.
[186] Krauss T, Pauer HU, Augustin HG. Prospective analysis of placenta
growth factor (PlGF) concentrations in the plasma of women with
normal pregnancy and pregnancies complicated by preeclampsia.
Hypertens.Pregnancy. 2004;23:101-11.
[187] Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ et
al. Vascular endothelial growth factor is increased in patients with
preeclampsia. Am.J.Reprod.Immunol. 1997;38:302-06.
[188] Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF et al.
Circulating angiogenic factors and the risk of preeclampsia. N.Engl.J
Med. 2004;350:672-83.
[189] Levine RJ, Karumanchi SA. Circulating Angiogenic Factors in
Preeclampsia. Clin.Obstet Gynecol 2005;48:372-86.
[190] Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF et al. Urinary
placental growth factor and risk of preeclampsia. JAMA 2005;293:77-85.
[191] Levine RJ, Qian C, Maynard SE, Yu KF, Epstein FH, Karumanchi SA.
Serum sFlt1 concentration during preeclampsia and mid trimester blood
pressure in healthy nulliparous women. Am.J.Obstet.Gynecol.
2006;194:1034-41.
[192] Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP et al. Soluble
endoglin and other circulating antiangiogenic factors in preeclampsia.
N.Engl.J Med. 2006;355:992-1005.
[193] Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular
endothelial growth factor immunoreactivity in normal pregnancy and in
pre-eclampsia. Br.J.Obstet.Gynaecol. 1997;104:223-28.
[194] Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S et al. Excess
placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to
endothelial dysfunction, hypertension, and proteinuria in preeclampsia.
J.Clin.Invest 2003;111:649-58.
[195] McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N.
Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is
increased throughout gestation in patients who have preeclampsia
develop. Am J Obstet Gynecol 2004;191:1240-46.
[196] Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA,
Karumanchi SA et al. Extra-placental expression of vascular endothelial
growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral
blood mononuclear cells (PBMCs) in normotensive and preeclamptic
pregnant women. Placenta 2005;26:563-73.
[197] Robinson CJ, Johnson DD, Chang EY, Armstrong DM, Wang W.
Evaluation of placenta growth factor and soluble Fms-like tyrosine
kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet
Gynecol 2006;195:255-59.
[198] Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar
LM et al. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia
but not in normotensive pregnancies with small-for-gestational-age
neonates: relationship to circulating placental growth factor. J
[199] Staff AC, Braekke K, Harsem NK, Lyberg T, Holthe MR. Circulating
concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and
maternal serum during pre-eclampsia. Eur.J Obstet Gynecol
Reprod.Biol. 2005;122:33-39.
[200] Stepan H, Faber R. Elevated sFlt1 level and preeclampsia with
parvovirus-induced hydrops. N.Engl.J.Med. 2006;354:1857-58.
[201] Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP
et al. First trimester placental growth factor and soluble fms-like tyrosine
kinase 1 and risk for preeclampsia. J Clin.Endocrinol.Metab
2004;89:770-75.
[202] Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS. Low maternal
serum levels of placenta growth factor as an antecedent of clinical
preeclampsia. Am.J.Obstet.Gynecol. 2001;184:1267-72.
[203] Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is
associated with reduced serum levels of placenta growth factor. Am J
Obstet Gynecol 1998;179:1539-44.
[204] Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A et al.
Overexpression of the soluble vascular endothelial growth factor
receptor in preeclamptic patients: pathophysiological consequences. J
Clin. Endocrinol. Metab 2003;88:5555-63.
[205] Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM et
al. Soluble endoglin contributes to the pathogenesis of preeclampsia.
Nat.Med. 2006;12:642-49.
[206] Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T et al.
Vascular endothelial growth factor ligands and receptors that regulate
human cytotrophoblast survival are dysregulated in severe preeclampsia
and hemolysis, elevated liver enzymes, and low platelets syndrome.
Am.J.Pathol. 2002;160:1405-23.
[207] Bujold E, Romero R, Chaiworapongsa T, Kim YM, Kim GJ, Kim MR et
al. Evidence supporting that the excess of the sVEGFR-1 concentration
in maternal plasma in preeclampsia has a uterine origin. J.Matern.Fetal
Neonatal Med 2005;18:9-16.
[208] Chaiworapongsa T, Romero R, Gotsch F, Espinoza J, Nien JK,
Goncalves L et al. Low maternal concentrations of soluble vascular
endothelial growth factor receptor-2 in preeclampsia and small for
gestational age. J.Matern.Fetal Neonatal Med 2008;21:41-52.
[209] Gotsch F, Romero R, Kusanovic JP, Chaiworapongsa T, Dombrowski
M, Erez O et al. Preeclampsia and small-for-gestational age are
associated with decreased concentrations of a factor involved in
angiogenesis: soluble Tie-2. J.Matern.Fetal Neonatal Med 2008;21:389-
402.
[210] Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP et al. The
change in concentrations of angiogenic and anti-angiogenic factors in
maternal plasma between the first and second trimesters in risk
assessment for the subsequent development of preeclampsia and small-
for-gestational age. J.Matern.Fetal Neonatal Med 2008;21:279-87.
[211] Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H et al. A
longitudinal study of angiogenic (placental growth factor) and anti-
angiogenic (soluble endoglin and soluble vascular endothelial growth
factor receptor-1) factors in normal pregnancy and patients destined to
develop preeclampsia and deliver a small for gestational age neonate.
J.Matern.Fetal Neonatal Med 2008;21:9-23.
[212] Lindheimer MD, Romero R. Emerging roles of antiangiogenic and
angiogenic proteins in pathogenesis and prediction of preeclampsia.
[213] Gotsch F, Romero R, Friel L, Kusanovic JP, Espinoza J, Erez O et al.
CXCL10/IP-10: a missing link between inflammation and anti-
angiogenesis in preeclampsia? J.Matern.Fetal Neonatal Med
2007;20:777-92.
[214] Bretelle F, Sabatier F, Blann A, D'Ercole C, Boutiere B, Mutin M et al.
Maternal endothelial soluble cell adhesion molecules with isolated small
for gestational age fetuses: comparison with pre-eclampsia. BJOG.
2001;108:1277-82.
[215] Clark BA, Halvorson L, Sachs B, Epstein FH. Plasma endothelin levels
in preeclampsia: elevation and correlation with uric acid levels and renal
impairment. Am.J.Obstet.Gynecol. 1992;166:962-68.
[216] Ness RB, Sibai BM. Shared and disparate components of the
pathophysiologies of fetal growth restriction and preeclampsia. Am J
[217] Poston L, Chappell LC. Is oxidative stress involved in the aetiology of
pre-eclampsia? Acta Paediatr.Suppl 2001;90:3-5.
[218] Redman CW, Sargent IL. Latest advances in understanding
preeclampsia. Science 2005;308:1592-94.
[219] Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA,
McLaughlin MK. Preeclampsia: an endothelial cell disorder.
[220] Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as
markers and mediators of endothelial cell dysfunction in preeclampsia.
Semin.Reprod.Endocrinol. 1998;16:17-31.
[221] Kraayenbrink AA, Dekker GA, van Kamp GJ, van Geijn HP.
Endothelial vasoactive mediators in preeclampsia. Am.J.Obstet.Gynecol.
1993;169:160-65.
[222] Schiff E, Ben-Baruch G, Peleg E, Rosenthal T, Alcalay M, Devir M et
al. Immunoreactive circulating endothelin-1 in normal and hypertensive
pregnancies. Am.J.Obstet.Gynecol. 1992;166:624-28.
[223] Higgins JR, Papayianni A, Brady HR, Darling MR, Walshe JJ.
Circulating vascular cell adhesion molecule-1 in pre-eclampsia,
gestational hypertension, and normal pregnancy: evidence of selective
dysregulation of vascular cell adhesion molecule-1 homeostasis in pre-
eclampsia. Am.J.Obstet.Gynecol. 1998;179:464-69.
[224] Gervasi MT, Chaiworapongsa T, Pacora P, Naccasha N, Yoon BH,
Maymon E et al. Phenotypic and metabolic characteristics of monocytes
and granulocytes in preeclampsia. Am.J.Obstet.Gynecol. 2001;185:792-
97.
[225] Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive
maternal inflammatory response to pregnancy. Am.J.Obstet.Gynecol.
1999;180:499-506.
[226] Redman CW, Sargent IL. Placental debris, oxidative stress and pre-
eclampsia. Placenta 2000;21:597-602.
[227] Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and
preeclampsia both produce inflammatory changes in peripheral blood
leukocytes akin to those of sepsis. Am.J.Obstet.Gynecol. 1998;179:80-
86.
[228] Barden A, Graham D, Beilin LJ, Ritchie J, Baker R, Walters BN et al.
Neutrophil CD11B expression and neutrophil activation in pre-
eclampsia. Clin.Sci.(Lond) 1997;92:37-44.
[229] Haller H, Ziegler EM, Homuth V, Drab M, Eichhorn J, Nagy Z et al.
Endothelial adhesion molecules and leukocyte integrins in preeclamptic
patients. Hypertension 1997;29:291-96.
[230] Chaiworapongsa T, Gervasi MT, Refuerzo J, Espinoza J, Yoshimatsu J,
Berman S et al. Maternal lymphocyte subpopulations (CD45RA+ and
CD45RO+) in preeclampsia. Am.J.Obstet.Gynecol. 2002;187:889-93.
[231] Erez O, Romero R, Kim SS, Kim JS, Kim YM, Wildman DE et al. Over-
expression of the thrombin receptor (PAR-1) in the placenta in
preeclampsia: a mechanism for the intersection of coagulation and
inflammation. J.Matern.Fetal Neonatal Med 2008;21:345-55.
[232] Than NG, Romero R, Erez O, Kusanovic JP, Tarca AL, Edwin SS et al.
A Role for Mannose-Binding Lectin, a Component of the Innate
Immune System in Pre-Eclampsia. Am.J.Reprod.Immunol. 2008.
[233] Arriaga-Pizano L, Jimenez-Zamudio L, Vadillo-Ortega F, Martinez-
Flores A, Herrerias-Canedo T, Hernandez-Guerrero C. The predominant
Th1 cytokine profile in maternal plasma of preeclamptic women is not
reflected in the choriodecidual and fetal compartments.
J.Soc.Gynecol.Investig. 2005;12:335-42.
[234] Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive
cytokines in women with preeclampsia. Am.J.Reprod.Immunol.
1998;40:102-11.
[235] Meekins JW, McLaughlin PJ, West DC, McFadyen IR, Johnson PM.
Endothelial cell activation by tumour necrosis factor-alpha (TNF-alpha)
and the development of pre-eclampsia. Clin.Exp.Immunol. 1994;98:110-
14.
[236] Sunder-Plassmann G, Derfler K, Wagner L, Stockenhuber F, Endler M,
Nowotny C et al. Increased serum activity of interleukin-2 in patients
with pre-eclampsia. J.Autoimmun. 1989;2:203-05.
[237] Teran E, Escudero C, Moya W, Flores M, Vallance P, Lopez-Jaramillo
P. Elevated C-reactive protein and pro-inflammatory cytokines in
Andean women with pre-eclampsia. Int.J.Gynaecol.Obstet.
2001;75:243-49.
[238] Vince GS, Starkey PM, Austgulen R, Kwiatkowski D, Redman CW.
Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor
receptors in women with pre-eclampsia. Br.J.Obstet.Gynaecol.
1995;102:20-25.
[239] Daniel Y, Kupferminc MJ, Baram A, Jaffa AJ, Fait G, Wolman I et al.
Plasma interleukin-12 is elevated in patients with preeclampsia.
Am.J.Reprod.Immunol. 1998;39:376-80.
[240] Dudley DJ, Hunter C, Mitchell MD, Varner MW, Gately M. Elevations
of serum interleukin-12 concentrations in women with severe pre-
eclampsia and HELLP syndrome. J.Reprod.Immunol. 1996;31:97-107.
[241] Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression
of inflammatory cytokines in placentas from women with preeclampsia.
[242] Saito S, Umekage H, Sakamoto Y, Sakai M, Tanebe K, Sasaki Y et al.
Increased T-helper-1-type immunity and decreased T-helper-2-type
immunity in patients with preeclampsia. Am.J.Reprod.Immunol.
1999;41:297-306.
[243] Williams MA, Farrand A, Mittendorf R, Sorensen TK, Zingheim RW,
O'Reilly GC et al. Maternal second trimester serum tumor necrosis
factor-alpha-soluble receptor p55 (sTNFp55) and subsequent risk of
preeclampsia. Am.J.Epidemiol. 1999;149:323-29.
[244] Kusanovic JP, Romero R, Hassan SS, Gotsch F, Edwin S,
Chaiworapongsa T et al. Maternal serum soluble CD30 is increased in
normal pregnancy, but decreased in preeclampsia and small for
gestational age pregnancies. J.Matern.Fetal Neonatal Med 2007;20:867-
78.
[245] Catalano PM. Management of obesity in pregnancy. Obstet.Gynecol.
2007;109:419-33.
[246] ACOG Committee Opinion number 315, September 2005. Obesity in
pregnancy. Obstet.Gynecol. 2005;106:671-75.
[247] ACOG Committee Opinion No. 351, November 2006: The overweight
adolescent: prevention, treatment, and obstetric-gynecologic
implications. Obstet.Gynecol. 2006;108:1337-48.
2005;365:785-99.
[249] Ness RB, Roberts JM. Heterogeneous causes constituting the single
syndrome of preeclampsia: a hypothesis and its implications.
[250] Ness RB, Roberts JM. Heterogeneous causes constituting the single
syndrome of preeclampsia: a hypothesis and its implications.
2005;365:785-99.
[252] Redman CW, Sargent IL. Latest advances in understanding
preeclampsia. Science 2005;308:1592-94.
[253] Roberts JM, Lain KY. Recent Insights into the pathogenesis of pre-
eclampsia. Placenta 2002;23:359-72.
[254] Noris M, Perico N, Remuzzi G. Mechanisms of disease: Pre-eclampsia.
Nat.Clin.Pract.Nephrol. 2005;1:98-114.
2005;365:785-99.
[256] Sibai BM, Ewell M, Levine RJ, Klebanoff MA, Esterlitz J, Catalano PM
et al. Risk factors associated with preeclampsia in healthy nulliparous
[257] von Dadelszen P, Magee LA, Roberts JM. Subclassification of
preeclampsia. Hypertens.Pregnancy 2003;22:143-48.
2005;365:785-99.
[260] Weinstein L. Syndrome of hemolysis, elevated liver enzymes, and low
platelet count: a severe consequence of hypertension in pregnancy. Am J
[261] Barton JR, Sibai BM. Prediction and prevention of recurrent
preeclampsia. Obstet.Gynecol. 2008;112:359-72.
[262] Weiss JL, Malone FD, Emig D, Ball RH, Nyberg DA, Comstock CH et
al. Obesity, obstetric complications and cesarean delivery rate--a
population-based screening study. Am.J.Obstet.Gynecol. 2004;190:1091-
97.
[263] Baeten JM, Bukusi EA, Lambe M. Pregnancy complications and
outcomes among overweight and obese nulliparous women. Am.J.Public
Health 2001;91:436-40.
[264] Callaway LK, Prins JB, Chang AM, McIntyre HD. The prevalence and
impact of overweight and obesity in an Australian obstetric population.
Med J.Aust. 2006;184:56-59.
[265] Kiran TS, Bethel J, Bhal PS. Correlation of abnormal second trimester
maternal serum alpha-fetoprotein (MSAFP) levels and adverse
pregnancy outcome. J.Obstet.Gynaecol. 2005;25:253-56.
[266] Rode L, Nilas L, Wojdemann K, Tabor A. Obesity-related complications
in Danish single cephalic term pregnancies. Obstet.Gynecol.
2005;105:537-42.
[267] Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW et al.
pregnancies in London. Int.J.Obes.Relat Metab Disord. 2001;25:1175-
82.
[268] Cnattingius S, Bergstrom R, Lipworth L, Kramer MS. Prepregnancy
weight and the risk of adverse pregnancy outcomes. N.Engl.J.Med
1998;338:147-52.
[270] Kumari AS. Pregnancy outcome in women with morbid obesity.
Int.J.Gynaecol.Obstet. 2001;73:101-07.
[271] O'Brien TE, Ray JG, Chan WS. Maternal body mass index and the risk
of preeclampsia: a systematic overview. Epidemiology 2003;14:368-74.
[272] Eskenazi B, Fenster L, Sidney S. A multivariate analysis of risk factors
for preeclampsia. JAMA 1991;266:237-41.
[274] Kumari AS. Pregnancy outcome in women with morbid obesity.
Int.J.Gynaecol.Obstet. 2001;73:101-07.
[275] Sebire NJ, Jolly M, Harris JP, Wadsworth J, Joffe M, Beard RW et al.
pregnancies in London. Int.J.Obes.Relat Metab Disord. 2001;25:1175-
82.
[276] Joffe GM, Esterlitz JR, Levine RJ, Clemens JD, Ewell MG, Sibai BM et
al. The relationship between abnormal glucose tolerance and
hypertensive disorders of pregnancy in healthy nulliparous women.
Calcium for Preeclampsia Prevention (CPEP) Study Group.
[277] Solomon CG, Seely EW. Brief review: hypertension in pregnancy : a
manifestation of the insulin resistance syndrome? Hypertension
2001;37:232-39.
[278] Innes KE, Wimsatt JH, McDuffie R. Relative glucose tolerance and
subsequent development of hypertension in pregnancy. Obstet.Gynecol.
2001;97:905-10.
[279] Kaaja R, Laivuori H, Laakso M, Tikkanen MJ, Ylikorkala O. Evidence
of a state of increased insulin resistance in preeclampsia. Metabolism
1999;48:892-96.
[280] Martinez AE, Gonzalez OM, Quinones GA, Ferrannini E.
Hyperinsulinemia in glucose-tolerant women with preeclampsia. A
controlled study. Am.J.Hypertens. 1996;9:610-14.
[281] Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R. First
trimester insulin resistance and subsequent preeclampsia: a prospective
study. J.Clin.Endocrinol.Metab 2002;87:1563-68.
[282] Duckitt K, Harrington D. Risk factors for pre-eclampsia at antenatal
booking: systematic review of controlled studies. BMJ 2005;330:565.
[283] Bryson CL, Ioannou GN, Rulyak SJ, Critchlow C. Association between
gestational diabetes and pregnancy-induced hypertension.
Am.J.Epidemiol. 2003;158:1148-53.
[284] Garner PR, D'Alton ME, Dudley DK, Huard P, Hardie M. Preeclampsia
in diabetic pregnancies. Am.J.Obstet.Gynecol. 1990;163:505-08.
[285] Lee CJ, Hsieh TT, Chiu TH, Chen KC, Lo LM, Hung TH. Risk factors
for pre-eclampsia in an Asian population. Int.J.Gynaecol.Obstet.
2000;70:327-33.
[286] Roberts JM, Gammill H. Insulin resistance in preeclampsia.
[287] Ros HS, Cnattingius S, Lipworth L. Comparison of risk factors for
preeclampsia and gestational hypertension in a population-based cohort
study. Am.J.Epidemiol. 1998;147:1062-70.
[288] Wakatsuki A, Ikenoue N, Okatani Y, Shinohara K, Fukaya T.
Lipoprotein particles in preeclampsia: susceptibility to oxidative
modification. Obstet.Gynecol. 2000;96:55-59.
[289] Gratacos E, Casals E, Sanllehy C, Cararach V, Alonso PL, Fortuny A.
Variation in lipid levels during pregnancy in women with different types
of hypertension. Acta Obstet.Gynecol.Scand. 1996;75:896-901.
[290] Thadhani R, Stampfer MJ, Hunter DJ, Manson JE, Solomon CG, Curhan
GC. High body mass index and hypercholesterolemia: risk of
hypertensive disorders of pregnancy. Obstet.Gynecol. 1999;94:543-50.
[291] Lorentzen B, Drevon CA, Endresen MJ, Henriksen T. Fatty acid pattern
of esterified and free fatty acids in sera of women with normal and pre-
eclamptic pregnancy. Br.J.Obstet.Gynaecol. 1995;102:530-37.
[292] Sibai BM, Sarinoglu C, Mercer BM. Eclampsia. VII. Pregnancy
outcome after eclampsia and long-term prognosis. Am.J.Obstet.Gynecol.
1992;166:1757-61.
[293] Chesley SC, Annitto JE, Cosgrove RA. The remote prognosis of
eclamptic women. Sixth periodic report. Am.J.Obstet.Gynecol.
1976;124:446-59.
[294] Hannaford P, Ferry S, Hirsch S. Cardiovascular sequelae of toxaemia of
pregnancy. Heart 1997;77:154-58.
[295] Girouard J, Giguere Y, Moutquin JM, Forest JC. Previous hypertensive
disease of pregnancy is associated with alterations of markers of insulin
resistance. Hypertension 2007;49:1056-62.
[296] Irgens HU, Reisaeter L, Irgens LM, Lie RT. Long term mortality of
mothers and fathers after pre-eclampsia: population based cohort study.
BMJ 2001;323:1213-17.
[297] Smith GC, Pell JP, Walsh D. Pregnancy complications and maternal risk
of ischaemic heart disease: a retrospective cohort study of 129,290
births. Lancet 2001;357:2002-06.
[298] Jonsdottir LS, Arngrimsson R, Geirsson RT, Sigvaldason H, Sigfusson
N. Death rates from ischemic heart disease in women with a history of
hypertension in pregnancy. Acta Obstet.Gynecol.Scand. 1995;74:772-76.
[299] King JC. Maternal obesity, metabolism, and pregnancy outcomes.
Annu.Rev.Nutr. 2006;26:271-91.
[300] Butte NF, Hopkinson JM, Nicolson MA. Leptin in human reproduction:
serum leptin levels in pregnant and lactating women. J
[301] Schubring C, Kiess W, Englaro P, Rascher W, Dotsch J, Hanitsch S et
al. Levels of leptin in maternal serum, amniotic fluid, and arterial and
venous cord blood: relation to neonatal and placental weight. J
[302] Hardie L, Trayhurn P, Abramovich D, Fowler P. Circulating leptin in
women: a longitudinal study in the menstrual cycle and during
pregnancy. Clin.Endocrinol.(Oxf) 1997;47:101-06.
[303] Highman TJ, Friedman JE, Huston LP, Wong WW, Catalano PM.
Longitudinal changes in maternal serum leptin concentrations, body
composition, and resting metabolic rate in pregnancy. Am.J
Obstet.Gynecol. 1998;178:1010-15.
[304] Highman TJ, Friedman JE, Huston LP, Wong WW, Catalano PM.
Longitudinal changes in maternal serum leptin concentrations, body
composition, and resting metabolic rate in pregnancy. Am.J
Obstet.Gynecol. 1998;178:1010-15.
[305] Nuamah MA, Sagawa N, Yura S, Mise H, Itoh H, Ogawa Y et al. Free-
to-total leptin ratio in maternal plasma is constant throughout human
pregnancy. Endocr.J 2003;50:421-28.
[306] Mastorakos G, Valsamakis G, Papatheodorou DC, Barlas I, Margeli A,
Boutsiadis A et al. The role of adipocytokines in insulin resistance in
normal pregnancy: visfatin concentrations in early pregnancy predict
insulin sensitivity. Clin.Chem. 2007;53:1477-83.
[307] Hauguel-De MS, Lepercq J, Catalano P. The known and unknown of
leptin in pregnancy. Am.J Obstet.Gynecol. 2006;194:1537-45.
[308] Islami D, Bischof P, Chardonnens D. Possible interactions between
leptin, gonadotrophin-releasing hormone (GnRH-I and II) and human
chorionic gonadotrophin (hCG). Eur.J Obstet.Gynecol.Reprod.Biol.
2003;110:169-75.
[309] Lappas M, Permezel M, Rice GE. Leptin and adiponectin stimulate the
release of proinflammatory cytokines and prostaglandins from human
placenta and maternal adipose tissue via nuclear factor-kappaB,
peroxisomal proliferator-activated receptor-gamma and extracellularly
regulated kinase 1/2. Endocrinology 2005;146:3334-42.
[310] Sivan E, Lin WM, Homko CJ, Reece EA, Boden G. Leptin is present in
human cord blood. Diabetes 1997;46:917-19.
[311] Sivan E, Whittaker PG, Sinha D, Homko CJ, Lin M, Reece EA et al.
Leptin in human pregnancy: the relationship with gestational hormones.
Am.J Obstet.Gynecol. 1998;179:1128-32.
[312] Korner A, Kratzsch J, Gausche R, Schaab M, Erbs S, Kiess W. New
predictors of the metabolic syndrome in children--role of
adipocytokines. Pediatr.Res. 2007;61:640-45.
[313] Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Efraty Y, Schiff E et al.
Determining the source of fetal adiponectin. J.Reprod.Med.
2007;52:774-78.
[314] Harigaya A, Nagashima K, Nako Y, Morikawa A. Relationship between
concentration of serum leptin and fetal growth. J.Clin.Endocrinol.Metab
1997;82:3281-84.
[315] Gomez L, Carrascosa A, Yeste D, Potau N, Rique S, Ruiz-Cuevas P et
al. Leptin values in placental cord blood of human newborns with
normal intrauterine growth after 30-42 weeks of gestation. Horm.Res.
1999;51:10-14.
[316] Jaquet D, Leger J, Levy-Marchal C, Oury JF, Czernichow P. Ontogeny
of leptin in human fetuses and newborns: effect of intrauterine growth
retardation on serum leptin concentrations. J.Clin.Endocrinol.Metab
1998;83:1243-46.
[317] Matsuda J, Yokota I, Iida M, Murakami T, Naito E, Ito M et al. Serum
leptin concentration in cord blood: relationship to birth weight and
gender. J.Clin.Endocrinol.Metab 1997;82:1642-44.
[318] Ong KK, Ahmed ML, Sherriff A, Woods KA, Watts A, Golding J et al.
Cord blood leptin is associated with size at birth and predicts infancy
weight gain in humans. ALSPAC Study Team. Avon Longitudinal Study
of Pregnancy and Childhood. J.Clin.Endocrinol.Metab 1999;84:1145-
48.
[319] Henson MC, Castracane VD. Leptin in pregnancy: an update.
Biol.Reprod. 2006;74:218-29.
[320] Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Schiff E, Sivan E. Cord
blood adiponectin in large-for-gestational age newborns.
[321] Buchanan TA, Metzger BE, Freinkel N, Bergman RN. Insulin sensitivity
and B-cell responsiveness to glucose during late pregnancy in lean and
moderately obese women with normal glucose tolerance or mild
gestational diabetes. Am.J.Obstet.Gynecol. 1990;162:1008-14.
[322] BURT RL. Peripheral utilization of glucose in pregnancy. III. Insulin
tolerance. Obstet.Gynecol. 1956;7:658-64.
[323] Butte NF. Carbohydrate and lipid metabolism in pregnancy: normal
compared with gestational diabetes mellitus. Am.J.Clin.Nutr.
2000;71:1256S-61S.
[324] Fisher PM, Sutherland HW, Bewsher PD. The insulin response to
glucose infusion in normal human pregnancy. Diabetologia 1980;19:15-
20.
[325] Lind T, Bell S, Gilmore E, Huisjes HJ, Schally AV. Insulin
disappearance rate in pregnant and non-pregnant women, and in non-
pregnant women given GHRIH. Eur.J.Clin.Invest 1977;7:47-52.
[326] Phelps RL, Metzger BE, Freinkel N. Carbohydrate metabolism in
pregnancy. XVII. Diurnal profiles of plasma glucose, insulin, free fatty
acids, triglycerides, cholesterol, and individual amino acids in late
normal pregnancy. Am.J.Obstet.Gynecol. 1981;140:730-36.
[327] Ryan EA, O'Sullivan MJ, Skyler JS. Insulin action during pregnancy.
Studies with the euglycemic clamp technique. Diabetes 1985;34:380-89.
[328] Spellacy Wn, Goetz Fc, Greenberg Bz, Ells J. Plasma Insulin In Normal
"Early" Pregnancy. Obstet.Gynecol. 1965;25:862-65.
[329] Catalano PM, Nizielski SE, Shao J, Preston L, Qiao L, Friedman JE.
Downregulated IRS-1 and PPARgamma in obese women with
gestational diabetes: relationship to FFA during pregnancy. Am.J.Physiol
[330] Desoye G, Schweditsch MO, Pfeiffer KP, Zechner R, Kostner GM.
Correlation of hormones with lipid and lipoprotein levels during normal
pregnancy and postpartum. J.Clin.Endocrinol.Metab 1987;64:704-12.
[331] Paradisi G, Biaggi A, Ferrazzani S, De CS, Caruso A. Abnormal
carbohydrate metabolism during pregnancy : association with
endothelial dysfunction. Diabetes Care 2002;25:560-64.
[332] Sivan E, Homko CJ, Chen X, Reece EA, Boden G. Effect of insulin on
fat metabolism during and after normal pregnancy. Diabetes
1999;48:834-38.
[333] Butte NF, Wong WW, Treuth MS, Ellis KJ, O'Brian SE. Energy
requirements during pregnancy based on total energy expenditure and
energy deposition. Am.J.Clin.Nutr. 2004;79:1078-87.
[334] Ehrenberg HM, Huston-Presley L, Catalano PM. The influence of
obesity and gestational diabetes mellitus on accretion and the
distribution of adipose tissue in pregnancy. Am.J.Obstet.Gynecol.
2003;189:944-48.
[335] Hytten FE, Chamberlain G. Clinical physiology in obstetrics. Oxford,
United Kingdom: Blackwell Scientific Publications, 1991.
[336] Kinoshita T, Itoh M. Longitudinal variance of fat mass deposition during
pregnancy evaluated by ultrasonography: the ratio of visceral fat to
subcutaneous fat in the abdomen. Gynecol.Obstet.Invest 2006;61:115-
18.
[337] Pipe NG, Smith T, Halliday D, Edmonds CJ, Williams C, Coltart TM.
Changes in fat, fat-free mass and body water in human normal
pregnancy. Br.J.Obstet.Gynaecol. 1979;86:929-40.
[338] Alberti KG, Zimmet P, Shaw J. Metabolic syndrome--a new world-wide
definition. A Consensus Statement from the International Diabetes
Federation. Diabet.Med. 2006;23:469-80.
[339] Fuglsang J, Skjaerbaek C, Frystyk J, Flyvbjerg A, Ovesen P. A
longitudinal study of serum adiponectin during normal pregnancy.
BJOG. 2006;113:110-13.
[340] Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Wiser A, Schiff E et al.
Maternal serum adiponectin levels during human pregnancy. J.Perinatol.
2007;27:77-81.
[341] Nien JK, Mazaki-Tovi S, Romero R, Erez O, Kusanovic JP, Gotsch F et
al. Plasma adiponectin concentrations in non-pregnant, normal and
overweight pregnant women. J.Perinat.Med 2007;35:522-31.
[342] Mazaki-Tovi S, Romero R, Kusanovic JP, Erez O, Vaisbuch E, Gotsch F
et al. Adiponectin multimers in maternal plasma. J.Matern.Fetal
Neonatal Med 2008;21:796-815.
[343] Chen J, Tan B, Karteris E, Zervou S, Digby J, Hillhouse EW et al.
Secretion of adiponectin by human placenta: differential modulation of
adiponectin and its receptors by cytokines. Diabetologia 2006;49:1292-
302.
[344] Ichida K, Moriyama T, Morita H, Kondo T, Yoshida S, Ohara N et al.
Plasma adiponectin concentrations and placental adiponectin expression
in pre-eclamptic women. Gynecol.Endocrinol. 2007;23:238-43.
[345] Mazaki-Tovi S, Kanety H, Pariente C, Hemi R, Efraty Y, Schiff E et al.
Determining the source of fetal adiponectin. J.Reprod.Med.
2007;52:774-78.
[346] Corbetta S, Bulfamante G, Cortelazzi D, Barresi V, Cetin I, Mantovani
G et al. Adiponectin expression in human fetal tissues during mid- and
late gestation. J.Clin.Endocrinol.Metab 2005;90:2397-402.
[347] Williams MA, Havel PJ, Schwartz MW, Leisenring WM, King IB,
Zingheim RW et al. Pre-eclampsia disrupts the normal relationship
between serum leptin concentrations and adiposity in pregnant women.
Paediatr.Perinat.Epidemiol. 1999;13:190-204.
[349] Anim-Nyame N, Sooranna SR, Steer PJ, Johnson MR. Longitudinal
analysis of maternal plasma leptin concentrations during normal
pregnancy and pre-eclampsia. Hum.Reprod. 2000;15:2033-36.
[350] Chappell LC, Seed PT, Briley A, Kelly FJ, Hunt BJ, Charnock-Jones DS
et al. A longitudinal study of biochemical variables in women at risk of
preeclampsia. Am J Obstet Gynecol 2002;187:127-36.
[351] Clausen T, Djurovic S, Reseland JE, Berg K, Drevon CA, Henriksen T.
Altered plasma concentrations of leptin, transforming growth factor-
beta(1) and plasminogen activator inhibitor type 2 at 18 weeks of
gestation in women destined to develop pre-eclampsia. Circulating
markers of disturbed placentation? Placenta 2002;23:380-85.
[352] Salomon LJ, Benattar C, Audibert F, Fernandez H, Duyme M, Taieb J et
al. Severe preeclampsia is associated with high inhibin A levels and
normal leptin levels at 7 to 13 weeks into pregnancy.
[353] Mise H, Sagawa N, Matsumoto T, Yura S, Nanno H, Itoh H et al.
Augmented placental production of leptin in preeclampsia: possible
involvement of placental hypoxia. J.Clin.Endocrinol.Metab
1998;83:3225-29.
[354] Vitoratos N, Chrystodoulacos G, Kouskouni E, Salamalekis E, Creatsas
G. Alterations of maternal and fetal leptin concentrations in hypertensive
disorders of pregnancy. Eur.J.Obstet.Gynecol.Reprod.Biol. 2001;96:59-
62.
[355] McCarthy JF, Misra DN, Roberts JM. Maternal plasma leptin is
increased in preeclampsia and positively correlates with fetal cord
concentration. Am.J.Obstet.Gynecol. 1999;180:731-36.
[357] Laivuori H, Kaaja R, Koistinen H, Karonen SL, Andersson S, Koivisto
V et al. Leptin during and after preeclamptic or normal pregnancy: its
relation to serum insulin and insulin sensitivity. Metabolism
2000;49:259-63.
[358] Teppa RJ, Ness RB, Crombleholme WR, Roberts JM. Free leptin is
increased in normal pregnancy and further increased in preeclampsia.
Metabolism 2000;49:1043-48.
[359] Bartha JL, Romero-Carmona R, Escobar-Llompart M, Comino-Delgado
R. The relationships between leptin and inflammatory cytokines in
women with pre-eclampsia. BJOG. 2001;108:1272-76.
[360] Gursoy T, Aliefendioglu D, Aslan AT, Gunduz M, Haberal A, Senes M
et al. Preeclampsia disrupts the normal physiology of leptin.
Am.J.Perinatol. 2002;19:303-10.
[361] Kafulafula GE, Moodley J, Ojwang PJ, Kagoro H. Leptin and pre-
eclampsia in black African parturients. BJOG. 2002;109:1256-61.
[362] Atamer Y, Erden AC, Demir B, Kocyigit Y, Atamer A. The relationship
between plasma levels of leptin and androgen in healthy and
preeclamptic pregnant women. Acta Obstet.Gynecol.Scand.
2004;83:425-30.
[363] Ning Y, Williams MA, Muy-Rivera M, Leisenring WM, Luthy DA.
Relationship of maternal plasma leptin and risk of pre-eclampsia: a
prospective study. J.Matern.Fetal Neonatal Med. 2004;15:186-92.
[364] Kocyigit Y, Bayhan G, Atamer A, Atamer Y. Serum levels of leptin,
insulin-like growth factor-I and insulin-like growth factor binding
protein-3 in women with pre-eclampsia, and their relationship to insulin
resistance. Gynecol.Endocrinol. 2004;18:341-48.
[365] Naruse K, Yamasaki M, Umekage H, Sado T, Sakamoto Y, Morikawa
H. Peripheral blood concentrations of adiponectin, an adipocyte-specific
plasma protein, in normal pregnancy and preeclampsia.
J.Reprod.Immunol. 2005;65:65-75.
[366] Kocyigit Y, Atamer Y, Atamer A, Tuzcu A, Akkus Z. Changes in serum
levels of leptin, cytokines and lipoprotein in pre-eclamptic and
normotensive pregnant women. Gynecol.Endocrinol. 2004;19:267-73.
[367] Haugen F, Ranheim T, Harsem NK, Lips E, Staff AC, Drevon CA.
Increased plasma levels of adipokines in preeclampsia: relationship to
placenta and adipose tissue gene expression. Am.J.Physiol
[368] Masuyama H, Nakatsukasa H, Takamoto N, Hiramatsu Y. Correlation
between soluble endoglin, vascular endothelial growth factor receptor -1
and adipocytokines in preeclampsia. J.Clin.Endocrinol.Metab 2007.
[369] Ouyang Y, Chen H, Chen H. Reduced plasma adiponectin and elevated
leptin in pre-eclampsia. Int.J.Gynaecol.Obstet. 2007;98:110-14.
[370] Savvidou MD, Sotiriadis A, Kaihura C, Nicolaides KH, Sattar N.
Circulating levels of adiponectin and leptin at 23-25 weeks of pregnancy
in women with impaired placentation and in those with established fetal
growth restriction. Clin.Sci.(Lond) 2008;115:219-24.
[371] Lu D, Yang X, Wu Y, Wang H, Huang H, Dong M. Serum adiponectin,
leptin and soluble leptin receptor in pre-eclampsia.
Int.J.Gynaecol.Obstet. 2006.
[372] Nakatsukasa H, Masuyama H, Takamoto N, Hiramatsu Y. Circulating
leptin and angiogenic factors in preeclampsia patients. Endocr.J.
2008;55:565-73.
[373] Herse F, Bai Y, Staff AC, Yong-Meid J, Dechend R, Zhou R.
Circulating and uteroplacental adipocytokine concentrations in
preeclampsia. Reprod.Sci. 2009;16:584-90.
[374] Adali E, Yildizhan R, Kolusari A, Kurdoglu M, Bugdayci G, Sahin HG
et al. Increased visfatin and leptin in pregnancies complicated by pre-
eclampsia. J Matern Fetal Neonatal Med 2009;1-7.
[375] Masuyama H, Segawa T, Sumida Y, Masumoto A, Inoue S, Akahori Y
et al. Different profiles of circulating angiogenic factors and
adipocytokines between early- and late-onset pre-eclampsia. BJOG.
2010;117:314-20.
[376] Samolis S, Papastefanou I, Panagopoulos P, Galazios G, Kouskoukis A,
Maroulis G. Relation between first trimester maternal serum leptin levels
and body mass index in normotensive and pre-eclamptic pregnancies--
role of leptin as a marker of pre-eclampsia: a prospective case-control
study. Gynecol.Endocrinol. 2010;26:338-43.
[377] Stepan H, Philipp A, Roth I, Kralisch S, Jank A, Schaarschmidt W et al.
Serum levels of the adipokine chemerin are increased in preeclampsia
during and 6 months after pregnancy. Regul.Pept. 2011;168:69-72.
[378] Molvarec A, Szarka A, Walentin S, Beko G, Karadi I, Prohaszka Z et al.
Serum leptin levels in relation to circulating cytokines, chemokines,
adhesion molecules and angiogenic factors in normal pregnancy and
preeclampsia. Reprod.Biol.Endocrinol. 2011;9:124.
[379] Masuyama H, Nobumoto E, Inoue S, Hiramatsu Y. Potential interaction
of brain natriuretic peptide with hyperadiponectinemia in preeclampsia.
Am.J.Physiol Endocrinol.Metab 2012;302:E687-E693.
[380] Laml T, Preyer O, Hartmann BW, Ruecklinger E, Soeregi G,
Wagenbichler P. Decreased maternal serum leptin in pregnancies
complicated by preeclampsia. J.Soc.Gynecol.Investig. 2001;8:89-93.
[381] Sattar N, Greer IA, Pirwani I, Gibson J, Wallace AM. Leptin levels in
pregnancy: marker for fat accumulation and mobilization? Acta
Obstet.Gynecol.Scand. 1998;77:278-83.
[382] Martinez-Abundis E, Gonzalez-Ortiz M, Pascoe-Gonzalez S. Serum
leptin levels and the severity of preeclampsia. Arch.Gynecol.Obstet.
2000;264:71-73.
[383] Chan TF, Su JH, Chung YF, Hsu YH, Yeh YT, Jong SB et al. Amniotic
fluid and maternal serum leptin levels in pregnant women who
subsequently develop preeclampsia. Eur.J.Obstet.Gynecol.Reprod.Biol.
2003;108:50-53.
[384] Celik O, Hascalik S, Ozerol E, Hascalik M, Yologlu S. Cerebrospinal
fluid leptin levels in preeclampsia: relation to maternal serum leptin
levels. Acta Obstet.Gynecol.Scand. 2004;83:519-23.
[385] Baksu A, Ozkan A, Goker N, Baksu B, Uluocak A. Serum leptin levels
in preeclamptic pregnant women: relationship to thyroid-stimulating
hormone, body mass index, and proteinuria. Am.J.Perinatol.
2005;22:161-64.
[386] Hendler I, Blackwell SC, Mehta SH, Whitty JE, Russell E, Sorokin Y et
al. The levels of leptin, adiponectin, and resistin in normal weight,
overweight, and obese pregnant women with and without preeclampsia.
[387] Dalamaga M, Srinivas SK, Elovitz MA, Chamberland J, Mantzoros CS.
Serum adiponectin and leptin in relation to risk for preeclampsia: results
from a large case-control study. Metabolism 2011;60:1539-44.
[388] Muy-Rivera M, Ning Y, Frederic IO, Vadachkoria S, Luthy DA,
Williams MA. Leptin, soluble leptin receptor and leptin gene
polymorphism in relation to preeclampsia risk. Physiol Res.
2005;54:167-74.
[389] Sugathadasa BH, Tennekoon KH, Karunanayake EH, Kumarasiri JM,
Wijesundere AP. Association of -2548 G/A polymorphism in the leptin
gene with preeclampsia/pregnancy-induced hypertension. Hypertens.
Pregnancy. 2010;29:366-74.
[390] Rigo J, Szendei G, Rosta K, Fekete A, Bogi K, Molvarec A et al. Leptin
receptor gene polymorphisms in severely pre-eclamptic women.
Gynecol.Endocrinol. 2006;22:521-25.
[391] Ramsay JE, Jamieson N, Greer IA, Sattar N. Paradoxical elevation in
adiponectin concentrations in women with preeclampsia. Hypertension
2003;42:891-94.
[392] Kajantie E, Kaaja R, Ylikorkala O, Andersson S, Laivuori H.
Adiponectin concentrations in maternal serum: elevated in preeclampsia
but unrelated to insulin sensitivity. J.Soc.Gynecol.Investig. 2005;12:433-
39.
[393] Suwaki N, Masuyama H, Nakatsukasa H, Masumoto A, Sumida Y,
Takamoto N et al. Hypoadiponectinemia and circulating angiogenic
factors in overweight patients complicated with pre-eclampsia.
Am.J.Obstet.Gynecol. 2006.
[394] Takemura Y, Osuga Y, Koga K, Tajima T, Hirota Y, Hirata T et al.
Selective increase in high molecular weight adiponectin concentration in
serum of women with preeclampsia. J.Reprod.Immunol. 2007;73:60-65.
[395] Nien JK, Mazaki-Tovi S, Romero R, Erez O, Kusanovic JP, Gotsch F et
al. Adiponectin in severe preeclampsia. J.Perinat.Med 2007;35:503-12.
[396] Fasshauer M, Waldeyer T, Seeger J, Schrey S, Ebert T, Kratzsch J et al.
Circulating high-molecular-weight adiponectin is upregulated in
preeclampsia and is related to insulin sensitivity and renal function.
Eur.J.Endocrinol. 2008;158:197-201.
[397] Liu Y, Zhu L, Pan Y, Sun L, Chen D, Li X. Adiponectin levels in
circulation and breast milk and mRNA expression in adipose tissue of
preeclampsia women. Hypertens.Pregnancy. 2012;31:40-49.
[398] Nanda S, Yu CK, Giurcaneanu L, Akolekar R, Nicolaides KH. Maternal
serum adiponectin at 11-13 weeks of gestation in preeclampsia. Fetal
Diagn.Ther. 2011;29:208-15.
[399] D'Anna R, Baviera G, Corrado F, Giordano D, Di Benedetto A, Jasonni
VM. Plasma adiponectin concentration in early pregnancy and
subsequent risk of hypertensive disorders. Obstet.Gynecol.
2005;106:340-44.
[400] D'Anna R, Baviera G, Corrado F, Giordano D, De VA, Nicocia G et al.
Adiponectin and insulin resistance in early- and late-onset pre-
eclampsia. BJOG. 2006;113:1264-69.
[401] Cortelazzi D, Corbetta S, Ronzoni S, Pelle F, Marconi A, Cozzi V et al.
Maternal and foetal resistin and adiponectin concentrations in normal
and complicated pregnancies. Clin.Endocrinol.(Oxf) 2007;66:447-53.
[402] Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Erez O, Gotsch F
et al. Maternal serum adiponectin multimers in preeclampsia. J
Perinat.Med 2009;37:349-63.
[403] Mori T, Shinohara K, Wakatsuki A, Watanabe K, Fujimaki A.
Adipocytokines and endothelial function in preeclamptic women.
Hypertens.Res. 2010;33:250-54.
[404] O'Sullivan AJ, Kriketos AD, Martin A, Brown MA. Serum adiponectin
levels in normal and hypertensive pregnancy. Hypertens.Pregnancy.
2006;25:193-203.
[405] Valdes ER, Lattes KA, Munoz HS, Barja PY, Papapietro KV. First-
trimester adiponectin and subsequent development of preeclampsia or
fetal growth restriction. Gynecol.Obstet.Invest 2011;72:152-56.
[406] Saarela T, Hiltunen M, Helisalmi S, Heinonen S, Laakso M.
Adiponectin gene haplotype is associated with preeclampsia. Genet.Test.
2006;10:35-39.
[407] Bienertova-Vasku J, Dostalova Z, Kankova K, Bienert P, Vasku A,
Unzeitig V. Is there any link between severe pre-eclampsia and defined
polymorphisms in leptin and adiponectin genes? J Obstet.Gynaecol.Res.
2008;34:858-64.
[408] Youpeng B, Wei X, Wei L, Jin J, Haiyan Y, Yuan Y et al. Relationships
among adiponectin gene polymorphisms, proteinuria and increased
blood pressure in the context of placental diseases. Hypertens.Res.
2010;33:1066-70.

Chapter VIII

Can We Predict Preeclampsia?

Irene Rebelo, M.D.
1,
, J oo Bernardes, M.D.
2
,
Eduardo Tejera, M.D.
3
and Belmiro Patrcio, M.D.
4

1
Department of Biological Sciences/Biochemistry of Faculty
of Pharmacy and Institute for Molecular and Cell Biology (IBMC),
University of Porto, Portugal
2
Center for Research in Health Technologies and Information Systems
(CINTESIS), Faculty of Medicine, University of Porto, Portugal;
Faculty of Medicine, University of Porto, Portugal;
So Joo Hospital of Porto, Portugal;
INEB Institute of Biomedical Engineering, Portugal
3
Postdoctoral Research, Department of Biological Sciences/Biochemistry
of Faculty of Pharmacy and Institute for Molecular and Cell Biology
(IBMC), University of Porto, Portugal
4
So Joo Hospital of Porto, Portugal

Corresponding authors Email: irebelo@ff.up.pt

Irene Rebelo, Joo Bernardes, Eduardo Tejera et al. 188
Introduction

Several recent studies and expert opinions suggest that current clinical
management of preeclampsia (PE) may be about to change, with accumulating
evidence in favour of a more personalized approach to patients, including new
prevention, diagnostic, treatment and short and long-term follow-up strategies
[1-9]. This chapter summarizes current guidelines for PE management, in
relation to the prediction of its development and course, and future
perspectives. The main goal is to focus on recent advances in PE prediction
long before its usual diagnosis. It is reasonable to presume that early and more
specific PE prediction may lead to effective prevention and management.

Current Management of Preeclampsia

General Considerations

Current management of PE remains based on diagnostic and treatment
strategies focused on the classification of hypertensive disorders of pregnancy,
in four major categories, widely explored in international guidelines [10-17].
PE diagnosis is achieved typically late, by definition after the 20
th
week of
gestation. Standardisation of management through current clinical guidelines
has been shown to be effective for reducing adverse maternal [18] and
perinatal outcomes [18,19] in spite of the different guidelines [20], as well as
the acknowledged non-compliance by many clinicians [21].
In this setting, this chapter summarizes the main aspects related to PE
prediction, considered in three major international guidelines (Tables I and II),
derived from: the American College of Obstetricians and Gynecologists
(ACOG) [10], the National Institute for Health and Clinical Excellence
(NICE) [11] and the World Health Organization (WHO) [12].

Blood Pressure Measurement

Blood pressure measurement remains the cornerstone of screening,
diagnosis and prediction of the severity of PE. The ACOG recommend blood
pressure assessment with mercury sphygmomanometer, with appropriate cuff,

Table 1. Summary of the American College of Obstetricians and Gynecologists (ACOG), National Institute for
Health and Clinical Excellence (NICE) and World Health Organization (WHO) guidelines for management of
hypertensive disorders of pregnancy: classification, definitions, screening, diagnosis and severity. PE: preeclampsia

Classification and
definitions
ACOG (2002) NICE (2011) WHO (2011)
- Chronic hypertension: systolic > 140 mmHg
or diastolic > 90 mmHg, before 20 weeks.
Equivalent to ACOG Equivalent to ACOG
ACOG (2002) NICE (2011) WHO (2011)
- Gestational hypertension: systolic > 140
mmHg or diastolic > 90 mmHg, after 20
weeks (without proteinuria).
- PE: gestational hypertension plus proteinuria
defined as > 0.3 g 24h or > 1+ random urine
- PE superimposed on chronic hypertension:
new-onset proteinuria, in a woman with
hypertension before 20 weeks, a sudden
increase in proteinria (if already present), a
sudden increase in hypertension or the
development of a HELLP syndrome,
headache, scotomata or epigastric pain.
Screening and
diagnosis
- Clinical: blood pressure assessment Equivalent to ACOG Equivalent to ACOG
- Laboratorial: proteinuria assessment. Equivalent to ACOG Equivalent to ACOG

- Additionally: use spot urinary
protein/creatinine, if proteinuria > 1+


Severity
ACOG (2002) NICE (2011) WHO (2011)
- Severe PE: if one or more of the following:
systolic > 160 mmHg or diastolic > 110
mmHg; proteinuria > 5 g in 24 h or > 3+ in
two urine samples 4 h apart; oliguria < 500 ml
24 h; cerebral or visual disturbances;
pulmonary edema or cyanosis; epigastric or
right quadrant pain; impaired liver function
(elevated liver enzymes); thrombocytopenia;
fetal growth restriction.
- Mild, moderate or severe hypertension, if
systolic/diastolic blood pressure 140-
149/90-99, 150-159/100-109 or > 160/110
mmHG, respectively. - Severe
preclampsia: severe hypertension plus
proteinuria, or mild to moderate
hypertension plus severe headache, visual
alterations, epigastric pain, vomiting,
papilloedema, signs of clonus, liver
tenderness , HELLP syndrome,
Equivalent to ACOG
ACOG (2002) NICE (2011) WHO (2011)
platelets < 100x10
9
/l or abnormal liver
enzymes (ALT or AST > 70 iu/L).

- Eclampsia: PE plus new-onset grand mal
seizures.
- HELLP syndrome: hemolysis,
thrombocytopenia and hepatic impairment
(elevated lactate dehydrogenase,
bilirubinemia, AST and ALT)

Table 2. Summary of the American College of Obstetricians and Gynecologists (ACOG), National Institute for
Health and Clinical Excellence (NICE) and World Health Organization (WHO) guidelines for management of
hypertensive disorders of pregnancy: monitoring, prevention and other recommendations. PE: preeclampsia

Monitoring
ACOG (2002) NICE (2011) WHO (2011)
- Maternal: platelet count, liver
enzymes, renal function, weekly, with
mild disease, or sooner, if disease
progression is questionable (on a daily
basis with severe PE).
- Maternal: blood pressure once week, twice
week or 4 times day, if mild, moderate or severe
gestational hypertension, and at least 4 times day,
in all PE cases; proteinuria at each visit, in mild
to moderate gestational hypertension and daily, in
severe cases. Weekly kidney function,
electrolytes, full blood count, transaminases and
bilirubin in severe gestational hypertension and
three times a week in moderate to severe PE.
Not mentioned.
- Fetal: daily fetal movements; weekly
NST, biophysical profile, or both;
testing twice weekly if IUGR or
oligohydramnios; ultrasound every 3
weeks for growth and amniotic fluid
assessment. Daily assessment if severe
PE.
- Fetal: ultrasound fetal growth and amniotic
fluid and dopplervelocimetry at 28-30 and 32-34
weeks, if chronic hypertension or mild to
moderate gestational hypertension or high-risk of
PE; same as before plus CTG, if severe
hypertension or PE.
Not mentioned.
Prevention - Usually proposed measures not
recommended.
- Keep dietary sodium intake low, in case of
chronic hypertension. Advise interval between a
pregnancy with hypertension and another
pregnancy lower than 10 years. Advise to keep a
BMI within the healthy range.
Not mentioned.


Prevention
ACOG (2002) NICE (2011) WHO (2011)
- Discuss suspension of angiotensin-converting
enzyme inhibitors, angiotensin II receptor
blockers and chlorotiazide, if pregnancy is
planned. Keep blood pressure < 150/100 mmHg
(or < 140/90, if target-organ damage).
Not mentioned.
- Aspirin 75 mg daily after 12 weeks until
delivery, in high-risk cases (previous
hypertensive disease, chronic renal or
autoimunne diseases, type 1 or 2 diabetes) or
when more than two moderate risk-factors are
present.
Equivalent to NICE,
including, in high-risk
cases, multiple
pregnancies. -
Additionally: calcium
supplementation where
dietary intake is low,
especially in case of high
risk of PE.
Other - Blood pressure should be taken with
mercury sphygmomanometer with
appropriate cuff, in an upright, or left
lateral recumbent position, with the
patient's arm at the heart level, after at
least 10 minutes after rest and no
tobacco or caffeine 30 minutes before.
Korotkoff phase V should be used to
establish diastolic blood pressure.

--

--

Can We Predict Preeclampsia? 193
in an upright, or left lateral recumbent position, with the patient's arm at the
heart level, after at least 10 minutes of rest and with no tobacco or caffeine 30
minutes before [10]. The NICE and the WHO do not provide any
recommendation on this issue, but the Canadian guidelines advise taking blood
pressure while the woman in sitting position and the arm at the level of the
heart [15]. In general, all consent that Korotkoff phase V should be used to
establish diastolic blood pressure [10-17].

Classification and Diagnosis

Classification of hypertensive disorders of pregnancy is not only the
proposed basis for the treatment but also for the prediction of their course,
with eclampsia as the most unpredictable and severe of all. However, while
there is a consensus on the criteria and definition of eclampsia and HELLP
syndrome, among the considered guidelines [10-17], there are some
differences in the criteria and definitions of the severity of the disease (Table
I). The ACOG and WHO guidelines define severe PE if one or more of the
following manifestations are present: systolic blood pressure > 160 mmHg or
diastolic > 110 mmHg, proteinuria > 5 g in 24 h or > 3+ in two urine samples
4 h apart, oliguria < 500 ml/24 h, cerebral or visual disturbances, pulmonary
edema or cyanosis, epigastric or right quadrant pain, impaired liver function
(elevated liver enzymes), thrombocytopenia or intrauterine growth restriction
(IUGR). On the other hand, the NICE guidelines consider hypertension as
mild, moderate or severe, when the systolic/diastolic blood pressures are 140-
149/90-99, 150-159/100-109 or > 160/110 mmHg, respectively. Moreover,
severe PE is defined as severe hypertension plus proteinuria or mild to
moderate hypertension plus severe headache, visual alterations, epigastric
pain, vomiting, papilloedema, signs of clonus, liver tenderness, HELLP
syndrome, platelet counts < 100x10
9
/l or abnormal liver enzymes (ALT or
AST > 70 IU/L) [11].

Maternal and Fetal Monitoring

After the diagnosis of PE has been established, maternal and fetal
monitoring are used to evaluate its course, namely in terms of severity.
Maternal and fetal monitoring should be performed, with increasing intensity,
when moving from chronic or gestational hypertension to PE or PE
superimposed on chronic hypertension, as well as from mild to severe.
However, there are diverse proposed monitoring policies, with differences in
detail and periodicity (Table II).
From the maternal point of view, the ACOG recommends weekly
assessment of platelet count, liver enzymes and renal function in mild disease
[10]. This should be performed earlier, if the disease progression is
questionable, namely on a daily basis, in severe PE. On the other hand, the
NICE guidelines are more detailed and extensive and propose maternal blood
pressure assessment once a week, twice a week or four times a day, in case of
mild, moderate or severe gestational hypertension, respectively, and at least
four times a day, in all PE cases [11]. It is also propose that proteinuria
assessment should be performed at each visit, in mild to moderate gestational
hypertension, and daily, in severe cases, as well as weekly assessment of
kidney function, electrolytes, full blood count, transaminases and bilirubin in
severe gestational hypertension, and three times a week in moderate to severe
PE [11]. Invasive hemodynamic monitoring is advised by the ACOG in
women with severe cardiac disease, renal disease, refractory hypertension,
pulmonary edema or unexplained oliguria [10].
From the fetal point of view the ACOG recommends in PE a daily fetal
movements count, weekly non-stress test, biophysical profile, or even both and
ultrasound every three weeks for growth and amniotic fluid assessment [10].
However, this should be performed twice weekly in the presence of IUGR or
oligohydramnios and daily if severe PE ensues [10].
On the other hand, the NICE guidelines propose ultrasound for fetal
growth and amniotic fluid assessment, and Doppler velocimetry at 28-30 and
32-34 weeks for chronic hypertension or mild to moderate gestational
hypertension or high-risk of PE, and the same plus cardiotocography, if severe
hypertension or PE ensue [11].

Prevention

Prevention of PE is the ultimate goal of early prediction. The NICE
recommends keeping a body mass index within the healthy range and a low
dietary sodium intake in case of chronic hypertension. It also advises an
interval between a pregnancy with hypertension and another pregnancy
inferior to 10 years.
Furthermore, it advises interruption of angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers and chlorotiazide when pregnancy
is planned and to keep blood pressure < 150/100 mmHg (or < 140/90 when
there is target-organ damage) [11].
The NICE and the WHO recommend a daily intake of 75 mg aspirin from
12 weeks gestation until delivery in high-risk pregnancies (previous
hypertensive disease, chronic renal disease, autoimmune diseases and type 1 or
2 diabetes mellitus) or when more than two moderate risk-factors are present
[11,12]. This recommendation, missed by the ACOG, is shared by most of the
other existing international guidelines [10-17].
The WHO recommends calcium supplementation when dietary intake is
low, especially in case of high risk of PE [11]. This recommendation is not
mentioned by the ACOG and NICE, but shared by the Canadian guidelines
[15].

Progresses in Early PE Prediction Using Biochemical Markers

The importance of predicting PE is supported by the fact that, even when
no treatment is available, the solely increment in maternal care and few
prophylactic measures can prevent or control the disease.
In the scientific literature related to PE, there are many studies on
prediction and early diagnosis, exploring several strategies and biomarkers. As
can be seen in Table III, the current trend has been through multivariate
approaches, i.e., combining several biochemical markers and Doppler
extracted measurements. This type of procedure is a consequence of the
multifactorial nature of the disease combined with the evidence that a single
biomarker lead to a low rate of prediction (low specificity and sensitivity). All
models include extensive clinical maternal information. However, if we
consider only the clinical maternal factors, i.e., maternal history of
hypertension (HP), diabetes, PE, as well as smoking habits and first trimester
diastolic blood pressure (DBP), systolic blood pressure (SBP) and body mass
index (BMI), we can only provide a detection rate or sensitivity of 50-63%,
with higher specificity and low false positive rate [22,23].
Angiogenesis is often proposed as a leading mechanism for PE, therefore
several angiogenic related proteins were included in the predictive models.
Several models emphasized the roll of angiogenic process in prediction the
onset [24-28]; it seems that it would be a maintenance area of research in
biomarkers prediction related to preeclampsia (despite some contradictory
results). Some authors found no statistical significance using various
biomarkers, i.e., sFLt-1, PIGF, VEGF-free [29-31] while others have a high
predictive values (greater than 90% in EO-PE), but usually with a high false
positive rate [32]. The differences observed (sometimes relatively large) in
these studies may not only be a consequence of the intrinsic variability of the
population, but also a result of different sample sizes, experimental methods,
changes in algorithm construction and/or statistical treatment of the variables,
and mainly, the gestational age considered in the study.
A recent review by Telang et al., [33] concerning patents related to PE
detection and diagnosis found that only 47 of the 284 consulted patents clearly
state the gestational age at which the biomarkers should be measured.
Interestingly, in their review most of the innovations followed a single
biomarker model rather than a multifactorial one.
Moreover, several patents submitted comprise the measurement of
angiogenic factors such as VEGF, sFlt-1, PIGF and PAPP-A, beta-human
chorionic gonadotropin.
The most recent inventions also include cell-free fetal DNA
quantification, several members of the insulin-like growth factor binding
proteins and other biomarkers. These results when coupled with the models
already presented, point out that the biomarker space was limited, therefore,
new strategies are necessary to explore other metabolic pathways of molecular
targets.
Obviously, there are some limitations in prediction. In most studies, the
prediction of early onset preeclampsia (EO-PE), or complicated PE leading to
premature delivery is more efficient than the late onset PE (LO-PE). This
limitation is not necessarily negative, as the high mortality rate is mainly
associated with early PE.
An important issue is the contribution of each variable to the predictive
model [22,23,29,30,32,34-36]. We can see from Table III that some
biomarkers basically provide no new information when combined and, in fact,
incorporating Doppler or maternal history information is sometimes enough to
remove any information provided by biomarkers such as PAPP-1, f-HCG or
sFLt-1 [30,32]. The models provide less than 70% prediction.
Implementations of biochemical variables will undoubtedly increase costs.
The study of cost-efficient strategy for early PE screening is a difficult but
feasible task. However, certain requirements are necessary, particularly
predictive value, the false positive rate, the cost of screening strategy and PE
prevalence [37-40]. The influence of false positive rate models is not strong in
the range 5-10%, while the detection of PE has a significant effect. In the
study of Shmueli et al. [37] the consideration of a 1.7 % prevalence of PE,

Table 3. Some examples of multivariable PE prediction models, including
Doppler and biochemical variables, with reference to their validity
and the recommended time of pregnancy for their use

Validity Time of
pregnancy

Doppler, MAP, PAPP-A
Doppler, MAP, PIGF
Doppler, MAP, PAPP-A,
PLGF

(5.0/36.0)
(5.0/37.6)
(5.0/37.8)

1st trimester

[22]

Doppler, PIGF,sFLT-1, Leptin

Bilateral Notch, PIGF,sFlt-1

33.3% and 56.3% of SEN for
90% and 80% SPE,
respectively
39.6 % and 56.3% of SEN for
90% and 80% SPE,
respectively

2nd trimester

[34]

MAP, PAPP-A

MAP, PIGF

MAP, PIGF, PAPP-A

MAP, PIGF, PAPP-A,
ADAM12

(5.0/53.0) (10.0/69.0) EO-PE
(5.0/32.0) (10.0/46.0) LO-PE
(5.0/54.0) (10.0/68.0) EO-PE
(5.0/35.0) (10.0/56.0) LO-PE
(5.0/54.0) (10.0/70.0) EO-PE
(5.0/38.0) (10.0/52.0) LO-PE
(5.0/56.0) (10.0/72.0) EO-PE
(5.0/40.0) (10.0/49.0) LO-PE

1st trimester

[35]

Doppler

Doppler + PIGF

(5.0/37.5) (10.0/43.8) EO-PE
(5/20.8) (10/28.3) LO-PE
(5.0/33.3) (10.0/46.7) EO-PE
(5.0/19.6) (10.0/29.4) LO-PE

1st trimester

[36]
hs-CRP 78.1% of SEN and 72.1% of
SPE
1st trimester [53]
HRG + Doopler 91% of SEN and 62% of SPE 1st trimester [54]
urine calcium/creatinine ratio 77% of SEN and 78% of SPE 20-24 weeks [55]

Notes: Without other information, data is reported as (false-positive rate/positive
prediction). Other nomenclatures used were: specificity (SPE), sensitivity (SEN),
early onset preeclampsia (EO-PE), late onset preeclampsia (LO-PE), mean arterial
blood pressure (MAP), pregnancy-associated plasma protein A (PAPP-A),
placental growth factor (PIGF), soluble fms-like tyrosine kinase-1 (sFlt-1),
ADAM metallopeptidase domain 12 (ADAM12), high-sensitivity C-reactive
protein (hs-CRP) and histidine-rich glycoprotein (HRG).
attest costs of 112 dollars, 10% of false detection rate, an EO-PE and LO-PE
detection of 65% and 40 % respectively, lead to a poor cost-efficient strategy
(considering other factors). Obviously, these parameters can be adjusted, for
instance, a prevalence of 1.7 is low compared to 3-5% reported, resulting in a
lower cost. Other authors confirmed that screening for sFlt1/PlGF ratio and
other markers, including ultrasound measurements could reduce the cost and
may improve the management of PE [38-40].
There are some scenarios in economic analysis that have not been
considered and require further studies. One of these elements is risk of future
cardiovascular events (and other diseases) in women with a history of PE.
Obviously we do not need to predict PE in order to know the future risk for
cardiovascular disease, however, during pregnancy cardiovascular dysfunction
emerges and therefore an increased risk of PE may indicate a higher risk of
ischemia, infarction, cardiovascular disease and hypertension. The link
between PE and future maternal and fetal risks can have a profound impact not
only on the correct biomarker selection and screening strategy, but also on
subsequent economic calculations.
Some metabolites may be used as early predictive markers of PE [41-45],
whereas in the genomic/proteomic area, a lack of predictive studies is detected
with just one work performed during the 2
nd
trimester (19-21 weeks) of
pregnancy [46]. There are several genomic/proteomic studies in PE but none
during early pregnancy [47-51]. These studies bring new markers associated
with the development of PE, including: VEGF, sFlt-1, endoglin, leptin and
TNF have been already explored in predictive studies while others such as
annexin A1, angiopoetins-like proteins and eNOS remain unknown in early
diagnosis. However, bioinformatic approaches are used to detect new
biomarkers [52]. It seems that the continued exploration of omics and
computational tools might improve considerably the biomarker space and
some of the hidden mechanism of PE pathogenesis.

Progresses in PE Prediction Using Biophysical Methods

The usefulness of Doppler in PE prediction in combination with
biochemical markers was previously presented; nevertheless, Doppler
measurement alone with maternal clinical information may also be a valuable
strategy [56-63].
The limited application of heart rate variability (HRV) analysis in clinical
practice is related to lack of systematic procedures for recording and analysis,
as well as inconsistent results [64-70]. However, the number of publications
related to the predictive capabilities of HRV or blood pressure variability
(BPV) analysis in prediction of gestational hypertension, has increased in
recent years [71, 73].
One of the first studies comparing maternal HRV analysis in normal and
preeclamptic pregnancies identified significant differences in autonomic
response between these two conditions [73]. Preeclampsia was associated with
a reduction in the autonomic response measured by spectral indexes in the low
and high frequency regions. Indeed, several studies have reported similar
results [74-78], associating PE with a RR (time interval between consecutive
R-peaks in the ECG) signal complexity reduction measured by different
entropic and informational parameters and related also to maternal age,
gestational age and even fetal gender. However, most of these studies have
performed the ECG recordings and analyses when clinical symptoms and
diagnosis were already present. Actually, few studies considered true
predictive conditions [56-63, 72, 79-82], which mean, a gestational age prior
to 20 weeks and no previous history of hypertension. A primarily research
found that women at risk of pregnancy-induced hypertension presented an
increased sympathovagal balance (low frequency/high frequency ratio) from
early pregnancy stages. However, predictive values were not evaluated [80].
Furthermore, the combined use of Doppler, maternal HRV and BPV led to a
70% prediction, with more than 85% specificity and sensitivity [72,79].
Nevertheless, a lack of uniformity in experimental protocols in these studies
exist; the recording time is not well defined, ranging from 30 min to 48 hours,
the spectral and/or complexity variables were calculated with different
procedures, and even non-uniform reference values were considered. Studies
with pathological events were composed of small sample size; in PE the
differences might also be associated with variations in the methodology used
for its diagnosis, as well as the influence of different severities of PE and drug
effects. All these situations open future challenge, both in basic research and
clinical applicability.
Recently, other biophysical approaches have been applied in PE prediction
with promising results including pulse wave analysis and skin capillary density
[63, 81]. Carty et al. [81] found a significant correlation between augmentation
index and blood pressure in normal and preeclamptic women, however, they
did not detect an increase in information, in comparison with the known PE
risk factors for the prediction, by using pulse wave parameters. Antonios et al.
[63] found that structural capillary rarefaction at 20-24 weeks of gestation
yielded a sensitivity of 87% with a specificity of 50%, whereas capillary
rarefaction at 27-32 weeks of gestation yielded a sensitivity of 75% and a
higher specificity of 77% at the cutoff of 8 capillaries/field. Multivariable
analysis shows that the most powerful and independent predictor of
preeclampsia was capillary rarefaction at 27-32 weeks. The model improved
when combined with Doppler measurements. These studies need to be
continued and expanded in the future.
Early second trimester fetal HRV has been assessed by fetal ultrasound
recording and the calculated parameters are identical to those derived from
maternal HRV [82,83]. Most studies have been performed in women already
diagnosed with PE therefore, they do not truly pertain to (early) prediction of
the disease. However, the promising results of Ursemet al. [82] obtained in
pregnancies with 10 to 12 weeks of gestation, described that variability in peak
systolic velocity and time-averaged velocity were decreased in women who
subsequently developed pregnancy-induced hypertension, encouraging
researchers to go deeper in this area [82].

Summary and Final Remarks

Important advances were presented in early diagnosis and prediction of
PE. Although the pathogenesis of PE remains unknown, research based on
direct clinical applications have been increasing. However, further research is
definitely needed on the early diagnosis and on more personalized
stratification of the disease regarding a more specific and effective prevention
and treatment management.
Current management of PE remains resumed at relatively simplistic
diagnosis and treatment measures, based on the classification of hypertensive
disorders of pregnancy considered in international guidelines. These
guidelines have been shown to be effective for reducing adverse outcomes, but
this decrease has not yet attained an acceptable level. The combination of
biochemical and Doppler measurements are dominant in the scientific
literature. Basically, an identification of an effective biomarker or a
combination of them is needed, in this sense, more bioinformatics and
statistical approaches may be of value.
Much research and standardization are necessary in the field of PE
prediction by biophysical approaches. However, it seems that there is
sufficient information to justify the effort and financial investment in order to
promote research in the prediction and prevention of PE.

References

[1] August P, Sibai BM. Preeclampsia: Clinical features and diagnosis. In:
Barss VA eds.UpToDate: Wolters Kluwer Health; 2013.
[2] Norwitz ER, Repke J. T. Preeclampsia: Management and prognosis. In:
Barss VA eds.UpToDate: Wolters Kluwer Health; 2013.
[3] Mustafa R, Ahmed S, Gupta A, Venuto RC. A comprehensive review of
hypertension in pregnancy. J. Pregnancy, 2012; 2012, 105918, doi:
10.1155/2012/105918.
[4] Payne B, Magee LA, von Dadelszen P. Assessment, surveillance and
prognosis in pre-eclampsia. Best Pract. Res. Clin. Obstet. Gynaecol.,
2011;25(4):449-62.
[5] ACOG Office of Communications. A push to end preeclampsia. 25 Mar
2013.
http://www.acog.org/About%20ACOG/News%20Room/News%20Relea
ses/2012/A%20Push%20to%20End%20Preeclampsia.aspx.
[6] Sibai BM. Publications Committee, Society for Maternal-Fetal
Medicine. Evaluation and management of severe preeclampsia before 34
weeks' gestation. Am. J. Obstet. Gynecol., 2011;205(3):191-8.
[7] Ciantar E, Walker JJ. Pre-eclampsia, severe pre-eclampsia and
hemolysis, elevated liver enzymes and low platelets syndrome: what is
new? Womens Health (LondEngl). 2011;7(5):555-69.
[8] Magee LA, Abalos E, von Dadelszen P, Sibai B, Easterling T,
Walkinshaw S, CHIPS Study Group. How to manage hypertension in
pregnancy effectively. Br. J. Clin. Pharmacol., 2011;72(3):394-401.
[9] Heidrich MB, Wenzel D, von Kaisenberg CS, Schippert C, vonVersen-
Hynck FM. Preeclampsia and long-term risk of cardiovascular disease:
what do obstetrician-gynecologists know? BMC Pregnancy Childbirth.
2013;13:61.
[10] ACOG Committee on Obstetric Practice. ACOG practice bulletin.
Diagnosis and management of preeclampsia and eclampsia. Number 33,
January 2002. American College of Obstetricians and Gynecologists.
Int. J. Gynaecol. Obstet., 2002;77(1):67-75.
[11] NICE clinical guideline 107. Hypertension in pregnancy. The
management of hypertensive disorders during pregnancy. National
Institute for Health and Clinical Excellence. United Kingdom 2011.
(http://www.nice.org.uk/nicemedia/live/13098/50418/50418.pdf,
accessed 2 July 2013).
[12] WHO Recommendations for Prevention and Treatment of Pre-
Eclampsia and Eclampsia. WHO Guidelines Approved by the
Guidelines Review Committee. Geneva: World Health Organization
2011.
[13] Milne F, Redman C, Walker J, Baker P, Black R, Blincowe J, Cooper C,
Fletcher G, Jokinen M, Moran PA, Nelson-Piercy C, Robson S, Shennan
A, Tuffnell A, Waugh J, PRECOG II Group. Assessing the onset of pre-
eclampsia in the hospital day unit: summary of the pre-eclampsia
guideline (PRECOG II). BMJ, 2009;339b:3129.
[14] Lowe SA, Brown MA, Dekker GA, Gatt S, McLintock CK, McMahon
LP, Mangos G, Moore MP, Muller P, Paech M, Walters B, Society of
Obstetric Medicine of Australia and New Zealand. Guidelines for the
management of hypertensive disorders of pregnancy 2008. Aust. N. Z. J.
Obstet. Gynaecol., 2009;49(3):242-6.
[15] Magee LA, Helewa M, Moutquin JM, von Dadelszen P, Hypertension
Guidelines Committee, STIRRHS Scholars. SOGC guidelines:
diagnosis, evaluation and management of the hypertensive disorders of
pregnancy. J. Obstet. Gynecol. Can., 2008;30(3):S1-48.
[16] Institute of Obstetricians and Gynecologists, Royal College of
Physicians of Ireland. The diagnosis and management of Pre-eclampsia
and eclampsia. Clinical practice guideline. Institute of Obstetricians and
Gynecologists. Ireland 2013. (http://www.rcpi.ie/content/docs/000001
/649_5_media.pdf, accessed 2 July 2013).
[17] Pottecher T, Luton D, Zupan V, Collet M. Multidisciplinary
management of severe pre-eclampsia. J. Gynecol. Obstet. Biol. Reprod.,
(Paris). 2009;38(4):351-7.
[18] Menzies J, Magee LA, Li J, MacNab YC, Yin R, Stuart H, Baraty B,
Lam E, Hamilton T, Lee SK, von Dadelszen P, Preeclampsia Integrated
Estimate of RiSk (PIERS) Study Group. Instituting surveillance
guidelines and adverse outcomes in preeclampsia. Obstet. Gynecol.,
2007;110(1):121-7.
[19] von Dadelszen P, Sawchuck D, McMaster R, Douglas MJ, Lee SK,
Saunders S, Liston RM, Magee LA, Translating Evidence-Based
Surveillance and Treatment Strategies (TESS) Group. The active
implementation of pregnancy hypertension guidelines in British
Columbia. Obstet. Gynecol., 2010;116(3):659-66.
[20] Menzies J, Magee LA, Macnab YC, Ansermino JM; Li J, Douglas MJ,
Gruslin A, Kyle P, Lee SK, Moore MP, Moutquin JM, Smith GN,
Walker JJ, Walley KR, Russell JA, von Dadelszen P. Current CHS and
NHBPEP criteria for severe preeclampsia do not uniformly predict
adverse maternal or perinatal outcomes. Hypertens. Pregnancy,
2007;26(4):447-62.
[21] Caetano M, Ornstein MP, Von Dadelszen P, Hannah ME, Logan AG,
Gruslin A, Willan A, Magee LA. A survey of Canadian practitioners
regarding the management of the hypertensive disorders of pregnancy.
Hypertens. Pregnancy, 2004;23(1):61-74.
[22] Akolekar R, Syngelaki A, Poon L, Wright D, Nicolaides KH. Competing
risks model in early screening for preeclampsia by biophysical and
biochemical markers. Fetal. Diagn. Ther., 2013;33(1):8-15.
[23] Caradeux J, Serra R, Nien JK, Prez-Sepulveda A, Schepeler M, Guerra
F, Gutirrez J, Martinez J, Cabrera C, Figueroa-Diesel H, Soothill P,
Illanes SE. First trimester prediction of early onset preeclampsia using
demographic, clinical, and sonographic data: a cohort study. Prenat.
Diagn., 2013;33(8):732-6.
[24] Teixeira PG, Reis ZS, Andrade SP, Rezende CA, Lage EM, Velloso EP,
Santana CA, Cabral AC. Presymptomatic prediction of preeclampsia
with angiogenic factors, in high risk pregnant women. Hypertens.
Pregnancy, 2013;32(3):312-20.
[25] Myers J, Kenny L, McCowan L, Chan E, Dekker G, Poston L, Simpson
N, North R, SCOPE consortium. Angiogenic factors combined with
clinical risk factors to predict preterm pre-eclampsia in nulliparous
women: a predictive test accuracy study. BJOG, 2013;120(10):1215
1223.
[26] Delic R, Stefanovic M, Krivec S, Weber V. Statistical regression model
of standard and new laboratory markers and its usefulness in prediction
of preeclampsia. J. Matern. Fetal. Neonatal Med., 2013;Jul 26.
[27] Stampalija T, Chaiworapongsa T, Romero R, Chaemsaithong P,
Korzeniewski SJ, Schwartz AG, Ferrazzi EM, Dong Z, Hassan SS.
Maternal plasma concentrations of sST2 and angiogenic/anti-angiogenic
factors in preeclampsia. J. Matern. Fetal. Neonatal Med., 2013;May 20.
[28] Moore AG, Young H, Keller JM, Ojo LR, Yan J, Simas TA, Maynard
SE. Angiogenic biomarkers for prediction of maternal and neonatal
complications in suspected preeclampsia. J; Matern. Fetal. Neonatal
Med., 2012;25(12):2651-7.
[29] Scazzocchio E, Figueras F, Crispi F, Meler E, Masoller N, Mula R,
Gratacos E. Performance of a first-trimester screening of preeclampsia in
a routine care low-risk setting. Am. J. Obstet. Gynecol., 2013;208(3):
203e1-203e10.
[30] Gmez-Arriaga PI, Herraiz I, Lpez-Jimnez EA, Gmez-Montes E,
Denk B, Galindo A. Uterine artery Doppler and sFlt-1/PlGF ratio:
usefulness in diagnosis of pre-eclampsia. Ultrasound Obstet. Gynecol.,
2013;41(5):530-537.
[31] Odibo AO, Rada CC, Cahill AG, Goetzinger KR, Tuuli MG, Odibo L,
Macones GA, England SK. First-trimester serum soluble fms-like
tyrosine kinase-1, free vascular endothelial growth factor, placental
growth factor and uterine artery Doppler in preeclampsia. J. Perinatol.,
2013;Apr 4:doi:10.1038/jp.2013.33.
[32] Poon LC, Syngelaki A, Akolekar R, Lai J, Nicolaides KH. Combined
screening for preeclampsia and small for gestational age at 11-13 weeks.
Fetal. Diagn. Ther., 2013;33(1):16-27.
[33] Telang MA, Bhutkar SP, Hirwani RR. Analysis of patents on
preeclampsia detection and diagnosis: a perspective. Placenta,
2013;34(1):2-8.
[34] Diguisto C, Le Gouge A, Piver E, Giraudeau B, Perrotin F. Second-
trimester uterine artery Doppler, PlGF, sFlt-1, sEndoglin, and lipid-
related markers for predicting preeclampsia in a high-risk population.
Prenat. Diagn., 2013;DOI: 10.1002/pd.4198.
[35] Kuc S, Koster MP, Franx A, Schielen PC, Visser GH. Maternal
characteristics, mean arterial pressure and serum markers in early
prediction of preeclampsia. PLoS One, 2013;8(5):e63546.
[36] Parra-Cordero M, Rodrigo R, Barja P, Bosco C, Rencoret G, Seplveda-
Martinez A; Quezada S. Prediction of early and late pre-eclampsia from
maternal characteristics, uterine artery Doppler and markers of
vasculogenesis during first trimester of pregnancy. Ultrasound Obstet.
Gynecol., 2013;41(5):538-544.
[37] Shmueli A, Meiri H, Gonen R. Economic assessment of screening for
pre-eclampsia. Prenat. Diagn., 2012;32(1):29-38.
[38] Schnettler W, Dukhovny D, Wenger J, Salahuddin S, Ralston S, Rana S.
Cost and resource implications with serum angiogenic factor estimation
in the triage of pre-eclampsia. BJOG, 2013;120(10):1224-32.
[39] Hadker N, Garg S, Costanzo C, Miller JD, Foster T, van der Helm W,
Creeden J. Financial impact of a novel pre-eclampsia diagnostic test
versus standard practice: a decision-analytic modeling analysis from a
UK healthcare payer perspective. J. Med. Econ., 2010;13(4):728-737.
[40] Hadker N, Garg S, Costanzo C, van der Helm W, Creeden J. Are there
financial savings associated with supplementing current diagnostic
practice for preeclampsia with a novel test? Learnings from a modeling
analysis from a German payer perspective. Hypertens. Pregnancy,
2013;32(2):105-119.
[41] Bahado-Singh RO, Akolekar R, Mandal R, Dong E, Xia J, Kruger M,
Wishart DS, Nicolaides K. Metabolomics and first-trimester prediction
of early-onset preeclampsia. J. Matern. Fetal. Neonatal Med., 2012;25
(10):1840-1847.
[42] Bahado-Singh RO, Akoler R, Mandal R, Dong E, Xia J, Kruger M,
Wishart DS, Nicolaides K. First-trimester metabolomic detection of late-
onset preeclampsia. Am. J. Obstet. Gynecol., 2013;208(1):58e51-57.
[43] Liu D, Chen SL, Wang CH, Luo XM, Huang FF. [Metabolic footprint in
conditioned culture medium of placental explants: a comparison between
early-onset and late-onset severe preeclampsia]. Nan Fang Yi Ke Da
XueXueBao., 2011;31(9):1547-1550.
[44] Odibo AO, Goetzinger KR, Odibo L, Cahill AG, Maccones GA, Nelson
DM, Dietzen DJ. First-trimester prediction of preeclampsia using
metabolomic biomarkers: a discovery phase study. Prenat. Diagn., 2011;
31(10):990-994.
[45] Fanos V, Atzori L, Makarenko K, Melis GB, Ferrazzi E. Metabolomics
application in maternal-fetal medicine. Bio. Med. Res. Int., 2013;ID
7205 14.
[46] Myers JE, Tuytten R, Thomas G, Laroy W, Kas K, Vanpoucke G,
Roberts CT, Kenny LC, Simpson NA, Baker PN, North RA. Integrated
Proteomics Pipeline Yields Novel Biomarkers for Predicting
Preeclampsia. Hypertension, 2013;61(6):1281-8.
[47] Behrouz GH, Farzaneh GS, Leila J,Jaleh Z,Eskandar KS. Presence of
auto-antibody against two placental proteins, annexin A1 and vitamin D
binding protein, in sera of women with pre-eclampsia. J. Reprod.
Immunol., 2013;Jul 2. pii: S0165-0378(13)00069-7. doi: 10.1016
/j.jri.2013.04.007.
[48] Delles C, Neisius U, Carty DM. Proteomics in hypertension and other
cardiovascular diseases. Ann. Med., 2012;44(1):S55-64.
[49] Lee HJ, Jeong SK, Na K, Lee MJ, Lim JS, Cha HJ, Cho JY, Kwon JY,
Kim H, Song SY,Yoo JS, Park YM, Kim H, Hancock WS, Paik YK.
Comprehensive genome-wide proteomic analysis of human placental
tissue for the chromosome-centric human proteome project. J. Proteome.
Res., 2013;12(6):2458-2466.
[50] White WM, Brost B, Sun Z, Rose C, Craici I, Wagner SJ, Turner ST,
Garovic VD. Genome-Wide Methylation Profiling Demonstrates
Hypermethylation in Maternal Leukocyte DNA in Preeclamptic
Compared to Normotensive Pregnancies. Hypertens. Pregnancy,
2013;32(3):257-269.
[51] Chen DB, Wang W. Human placental microRNAs and preeclampsia.
Biol. Reprod., 2013;88(5):130.
[52] Tejera E, Bernardes J, Rebelo I. Preeclampsia: a bioinformatics
approach through protein-protein interaction networks analysis. BMC.
Syst. Biol., 2012;6:97.
[53] Kashanian M, Aghbali F, Mahali N. Evaluation of the diagnostic value
of the first-trimester maternal serum high-sensitivity C-reactive protein
level for prediction of pre-eclampsia. J. Obstet. Gynaecol. Res., 2013;Jul
22, doi:10:1111/jog.12105.
[54] Bolin M, Wikstrm AK, Wiberg-Itzel E, Olsson AK, Ringvall M,
Sundstrm-Poromaa I, Axelsson O, Thilaganathan B, kerud H.
Prediction of preeclampsia by combining serum histidine-rich
glycoprotein and uterine artery Doppler. Am. J. Hypertens., 2012;25(12):
1305-10.
[55] Vahdat M,Kashanian M,Sariri E, Mehdinia M. Evaluation of the value
of calcium to creatinine ratio for predicting of pre-eclampsia. J. Matern.
Fetal. Neonatal Med., 2012;25(12):2793-4.
[56] Lai J, Poon LC, Pinas A, Bakalis S, Nicolaides KH. Uterine artery
Doppler at 30-33 weeks' gestation in the prediction of preeclampsia.
Fetal Diagn. Ther., 2013;33(3):156-63.
[57] D'Antonio F, Hamilton P, Pinnock R, Bhide A, McVeigh G,
Thilaganathan B. Comparison of wavelet transform and time-domain
analysis of second trimester uterine artery Doppler waveforms in
screening for pre-eclampsia. Fetal Diagn. Ther., 2013;33(3):189-93.
[58] Myatt L, Clifton RG, Roberts JM, Spong CY, Hauth JC, Varner MW,
Wapner RJ, Thorp JM Jr, Mercer BM, Grobman WA, Ramin SM,
Carpenter MW, Samuels P, Sciscione A, Harper M, Tolosa JE, Saade G,
Sorokin Y, Anderson GD, NICHD, MFMU. The utility of uterine artery
Doppler velocimetry in prediction of preeclampsia in a low-risk
population. Obstet. Gynecol., 2012;120(4):815-22.
[59] Demers S, Bujold E, Arenas E, Castro A, Nicolaides KH. Prediction of
Recurrent Preeclampsia Using First-Trimester Uterine Artery Doppler.
Am. J. Perinatol., 2013;Mar 18.
[60] Caradeux J, Serra R, Nien JK, Prez-Sepulveda A, Schepeler M, Guerra
F, Gutirrez J, Martnez J, Cabrera C, Figueroa-Diesel H, Soothill P,
Illanes SE. First trimester prediction of early onset preeclampsia using
demographic, clinical, and sonographic data: a cohort study. Prenat.
Diagn., 2013;33(8):732-6.
[61] Bhattacharyya SK, Kundu S, Kabiraj SP. Prediction of preeclampsia by
midtrimester uterine artery Doppler velocimetry in high-risk and low-
risk women. J. Obstet. Gynaecol India, 2012;62(3):297-300.
[62] Jamal A, Abbasalizadeh F, Vafaei H, Marsoosi V, Eslamian L.
Multicenter screening for adverse pregnancy outcomes by uterine artery
Doppler in the second and third trimester of pregnancy. Med. Ultrason.,
2013;15(2):95-100.
[63] Antonios TF, Nama V, Wang D, Manyonda IT. Microvascular
Remodelling in Preeclampsia: Quantifying Capillary Rarefaction
Accurately and Independently Predicts Preeclampsia. Am. J. Hypertens.,
2013;26(9):1162-9.
[64] Faber R, Baumert M, Stepan H, Wessel N, Voss A, Walther T.
Baroreflex sensitivity, heart rate, and blood pressure variability in
hypertensive pregnancy disorders. Journal of Human Hyperten.,
2004;18(10):707712.
[65] Eneroth-Grimfors E, Westgren M, Ericson M, Ihrman-Sandahl C,
Lindblad LE. Autonomic cardiovascular control in normal and pre-
eclamptic pregnancy. Acta Obstet. Gynecol. Scand., 1994;73(9):680-4.
[66] Yang CC, Chao T, Kuo TB, Yin CS, Chen HI. Preeclamptic pregnancy
is associated with increased sympathetic and decreased parasympathetic
control of HR. Am. J. Physiol. Heart Circ. Physiol., 2000;278(4):
H1269H1273.
[67] Dyer RA, Anthony J, Ledeboerb Q, Jamesa MF. Cardiovascular
responses to the change from the left lateral to the upright position in
pregnant hypertensives. Int. J. of Gynaecol. Obstet., 2004;84(3):208
213.
[68] Tejera E, Areias MJ, Rodrigues AI, Rama A, Nieto-Villar JM, Rebelo
I. Relationship between heart rate variability indexes and common
biochemical markers in normal and hypertensive third trimester
pregnancy. Hypertens. Pregnancy, 2012;31(1):59-69.
[69] Tejera E, Areias MJ, Rodrigues A, Nieto-Villar JM, Rebelo I. Blood
pressure and heart rate variability complexity analysis in pregnant
women with hypertension. Hypertens. Pregnancy, 2012;31(1):91-106.
[70] Tejera E, Areias MJ, Rodrigues A, Rama A, Nieto-Villar JM, Rebelo I.
Artificial neural network for normal, hypertensive, and preeclamptic
pregnancy classification using maternal heart rate variability indexes. J.
Matern. Fetal Neonatal Med., 2011;24(9):1147-51.
[71] Ayala DE, Hermida RC. Ambulatory blood pressure monitoring for the
early identification of hypertension in pregnancy. Chronobiol. Int., 2013;
30(1-2):233-59.
[72] Malberg H, Bauernschmitt R, Voss A, Walther T, Faber R, Stepan H,
Wessel N. Analysis of cardiovascular oscillations: a new approach to the
early prediction of pre-eclampsia. Chaos, 2007;17(1):015113..
[73] Eneroth-Grimfors E, Westgren M, Ericson M, Ihrman-Sandahl C,
Lindblad LE. Autonomic cardiovascular control in normal and pre-
eclamptic pregnancy. Acta Obstet. Gynecol. Scand., 1994;73(9):680-4.
[74] Hermida RC, Ayala DE, Mojn A, Fernndez JR, Silva I, Ucieda R,
Iglesias M. High sensitivity test for the early diagnosis of gestational
hypertension and preeclampsia. I. Predictable variability of
cardiovascular characteristics during gestation in healthy and
hypertensive pregnant women. J. Perinat. Med., 1997;25(1):101-9.
[75] Ayala DE, Hermida RC, Mojn A, Fernndez JR, Silva I, Ucieda R,
Iglesias M. Blood pressure variability during gestation in healthy and
complicated pregnancies. Hypertension, 1997;30(3Pt2):611-8.
[76] Ekholm EM, Tahvanainen KU, Metsl T. Heart rate and blood pressure
variabilities are increased in pregnancy-induced hypertension. Am. J.
Obstet. Gynecol., 1997;177(5):1208-12.
[77] Eneroth E, Storck N. Preeclampsia and maternal heart rate variability.
Gynecol. Obstet. Invest., 1998;45(3):170-3.
[78] Salazar C, Torres J, Nieto-Villar JM. Non-linear Analysis Approach of
Maternal Heart Rate Patterns in Normal and Pre-eclamptic Pregnancies.
CMMM, 2003;5(34):219226.
[79] Walther T, Wessel N, Malberg H, Voss A, Stepan H, Faber R. A
combined technique for predicting pre-eclampsia: concurrent
measurement of uterine perfusion and analysis of heart rate and blood
pressure variability. J. Hypertens., 2006;24(4):747-50.
[80] Pal GK, Shyma P, Habeebullah S, Shyjus P, Pal, P. Spectral analysis of
heart rate variability for early prediction of pregnancy-induced
hypertension. Clin. Exp. Hypertens, 2009;31(4):330-41.
[81] Carty DM, Neisius U, Rooney LK, Dominiczak AF, Delles C. Pulse
wave analysis for the prediction of preeclampsia. J. Hum. Hypertens,
2013:Jul 18, doi:10.1038/jhh.2013.64.
[82] Ursem NTC, Clark EB, Keller BB, Hop WC, Wladimiroff JW. Do heart
rate and velocity variability derived from umbilical artery velocity
waveforms change prior to clinical pregnancy-induced hypertension?
Ultrasound Obstet. Gynecol., 1999;14(4):244249.
[83] Yum MK, Kim CR, Park EY, Kim JH. Instability and frequency-domain
variability of heart rates in fetuses with or without growth restriction
affected by severe preeclampsia. Physiol. Meas., 2004;25(5):11051113.


Chapter IX

Can We Prevent Preeclampsia?
Pharmacologic Prevention
of Preeclampsia

Sara De Carolis, M.D., Elvira di Pasquo, M.D.
,
Sergio Ferrazzani, M.D., Serafina Garofalo, M.D.,
Carmelinda Martino, M.D., Angela Botta, M.D.,
Silvi Salvi, M.D., Sascia Moresi, M.D.,
Gelsomina Del Sordo, M.D. and Antonio Lanzone, M.D.
Department of Obstetrics and Gynaecology,
Catholic University of Sacred Heart, Rome, Italy

Introduction

Women with history of preeclampsia and other hypertensive disorders of
pregnancy are at high risk for preeclampsia in their subsequent pregnancies.
The overall recurrence rate of preeclampsia reported is 15% to 18% but, in
presence of a previous severe preeclampsia or hemolysis, elevated liver
enzymes, and low platelets (HELLP) syndrome, this rate rises to 47% [1].

Corresponding author: Elvira di Pasquo, MD, Dept. of Obstetrics and Gynaecology, Catholic
University of Sacred Heart, L. go Agostino Gemelli 1,00168 Rome, Italy.
Email: elviradp1@hotmail.it
Sara De Carolis, Elvira di Pasquo, Sergio Ferrazzani et al. 212
Moreover, women with preeclampsia associated with a low-birth-weight
(<2500 g) infant, have a doubled recurrence rate in their second pregnancy [2].
The earlier preeclampsia is diagnosed during pregnancy, the greater the
likelihood of recurrence. Sibai et al. demonstrated that nulliparous women
with a diagnosis of preeclampsia before 30 weeks of gestation have a
recurrence rate of about 40% during a subsequent pregnancy [3]. These
findings can be explained by the observation that some women, especially
those with an early-onset severe preeclampsia, are found to have underlying
conditions such as acquired and inherited thrombophilias or other autoimmune
and metabolic diseases (e.g. Lupus Erythematosus Systemic, Type 1 diabetes).
Molecular or protein anomalies of thrombophilia are found in 68% of women
with severe preeclampsia. These findings suggest that women with history of
severe preeclampsia should be tested for thrombophilias [4].
However, in the majority of the cases, the etiology of the disease remains
unknown. Some theories suggest that placental ischemia is responsible of an
abnormal vascular, immune and inflammatory response causing preeclampsia.
In particular, inflammation appears to play a significant role in the
pathogenesis of the disease. Some studies showed that inflammatory cytokines
(TNF, interleukin-6) and other soluble markers of neutrophil activation are
elevated in preeclamptic women. Inflammation is also associated with
vasospasm, activation of the coagulation system and with an abnormal
haemostasis [5, 6]. Various investigators observed that, in different materials
and fetal tissues, there is an abnormal prostaglandin production and
metabolism with an increased thromboxane A2/prostacyclin ratio. It is still
unclear if this could be an effect rather than a cause of preeclampsia [7].

The Role of Low-Dose Aspirin

Since inflammation appears to have an important role in the pathogenesis
of preeclampsia, some investigators have evaluated the role of aspirin in the
prevention and in the therapy of the disease. Aspirin is an anti-platelet drug.
By processing prostaglandin H2, platelets produce thromboxane, which
induces aggregation and vasoconstriction. Cyclo-oxigenase (COX) is the
enzyme necessary for the conversion of arachidonic acid into prostaglandin
H
2
. At low concentrations (75-150 mg per day) and over longer periods,
aspirin rapidly and selectively acetylates a serine residue in COX, leading its
irreversible inhibition. The possible benefits from aspirin in the prevention of
preeclampsia and its vascular complications derive both from its anti-
Can We Prevent Preeclampsia? 213
inflammatory action and from its effect on restoring the balance between
thromboxane and prostacyclin [8]. Although aspirin crosses the placenta, low
dose aspirin is safe and large randomised trials demonstrated no increase of
congenital anomalies, miscarriages, placental abruptio and fetal or neonatal
bleedings [9, 10].
Women with a previous preeclampsia are considered at high risk for
recurrence. The guidelines of National Institute for Health and Care
Excellence (NICE) on quality standard for antenatal care, recommends the
prescription of 75 mg to take daily from 12 weeks until at least 36 weeks of
gestation to these women [11].
The 2007 Cochrane review about anti-platelets agents for preventing
preeclampsia and its complications (37,560 women, 59 randomised clinical
trials), clearly demonstrated that low doses of anti-platelet agents
administrated before 20 gestational weeks can improve pregnancy outcome in
women at risk, including women with previous preeclampsia. Although there
is no statistical difference in RR based on maternal risk, there is a significant
increase in the absolute risk reduction of preeclampsia for high risk (risk
difference (RD) -5.2% (-7.5, -2.9), NNT 19 (13, 34)) compared with moderate
risk women (RD -0.84 (-1.37, -0.3), NNT 119 (73, 333)). A reduction of 17%
in the incidence of preeclampsia, of 8% in the incidence of preterm delivery,
of 10% in the incidence of low birth weight infants and of 14% in perinatal
mortality was reported in the treated group. However in this review, studies
with different design and heterogeneous respect to maternal characteristics and
week of anti-platelet agents administration were combined [12]. Two meta-
analysis studies evaluating benefits of aspirin in high-risk and low-risk
women, showed results similar to those in the Cochrane review for both
pregnancy (in term of incidence of preeclampsia) and fetal outcome[13][14].
Considering the role of aspirin in the prevention of recurrent preeclampsia,
it is important to focus on the time of its administration. Recent meta-analysis
compared the effectiveness of early (16 weeks) vs. late (>16 weeks)
administration in reducing the risk of adverse pregnancy outcomes and
perinatal death. The most recent study by Roberge et al., including 42 RCT
and 27,222 women, clearly showed that aspirin administration 16 weeks
significantly reduces severe preeclampsia (RR 0.47 CI 0.36-0.62), perinatal
death and fetal growth restriction[15]. Bujold et al. had previously showed the
same results in term of prevention of preeclampsia and fetal growth restriction
with an early administration of aspirin (RR 0.47 CI 0.61-0.99) [16].
Furthermore, two studies published in 2012 showed that the early
administration of low-dose aspirin in women at risk for preeclampsia reduces
the risk of severe but not mild preeclampsia and the risk of preterm (<37
weeks) but not at term preeclampsia [17, 18]. (Table 1)

Table 1. Meta-analysis of aspirin for the prevention of recurrent
preeclampsia

References Trials (n) Women
(n)
Relative Risk (RR) or Odds Ratio
(OR)
Prevention of preeclampsia in high risk vs. low-risk women
Trivedi [13]
(2011)
19 28237 High risk: RR 0.79(0.65-0.97)*
Low risk: OR 0.86 (0.64-1.17)
Ruano [14]
(2005)
22 35598 High risk: RR 0.87 (0.79-0.96)*
Low risk: RR 0.95 (0.81-1.11)
Prevention of preeclampsia based on gestational age at randomization to
aspirin
Roberge [15]

(2013)
42 27222 Aspirin 16 weeks: RR 0.47 (0.36-
0.62)*
Aspirin > 16 weeks: RR 0.78 (0.61-
0.99)*
Bujold [16]
(2010)
34 11348 Aspirin 16 weeks: RR 0.47 (0.34-
0.65)*
Aspirin > 16 weeks: RR 0.81(0.63-
1.03)
Prevention of preeclampsia in specific subgroups
Roberge [17]

(2012)
4 392 Aspirin16 weeks:
SEVERE preeclampsia: RR 0.22
(0.08-0.57)*
MILD preeclampsia.: RR
0.811(0.33-1.96)
Roberge [18]
(2012)
5 536 Aspirin 16 weeks:
PRETERM preeclampsia: RR
0.11(0.04-0.33)*
TERM preeclampsia: RR 0.98
(0.42-2.33)
*Statistically significant results.

In conclusion, there are contradictory findings between large trials and
systematic reviews about the use of aspirin for the prevention of preeclampsia.
Although individual large studies did not show significant benefits of aspirin
therapy, meta-analyses continue to show that aspirin improves pregnancy
outcome in women at high risk included those with a previous preeclampsia.
An early administration of low-dose aspirin could have an important effect on
pregnancy outcome. However, it is still unclear when we should start to
administrate aspirin because of the lack of strong evidences about the role of
this drug on placentation and on endothelial dysfunction.

The Role of Low Molecular Weight
Heparin

Low molecular weight heparin (LMWH) is the preferred anticoagulant
agent in pregnancy. It shows no transplacental passage, no increase in the
incidence of fetal haemorrhage and teratogenicity and it is not secreted in
breast-milk [19, 20]. Heparin-binding epidermal growth factor (HB-EGF) is
expressed within the villos trophoblast of the human placenta during the first
trimester. It is responsible of trophoblast differentiation favouring the process
of placentation. HB-EGF levels are reduced in preeclamptic pregnancies and
this is associated with decreased trophoblast invasion and increased
trophoblast apoptosis. LMWH is able to increase the expression of HB-EGF.
Some studies demonstrated that LMWH is able to prevent trophoblast
apoptosis, stimulate matrix metalloproteinase (MMPs) involved in the
invasion, control sFlt1 distribution [21]. There is a high prevalence of
placental thrombotic lesions in patients with adverse pregnancy outcome,
regardless if they had or had not detectable thrombophylic conditions. This
suggests that placental thrombosis with insufficient utero-placental circulation
may play a central role in the pathogenesis of pregnancy complication [22,
23]. However, results of clinical trials about the use of antithrombotic
prophylaxis with heparin are still controversial. A 2012 Italian randomized
controlled clinical trial (HAPPY trial) was designed to evaluate the role of
heparin in 135 women with a previous adverse pregnancy outcome
(preeclampsia, HELLP syndrome, fetal growth restriction, and placental
abruptio). 67 women were treated with a prophylactic dose of 3800 IU/day of
nadroparin while 68 women received no treatment. The trial demonstrated no
advantages in term of pregnancy outcome in the treated group respect to the
controls, despite similar baseline characteristics [24]. Conversely, a
prospective pilot study by Conserva et al., demonstrated that LMWH alone in
non-thrombophilic women with a previous history of an abnormal pregnancy
outcome (included preeclampsia and fetal growth restriction), significantly
improves the outcome of a subsequent pregnancy [25]. Another Italian study
had previously investigated the role of LMWH in the recurrence rate of
preeclampsia in women homozygotes for angiotensin-converting enzyme-D
(ACE D) allele. These women, treated with delteparin 5000 UI/day throughout
the pregnancy, reported statistically significant lower incidence of
preeclampsia (p<0.01), fetal growth restriction (p<0.0007) and had a higher
birth weight (p<0.001) [26].

The Association of LMWH and Low-Dose
Aspirin in the Prophylaxis of Recurrent
Preeclampsia

As previously explained, an abnormal inflammatory reaction and an
abnormal activation of the coagulation cascade can contribute to the
development of preeclampsia. Both LMWH and low-dose aspirin have an anti-
inflammatory effects and, at the same time, an important effect on coagulation
system. A point of great obstetrical interest is to evaluate if the combined
therapy could positively affect the pregnancy outcome in women with a
previous history of preeclampsia. In 2006, a study by Ferrazzani et al.
enrolling 54 patients with a previous severe preeclampsia, evaluated
pregnancy and neonatal outcomes in a group treated with low-dose aspirin
alone vs. women treated with both, low-dose aspirin and LMWH. LMWH
(enoxaparine 4000 UI/day) was prescribed soon after a positive pregnancy test
result and was continued until delivery, while aspirin was prescribed from the
day 22 of the menstrual cycle and stopped at the first day of menstrual cycle or
continued until 36 weeks in case of pregnancy. The recurrence rate of
preeclampsia was 30% in the low-dose aspirin arm vs. 3% in low-dose aspirin-
LMWH arm (p<0.0001). Moreover, in the latter group there was a general
improvement of the gestational age at delivery, of the birth weight and the
birth weight percentile and a significant reduction of low-birth weight infants.
Despite the limitations including the small sample size and the absence of
randomization, the study strongly suggested that thromboprophylaxis with
aspirin, in association with LMWH could improve pregnancy outcome[27]. A
pilot randomised controlled trial (NOH-PE trial) published in 2011, confirmed
the results of the previous study in 224 women (Table 2). This trial showed
that the addiction to low-dose aspirin of a prophylactic dose of enoxaparin
starting from the positive pregnancy test in women with a previous severe
preeclampsia lowers the risk of developing preeclampsia and severe
preeclampsia. Even better neonatal outcome were reported in terms of
gestational week at delivery, Apgar< 7 at 5 min, Ph< 7.15 in umbilical cord
and ICU admissions. According with the authors, the main strength of this
work was randomisation but this wasnt a placebo-controlled study [28].
Further studies are necessary to clarify the benefits of this association but,
despite low bedside effects, it seems to have an emerging and important role in
the prevention of recurrent preeclampsia and in other placenta-related
pregnancy complications.

Table2. Pregnancy and neonatal outcome in two studies
about the association of low-dose-aspirin (LDA)
and low-molecular-weight heparin (LMWH)

Ferrazzani et al. (2006)
[27]
Gris et al. (2011)
[28]

LDA
(n=23)
LDA+LWMH
(n=31)
p-
value
LDA
(n=96)
LDA+LWMH
(n=101)
p-
value
Preeclampsia 7
(30%)
1
(3%)
<0.01 17
(16.7%)
6
(5.8%)
0.014
Mean
gestational
age at
delivery
(weeks)

34.8

36.4

<0.05

37.9

39.0

0.002
Mean birth
weight (g)
2017.0 2600.0 <0.01 2765.0 2835.0 0.11
Mean birth
weight
percentile

22.0

39.9

<0.01

40.0

43.0

0.14

The Prevention of Preeclampsia
in Women with Thrombophilia

There is a 35% recurrence rate after hypertensive disorders of pregnancy
before 34 weeks gestation in women with inheritable thrombophilia [29]. It is
well known that women with antiphospholipid syndrome have a better
pregnancy outcome when treated with a combination of aspirin and LMWH
than with aspirin alone [30]. Recently, the use of this combination therapy has
been investigated also in inheritable thrombophilia. However, data are still
debatable. The FRUIT-RCT was designed to demonstrate that adding LMWH
to aspirin reduces the rate of recurrent preeclampsia and other early-onset
hypertensive (<34 weeks gestation) disorders in women with inheritable
disorders without antiphopholipid antibodies. In this trial, LMWH was
prescribed between 6 and 12 weeks of gestation after ultrasonograhic
confirmation of pregnancy and was continued until the onset of labour.
Women received a dose of 5000UI of delteparin (2500 UI below 50 Kg and
7500 UI above 80 Kg). Aspirin (80 mg/day) was started before 12 weeks of
gestation and continued until 36 weeks. Data clearly demonstrated that
LMWH with aspirin reduced the recurrence of hypertensive disorder before 34
gestational weeks (p=0.012, risk difference 8.7%). Furthermore, in the aspirin-
alone group, more subjects had preeclampsia before 34 weeks with an
important gain in terms of fetal lung maturity [31].

Conclusion

Data about the prevention of recurrent preeclampsia are still debatable.
However, recent data seems to favour the usage of the combination therapy
both in thrombophilic and in non-thrombophilic women. Further randomized
controlled trials are necessary to define the role and the clinical efficacy of
heparin, aspirin and the combination of these two drugs. Another point of
interesting could be to define the period for starting therapy in order to obtain
the maximum effect on placentation, that seems to be the key of preeclampsia.

References

[1] Mendilcioglu I, Trak B, Uner M et al. Acta Obstet Gynaecol Scand.,
2004, 83:1044-1048.
[2] Campbell DM, MacGillivray I, Carr-Hill R. Preeclampsia in second
pregnancy. Br. J. ObstetGynaecol., 1985 92: 131-140.
[3] Sibai BM, el-Nazer A, Gonzalez-Ruiz A. Severe preeclampsia-
eclampsia in young primigravid women: subsequent pregnancy outcome
and remote prognosis. Am. J. ObstetGynaecol,, 155:1011-6.
[4] Kupferminc MJ, Steinman N, EldorA et al. Severe preeclampsia is
associated with genetic thrombophilic mutations. 11th World congress of
ISSHP, 1998: 101, Japan.
[5] Shamshirsaz AA, Paidas M, Krikun G. Preeclampsia, hypoxia and
inflammation. J. Pregnancy, 2012; 2012: 374047.
[6] Sharma A, Satyam A, Sharma JB. Leptin, IL-10 and inflammatory
markers (TNF-alpha, IL-6 and IL-8) in pre-eclamptic, normotensive
pregnant and healthy non-pregnant women. Am. J. ReprodImmunol.,
2007 58:21-30.
[7] Brown HL, Klein L, Waitzman M. Plasma and amniotic fluid
prostacyclin and thromboxane in mild pregnancy-induced hypertension.
Am. J. Perinatol., 1987 4:152-4.
[8] Duley L, Henderson.Smart D, Knight M et al. Antiplatelet drugs for
prevention of preeclampsia and its consequences: systematic review.
BMJ, 2001, 322: 329-333.
[9] Norgard B, Puho E, Czeizel AE et al. Aspirin use during early
pregnancy and the risk of congenital abnormalities: a population based
control study. Am. J. Obstet. Gynaecol., 2005 192: 922-923.
[10] Askie LM, Duley L, Henderson-Smart DJ et al. Antiplatelet agents for
prevention of preeclampsia: a meta-analysis of individual patients data.
Lancet, 2007 369: 1791-1798.
[11] RCOG statement on NICE quality standard for antenatal care, 17 Sept
2012 available URL http://www.nice.org.uk/QS22.
[12] Antenatal agents for preventing preeclampsia and its complications,
Cochrane review, 2007.
[13] Trivedi NA. A meta-analysis of low-dose aspirin for prevention of
preeclampsia. J. Postgrad. Med., 2011 57:91-95.
[14] Ruano R, Fontes RS, Zugaib M. Prevention of preeclampsia with low-
dose aspirin: a systematic reviewand meta-analysis of the main
randomized controlled trials. Clinics, 200560: 407-414.
[15] Roberge S, Nicolaides KH, Demers S et al. Prevention of perinatal death
and adverse perinatal outcome using low-dose aspirin: a meta-analysis.
Ultrasound Obstet. Gynaecol., 2013, 41: 491-499.
[16] Bujold E, Roberge S, Lacasse Y, Bureau M et al. Prevention of
preeclampsia and intrauterine growth restriction with aspirin started in
early pregnancy : a meta-analysis. ObstetGynaecol., 2010 116: 402-414.
[17] Roberge S, Gigure Y, Villa P et al. Early administration of low-dose
aspirin for the prevention of severe and mild preeclampsia: a systematic
review and meta-analysis. Am. J. Perinatol., 2012 29:551-6.
[18] Roberge S, Villa P, Nicolaides K, Gigure Y, Early administration of
low-dose aspirin for the prevention of preterm and term preeclampsia: a
systematic review and meta-analysis.Fetal Diagn. Ther.,2012 31(3):141-
6.
[19] Deruelle P, Coulon C. The use of low-molecular-weight heparins in
pregnancy: How safe are they? Curr. Opin. Obstet. Gynaecol. 2007 19:
573-577.
[20] American Academy of PediatricsCommitee on Drugs. Transfer of drugs
and other chemicals into human milk. Pediatrics, 2001 108: 776-789.
[21] DIppolito S, Ortiz AS, Veglia M et al. Low molecular weight heparin in
obstetric care: a reviewof literature. Reprod. Sci., 2011 18:602-613.
[22] Kwak-Kim J, Yang KM, Gilman-Sachs A, Recurrent pregnancy loss: a
disease of inflammation and coaugulation. J. Obstet. Gynaecol. Res.,
2009 35:609-622.
[23] Kingdom JC, Kaufmann P. Oxygen and placental villous development:
origin of fetal hypoxia. Placenta, 1997 18: 613-621.
[24] Martinelli I, Ruggenenti P, Cetin I et al. Heparin in pregnant women
with previous placenta-mediated pregnancy complications: a
prospective, randomized, multicenter, controlled clinicaltrial. Blood,
2012 119: 3269-75.
[25] Conserva V, Muggiasca M, Arrigoni L et al. Recurrence and severity of
abnormal pregnancy outcome in patients treated by low-molecular-
weight heparin: a prospective pilot study. J. Matern. Fetal Neonatal.
Med., 2012 25:1467-73.
[26] Mello G, Parretti E, Fantini C et al. Low-Molecular-Weight Heparin
lowers the rate of preeclampsia and restores the physiological vascular
changes in Angiotensin- Converting Enzyme DD women, Hypertension,
2005, 45: 86-91.
[27] Ferrazzani S, DAlessio MC, Fatigante G et al. Prophylaxis of recurrent
preeclampsia: low-molecular weight heparin plus low dose aspirin
versus low-dose-aspirin alone, Hypertens Pregnancy, 2006 25: 115-127.
[28] Gris JC, Chauleur C, Molinari N. Addition of enoxaparin to aspirin for
the secondary prevention of placental vascular complications in women
with severe pre-eclampsia. The pilot randomised controlled NOH-PE
trial. Thromb Haemost., 2011 106:1053-61.
[29] Kalk JJ, Huisjes AJ, de Groot CJ et al. Recurrence rate of preeclampsia
in women with thrombophilia influenced by low-molecular-weight
heparin treatment? Neth. J. Med., 2004 62: 83-7.
[30] Ruiz-Irastorza G, Crowther M, Branch W et al. Antiphospholipid
syndrome. Lancet, 2010376:1498-1509.
[31] de Vries JI, van Pampus MG, Hague WM, Low-molecular-weight
heparin added to aspirin in the prevention of recurrent early-onset pre-
eclampsia in women with inheritable thrombophilia: the FRUIT-RCT. J.
Thromb. Haemost, 2012 10:64-72.


Chapter X

Can Calcium Prevent
Preeclampsia?

Tamar Tzur, M.D. and Eyal Sheiner, M.D., Ph.D.
*

Department of Obstetrics & Gynecology, Faculty of Health Sciences,
Soroka University Medical Center, Ben-Gurion University of the Negev,
Beer-Sheva, Israel

Introduction

Preeclampsia complicates 28% of pregnancies and greatly contributes to
maternal and perinatal morbidity and mortality worldwide. [1] Unique to
human pregnancy, preeclampsia is a multisystem disorder whose precise
etiology is unknown. It is characterized by an abnormal vascular response to
placentation and is associated with increased systemic vascular resistance,
enhanced platelet aggregation, activation of the coagulation system, and
endothelial-cell dysfunction. The clinical findings of preeclampsia can
manifest in a variety of ways. The disorder is heterogeneous; hence
pathogenesis and clinical findings can differ in women with different risk
factors. [2] There is a constant search for markers that will enable

*
Corresponding author: Eyal Sheiner MD, PhD, Soroka University Medical Center, P.O. Box
151, Beer-Sheva, Israel, Tel: +972-8-640-3902; Fax: +972-8-640-3102, E-mail:
sheiner@bgu.ac.il
Tamar Tzur and Eyal Sheiner 224
identification during the early stage of pregnancy, women at risk to develop
preeclampsia later on. [3-5]
Likewise, strategies to reduce the risk of hypertensive disorders of
pregnancy have received considerable attention. [6-21]
A number of recognized markers were investigated for this purpose,
among them vascular endothelial growth factor (VEGF) and its soluble
receptor (sFlt-1). However, these markers have low specificity and sensitivity,
and appeared to predict preeclampsia only a few weeks before the onset of
clinical symptoms. [22] Currently, women at risk are identified on the basis of
epidemiological and clinical risk factors, but the diagnostic criteria of
preeclampsia remain variable, with no precise biomarker. Treatment remains
good prenatal care, timely diagnosis, proper management, and judicious
delivery. [2]
There are several factors that can that can be addressed before pregnancy
such as weight control and control of diabetes mellitus and hypertension (if
present) for at least several months before conception and throughout
pregnancy. [23] Other methods can be addressed after the beginning of the
pregnancy to prevent or reduce the incidence of preeclampsia. [2]

Calcium in Pregnancy

Because the etiology of the disease is unknown, the interventions have
been used in an attempt to correct theoretical pathophysiologic abnormalities
in preeclampsia. [10-13]
As a normal pregnancy progresses, there is a decrease in overall level of
calcium in the maternal blood due to a delusional drop in albumin
concentration, and because of the high consumption of calcium by the fetus in
the course of its development.

[24] The concentration of calcium in the serum
must be maintained within a narrow range because of the critical role it plays
in a wide array of cellular functions, especially those involved in
neuromuscular activity, secretion, and signal transduction. [25] Calcium
reduces smooth muscle contractility and vasoconstriction mainly by its effect
on the parathyroid and intracellular calcium. [26] It may also have an indirect
effect on smooth muscle function by increasing magnesium levels. [27]
Calcium supplementation is attractive as a potential intervention to reduce
the risk of a woman developing preeclampsia. Furthermore, the possibility of
calciums protective effect on the risk of hypertension during childhood makes
this even more attractive. [28] It is relatively cheap and readily available. Also,
Can Calcium Prevent Preeclampsia? 225
it is likely to be safe for the woman and her fetus. A theoretical risk of
increased renal tract stone formation has not been substantiated, and no other
adverse effects of calcium supplementation have been documented. [29]

Calcium Intake and Hypertensive
Disorders

An inverse relationship between calcium intake and hypertensive
disorders of pregnancy was first described in 1980. This was based on the
observation that Mayan Indians in Guatemala, who traditionally soak their
corn in lime before cooking, had a high calcium intake and a low incidence of
preeclampsia and eclampsia.

[27]
Evidence from other epidemiological and clinical studies showed low
prevalence of preeclampsia in places where the diet contained high levels of
calcium. [24-32] Subsequently, a number of researchers have investigated
whether calcium supplementation affects the incidence and severity of
preeclampsia.

Calcium Supplementation

Bucher et al.

[6], in a systematic review that included fourteen randomized
trials and involved 2459 women, showed a reduction in systolic blood pressure
of -5.40 mmHg and in diastolic blood pressure of -3.44 mmHg in women
taking calcium supplements. The odds ratio for preeclampsia in women with
calcium supplementation compared with placebo was 0.38. They came to
enthusiastic conclusions that calcium supplementation during pregnancy leads
to an important reduction in systolic and diastolic blood pressure and
preeclampsia. They concluded that, while pregnant women at risk of
preeclampsia should consider taking calcium, many more patient events are
needed to confirm calcium's impact on maternal and fetal morbidity.

[6]
This optimism was not confirmed by a large trial in the USA that was
conducted in 1997. [33] This study pointed to the differences in design and a
low dietary calcium intake in the populations studied in the previous trials,
which limited acceptance of the data. In this study, 4589 healthy nulliparous
women who were 13 to 21 weeks pregnant were randomly assigned to receive
daily treatment with either 2 g of elemental calcium or placebo for the
remainder of their pregnancies. The study results disregarded any link between
calcium supplementation and the incidence of preeclampsia, pregnancy-
associated hypertension, or adverse perinatal outcomes.

[34]
The discrepancies have elicited discussion in the literature. Villar [34], in
a systematic review, included only randomized, double-blind, controlled trials
of calcium supplementation during pregnancy. In view of the heterogeneity of
the results included in the meta-analysis, a stratified analysis by baseline
dietary calcium intake (mean calcium intake in the population of 900 mg/d)
was conducted. On the basis of the results of the 5 randomized controlled trials
available, the risk of high blood pressure was lower in women with low
baseline dietary calcium (typical relative risk (TRR): 0.49). Of the 4 trials in
which subjects had adequate dietary calcium, the TRR of high blood pressure
was 0.90. The risk of preeclampsia was considerably reduced in the 6 trials
conducted in populations with low-calcium diets (TRR: 0.32), but was not
reduced as much in women enrolled in the 4 trials with adequate-calcium diets
(TRR: 0.86). On the basis of these results, it seems clear that calcium
supplementation during pregnancy for women with deficient calcium intake is
a promising preventive strategy for preeclampsia. Calcium supplementation in
pregnancy should be evaluated definitively in an adequately sized trial
conducted in a population with a low calcium intake because this is the most
likely population to benefit from such a nutritional intervention. Long-term
health benefits for the offspring are also an attractive possibility.
Later, the WHO [35] conducted a large trial in communities with low
dietary calcium intake (calcium < 600 mg/d). It recruited 8325 women to
receive supplements (1.5 g calcium/d or placebo) throughout pregnancy. Over
all, there was a reduction in the severe preeclamptic complications index (risk
ratio: 0.76). The severe maternal morbidity and mortality index was also
reduced in the supplementation group (risk ratio: 0.80). Preterm delivery (the
neonatal primary outcome) and early preterm delivery tended to be reduced
among women who were 20 years of age (risk ratio: 0.82; risk ratio: 0.64,
respectively). The neonatal mortality rate was lower (risk ratio: 0.70) in the
calcium group. They concluded that calcium supplement did not prevent
preeclampsia but did reduce its severity, maternal morbidity, and neonatal
mortality, albeit these were secondary outcomes.

A Cochrane Review

A Cochrane review from 2010 that examined the same question did,
indeed, conclude that calcium supplementation appears to approximately halve
the risk of preeclampsia. [36] They searched in the Cochrane library for
randomized trials comparing at least 1 gram of calcium daily during pregnancy
with placebo. Twelve studies of good quality were found. The risk of high
blood pressure was reduced with calcium supplementation rather than placebo
(11 trials, 14,946 women: relative risk (RR) 0.70). There was also a reduction
in the risk of preeclampsia associated with calcium supplementation (12 trials,
15,206 women: RR 0.48).

Calcium and Fetoplacental Circulations

Carroly et al. [37] postulated that calcium supplementation of calcium-
deficient pregnant women would lower vascular resistance in uteroplacental
and fetoplacental circulations. In a randomized, placebo-controlled, double-
blind trial, they assessed by Doppler ultrasound the pulsatility index (PI) and
resistance index (RI) (uterine and umbilical arteries) and the presence of
bilateral uterine artery diastolic notching in 510 healthy, nulliparous
Argentinean women with deficient calcium intake, between 20 and 36 weeks'
gestation. The average umbilical and uterine artery RI and PI tended to be
lower in the supplemented group at each study week. Differences became
statistically significant for umbilical artery RI and PI from 32 and 36 weeks,
respectively. Estimated probabilities of bilateral uterine artery diastolic
notching trended toward lower values in calcium-supplemented women. They
concluded that calcium supplementation of pregnant women with deficient
calcium intake may affect uteroplacental and fetoplacental blood flow by
preserving the vasodilation of normal gestation.
The main problem that prevents a clear conclusion and precise
recommendation, despite intensive research, is the great differences between
the studies. The trials differ in their populations (low-risk or high-risk for
hypertensive disorders of pregnancy), study design (randomization, double-
blind, or use of a placebo), gestational age at enrollment (20 to 32 weeks of
gestation), sample size in each group (range 22 to 4,151), dose of elemental
calcium used (156 to 2,000 mg/day), and definition of hypertensive disorders
of pregnancy used. Another important thing to note is that none of the
published randomized trials with calcium supplementation included women
with a history of preeclampsia.
Therefore, the benefit of calcium supplementation for recurrent
preeclampsia prevention remains unclear.

Table 1. Calcium level and the prediction of preeclampsia .

Coordinates of the Curve
Test Result Variable(s) :trimester_1_min_test_result
Positive if >/= to
a
Sensitivity 1 - Specificity
5.0000 1.000 1.000
6.1000 1.000 1.000
6.3500 1.000 1.000
6.8500 1.000 .999
7.2500 1.000 .999
7.3500 1.000 .999
7.4500 1.000 .998
7.5500 1.000 .998
7.6500 1.000 .998
7.7500 1.000 .997
7.8500 1.000 .996
7.9500 .994 .994
8.0500 .981 .991
8.1500 .981 .985
8.2500 .981 .977
8.3500 .969 .965
8.4500 .938 .945
8.5500 .888 .924
8.6500 .839 .887
8.7500 .783 .842
8.8500 .696 .782
8.9500 .634 .713
9.0500 .553 .632
9.1500 .453 .538
9.2500 .391 .443
9.3500 .298 .338
9.4500 .211 .260
9.5500 .155 .197
9.6500 .112 .142
9.7500 .087 .099
9.8500 .075 .067

Coordinates of the Curve
Test Result Variable(s) :trimester_1_min_test_result
Positive if >/= to
a
Sensitivity 1 - Specificity
9.9500 .043 .045
10.0500 .031 .029
10.1500 .019 .020
10.2500 .012 .013
10.3500 .006 .009
10.4500 .000 .007
10.5500 .000 .005
10.6500 .000 .003
10.7500 .000 .002
10.8500 .000 .002
11.0000 .000 .001
11.2000 .000 .000
11.6000 .000 .000
12.9000 .000 .000
The test result variable(s): trimester_1_min_test_result has at least one tie between the
positive actual state group and the negative actual state group.
a. The smallest cutoff value is the minimum observed test value minus 1, and the
largest cutoff value is the maximum observed test value plus 1. All the other
cutoff values are the averages of two consecutive ordered observed test values.

Calcium Level and Prediction
of Preeclampsia

Recently, our group in Soroka University Medical Center conducted a
retrospective population-based study in order to examine whether low calcium
level in the first trimester and first half of pregnancy is associated with a high
prevalence of obstetric complications and adverse perinatal outcomes,
especially hypertensive disorders. [38] The study population included all
registered births in our institute between 2001 and 2011. The advantages of
our study were the use of two combined reliable databases that made it
possible to obtain laboratory data regarding levels of calcium during the first
trimester of pregnancy. The institutional computerized birth database was
combined with the laboratory database. When multiple measurements of
calcium per woman were available for the first trimester, the lowest value was
extracted from the laboratory data. Indeed, the population in our medical
center is heterogeneous. Soroka University Medical Center serves about a
million people, the entire population of the Negev, the southern region of
Israel, including populations from different cultures and probably different
nutritional patterns.
Each pregnant woman was placed in one of the following categories
according to the results of her serum calcium test: normal (8.810.6 mg/dL),
low (<8.8 mg/dL). In addition, the continuous value of calcium in prediction
of preeclampsia was measured in ROC curves. The study population included
111,593 deliveries, of which 5,249 women (4.7%) had serum calcium levels
measured during the first trimester of pregnancy. Of the final study group,
16% (841) had low serum calcium levels and 84% (4392) had normal levels.
Women with hypocalcaemia during the first trimester were significantly
more likely to be grandmultiparous Bedouin parturients. There was no
significant difference between the groups regarding gestational age at delivery
(p=0.951).
There was also no significant difference between the study groups
regarding mild preeclampsia (p=0.312), severe preeclampsia (p=0.092), and
any hypertensive disorders (p=0.083). No significant differences regarding
neonatal outcomes were found between the study groups.
Receiver operating characteristic (ROC) curve analysis was used to
describe the relationship between the sensitivity (true-positive rate) and the
false-positive rate for the calcium level during the first trimester of pregnancy,
and the prediction of preeclampsia. Table 1 shows that no significant
association was noted between serum calcium levels during the first trimester
of pregnancy and the risk of preeclampsia, for example: Calcium level of 8.8
mg/dL (defined as the low border of the normal level), had a sensitivity of
69% but an extremely low specificity of only 22% in the prediction of
preeclampsia. Calcium level of 7.8 mg/dL (defined as hypocalcaemia), had a
sensitivity of 99% despite a specificity of 1% in the prediction of
preeclampsia. It is noteworthy that a test with perfect discrimination has an
ROC curve that passes through the upper left corner (100% sensitivity, 100%
specificity). The area under the curve (AUC) was calculated to provide a
summary of the diagnostic accuracy of the criterion. p value <0.05 was
considered statistically significant. No significant association was noted
between serum calcium levels during the first trimester or the first half of
pregnancy, and the risk of mild (Figure 1A) or severe (Figure 1B)
preeclampsia. AUC for serum calcium level was low and the graph was flat
and far from the upper left corner for both mild preeclampsia (AUC=0.466;
SE=0.022, 95%CI 0.4240.508, p=0.117) and severe preeclampsia
(AUC=0.492; SE=0.038, 95%CI 0.4180.566, p=0.821).

Figure 1. Receiver Operating Characteristic (ROC) curve analysis relationship
between uncorrected calcium level during the first half of pregnancy, and preeclampsia
(a= mild; b=severe).
A. mild preeclampsia

B. severe preeclampsia

A second analysis was performed after correcting calcium levels for
albumin. Again, no significant difference between the study groups regarding
all obstetrical complications that were examined were noted, including mild
preeclampsia (p=0.999), severe preeclampsia (p=0.168), and any hypertensive
disorders (p=0.452).
Our retrospective cohort study reveals that low serum calcium
concentration during the first trimester of pregnancy is not a risk factor for
preeclampsia. Therefore, a blood test for calcium serum levels cannot be a
predictor of preeclampsia later in pregnancy.

Summary

The benefits of calcium supplementation during pregnancy in reducing the
incidence of hypertensive disorders have been extensively evaluated.
An evidence-based review by the United States Food and Drug
Administration concluded that the relationship between calcium and risk of
hypertension in pregnancy is inconsistent and inconclusive. In contrast, a
Cochrane review published in 2010 evaluated the effects of calcium
supplementation during pregnancy on hypertensive disorders of pregnancy and
related outcomes and concluded differently. The authors concluded that
calcium supplementation halves the risk of preeclampsia, with the greatest
effect being in women with low baseline calcium intake and those at high risk
for development of preeclampsia.
There is probably no benefit to routine calcium supplementation for all the
population, but for women in whom baseline dietary calcium intake is
inadequate, or populations at high risk for preeclampsia due to age, ethnicity,
and history of previous preeclampsia, it may reduce the risk of preeclampsia.
In summary, there is no clear conclusion or general recommendation about
calcium supplements as a way to reduce the risk of preeclampsia even though
calcium supplementation is safe, cheap, and available, and therefore might be
used in high risk populations.

References

[1] Duley L. The global impact of pre-eclampsia and eclampsia. Semin
Perinatol 2009; 33:130.
[2] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. The Lancet 2005;
365(9461):785.
[3] Tzur T, Weintraub AY, Sergienko R, Sheiner E. Can anemia in the first
trimester predict obstetrical complications later in pregnancy? J Matern
Fetal Neonatal Med 2012; 25:2454.
[4] Tzur T, Weintraub AY, Sergienko R, Sheiner E. Can leukocyte count
during the first trimester of pregnancy predict later gestational
complications? Arch Gynecol Obstet 2013; 287(3):421.
[5] Tzur T, Sheiner E. Is there an association between platelet count during
the first trimester and preeclampsia or other obstetric complications later
in pregnancy? Hypertens Pregnancy 2013; 32:74.
[6] Bucher HC, Guyatt GH, Cook RJ, Hatala R, Cook DJ, Lang JD, Hunt D.
Effect of calcium supplementation on pregnancy-induced hypertension
and preeclampsia: a meta-analysis of randomized controlled trials.
JAMA 1996; 275(14):1113.
[7] Carroli G, Duley L, Belizan JM, Villar J. Calcium supplementation
during pregnancy: a systematic review of randomised controlled trials.
Br J Obstet Gynaecol 1994; 101(9)753.
[8] CLASP (Collaborative Low-dose Aspirin Study in Pregnancy)
Collaborative Group. CLASP: A randomised trial of low-dose aspirin for
the prevention and treatment of pre-eclampsia among 9364 pregnant
woman. Lancet 1994; 343:619.
[9] ECPPA (Estudo Collaborativo para Preveno da Pre-eclampsiacom
Aspirina) Collaborative Group. ECPPA: randomised trial of low dose
aspirin for the prevention of maternal and fetal complications in high
risk pregnant woman. Br J Obstet Gynaecol 1996; 103(1):39.
[10] Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin
precursor, supplementation for pregnancy uncomplicated by pre-
eclampsia or intrauterine growth restriction. Cochrane Database Syst
Rev 2006; (3):CD003402.
[11] Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive
drug therapy for mild to moderate hypertension during pregnancy.
Cochrane Database Syst Rev 2006; 3:CD003402.
[12] Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for
prevention of pre-eclampsia and related problems: a systematic review
and a commentary. BJOG 2007; 114:933.
[13] Askie LM, Duley L, Henderson-Smart DJ, Stewart LA. PARIS
Collaborative Group. Antiplatelet agents for prevention of pre-
eclampsia: A meta-analysis of individual patient data. Lancet 2007;
369:1791.
[14] Olsen SF, Secher NJ, Tabor A, Weber T, Walker JJ, Gluud C.
Randomised clinical trials of fish oil supplementation in high risk
pregnancies. Fish Oil Trials in Pregnancy (FOTIP) Team. BJOG 2000;
107:382.
[15] Olafsdottir AS, Skuladottir GV, Thorsdottir I, Hauksson A,
Thorgeirsdottir H, Steingrimsdottir L. Relationship between high
consumption of marine fatty acids in early pregnancy and hypertensive
disorders in pregnancy. BJOG 2006; 113:301.
[16] Trumbo PR, Ellwood KC. Supplemental calcium and risk reduction of
hypertension, pregnancy-induced hypertension, and preeclampsia: an
evidence-based review by the US Food and Drug Administration. Nutr
Rev 2007; 65:78.
[17] Spinnato JA 2nd. New therapies in the prevention of preeclampsia. Curr
Opin Obstet Gynecol 2006; 18:601.
[18] Spinnato JA 2nd, Freire S, Pinto e Silva JL, Cunha Rudge MV, Martins-
Costa S, Koch MA, et al. Antioxidant therapy to prevent preeclampsia: a
randomised controlled trial. Obstet Gynecol 2007; 110:1311.
[19] Villar J, Purwar M, Merialdi M, Zavaleta N, Tien NN, Anthony J. WHO
randomised trial of vitamin C & E supplementation among women at
high risk for preeclampsia and nutritional deficiency. Am J Obset
Gynecol 2007; 197:S4.
[20] Kupferminc MJ, Fait G, Many A, Lessing JB, Yair D, Bar-Am A, et al.
Low-molecular-weight heparin for the prevention of obstetric
complications in women with thrombophilias. Hypertens Pregnancy
2001; 20:35.
[21] Sergio F, Maria Clara D, Gabriella F, Giorgia S, Sara De Carolis,
Giancarlo P, et al. Prophylaxis of recurrent preeclampsia: Low-
molecular-weight heparin plus low-dose aspirin versus low-dose aspirin
alone. Hypertens Pregnancy 2006; 25:115.
booking: systematic review of controlled studies. BMJ 2005;
330(7491):565.
[23] Villamor E, Cnattingius S. Interpregnancy weight change and risk of
adverse pregnancy outcomes: a population-based study. Lancet 2006;
368:1164.
[24] Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, Rouse DJ, Spong
CY. Williams Obstetrics. 23rd ed. New York: McGraw-Hill Professional
Publishing, 2010.
[25] Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J.
Harrison's Principles of Internal Medicine. 18th ed. New York:
McGraw-Hill Medical, 2012.
[26] Belizan JM, Villar J. The relationship between calcium intake and
edema, proteinuria, and hypertension-gestosis: an hypothesis Am J Clin
Nutr 1980; 33:2202.
[27] Belizan JM, Villar J, Zalazar A, Rojas L, Chan D, Bryce GF.
Preliminary evidence of the effect of calcium supplementation on blood
pressure in normal pregnant women. Am J Obstet Gynecol 1983;
146:175.
[28] Belizan JM, Villar J, Repke J. The relationship between calcium intake
and pregnancy-induced hypertension: up-to-date evidence. Am J Obstet
Gynecol 1988; 158:898.
[29] Hofmeyr GJ, Duley L, Atallah A. Dietary calcium supplementation for
prevention of pre-eclampsia and related problems: a systematic review
and commentary. BJOG 2007; 114(8):933. Epub 2007 Jun 12.
[30] Repke J, Villar J, Bergel E, Belizan JM. The effect of iron absorption in
patients receiving calcium supplementation. 9
th
Annual Meeting of the
Society of Perinatal Obstetricians; 1989 February 1-4; New Orleans,
Louisiana, USA. 1989:512.
[31] Villar J, Belizan JM, Fischer PJ. Epidemiologic observations on the
relationship between calcium intake and eclampsia. Int J Gynaecol
Obstet 1983; 21:271.
[32] Villar J, Repke J, Belizan JM, Pareja G. Calcium supplementation
reduces blood pressure during pregnancy: results of a randomized
controlled clinical trial. Obstet Gynecol 1987; 70:317.
[33] Levine RJ, Hauth JC, Curet LB, Sibai BM, Catalano PM, Morris CD, et
al. Trial of calcium to prevent preeclampsia. N Engl J Med 1997;
337(2):69.
[34] Villar J, Belizan JM. Same nutrient, different hypotheses: disparities in
trials of calcium supplementation during pregnancy. Am J Clin Nutr
2000; 71(Suppl:137):5S.
[35] Villar J, Abdel-Aleem H, Merialdi M, Mathai M, Ali M, Zavaleta N, et
al. World Health Organisation randomized trial of calcium
supplementation among low calcium intake pregnant women. Am J
Obstet Gynecol 2006; 194:639.
[36] Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium
supplementation during pregnancy for preventing hypertensive disorders
and related problems. Cochrane Database Syst Rev 2010; (8).
[37] Carroli G, Merialdi M, Wojdyla D, Abalos E, Campodonico L, Yao S,
Gonzalez R, Deter R, Lindheimer M, Van Look P. Effects of calcium
supplementation on uteroplacental and fetoplacental blood flow in low-
calcium-intake mothers: a randomized controlled trial. Obstet Gynecol
2010; 202(1):45, e1, e9.
[38] Weintraub AY, Tzur T, Gabbay A, Shoham-Vardi I, Sergienko R,
Sheiner E. Can first trimester calcium levels predict gestational diabetes
mellitus and hypertensive disorders? Presented at the 7th International
DIP Symposium - Diabetes, Hypertension, Metabolic Syndrome &
Pregnancy, Florence, Italy, March 13-16, 2013.

Chapter XI

Hypertensive Disease of
Pregnancy and Maternal
Morbidity and Mortality

J amie O. Lo, M.D.
*
, J ohn F. Mission, M.D.
and Aaron B. Caughey, M.D., Ph.D.
Oregon Health & Science University, Portland, OR, US

Introduction

Hypertensive disorders are among the leading causes of pregnancy-related
maternal death worldwide. Hypertension is one of the most commonly
reported health conditions among pregnant women and complicates 5 to 10
percent of all pregnancies [1, 2]. Alongside infection and hemorrhage,
hypertensive disorders in pregnancy help to comprise the 3 most common
causes of maternal mortality worldwide. It has been reported that in the United
States from 1991 to 1997 almost 16 percent of 3,201 maternal deaths resulted
from pregnancy-related hypertension complications [3].

*
Corresponding author: Jamie O Lo, MD, 3181 SW Sam Jackson Park Road, Mail Code L466,
Portland, Oregon 97239, Phone: (503) 679-2025, Fax: (503) 494-4473, Email:
Loj@ohsu.edu
Jamie O. Lo, John F. Mission and Aaron B. Caughey 238
Pregnancy-related hypertension is categorized as chronic hypertension,
gestational hypertension, preeclampsia (consisting of mild preeclampsia,
superimposed preeclampsia, and severe preeclampsia), and eclampsia. The
most serious form of hypertension in pregnancy is preeclampsia, alone or
superimposed on chronic hypertension. There is some association between the
groups as women with non-proteinuric hypertension (i.e., gestational
hypertension) are at risk for developing superimposed preeclampsia, and about
17 percent of patients with gestational hypertension subsequently develop
preeclampsia [4]. Preeclampsia occurs at greater rates in nulliparous women
and at the extremes of maternal age in both younger and older women; women
aged 35 years or older are also at increased risk for chronic hypertension with
superimposed preeclampsia. Common additional preeclampsia risk factors
include: chronic medical conditions such as renal disease, systemic lupus
erythematosus, anti-phospholipid antibody syndrome, as well as multiple
gestations, race/ethnicity (particularly African-American), lower
socioeconomic status, and obesity. Some other more interesting risk factors
include shorter cohabitation time and having a mother-in-law with previous
preeclampsia.
There has been an increasing trend of pregnancy-related hypertensive
disorders, including chronic hypertension, gestational hypertension and
preeclampsia [5] that are associated with increased rates of maternal mortality
and morbidity, especially in cases of severe preeclampsia or eclampsia [6].
The incidence of eclampsia in the United States in 1998 was approximately 1
in 3250 and in the United Kingdom, approximately 1 in 2000 [7, 8], but has
declined since secondary to improved antenatal care and use of magnesium
sulfate [9, 10].

Definition of Maternal Mortality

World Health Organization (WHO)

The WHO uses the International Classification of Diseases, 10
th
edition
(ICD-10), which defines maternal death as the death of a woman while
pregnant or within 42 days (or 1 year for late maternal deaths) of termination
of pregnancy, irrespective of the duration and site of the pregnancy, from any
cause related to or aggravated by the pregnancy or its management, but not
from accidental or incidental causes.

Hypertensive Disease of Pregnancy and Maternal Morbidity ... 239
Center for Disease Control (CDC) and American College
of Obstetrics and Gynecology (ACOG)

The CDC and ACOG defines pregnancy-associated death as the death of
any woman, from any cause, while pregnant or within 1 calendar year of
termination of pregnancy, regardless of the duration and the site of pregnancy.
A pregnancy-related death is a pregnancy- associated death resulting from 1)
complications of the pregnancy itself, 2) the chain of events initiated by the
pregnancy that led to death, or 3) aggravation of an unrelated condition by the
physiologic or pharmacologic effects of the pregnancy that subsequently
caused death.

Definitions and Classifications of
Hypertensive Disorders of Pregnancy

Chronic Hypertension

Chronic hypertension is defined as hypertension ( 140 mmHg or diastolic
blood pressure 90 mmHg) that is observable before pregnancy or diagnosed
before 20 weeks of gestation. Hypertension that is first diagnosed after 20
weeks gestation and persists for greater than 12 weeks postpartum is also
considered chronic hypertension [11].


Gestational hypertension is defined as hypertension ( 140mmHg or
diastolic blood pressure 90mmHg) that develops in pregnancy after 20
weeks gestation and resolves before 12 weeks postpartum in the absence of
proteinuria (< 300mg of protein in 24 hours) [11].

Preeclampsia

Preeclampsia occurs as a spectrum and is divided into mild and severe
forms. It is typically characterized as new-onset hypertension ( 140mmHg or
diastolic blood pressure 90mmHg) and proteinuria (300mg of protein in 24
hours) diagnosed in pregnancy often after 20 weeks gestation [11]. Systemic
complications of preeclampsia include renal, hematological, hepatic,
neurologic, or pulmonary function. Preeclampsia can also cause fetal growth
restriction or placental abruption. The findings that make the diagnosis of
preeclampsia more certain are listed in Table 1 [11].

Table 1. Diagnosis of severe preeclampsia

Diagnostic criteria of severe preeclampsia
Diagnostic criteria for severe preeclampsia
Blood pressure 160 mm Hg systolic or 110 mm Hg diastolic on two
occasions at least six hours apart
Proteinuria 5 g per 24 hour
Platelet counts <100,000 cells/mm3
Serum transaminase concentration twice normal
Persistent headache or other cerebral or visual disturbances
Persistent epigastric or right upper quadrant pain
Oliguria of less than 500 mL in 24 hours
Fetal growth restriction
Pulmonary edema or cyanosis
Laboratory findings associated with increased likelihood of preeclampsia
Increased serum creatinine levels (>1.2 mg/dL unless previously elevated)
Evidence of microangiopathic hemolytic anemia (with increased lactic-
acid dehydrogenase)
Increased uric acid

Chronic Hypertension with Superimposed Preeclampsia

Chronic hypertension with superimposed preeclampsia is defined as
chronic hypertension in the setting of new onset worsening blood pressures,
proteinuria (300mg of protein in 24 hours), thrombocytopenia, or any other
systemic features of the preeclampsia syndrome [11].

Morbidity and Mortality of Hypertensive
Disorders

Both eclamptic and non-eclamptic hypertensive disorders are associated
with increased maternal mortality, especially in developing countries.
Eclampsia is a medical and obstetric emergency that has been associated with
serious complications such as renal failure, pulmonary edema, hepatic failure,
disseminated intravascular coagulopathy (DIC), and stroke. The incidence and
death from eclampsia has been significantly reduced in developed countries,
but it continues to remain an issue in developing countries. Of a total of
600,000 annual global maternal deaths, it is estimated that greater than 70,000
(12%) are secondary to pre-eclampsia and eclampsia [12, 13, 14, 15]. A large
study in 2007 reviewed 45,960 deliveries over a 20 year period (1985-2005) in
India and reported a total of 202 maternal deaths [10]. Amongst the cases of
maternal death, hypertensive disorders contributed to 62 (31%) and eclampsia
to 50 (24.7%) of the deaths [10]. Maternal deaths occurred in 23.9 percent of
all eclamptic term gestations and 8.9 percent of all eclamptic preterm
gestations [10]. There is a stronger association between maternal mortality and
patients with preeclamptic disorders in the setting of hemolysis, elevated liver
enzymes, and low platelet count (HELLP) or partial HELLP syndrome [10]. A
prior study of 54 maternal deaths in women with HELLP syndrome noted that
events associated with maternal mortality included hemorrhagic stroke (45%),
cardiopulmonary arrest (40%), DIC (39%), adult respiratory distress syndrome
(28%), renal failure (28%), hepatic hemorrhage (20%), and hypoxic ischemic
encephalopathy (16%) [16].
Women with preeclampsia and eclampsia have an increased risk of 3- to
25-fold for serious complications such as pulmonary edema, abruption,
aspiration pneumonia, renal failure, hepatic failure, disseminated intravascular
coagulopathy (DIC), and stroke [17]. The most common cause of death in
patients with eclampsia was hemorrhagic stroke, which resulted in as many as
60 percent of all eclampsia-related deaths [18, 19]. A different study noted that
the most frequent cause of mortality in patients with eclamptic disorders was
the presence of pulmonary edema [10]. Another case series of 28 women with
severe preeclampsia and eclampsia-related stroke noted a 54 percent maternal
mortality [19]. Women with preeclampsia and eclampsia also have an
increased frequency of blood transfusions and need for mechanical ventilation
compared to normotensive women. A different study reported that the most
common cause of mortality in women with preeclamptic disorders was the
development of hemolysis, elevated liver enzymes, and low platelet count
(HELLP) or partial HELLP syndrome [10]. Although the incidence and death
from eclampsia has been significantly reduced in developed countries, it still
remains a problem in developing countries.

Worldwide Trends of Hypertensive
Disorders

In 1997-2002, the leading cause of death in developed countries was
hypertension (16.1%) followed by embolism (14.9%) and hemorrhage (13.4%)
[20]. A 2009 study in the Netherlands noted that maternal mortality increased
from 1983 to 2005 and preeclampsia remained the number one direct cause
during the study period [21]. Of the maternal deaths, most cases were
associated with high systolic blood pressure and low platelet counts with
cerebral hemorrhage as the leading cause of death [21].
The WHO examined 34 datasets (35,197 maternal deaths) worldwide from
1997 to 2002 and noted regional differences in maternal death (Table 2) [20].
In industrialized countries, it was estimated that preeclampsia complicates
between 3 and 5 percent of pregnancies [20]. Alternatively, in Africa, the
leading cause of death is hemorrhage (33.9%) followed by infection (9.7%)
and hypertension (9.1%) [20]. Similarly in Asia, the leading cause of death is
hemorrhage (30.8%) followed by infection (11.6%) and hypertension (9.1%)
[20]. In Latin America and the Caribbean the leading cause of death is
hypertension (25.7%) followed by hemorrhage (20.8%) and obstructed labor
(13.4%) [20]. Pregnancy-related hypertensive disorders are annually
responsible for approximately 25,000 maternal deaths in Africa, 22,000
maternal deaths in Asia, 3,800 maternal deaths in Latin American and the
Caribbean, and 150 maternal deaths in industrialized countries
6
. Maternal
mortality is mostly attributable to eclampsia; in Africa, Asia, Latin America
and the Caribbean 10 percent of all maternal deaths were caused by eclampsia
[12].

Table 2. Distribution of causes of maternal mortality worldwide [20].

Developed
Countries
Africa Asia Latin American and
the Caribbean
Number of datasets 11
Maternal deaths 16,089
Hemorrhage 30.8%
Hypertensive
disorders
9.1%
Sepsis/Infection 11.6%

Pregnancy-related deaths secondary to non-eclamptic hypertensive
disorders has increased in incidence from 3 percent in 1993-1997 to 23 percent
in 2001-2005 [10]. Alternatively, the incidence of eclampsia has been
decreasing because it is somewhat preventable by adequate prenatal care and
therapy for seizure prophylaxis. In India, the incidence of maternal deaths is
declining secondary to a decrease in eclamptic disorders from 43 percent in
1985-1989 to 8.8 percent in 2001-2005 [10].

United States Trends of Hypertensive
Disorders and Maternal Mortality

The rate of maternal chronic hypertension has almost doubled in the
United States in the past two decades [22]. It had previously increased only by
16 percent during the 1990s, but has increased by 67 percent from 2000 to
2009, largely secondary to the obesity epidemic and the increase in maternal
age [22]. Rates of chronic hypertension have increased for all racial groups
and women of Hispanic ethnicity with the largest increase among non-
Hispanic black women (by 87%) [22]. The 2011 National Vital Statistic
Report reported an increased incidence of chronic hypertension in all pregnant
women from 12.7 per 1,000 in 2009 up from 11.9 in 2008. The rates of
chronic hypertension were also noted to increase steadily with age, whereas
rates of gestational hypertension were stable for women under 40 years but
increased sharply after age 40 [22].
In 2009, a prior study noted that there were linear increasing trends in the
United States significant for all types of hypertensive disorders except for mild
preeclampsia [5]; chronic hypertension had the highest increase. The study
also noted that the prevalence of hypertensive disorders among delivery
hospitalizations increased significantly from 67.2 per 1,000 deliveries in 1998
to 81.4 per 1,000 deliveries in 2006 [5]. In the United States, the incidence of
gestational hypertension affects approximately 2 to 3 percent of pregnancies
and preeclampsia complicates about 3 percent of pregnancies [5, 9]. The
prevalence of hospitalizations with eclampsia or severe preeclampsia is
notable for a moderate increase from 9.4 in 1998 to 12.5 in 2006 per 1,000
deliveries [5]. The rising incidence of chronic hypertension, gestational
hypertension and preeclampsia is most likely a result of changes in maternal
characteristics (i.e., maternal age and pre-pregnancy weight) [6].
In the United States, from 1991 to 1997, almost 16 percent of 3,201
maternal deaths were associated with pregnancy-related hypertension and
complications of hypertensive disorders [3]. A prior study of 790 maternal
deaths in the United States from complications of preeclampsia or eclampsia
reported that 7 percent were attributed to hemolysis, elevated liver enzymes,
and low platelet count while 4 percent were from abruption [23]. As a result of
improved access to antenatal care, early delivery of women with severe
preeclampsia, and the utilization of magnesium sulfate, the age-adjusted
incidence of eclampsia has decreased from 10.4 per 10,000 deliveries between
1987 and 1995 to 8.2 per 10,000 deliveries between 1996 and 2004 in the
United States [9].

Hypertensive Disorders and Racial/Ethnic
Disparities

A prior population-based study in New York State from 1993 to 2002
examined trends of hypertensive disorders of pregnancy by racial/ethnic
subgroups (Table 3). They noted higher rates of preeclampsia among non-
diabetic African-American and Hispanic women compared to Caucasian
women regardless of neighborhood poverty level [24]. This disparity between
racial/ethnic groups was noted to have increased over the decade with
significant, but smaller, differences between hypertension rates of Hispanic
and Caucasian women observed over time in New York State [24]. A 2010
review examined the existing literature regarding racial/ethnic disparities in
obstetrics outcomes among African-American, Hispanic, American
Indian/Alaska Native, and Asian/Pacific Islander women [25]. This study
reported that hypertensive disorders of pregnancy were more common in
African-American women, which may be attributable to excess cases of pre-
pregnancy hypertension [24, 26, 27]. Among Asian women, the study noted
that Filipina and Samoan women have risks higher than women from other
subgroups [28, 29, 30]. A different study reported that Asian paternity is
associated with a reduced preeclampsia risk and racial/ethnic discordance
between parents associated with a small increased risk [31].

Table 3. Rates of hypertensive disorders during pregnancy among different racial/ethnic groups [24]

Incidence N
Chronic
hypertension
Gestational
hypertension
Preeclampsia
Superimposed
preeclampsia
Severe
preeclampsia
and eclampsia
Total
White 1.8 0.7 5.5
Hispanic 1.2 1.0 6.2
African
American
1.5 1.2 8.5
Other 1.2 0.9 5.5
Note: Tanaka et al. Data from New York State, 1993-2002. Rate = # of events/100 hospitalizations with delivery.
A study in 2005 reported maternal mortality rates for Caucasian women
were 11.7 per 100,000 live births, 9.6 for Hispanic women, and 39.2 for non-
Hispanic black women [32]. Another study in 2007 examined the prevalence
and case-fatality rates among African American and Caucasian women for
preeclampsia, eclampsia, abruption placentae, placenta previa, and postpartum
hemorrhage using national data sets from 1988 to 1999 [33]. This study
determined that there was not a significantly greater prevalence rate amongst
African American women compared to Caucasian women, but African-
American women with these conditions had twice the likelihood of mortality
than Caucasian women [33]. In addition, African-American women were also
at an increased risk of severe complications including need for mechanical
ventilation and blood transfusion and are 3.1 times more likely to die from
preeclampsia or eclampsia compared with Caucasian women [17, 23].
Currently, there is scant literature on racial differences in biological mediators
of preeclampsia, so to better understand disparities in hypertensive disorders,
further studies in these areas are needed.

Emergent Therapy for Hypertensive
Emergency with Preeclampsia or
Eclampsia

Hypertensive emergency in a pregnant or postpartum woman with
preeclampsia or eclampsia is defined as an acute-onset, sustained (15
minutes), severe hypertension (160 mm Hg systolic or 110 mm Hg
diastolic). The most important predictor of cerebral hemorrhage and infarction
in these patients is severe systolic hypertension and it is often the main factor
in maternal deaths from aortic dissection [34, 35]. It can lead to complications
as cerebral hemorrhage and maternal death if not treated expeditiously. As a
result, to reduce the morbidity and mortality in women with preeclampsia or
eclampsia, management and avoidance of severe systolic and diastolic
hypertension is important [35]. The initiation of management guidelines for
preeclampsia and eclampsia in the United States and increased awareness of
the importance of blood pressure reduction has helped decrease the incidence
of maternal complications including stroke and maternal mortality [36, 37].
Likewise, the advent of pregnancy hypertension guidelines in the United
Kingdom was also associated with notably improved care of preeclampsia and
eclampsia patients and decreased maternal mortality likely secondary to a
reduction in cerebral and respiratory complications [34, 38].

Acute Hypertension

The goal of anti-hypertensive therapy is not to normalize blood pressures,
but to achieve a range of mild blood pressure elevation (e.g. 140-159/90-100
mmHg) to prevent prolonged exposure to severe systolic/diastolic
hypertension, with subsequent loss of cerebral vasculature auto-regulation
[35]. Commonly used and recommended acute first-line therapy includes both
labetalol and hydralazine (Table 4) [11, 35]. Intravenous labetalol, a mixed
beta- and alpha-receptor blocker, can be effective and is used commonly in
pregnancy with many years of experience. Guidelines recommend starting
with 20 mg intravenously followed at 10 minute intervals by doses of 40mg,
then 80mg, then 80mg for a total of 220mg [11, 35]. A drop in blood pressure
is anticipated within 5-10 minutes. If the desired blood pressure range is not
accomplished, then drug substitution is recommended. Intravenous
hydralazine, an alpha-receptor blocker, is also commonly recommended.
However, a prior a meta-analysis noted higher rate of complications in
comparison to labetalol, but without sufficient data to recommend one drug
over the other [39]. The dosing of hydralazine starts with 5mg intravenously or
10mg intramuscularly followed at 20 minute intervals a 5-10mg bolus
depending upon the initial response. A decrease in blood pressure is expected
within 10-30 minutes. When optimal blood pressure control has been
achieved, repeat anti-hypertensive dosing as needed (usually about 3 hours). If
blood pressure goals are not met with a total of 20 mg intravenously or 30mg
intramuscularly, another anti-hypertensive medication should be considered
[11, 35]. Uncommonly, both intravenous medications, labetalol and
hydralazine, will fail to resolve acute-onset, severe hypertension consecutive
appropriate doses are administered as outlined in Table 3. If this occurs, an
emergent consultation is recommended with an anesthesiologist, maternal-fetal
medicine subspecialist, or critical care specialist to discuss second-line
intervention [35], which includes continuous intravenous labetalol or
nicardipine [35]. There is less data on use of calcium channel blockers for this
clinical scenario, but oral nifedipine can also be used; begin with 10mg orally
and repeat every 30 minutes if necessary up to 5 doses [11, 40]. A prior
double-blind randomized control trial determined similar efficacy with oral
nifedipine and intravenous labetalol regimens for acute management of severe
hypertension [40].

Table 4. Treatment for acute hypertension [11, 35]

Drug Dose Concerns or Comments
Labetalol 20mg IV then 40-80mg every
10 minutes for total of 220mg
May increase risk of neonatal
bradycardia
Hydralazine 5mg IV or 10mg IM then 5-
10mg every 20 min for total of
20mg IV or 30mg IM.
May increase risk of maternal
hypotension
Nifedipine 10mg po then every 30 min up
to 5 doses
Tachycardia, palpitations, headache

Management and Prevention of Eclampsia

Table 5. Randomized controlled trials of magnesium sulfate prophylaxis
versus placebo or active drug.

Study Seizures/Total (%) Comparison
Magnesium Control
Magpie Trial [41]
Preeclampsia
40/5,055 (0.8) Placebo 96/5055
(1.9)
RR = 0.42
(0.26-0.60)
Belfort et al. [42]
Severe preeclampsia
7/831 (0.8) Nimodipine 21/819
(2.6)
RR=0.33
(0.14-0.77)
Lucas et al. [43] All
hypertensives
0/1,049 (0) Phenytoin 10/1089
(0.9)
P<.001

The prevention of eclamptic convulsions in the setting of preeclampsia has
been well studied. Among the different therapies studied, magnesium sulfate
remains the first-line treatment for seizure prophylaxis in severe preeclampsia
and for seizure management in eclampsia (Table 5). In 2002, the Magpie Trial
was a randomized placebo-controlled trial that studied 10,141 women with
preeclampsia (BP140/90, 1+ proteinuria) and compared treatment with
intravenous magnesium sulfate versus placebo. The study found that
magnesium sulfate given as a 4gm intravenous load and 1gm/hr maintenance
dose significantly halved the risk of eclampsia, thus reducing the risk of
maternal death. The following year, in 2003, another randomized control trial
of 1650 women compared magnesium sulfate and nimodipine for seizure
prophylaxis in women with severe preeclampsia [42]. The study demonstrated
that for seizure prophylaxis, magnesium sulfate was more effective than
nimodipine (2.6 percent vs. 0.8 percent, P=0.01). Another randomized control
trial in 2005 studying 2138 women compared phenytoin and magnesium
sulfate for the prevention of eclamptic convulsions in pregnant women with
hypertension [43]. This study observed that 10 of 1089 women who were
randomly assigned to phenytoin had eclamptic convulsions compared to none
of the 1049 women randomly assigned to magnesium and concluded that
magnesium sulfate was superior to phenytoin when given prophylactically for
eclamptic seizures to women with peripartum hypertension [43]. A 2010
Cochrane review examined 15 trials comparing magnesium sulfate with other
anticonvulsants for women with preeclampsia [44]. The conclusion of this
meta-analysis was that magnesium sulfate is superior to placebo, phenytoin,
and nimodipine and decreases the risk of eclampsia by more than half. In some
practices, a higher magnesium dosing regimen (6 gm intravenous load and 2
gm/hr maintenance dose) is used, but there are no studies demonstrating that
this regimen has a greater reduction in seizures than the dosing regimen used
in the Magpie Trial of 4gm load and then 1gm/hr maintenance. Therefore, in
women with preeclampsia, we recommend the 4gm load / 1gm/hr dosing to
decrease side effects and complications from magnesium toxicity.

Prevention of Hypertensive Disease

Due to the ongoing burden of disease, prevention of hypertensive disease
in pregnancy is an area of significant research interest. A variety of methods
have been evaluated by randomized trials to prevent hypertension and
preeclampsia including bedrest, dietary manipulation, anti-hypertensive drugs,
anti-oxidants, and anti-thrombotic drugs with modest benefit at best.
Currently, there is no broadly preventative therapy for preeclampsia.

Bedrest

Bedrest or activity restriction, with or without hospitalization, was
previously thought to improve pregnancy outcomes. However, currently there
is insufficient evidence to clearly guide clinical practice. A Cochrane review in
2005 [45] examined 4 small trials (449 women); 2 trials compared strict
bedrest with some bedrest, in the hospital, in women with preeclampsia
proteinuric hypertension and found no difference. Two other trials compared
some bedrest in the hospital with routine activity at home for non-
proteinuric hypertension and noted that some rest was associated with a
reduced risk of severe hypertension. As bedrest and restricted activity is
disruptive to womens lives, expensive, and increases the risk for
thromboembolism, bedrest is not recommended in women with stable chronic
or gestational hypertension, but reduced activity may be beneficial in women
with preeclampsia or not adequately controlled hypertension.

Diet Modification

Initial diet research efforts examined salt restriction for preeclampsia
prevention which resulted in years of diuretic therapy [46]. However it was
determined by clinical studies that diuretic therapy was not helpful for
preeclampsia prevention and is no longer practiced. The first randomized trial
performed by Knuist et al. in 1998 demonstrated that sodium restriction was
ineffective in preeclampsia prevention [47]. Other diet manipulation research
involved studies in the 1980s which examined low dietary calcium intake and
an increased risk for gestational hypertension with contradictory results [48,
49]. Subsequent studies, including a large trial by the NICHD [50], examining
4589 nulliparous women have since noted that unless women were calcium
deficient, supplementation was not beneficial [51, 52]. Fish oil has also been
studied for diet manipulation given its composition of cardioprotective fatty
acids that help decrease inflammatory-mediated atherogenesis. However,
several randomized trials have noted no benefit from fish oil [53, 54] and one
observational trial reported a potential harmful association [55].

Anti-Hypertensive Medications

In addition to diet manipulation, antihypertensive drugs have been
explored for preeclampsia prevention. Currently there are no established
recommendations for initiation of treatment in pre-existing hypertension. This
is an area of ongoing research as the benefit of initiating anti-hypertensive
treatment in patients with chronic hypertension not currently on medications is
controversial. Anti-hypertensive treatment is to prevent maternal stroke and
other sequelae of severe hypertension, but does not affect the course of
preeclampsia. Initially diuretics were studied by several groups who noted a
decreased incidence of edema, hypertension, and preeclampsia [56, 57].
Diuretics subsequently became highly advocated with up to 40% of pregnant
women being treated with continuous diuretic therapy in pregnancy [58].
However, a more recent Cochrane review [59] evaluated five randomized
trials and found no clear benefit from the use of diuretics for preeclampsia
prevention. Given the adverse effects found in the meta-analysis, the use of
diuretics for the prevention of preeclampsia was not recommended. Because
patients with chronic hypertension are at increased risk for preeclampsia, there
have been many studies on different antihypertensive drugs to reduce the
incidence of superimposed preeclampsia [51, 60]. In 2007, a Cochrane review
examined 47 randomized control trials comparing different anti-hypertensive
drugs [61]. Of the 47 trials, 28 were randomized placebo-controlled trials
comparing calcium channel blockers versus placebo or beta blockers versus
placebo [61]. These studies all concluded that treating with a calcium channel
blocker or beta blocker was superior to placebo for women with preeclampsia
[61]. The other 19 randomized trials compared beta-blockers, methyldopa, and
calcium channel blockers. These studies concluded that beta blockers were
better than methyldopa in the treatment of severe hypertension, but there was
no difference in preeclamptic women [61]. There was no difference in the
treatment of severe hypertension among beta blockers versus calcium channel
blockers or calcium channel blockers versus methyldopa. In the setting of
preeclampsia, there was no difference between beta blockers versus calcium
channel blockers as treatment [61].

Anti-Oxidants

Prior studies have noted that women with preeclampsia are found to have
reduced levels of vitamins C and E [62]. Thus, randomized studies were
conducted to evaluate whether supplementation of these two vitamins would
improve oxidative capability. A randomized, double-blind placebo controlled
Maternal-Fetal-Medicine Units Network trial compared vitamin C and E to
placebo in 10,154 women and concluded that supplementation with
antioxidant vitamins did not reduce the incidence of preeclampsia compared to
placebo [63]. Vitamin D has been studied as well and there was no benefit in
the prevention of preeclampsia [49].

Anti-Thrombotic Therapy

Antithrombotic agents have been previously considered for reduction of
preeclampsia because preeclampsia is characterized by endothelial cell
dysfunction, vasospasm, activation of platelets and the coagulation-hemostasis
system. Low-dose aspirin has been well studied; the first randomized control
study examining its effect on preeclampsia prevention was in 1986 by
Wallenburg et al. [64]. This study noted a significant reduction in the
incidence of preeclampsia thus encouraging numerous trials worldwide. A
meta-analysis in 2007 by Askie et al. noted that in patients assigned to receive
antiplatelet agents, the relative risk of preeclampsia was decreased
significantly by 10% for development of preeclampsia, superimposed
preeclampsia, preterm delivery, or any pregnancy with an adverse outcome
[65]. However, the number-needed-to-treat is 500 and 167 women to reduce
the incidence of preeclampsia to 2 percent and 6 percent respectively [65]. In
1998, the National Institute of Child Health and Development (NICHD)
performed a double-blind, randomized, placebo-controlled trial examining the
effects of low-dose aspirin in high-risk women with a history of preeclampsia,
multi-fetal gestation, chronic hypertension, or insulin-dependent diabetes and
noted no reduction in incidence of preeclampsia [66]. A more recent meta-
analysis in 2003 examined 14 randomized control trials and concluded that
low-dose aspirin reduces the risk of perinatal death and preeclampsia in
women with historical risk factors such as a previous history of preeclampsia,
chronic hypertension, diabetes and renal disease. The review recommended
that practitioners individualize the use of low-dose aspirin to prevent recurrent
preeclampsia [67]. There have also been several observational trials to
evaluate heparin treatment for women with a history of preeclampsia. An
observational study by Sergio et al. in 2006 noted that in women with a history
of severe early-onset preeclampsia prophylaxis with low-molecular-weight
heparin plus low-dose aspirin improved pregnancy outcomes compared with
those given low-dose aspirin alone [68]. However, there is no current accepted
recommendation regarding anti-thrombotic agents for the use of preeclampsia
prevention.

Long-Term Outcomes

Although it is less common in developed countries to experience maternal
mortality from pregnancy-related hypertensive disease, there are severe
morbidities (e.g. chronic hypertension and chronic renal disease) associated
with preeclampsia and eclampsia that can lead to long-term mortality. Women
with pregnancy-related hypertensive disease should be advised regarding
potential long-term risks including increased cardiovascular morbidity,
cerebrovascular disease, renal, and neurological sequelae. Commonly,
pregnancy-related hypertension resolves within 3 months postpartum, but
persistent postpartum hypertension increases the likelihood that the woman
has chronic hypertension. In 2007, the MAGPIE Trial Follow-up
Collaborative Group noted that 20 percent of 3375 preeclamptic women when
evaluated at a median of 26 months postpartum had hypertension [69].
Additionally, it was noted that an earlier gestational age of preeclampsia onset
and delivery in the first pregnancy is associated with an increased recurrence
risk in a subsequent pregnancy. A study in Finland from 2009 examined
536,419 Finnish women with preeclampsia in their first pregnancy and
delivered between 32 and 36 weeks and observed a significant increase in
incidence of preeclampsia in their second pregnancy (25 versus 14 percent)
compared with women who delivered after 37 weeks [70]. Another study from
Finland followed 896 women noted that based on the diagnosis in the initial
pregnancy, a 58 to 94 percent recurrence risk of hypertensive disorder in the
second pregnancy was noted [71]. A different study of 187 women with
eclampsia in the first pregnancy reported that 33 percent had a hypertensive
disorder in a subsequent pregnancy and 5 percent had recurrent eclampsia
[72].
A large systematic review and meta-analysis in 2007 evaluated the long-
term risks for cardiovascular disease in women with preeclampsia noted a
statistically significant increased risk of hypertension, ischemic heart disease,
stroke, and venous thromboembolism [73]. The study reported relative risks
(RR) (95% confidence intervals (CI)) for hypertension as 3.70 (2.70 to 5.05)
after 14.1 years weighted mean follow-up, for ischemic heart disease 2.16
(1.86 to 2.52) after 11.7 years, for stroke 1.81 (1.45 to 2.27) after 10.4 years,
and for venous thromboembolism 1.79 (1.37 to 2.33) after 4.7 years. Mortality
after preeclampsia was overall increased with a RR of 1.49 (1.05 to 2.14) after
14.5 years. A different large systematic review and meta-analysis in 2008
studied 15 case-control and cohort studies and demonstrated that relative to
women with uncomplicated pregnancies, women with a history of
preeclampsia/eclampsia had twice the risk of subsequent cardiac disease,
cerebrovascular disease, peripheral arterial disease, and cardiovascular
mortality [49]. This study also reported a linear relationship between the
severity of preeclampsia and eclampsia and the risk of cardiac disease [74].
Eclamptic seizures were previously not considered to result in significant
long-term sequelae, but more recent literature established that long-term
persistence of brain white matter lesions incurred at the time of eclamptic
convulsions [75, 76]. Magnetic resonance imaging is utilized in these studies
to demonstrate that an increased incidence of cerebral white matter lesions and
severity compared to controls [75, 76]. At a mean of 7.1 years, one study noted
40 percent of previously eclamptic women had larger aggregate white matter
lesions compared with 17 percent of controls, but no clinical relevance was
established. In 2012, a case-control study in the Netherlands observed that
formerly eclamptic women express lower vision-related quality of life than
controls in part because of the presence of white matter lesions [77].
Preeclamptic women are also at an increased risk of developing future
renal disease. A large retrospective study of women with a prior history of
preeclampsia over 4 decades noted a fourfold increased risk of subsequent
end-stage renal disease, but a low overall absolute risk of renal failure [78].

Conclusion

Hypertensive disorders in pregnancy remain among the leading causes of
maternal mortality worldwide. In order to significantly reduce mortality the
most important tool at this time is in controlling severe range blood pressures
( 160/110). Preeclampsia affects about 3 percent of pregnancies, and all other
hypertensive disorders complicate approximately 5 to 10 percent of
pregnancies in the United States. Despite the increasing incidence of
hypertension in pregnancy, we are currently unable to predict which patients
will develop preeclampsia. Hypertensive disorder related maternal deaths are
largely associated with hemorrhagic stroke; however, contributing factors
aside from systemic blood pressure alone are poorly understood and further
investigation is needed to define the patient at risk of stroke. New research
opportunities to better define treatment strategies aimed at improving maternal
and fetal outcomes are needed. In addition, further studies are necessary to
better understand the heterogeneity in outcomes and risk factors for all types
of hypertensive disorders.

Acknowledgments

None.

References

[1] Wagner SJ, Barac S, Garovic VD. Hypertensive pregnancy disorders:
current concepts. J Clin Hypertens. 2007;9:560-6.
[2] Martin JN, Hamilton BE, Sutton PD, et al. Births: Final Data for 2006.
Natl Vital Stat Rep 2009 Vol. 57 (7)
[3] Berg CJ, Chang J, Callaghan WM, et al: Pregnancy-related mortality in
the United States 1991-1997. Obstet Gynecol 2003;101:289
[4] Saudan P, Brown MA, Buddle ML, Jones M. Does gestational
hypertension become pre-eclampsia? BJOG. 1998;105:1177-1184.
[5] Kuklina EV, Ayala C, Callaghan WM. Hypertensive disorders and
severe obstetric morbidity in the United States. Obstet Gynecol.
2009;113(6):1299-1306.
[6] *Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia
and the other hypertensive disorders of pregnancy. Best Pract Res Clin
Obstet Gynaecol. 2011;25(4):391-403. *This is a review article
summarizing the spectrum of hypertensive disorders in pregnancy.
[7] Ventura SJ, Martin JA, Curtin SC, et al. Births: Final data for 1998.
National Vital Statistics Reports. 2000; 48(3)
[8] Royal College of Obstetricians and Gynaecologist. The management of
severe pre-eclampisa. RCOG Guideline. 2006; 10A:1
[9] Wallis AB, Saftlas AF, Hsia J, et al. Secular trends in the rates of pre-
eclampsia, eclampsia, and gestational hypertension in the United States,
1987-2004. Am J Hypertens. 2009;21:521-526.
[10] Chhabra S, Kakani A. Maternal mortality due to eclamptic and non-
eclamptic hypertensive disorders: A challenge. Journal of Obstetrics and
Gynecology. 2007;27(1): 25-29.
Working Group on High Blood Pressure in Pregnancy. Am J Obstet
Gynecol 2000. 183(1):S1-S22.
[12] Duley L. Maternal mortality associated with hypertensive disorders of
pregnancy in Africa, Asia, Latin America and Caribbean. British Journal
of Obstetrics and Gynecology. 1992. 99:547-553
[13] Walker GJ, Ashley DE, McCaw AM, Bernard GW. Maternal mortality
in Jamaica. 1986. Lancet. 1:486-488.
[14] Zarcian A. Hypertensive disorder of pregnancy. International Journal of
Gynecology and Obstetrics. 2004;87:194-198.
[15] Yucesoy G, Ozkan S, Bodur H, Tan T, Caliskan E, Vural B et al.
Maternal and perinatal oucome in pregnancies complicated with
hypertensive disorders of pregnancy: a seven year experience of a
tertiary care center. Archives of Gynecology and Obstetrics. 2005.
273:43-49.
[16] Isler CM, Rinehart BK, Terrone DA, et al. Maternal mortality associated
with HELLP (hemolysis, elevated liver enzymes, and low platelets)
syndrome. Am J Obstet Gynecol. 1999;181(4):924-8.
[17] Zhang J, Meikle S, Trumble A. Severe maternal morbidity associated
with hypertensive disorders in pregnancy in the United States. Hypertens
Pregnancy. 2003;22(2):203-12.
[18] Beck DW, Menezes MB. Intracerebral hemorrhage in a patient with
eclampsia. JAMA. 1981;246:1442-3.
[19] Martin JN Jr, Thigpen BD, Moore RC, Rose CH, Cushman J, May W.
Stroke and severe preeclampsia and eclampsia: a paradigm shift
focusing on systolic blood pressure. Obstet Gynecol 2005;105:246-54.
[20] Khan KS, Wojdyla D, Say L, et al: WHO analysis of causes of maternal
death: A systematic review. Lancet. 2006;367:1066-1074
[21] Schutte JM, Steegers EAP, Schuitemaker NEW, et al. Rise in maternal
mortality in the Netherlands. BJOG. 2010;117(4):399-406.
[22] Martin JN, Hamilton BE, Ventura SJ, et al. Births: Final Data for 2009.
Natl Vital Stat Rep 2011 Vol. 60(1)
[23] Mackay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from
preeclampsia and eclampsia. Obstet Gynecol. 2001;97(4):533-538.
[24] Tanaka M, Jaamaa G, Kaiser M, et al. Racial Disparity in Hypertensive
Disorders of Pregnancy in New York State: A 10-year Longitudinal
Population-Based Study. Am J Public Health. 2007;97(1):163-170.
[25] Bryant AS, Worioloh A, Caughey AB, Washington AE. Racial/ethnic
disparities in obstetric outcomes and care: prevalence and determinants.
Am J Obstet Gynecol. 2010;202(4):335-43.
[26] Healy AJ, Malone FD, Sullivan LM, et al. Early access to prenatal care:
implications for racial disparity in perinatal mortality. Obstet Gynecol.
2006;107(3):62531
[27] Samadi AR, Mayberry RM, Zaidi AA, Pleasant JC, McGhee N, Jr., Rice
RJ. Maternal hypertension and associated pregnancy complications
among African-American and other women in the United States. Obstet
Gynecol. 1996;87(4):55763.
[28] Wong LF, Caughey AB, Nakagawa S, Kaimal AJ, Tran SH, Cheng YW.
Perinatal outcomes among different Asian-American subgroups. Am J
Obstet Gynecol. 2008;199(4):382, e16.
[29] Rao AK, Daniels K, El-Sayed YY, Moshesh MK, Caughey AB.
Perinatal outcomes among Asian American and Pacific Islander women.
Am J Obstet Gynecol. 2006;195(3):8348.
[30] Rao AK, Cheng YW, Caughey AB. Perinatal complications among
different Asian-American subgroups. Am J Obstet Gynecol.
2006;194(5):e3941.
[31] Caughey AB, Stotland NE, Washington AE, Escobar GJ. Maternal
ethnicity, paternal ethnicity, and parental ethnic discordance: predictors
of preeclampsia. Obstet Gynecol 2005;106(1):15661.
[32] Kung HC, Hoyert DI, Xu J, Murphy SL. Deaths: final data for 2005.
Natl Vital Stat Rep. 2008;56:1-120.
[33] Tucker MJ, Berg CJ, Callaghan WM, Hsia J. The Black-White disparity
in pregnancy-related mortality from 5 conditions: differences in
prevalence and case-fatality rates. Am J Public Health. 2007;97(2):247-
51.
[34] Saving Mothers Lives: reviewing maternal deaths to make motherhood
safer: 2006-08. The Eighth Report on Confidential Enquiries into
Maternal Deaths in the United Kingdom. Centre for Maternal and Child
Enquiries (CMACE). BJOG. 2011;118(suppl 1):1-203.
[35] Committee opinion no. 514: emergent therapy for acute-onset, severe
hypertension with preeclampsia or eclampsia. Committee on Obstetric
Practice. Obstet Gynecol. 2011;118(6):1465-8.
[36] Menzies J, Magee LA, Li J, et al. Instituting surveillance guidelines and
adverse outcomes in preeclampsia. Preeclampsia Integrated Estimate of
Risk (PIERS) Study Group. Obstet Gynecol. 2007;110:121-7.
[37] Von Dadelszen P, Sawchuck D, McMaster R, et al. The active
implementation of pregnancy hypertension guidelines in British
Columbia. Translating Evidence-Based Surveillance and Treatment
Strategies (TESS) Group. Obstet Gynecol. 2010;116:659-66.
[38] Tuffnell DJ, Jankowicz D, Lindow SW et al. Outcomes of severe pre-
eclampsia/eclampsia in Yorkshire 1999/2003. BJOG. 2005;112(7):875-
880.
[39] Magee LA, Cham C, Waterman EJ, et al. Hydralazine for treatment of
severe hypertension in pregnancy: meta-analysis. BMJ. 2003;327(7421):
955-60.
[40] Raheem IA, Saaid R, Omar SZ, Tan PC. Oral nifedipine versus
intravenous labetalol for acute blood pressure control in hypertensive
emergencies of pregnancy: a randomized trial. BJOG. 2012;119(1):78-
85.
[41] Altman D, Carroli G, Duley L, et al. Magpie Trial Collaboration Group.
Do women with pre-eclampsia and their babies benefit from magnesium
sulfate? The Magpie trial: a randomized placebo-controlled trial. Lancet.
2002; 359(9321):1877-90.
[42] Belfort MA, Anthony J, Saade GR, Allen JC. A comparison of
magnesium sulfate and nimodipine for the prevention of eclampsia.
NEJM. 2003;348(4):304-11.
[43] Lucas MJ, Leveno KJ, Cunningham FG. A comparison of magnesium
sulfate with phenytoin for the prevention of eclampsia. NEJM.
1995;333(4):201-205.
[44] Duley L, Gulmezoglu AM, Henderson-Smart DJ, Chou D. Magnesium
sulfate and other anticonvulsants for women with preeclampsia.
Cochrane Database Syst Rev. 2010(11):CD000025.
[45] Meher S, Abalos E, Carroli G. Bed rest with or without hospitalisation
for hypertension during pregnancy. Cochrane Database Syst Rev 2005.
19(4);CD003514.
[46] De Snoo K. The prevention of eclampsia. Am J Obstet Gynecol.
1937;34:911-939.
[47] Knuist M, Bonsel GJ, Zondervan HA, et al. Low sodium diet and
pregnancy-induced hypertension: A multicenter randomized controlled
trial. Br J Obstet Gynaecol. 1998; 105(4):430-434.
[48] Lopez-Jaramillo P, Narvaez M, Weigel RM, et al. Calcium
supplementation reduces the risk of pregnancy-induced hypertension in
an Andes population. BJOG. 1989;96:648.
[49] Marya RK, Rathee S, Manrow M. Effect of calcium and vitamin D
supplementation on toxaemia of pregnancy. Gynecol Obstet Invest.
1987;24:38.
[50] Levine RJ, Hauth JC, Curet LB, et al. Trial of calcium to prevent
preeclampsia. NEJM. 1997;337:69.
[51] Sibai BM, Cunningham FG. Prevention of preeclampsia and eclampsia.
Chesleys Hypertensive Disorders of Pregnancy. 3
rd
Ed. New York,
Elsevier, 2009, pg 213-225.
[52] Atallah AN, Hofmeyr GJ, Duley L. Calcium supplementation during
pregnancy for preventing hypertensive disorders and related problems.
Cochrane Database Syst Rev. 2002;1:CD001059.
[53] Makrides M, Duley L, Olsen SF. Marine oil, and other prostaglandin
precursor, supplementation for pregnancy uncomplicated by pre-
eclamspia or intrauterine growth restriction. Cochrane Database Syst.
Rev. 2006;3:CD003402.
[54] Olsen SF, Secher NJ, Tabor A, et al. Randomized clinical trials of fish
oil supplementation in high risk pregnancies. Fish Oil Trials In
Pregnancy (FOTIP) Team. BJOG. 2000;107:382.
[55] Olafsdottir AS, Skuladottir GV, Thorsdottir I, et al. Relationship
between high consumption of marine fatty acids in early pregnancy and
hypertensive disorders in pregnancy. BJOG. 2006;113:301.
[56] Finnerty FA, Buchholz JH, Tuckman J. Evaluation of chlorothiazide
(Diuril) in the toxemias of pregnancy. JAMA. 1958; 166:141.
[57] Flowers CE, Grizzle JE, Easterline WE, et al. Chlorothiazide as a
prophylaxis against toxemia of pregnancy. A double blind study. Am J
Obstet Gynecol. 1962;84:919.
[58] Gray MJ. Use and abuse of thiazides in pregnancy. Clinical Obstetrics
and Gynecology. 1968;11(2):568-78.
[59] Churchill D, Beever GD, Meher S, et al. Diuretics for preventing pre-
eclampsia. Cochrane Database Syst Rev. 2007;1:CD004451.
[60] Sibai BM. Chronic Hypertension in Pregnancy. Obstet Gynecol. 2002;
100:369-377.
[61] Abalos E, Duley L, Steyn DW, Henderson-Smart DJ. Antihypertensive
drug therapy for mild to moderate hypertension during pregnancy.
Cochrane Data base Syst Review. 2007; CD002252
[62] Raijmakers MT, Dechend R, Poston L. Oxidative stress and
preeclampsia: Rational for antioxidant clinical trials. Hypertension.
2004; 44:374.
[63] Roberts JM, Myatt L, Spong CY, et al. Vitamins C and E to prevent
complications in pregnancy-associated hypertension. NEJM.
2010;362(14):1282-91.
[64] Wallenburg HCS, Dekker A, Makovitz JW, Rotmans P. Low dose
aspirin prevents pregnancy-induced hypertension and preeclampsia in
angiotensin-sensitive primigravidae. Lancet. 1986;1:1-3.
[65] Askie LM, Henderson-Smart DJ, Stewart LA. Antiplatelet agents for the
prevention of preeclampsia: A meta-analysis of individual data. Lancet.
2007; 369:179.
[66] Caritis SN, Sibai BM, Hauth J, et al. Low-dose aspirin to prevent
preeclampsia in women at high risk. NEJM. 1998;338:701-705.
[67] Coomarasamy A, Honest H, Papaioannou S, et al. Aspirin for prevention
of preeclampsia in women with historical risk factors: A systemic
review. Obstet Gynecol. 2003;101(6):1319-32.
[68] Sergio F, Clara DM, Galbriella F, et al. Prophylaxis of recurrent
preeclampsia: Low molecular weight heparin plus low-dose aspirin
versus low-dose aspirin alone. Hypertension Pregnancy. 2006; 25:115.
[69] Magpie Trial Follow-up Collaborative Group: The Magpie Trial: a
randomized trial comparing magnesium sulphate with placebo for pre-
eclampsia. Outcome for women at 2 years. BJOG. 2007;114(3):300-309.
[70] Lykke JA, Paidas MJ, Langhoof-Roos J: Recurring complications in
second pregnancy. Obstet Gynecol. 2009;113(6):1217-24.
[71] Hjartardottir S, Leifsson B, Geirsson R, et al. Recurrence of
hypertensive disorder in second pregnancy. Am J Obstet Gynecol. 2006;
194:916-920.
[72] Bellamy L, Casas JP, Hingorani AD, et al. Pre-eclampsia and risk of
cardiovascular disease and cancer in later life: Systemic review and
meta-analysis. BMJ. 2007;335:974.
[73] Mcdonald SD, Malinowski A, Zhou Q, et al. Cardiovascular sequelae of
preeclampsia/eclampsia: a systemic review and meta-analyses. Am Heart
J. 2008;156(5):918-30.
[74] Aukes AM, de Groot JC, Aarnoudse JG, et al. Brain lesions several
years after eclampsia. Am J Obstet Gynecol. 2009;200(5):504
[75] Aukes AM, de Groot JC, Wiegman MJ, et al. Long-term cerebral
imaging after pre-eclampsia. BJOG. 2012;119(9):1117-22.
[76] Wiegman MJ, de Groot JC, Jansonius NM, et al. Long-term visual
functioning after eclampsia. Obstet Gynecol. 2012;119(5):959-66.
[77] Vikse BE, Irgens LM, Leivestad T, et al. Preeclampsia and the risk of
end-stage renal disease. NEJM. 2008;359:800.
[78] Chesley SC, Annitto JE, Cosgrove RA. The remote prognosis of
eclamptic women. Sixth periodic report. Am J Obstet Gynecol.
1976;124:446-459.

Chapter XII

From Molecular Mechanisms
to Treatment Options

Christos Iavazzo, M.D., M.Sc., Ph.D.

Iaso Maternity Hospital, Athens, Greece
Nea Ionia, Athens, Greece

Introduction

Preeclampsia is a systemic disorder affecting many organ systems. It is
defined according to the National Blood High Pressure Education Programme
Working Group on High Blood Pressure in Pregnancy criteria including:
elevated blood pressure > 140 mm Hg systolic and > 90 mm Hg diastolic,
proteinuria > 0.3 g/24 h, and leg edema [1,2]. Severe preeclampsia is
characterised by elevated blood pressure > 160 mm Hg systolic and > 110 mm
Hg diastolic, proteinuria > 5 g/24 h, oliguria < 500 cc / 24 h, headaches,
epigastric pain, vomiting, visual disturbance, low platelets, and elevated liver
function tests [3,4].
Severe preeclampsia and eclampsia are rather rare conditions with an
incidence reaching 5/100 and 5/10000, respectively. Preeclampsia is a
pregnancy-specific syndrome and is associated with significant maternal and
fetal morbidity and mortality especially before 34 weeks [3,4].

Tel.: 00306948054119; Email: christosiavazzo@hotmail.com
Christos Iavazzo 262
A failure of trophoblastic invasion of the maternal spiral arteries leading
to inadequate uteroplacental flow are implicated in the pathology. Most
commonly, preeclampsia occurs in healthy nulliparous women [5]. However,
multiparous pregnant women with a new partner have an increased risk of
preeclampsia similar to that of nulliparous women [6,7]. Women with a
history of preeclampsia in a prior pregnancy are also at an increased risk of
developing preeclampsia in future pregnancies [6,8].
A history of preeclampsia in the fathers mother also confers an increased
risk [6,9,10]. Several medical conditions, such as chronic hypertension,
diabetes mellitus, renal disease and hypercoagulative conditions are associated
with increased preeclampsia risk. Additionally, obstetrical conditions with
increased placental mass increase the risk of preeclampsia. These include
hydatiform mole and multifetal gestation.
Normal pregnancy is thought to be a condition of mild systemic
inflammatory response [11-14]. Some evidence from this systemic
inflammatory response comes from measuring circulating cytokines. In
preeclampsia a similar but exaggerated response occurs. The mechanisms
responsible for the pathogenesis of preeclampsia have not yet been clearly
identified, but reduced uterine perfusion and placental ischemia are important
initiating events in this disorder and inflammatory cytokines are thought to
link placental ischemia with cardiovascular and renal dysfunction symptoms
seen in this disorder [15,16].
The aim of this chapter is to clarify the possible molecular mechanisms of
preeclampsia pathogenesis and based on them to explain the treatment options.

Molecular Mechanisms

Many molecular mechanisms contribute to the pathogenesis of
preeclampsia. Placental hypoxia and ischemia, relaxin effect, altered
angiogenic balance, systemic inflammation, and dysregulation of renin -
angiotensin system are mechanisms which lead to the pathogenesis of
pre-eclampsia, although it is unknown whether the mechanisms act
independently or have synergistic effects.

From Molecular Mechanisms to Treatment Options 263
A. Placental Hypoxia and Ischemia

Impaired trophoblast invasion and inadequate maternal spiral artery
remodelling results in placental ischemia and hypoxia [17]. It is unknown,
however, whether abnormal placentation leads to systemic vascular
dysfunction and the appearance of preeclampsia [18]. Moreover, defective
trophoblast invasion and inadequate maternal spiral remodelling frequently
results to intrauterine growth restriction or other complications of pregnancy
(e.g. preterm labor) without preeclampsia even to normal full term pregnancy
[19-23]. Women living in high altitudes are shown to have an increased risk of
developing pre-eclampsia, while cigarette smoking is associated with a
reduced risk for preeclampsia [24]. Experiments in animals suggest placental
hypoxia contributes to preeclampsia by upregulating soluble antiangiogenic
factors, inflammatory cytokines, downregulating angiogenic and vasodilator
factors [20-23].
Furthermore, in pregnant mice, an absence of 2-methoxyoestradiol
(2-ME), a natural metabolite of estradiol results in a deficient of catechol-o-
methy-stransferase (COMT). These animals showed a preeclampsia like
phenotype. The addition of 2-ME was shown to improve preeclampsia,
suppresses placental hypoxia and sflt-1 expression. It is, however, unclear
whether or not decreased COMT is the cause of the consequence of impaired
placentation [25].

B. The Role of Relaxin in Pre-Eclampsia

Relaxin is produced by the corpus luteus of the ovary and rises early in
pregnancy, and chorionic gonadotropin produced by the placenta is a major
stimulus for relaxin secretion during pregnancy [26].
Relaxin has renal vasodilatory effect and it also diminishes the relaxin
vasocontructor response to angiotensin II [27,28]. Moreover, reduced
myogenic reactivity of small renal arteries is observed after relaxin
administration. Recently, it has been proposed that relaxin via relaxin receptor
upregulates vascular gelatinase activity during pregnancy, contributing to renal
vasodilation through activation of endothelial endothelin B (ET
B
) receptor
which activates nitric oxide synthase III and the production of NO [27-30].
Thus, increased vascular gelatinase activity by relaxin is thought to be a
proximal step in the vasodilatory pathway of pregnancy [30].
Circulating levels of immunoreactive relaxin have been reported to be
similar in women with preeclampsia and normal pregnancy [29]. However,
whether circulating relaxin bioactivity may be deficient during the disease is
uncertain. Furthermore, mutations or polymorphisms of the ET
B
receptor or of
endothelial NO synthase that reduce activity may predispose a woman to
preeclampsia by impairing trophoblast invasion on the one hand or by
compromising maternal endothelial behaviour on the other [31, 32].

C. Angiogenic Factors

A variety of angiogenic factors are produced from the human placenta.
The most important between them are the vascular endothelial growth factor
(VEG F) and the placental growth factor (PIGF) [33-38]. VEGF is an
endothelial-specific mitogen that plays a key role in promoting angiogenesis.
VEGF stabilizes endothelium in mature blood vessels [33-38]. VEGFS
activities are mediated primarily by its interaction with two high-affinity
receptors tyrosine kinases kinase insert domain region (KDR or VEGF R-
2) and fms-like tyrosine kinase-1 or flt-1) [39-43]. Both receptors are
expressed on vascular endothelial cell surface. PIGF is also an angiogenic
growth factor that is thought to amplify VEGF signalling by displacing VEGF
from the flt-1 receptor and allowing it to bind to the more active kinase insert
domain (KDT) receptor [44-48].
Recent research has shown that soluble flt-1 is released by the placenta
into the maternal circulation and that contributes to the hypertension,
proteinuria and endothelial cell dysfunction associated with pre-eclampsia [49-
54]. Sflt-1 antagonizes both VEGF and PIGF by binding them in the
circulation and preventing interaction with their endogenous receptors. New
variants of sflt-1 have been discovered such as sflt1-14, which is also a potent
VEGF inhibitor. The level of SFLt-1 in the plasma of women with
preeclampsia is elevated and that of VEGF is diminished in comparison with
that of the women with complicated pregnancies. Furthermore, administration
of sflt-1 to rats resulted in elevated blood pressure, and proteinuria, indicating
that excessive placenta-derived sflt-1 max contributes to pre-eclampsia
[49-51].
Factors responsible for excessive production of self-1 in preeclampsia
have not been identified. However, recently it has been found that angiotensin
II type 1 (AT) receptor auto antibodies which occur in women with
preeclampsia, contribute to increased production of sflt-1 [52,53]. Thus, IgG
from women with pre-eclampsia stimulates the synthesis and secretion of sflt-
1, via AT
1
receptor activation in human placental villous explants and human
trophoblast cells. Another factor which contributes to increased production of
sflt-1 is the hypoxic placenta. Under other pathophysiological conditions such
as cancer, hypoxia generally stimulates angiogenic signalling, it remains
poorly understood why hypoxic placenta produces the molecules that suppress
angiogenesis in preeclampsia [52-54].
Soluble endoglin, is another antiangiogenic protein, which acts to get in
combination with sflt-1 to induce a severe-preeclampsia like syndrome in
pregnant rats [52-55]. Circulating soluble endoglin levels increased markedly
beginning 2 to 3 months before the onset of preeclampsia. An increased level
of soluble endoglin was usually accompanied by an increased ratio of sflt-1
[52-55].
Experimental data have been shown VEGF stimulates the production of
both nitric oxide (NO) and PGI
2
. On the other hand, a high concentration of
asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial
nitric oxide synthase has been found in pre-eclamptic women. Women with
bilateral notches who later developed pre-eclampsia had a striking elevation in
the concentration of the NO synthase inhibitor [37,49,56].
ADMA is normally metabolized to citrulise through the action of
dimethylarginine-dimethyldyaminohydrolase I, II (DDAH I, II). Oxidative
stress seen in pre-eclampsia also diminishes the action of the alone enzymes
leading to high concentration of ADMA [49,56].

D. Inflammatory Cytokines in the Pathophysiology
of Preeclampsia

Natural killer (NK) cells, dendritic cells and macrophages are mediators of
innate immunity [14]. Macrophages and dendritic cells are the major antigen-
presenting cells in the uterus, and they facilitate adaptation of the immune
response to prevent rejection of the embryo [57,58]. A number of studies have
found a statistically significant increase in macrophages and dendritic cells in
preeclamptic placentas compared to placentas from normotensive pregnancies
[59-64]. An increase in the concentration of cytokines, molecules capable of
recruiting macrophages and dentritic cells have also been found in
preeclamptic placentas. The increased presence of cytokines, macrophages and
dendritic cells in pre-eclamptic placentas supports the hypothesis that an
inflammatory milieu present in women with pre-eclampsia [65-68].
Reduced uterine perfusion during pregnancy is an important initialling
event in preeclampsia. Inflammatory cytokines are thought to link placental
ischemia with cardiovascular and renal dysfunction [69]. For example,
conflicting results are found regarding the role of circulating IL-6 and TNF-
alpha in a review of the current literature. Many authors believe that
circulating levels of TNF-alpha and IL-6 are enhanced in preeclamptic patients
compared with normotensive and non-pregnant women [70-72]. In two
different studies, Guven et al. and Tosun et al. had recently shown that
maternal serum levels of IL-6 and TNF-alpha are significantly increased in
preeclamptic patients rising in a way that higher levels are found in patients
with severe compared to mild preeclampsia [61,62]. Additionally, there has
been an active research for circulating factors such as TNF-alpha, IL-6, IL-
1alpha, IL-1beta, asymmetrical dimethyl arginine that may contribute in the
mechanisms underlying preeclampsia. Trying to explain such findings,
Cachovic et al. showed that the fractional secretion of TNF-alpha is
significantly reduced in preeclamptic women and for this reason they suggest
that the decreased clearance and altered renal excretion of TNF-alpha may
lead to preeclampsia [64]. On the contrary others did not manage to identify a
correlation between maternal serum levels of IL-6 or TNF-alpha and
preeclampsia [72,73]. Based on their results concluded that preeclampsia
screening based on cytokines such as IL-6 or TNF-alpha is not proposed.
Furthermore, there is no information about maternal blood concentrations of
IL-6 and TNF-alpha in women with preeclampsia long time after delivery.
In normal pregnancy TNF-a is low in the first trimester and subsequently
increases with advancing gestation age. Some studies report higher TNF-a
levels in women with established preeclampsia. Increased levels of TNF-a
antigen and mRNA have been described in placental tissue from preeclamptic
women [67-69]. The source of excess TNF-alpha in preeclampsia remains
unclear. Histological observations in near term placental bed biopsies,
although still conflicting, indicate higher local expression of these cytokines in
preeclamptic patients. Decidual monocytes and macrophages are also a rich
source of TNF-alpha [63]. The elevated secretion of TNF-alpha by placental
villous tissue in response to hypoxia causes a reduction of endothelial cell
viability and up-regulates the expression of the adhesion molecule E-selectin
by the endothelial cell. It is possible that syncytiotrophoblast could synthesize
and release excessive amounts of proinflammatory cytokines such as TNF-
alpha or IL-6, but an analysis of production from chorionic villous explants
failed to show the expected increase in protein or mRNA for TNF-alpha, IL-6,
IL-1alpha, and IL-1beta when tissue from preeclampsia compared to normal
pregnancy [61-67]. Additionally, although peripheral and uterine vein blood
concentrations of TNF-alpha were increased relative to control, there was no
gradient between the two sources. Thus, there is no convincing evidence that
the preeclampsia placenta disseminates inflammatory cytokines into the
maternal circulation [66,67]. In parallel, in vitro in a dually perfused placental
cotyledon, most of placental TNF-alpha was released to the maternal size
confirming the importance of placentally produced inflammatory mediators in
the induction of the maternal systemic changes. Hypoxia increases TNF-alpha
synthesis by placental villous tissue in vitro. Additionally, chemicals which
trigger placental oxidative stress also stimulates elevated TNF-alpha
production by villous explants [68,69]. On the other hand, NO hypoxia-driven
changes in IL-6 synthesis by placental explants were documented [71,72].
These data to contradict the finding that preeclampsia is associated with
decreased placental IL-6 production.
Because TNF-a may impair insulin signalling inhibit lipoprotein lipase
induce PAI-1 and directly contribute to endothelial dysfunction, this cytokine
may be involved in the pathogenesis of pre-eclampsia. There are also findings
showing that chronic infusion of IL-6 into normal pregnant rats stimulates the
renin-angiotensin system (PAS) [74,75].

E. Activation of Renin-Angiotensin System (RAS)

Renin-Angiotensin system is the one that controls blood pressure [76,77].
The expression of rennin mRNA was detected in human deciduas,
macrophages, chorioamniotic membrane and vascular smooth muscle cells
[76]. Angiotensin II receptor type I (AT
1
) was shown to be localized both in
villous and extravillus trophoblasts and this AT
1
responds to exogenously
administrated angiotensin II. The circulating level of angiotensin II increases
as the pregnancy advances [77-79]. In pre-eclampsia, the circulating level of
angiotensin is rather decreased, despite the fact that the vascular sensitivity to
angiotensin is elevated in hypertensive pregnanct women [77,80].
The AT
1
receptor gene expression was higher in placenta than in deciduas
for both normal and pre-eclamptic women [78]. However, the deciduas of
preeclamptic women has a significantly higher AT
1
receptor gene expression
than normal pregnant women. It has been found that the gene encoding the
AT
1
-receptor was upregulated in the deciduas of preeclamptic women but not
in normal control. Circulating agonistic autoantibodies directed at the
angiotensin II type 1 receptor (AT
1
-AA
s
) have been discovered in women with
preeclampsia [78,79].
Thus the increased decidual AT-1 expression in pre-eclampsia may be the
initial step for a profound RAS activation. Furthermore, the presence of AT
1
-
AA
s
is able to activate cells via the AT
1
receptor and initiate signaling events
that could contribute to development of preeclampsia [76-78]. Thus, release of
soluble flt-1 can be triggered by angiotensin II stimulation, raising an
imbalance between angiogenic vascular endothelial growth factors and
antiangiogenic soluble factors [77]. Zhou et al. have shown that the inhibition
of AT
1
administration of losartan or FK506 resulted in reduced SVEGFR-1
[42]. Thus, maternal SVEGFR-1 can be elevated not only by poor placentation
but also by AT
1
activation in which angiotensin II and AT
1
-AA
s
are potentially
implicated [42].

Treatment

Delivery of the placenta remains the only known treatment for
preeclampsia, suggesting that the placenta is the principal contributor to the
pathogenesis of it [81-85]. It is well known that the first step for the
development of preeclampsia is the inadequate placental cytotrophoblast
invasion impaired throphoblast invasion and inadequate maternal spiral artery
remodeling which result in placental ischemia and hypoxia [86,87]. However,
placental ischemia does not always generate the clinical symptoms of
preeclampsia.
Delivery is the cure of preeclampsia, however the mother should be
stabilised. Fetal indications for delivery in preeclampsia include severe
intrauterine growth restriction, non-reassuring fetal surveillance, and
oligohydramnios. Maternal indications for delivery in preeclampsia include
gestational age of 38 weeks or greater, platelet count < 100,000/mm3,
progressive deterioration of hepatic or renal function, suspected placental
abruption, persistent severe headaches, visual changes, epigastric pain or
vomiting, and eclampsia. Delivery route should be based on obstetric
indications as no advantages are mentioned in favor of caesarean section [81,
85-88]. During delivery, the main goals are to prevent seizures and control
hypertension. Moreover, ergometrine should not be used in cases of severe
preeclampsia and eclampsia as it could further increase the blood pressure
[87,88].
Regarding prevention of preeclampsia, a recent Cochrane review suggests
that oral administration of 75-150 mg aspirin/day reduces preeclampsia rates
by 17%, and neonatal mortality by 14% [86]. It is known that aspirin inhibits
thromboxane production induced by preeclampsia [89,90].
The management of preeclampsia aims to offer continued maternal and
fetal monitoring, blood pressure control, seizures prevention, fetal pulmonary
maturation, and finally delivery at the optimal time. Moreover, genetic factors
influence the pathogenetic mechanisms. The inherited nature of
preeclampsia is known, and for this reason extensive genetic studies have
been undertaken [85,88]. Pharmacogenomics offers the prospect of
individualized patient treatment, ensuring swift introduction of optimal
treatment whilst minimizing the use of inappropriate or ineffective drugs, and
so can lead to individualized use of antiplatelet agents, alpha and beta
blockers, calcium channel blockers, and magnesium sulfate [89-92]. There is a
need of cooperation between obstetricians, anaesthesiologists, nephrologists,
and midwives.
Preterm pregnancies complicated by moderate preeclampsia should be
extended in order to achieve pulmonary maturation by administration of
corticosteroids. Such patients should be hospitalized and observed for either
maternal or fetal compromise. Regular assessment of blood pressure, urine
output, fluid balance, maternal reflexes, respiratory rate, and oxygen saturation
[86-88]. The laboratory tests include hemoglobin level, hematocrit, platelet
count, serum creatinine level, serum uric acid level, serum transaminase level,
lactic acid dehydrogenase level, coagulation profile, and urine protein
collection (12 or 24 hour) [89-93].
Conservative management of preeclampsia includes antihypertensives
(e.g. intravenous hydralazine or labetalole; see chapter 1), and an agent against
seizure activity (e.g. MgSO4) [88-93]. As preeclampsia is characterized by
vasoconstriction and intravascular depletion, diuretics are not included as a
first-line treatment option. Moreover, atenolol is associated with intrauterine
growth restriction, angiotensin converting enzyme inhibitors, and angiotensin
receptor-blocking drugs have fetal adverse effects, and for these reasons
should be avoided [92-94].
Usually, methyldopa, labetalol and oxprenolol are first-line options,
whereas hydralazine, nifedipine and prazosin are used as second-line options
[88-93, 95-97]. Acute management of severe preeclampsia includes oral or
intravenous use of labetalol, oral use of nifedipine or intravenous use of
hydralazine. Fetal monitoring with continuous cardiotocogram is proposed
during and for 30 minutes after intravenous drugs [95-97]. More specifically,
10 mg hydralazine is administered intravenously slowly, with repeat doses of 5
mg if it is necessary. Intravenous hydralazine is associated with maternal or
fetal side effects (e.g. placental abruption) [95-97]. If blood pressure is still
uncontrolled, 50 mg labetalol should be administered intravenously slowly
with repeat dose of 50 mg after 20 minutes [95-97]. Labetalol should be
avoided in patients with asthma or congestive heart failure. Oral
administration (not sublingually) of nifedipine is preferred in a dose of 10 mg
[95-97]. However, it should be reminded that nifedipine interacts with MgSO4
causing muscle weakness, severe hypotension and fetal distress [95-97].
MgSO4 is the option of choice for the treatment of women at risk for
eclampsia. MgSO4 has been shown to be superior to phenytoin or diazepam
for the treatment of eclamptic seizures [88,89,93]. According to the Magpie
trial, MgSO4 use has a 58% lower risk of an eclamptic seizure [93]. The
loading dose is 4 g in 5-10 minutes, followed by 1 g/h for 24 hours. In case of
recurrent seizures, a bolus 2 g dose of MgSO
4
is further infused. It should be
mentioned that MgSO4 should be continued for 24 hours after delivery.
Respiratory rate should be > 16 breaths/minute, urine output > 25 ml/h, and
patellar reflexes present [88,89,93]. With increasing levels of MgSO4, the
following may occur: i. 3.8-5.0 mmol/l flushing, ii. > 5.0 mmol/l loss of
tendon reflexes, iii. > 6.0 mmol/l respiratory depression, iv. 6.3-7.1 mmol/l
respiratory, and v. > 12.0 cardiac arrest. Calcium gluconate (1 g over 10
minutes) is the counterpoison in case of respiratory depression.
After delivery, signs and symptoms of preeclampsia resolve in a variable
time during puerperium. However, careful review before discharge is proposed
as there is still a risk of late seizures. It is known that 44% of eclampsia occurs
in the puerperium. For this reason, anti-hypertensive treatment should be
continued postpartum.

Conclusion

Preeclampsia is a common complication of pregnancy presenting as a
complex syndrome with a multivariate pathogenesis. The chapter clarified
possible molecular mechanisms of preeclampsia pathogenesis and based on
them explained the treatment options. Molecular mechanisms contribute to the
pathogenesis of preeclampsia such as placental hypoxia and ischemia, relaxin
effect, altered angiogenic balance, systemic inflammation, and dysregulation
of renin - angiotensin system. Taken into account all these mechanisms, the
management of preeclampsia aims to offer continued maternal and fetal
monitoring, blood pressure control, seizures prevention, fetal pulmonary
maturation, and finally delivery at the optimal time.

References

[1] Walker JJ. Pre-eclampsia. Lancet. 2000;356(9237):1260-5.
[2] Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC, Hauth JC,
Wenstrom KD Hypertensive disorders in pregnancy in: Williams
Obstetrics, 21
st
ed, McGraw-Hill, New York 2001;p.567-618.
[3] Walker JJJ. Pre-eclampsia. Lancet, 2000;356:1260-1265.
[4] Cunningham FG, Gant NF, Leveno KJ, Gilstrap LC, Hauth JC,
Wenstrom KD. Hypertensive disorders in pregnancy in: Williams
Obstetrics, 21
st
ed, McGraw-Hill, New York 2001, p. 567-618.
[5] Hauth JC, Ewell MG, Levine RJ, Esterlitz JR, Sibai B, Curet LB,
Catalano PM, Morris CD. Pregnancy outcomes in healthy nulliparas
who developed hypertension. Calcium for Preeclampsia Prevention
Study Group. Obstet Gynecol. 2000;95(1):24-8.
[6] Hanna N, Hanna I, Hleb M, Wagner E, Dougherty J, Balkundi D,
Padbury J, Sharma S. Gestational age-dependent expression of IL-10
and its receptor in human placental tissues and isolated cytotrophoblasts.
J. Immunol. 2000;164(11):5721-8.
[7] Tubbergen P, Lachmeijer AM, Althuisius SM, Vlak ME, van Geijn HP,
Dekker GA. Change in paternity: a risk factor for preeclampsia in
multiparous women? J Reprod Immunol. 1999;45(1):81-88.
[8] Barton JR, Sibai BM.Prediction and prevention of recurrent
preeclampsia. Obstet Gynecol. 2008;112(2 Pt 1):359-372.
[9] Hauth JC, Ewell MG, Levine RJ, Esterlitz JR, Sibai B, Curet LB,
Catalano PM, Morris CD. Pregnancy outcomes in healthy nulliparas
who developed hypertension. Calcium for Preeclampsia Prevention
Study Group. Obstet Gynecol, 2000;95:24-28.
[10] Esplin MS, Fausett MB, Fraser A, Kerber R, Mineau G, Carrillo J,
Varner MW. Paternal and maternal components of the predisposition to
preeclampsia. N Engl J Med. 2001;344(12):867-872.
[11] Arntzen KJ, Liabakk NB, Jacobsen G, Espevik T, Austgulen R. Soluble
tumor necrosis factor receptor in serum and urine throughout normal
pregnancy and at delivery. Am. J. Reprod Immunol. 1995;34(3):163-9.
[12] Borzychowski AM, Sargent IL, Redman CW. Inflammation and pre-
eclampsia. Semin Fetal Neonatal Med. 2006;11(5):309-16.
[13] LaMarca BD, Ryan MJ, Gilbert JS, Murphy SR, Granger
JP.Inflammatory cytokines in the pathophysiology of hypertension
during preeclampsia. Curr. Hypertens Rep. 2007;9(6):480-5.
[14] Kupferminc MJ, Peaceman AM, Wigton TR, Rehnberg KA, Socol ML.
Tumor necrosis factor-alpha is elevated in plasma and amniotic fluid of
patients with severe preeclampsia. Am. J. Obstet Gynecol.
1994;170(6):1752-7; discussion 1757-9.
booking: systematic review of controlled studies. BMJ.
2005;330(7491):565.
[16] Sibai B, Dekker G, Kupferminc M. Pre-eclampsia. Lancet.
2005;365(9461):785-799.
[17] Malek A, Sager R, Schneider H. Effect of hypoxia, oxidative stress and
lipopolysaccharides on the release of prostaglandins and cytokines from
human term placental explants. Placenta. 2001;22 Suppl A:S45-50.
[18] Hung TH, Charnock-Jones DS, Skepper JN, Burton GJ. Secretion of
tumor necrosis factor-alpha from human placental tissues induced by
hypoxia-reoxygenation causes endothelial cell activation in vitro: a
potential mediator of the inflammatory response in preeclampsia. Am. J.
Pathol. 2004;164(3):1049-61.
[19] Bdolah Y, Lam C, Rajakumar A, Shivalingappa V, Mutter W, Sachs BP,
Lim KH, Bdolah-Abram T, Epstein FH, Karumanchi SA. Twin
pregnancy and the risk of preeclampsia: bigger placenta or relative
ischemia? Am. J. Obstet Gynecol. 2008;198(4):428.e1-6.
[20] Furuya M, Ishida J, Aoki I, Fukamizu A. Pathophysiology of
placentation abnormalities in pregnancy-induced hypertension. Vasc
Health Risk Manag. 2008;4(6):1301-13.
[21] Huang SJ, Chen CP, Schatz F, Rahman M, Abrahams VM, Lockwood
CJ. Pre-eclampsia is associated with dendritic cell recruitment into the
uterine decidua. J. Pathol. 2008;214(3):328-336.
[22] Zamudio S. High altitude hypoxia and preeclampsia. Front Biosci.
2007;12:2967-2977.
[23] Xiong X, Wang FL, Davidge ST, Demianczuk NN, Mayes DC, Olson
DM, Saunders LD. Maternal smoking and preeclampsia. J. Reprod Med.
2000;45(9):727-732.
[24] Karumanchi SA, Bdolah Y. Hypoxia and sFlt-1 in preeclampsia: the
"chicken-and-egg" question. Endocrinology. 2004;145(11):4835-7.
[25] Kanasaki K, Palmsten K, Sugimoto H, Ahmad S, Hamano Y, Xie L,
Parry S, Augustin HG, Gattone VH, Folkman J, Strauss JF, Kalluri R.
Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is
associated with pre-eclampsia. Nature. 2008;453(7198):1117-1121.
[26] Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal
vasodilator in conscious rats. J. Clin Invest. 1999;103(4):525-533.
[27] Jeyabalan A, Novak J, Danielson LA, Kerchner LJ, Opett SL, Conrad
KP. Essential role for vascular gelatinase activity in relaxin-induced
renal vasodilation, hyperfiltration, and reduced myogenic reactivity of
small arteries. Circ. Res. 2003;93(12):1249-1257.
[28] Davison JM, Homuth V, Jeyabalan A, Conrad KP, Karumanchi SA,
Quaggin S, Dechend R, Luft FC. New aspects in the pathophysiology of
preeclampsia. J. Am. Soc Nephrol. 2004;15(9):2440-2448.
[29] Szlachter BN, Quagliarello J, Jewelewicz R, Osathanondh R, Spellacy
WN, Weiss G. Relaxin in normal and pathogenic pregnancies. Obstet
Gynecol. 1982;59(2):167-170.
[30] Hsu SY, Nakabayashi K, Nishi S, Kumagai J, Kudo M, Sherwood OD,
Hsueh AJ. Activation of orphan receptors by the hormone relaxin.
Science. 2002;295(5555):671-674.
[31] Martin D, Conrad KP. Expression of endothelial nitric oxide synthase by
extravillous trophoblast cells in the human placenta. Placenta.
2000;21(1):23-31.
[32] Goligorsky MS, Budzikowski AS, Tsukahara H, Noiri E. Co-operation
between endothelin and nitric oxide in promoting endothelial cell
migration and angiogenesis. Clin. Exp. Pharmacol. Physiol.
1999;26(3):269-271.
[33] Levine RJ, Maynard SE, Qian C, Lim K-H, England LJ, Yo KF,
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, Sibai BM,
Sukhatme VP, Karumanchi SA. Circulating angiogenic factors and the
risk of preeclampsia. New Eng J. Med, 2004;350:672-683.
[34] Maharaj AS, Walshe TE, Saint-Geniez M, Venkatesha S, Maldonado
AE, Himes NC, Matharu KS, Karumanchi SA, D'Amore PA. VEGF and
TGF-beta are required for the maintenance of the choroid plexus and
ependyma. J. Exp Med. 2008 Feb 18;205(2):491-501.
[35] Dvorak HF. Vascular permeability factor/vascular endothelial growth
factor: a critical cytokine in tumor angiogenesis and a potential target for
diagnosis and therapy. J. Clin. Oncol. 2002 Nov 1;20(21):4368-4380.
[36] Autiero M, Luttun A, Tjwa M, Carmeliet P. Placental growth factor and
its receptor, vascular endothelial growth factor receptor-1: novel targets
for stimulation of ischemic tissue revascularization and inhibition of
angiogenic and inflammatory disorders. J. Thromb. Haemost.
2003;1(7):1356-1370.
[37] Kendall RL, Wang G, Thomas KA. Identification of a natural soluble
form of the vascular endothelial growth factor receptor, FLT-1, and its
heterodimerization with KDR. Biochem. Biophys. Res. Commun.
1996;226(2):324-328.
[38] Kendall RL, Thomas KA. Inhibition of vascular endothelial cell growth
factor activity by an endogenously encoded soluble receptor. Proc. Natl
Acad Sci USA. 1993;90(22):10705-10709.
[39] Wathn KA, Tuutti E, Stenman UH, Alfthan H, Halmesmki E, Finne P,
Ylikorkala O, Vuorela P. Maternal serum-soluble vascular endothelial
growth factor receptor-1 in early pregnancy ending in preeclampsia or
intrauterine growth retardation. J. Clin. Endocrinol. Metab. 2006;91(1):
180-184.
[40] Thomas CP, Andrews JI, Liu KZ. Intronic polyadenylation signal
sequences and alternate splicing generate human soluble Flt1 variants
and regulate the abundance of soluble Flt1 in the placenta. FASEB J.
2007;21(14):3885-3895.
[41] Sela S, Itin A, Natanson-Yaron S, Greenfield C, Goldman-Wohl D,
Yagel S, Keshet E. A novel human-specific soluble vascular endothelial
growth factor receptor 1: cell-type-specific splicing and implications to
vascular endothelial growth factor homeostasis and preeclampsia. Circ.
Res. 2008;102(12):1566-1574.
[42] Zhou CC, Ahmad S, Mi T, Abbasi S, Xia L, Day MC, Ramin SM,
Ahmed A, Kellems RE, Xia Y. Autoantibody from women with
preeclampsia induces soluble Fms-like tyrosine kinase-1 production via
angiotensin type 1 receptor and calcineurin/nuclear factor of activated T-
cells signaling. Hypertension. 2008;51(4):1010-1019.
[43] Ahmad S, Ahmed A. Elevated placental soluble vascular endothelial
growth factor receptor-1 inhibits angiogenesis in preeclampsia. Circ Res.
2004;95(9):884-91.
[44] Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer.
2003;3(10):721-732.
[45] Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM,
Epstein FH, Romero R, Thadhani R, Karumanchi SA; CPEP Study
Group. Soluble endoglin and other circulating antiangiogenic factors in
preeclampsia. N Engl J Med. 2006;355(10):992-1005. Erratum in: N
Engl J. Med. 2006;355(17):1840.
[46] He H, Venema VJ, Gu X, Venema RC, Marrero MB, Caldwell RB.
Vascular endothelial growth factor signals endothelial cell production of
nitric oxide and prostacyclin through flk-1/KDR activation of c-Src. J.
Biol. Chem. 1999;274(35):25130-25135.
[47] Vallance P, Leone A, Calver A, Collier J, Moncada S. Accumulation of
an endogenous inhibitor of nitric oxide synthesis in chronic renal failure.
Lancet. 1992;339(8793):572-575.
[48] Savvidou MD, Hingorani AD, Tsikas D, Frlich JC, Vallance P,
Nicolaides KH. Endothelial dysfunction and raised plasma
concentrations of asymmetric dimethylarginine in pregnant women who
subsequently develop pre-eclampsia. Lancet. 2003;361(9368):1511-
1517.
[49] Danielson LA, Sherwood OD, Conrad KP. Relaxin is a potent renal
vasodilator in conscious rats. J. Clin. Invest. 1999;103(4):525-533.
[50] Conrad KP, Colpoys MC. Evidence against the hypothesis that
prostaglandins are the vasodepressor agents of pregnancy. Serial studies
in chronically instrumented, conscious rats. J. Clin. Invest.
1986;77(1):236-245.
[51] Danielson LA, Conrad KP. Acute blockade of nitric oxide synthase
inhibits renal vasodilation and hyperfiltration during pregnancy in
chronically instrumented conscious rats. J. Clin. Invest. 1995;96:482-
490.
[52] Morgan T, Craven C, Ward K. Human spiral artery renin-angiotensin
system. Hypertension. 1998;32(4):683-687.
[53] Zhou CC, Ahmad S, Mi T, Xia L, Abbasi S, Hewett PW, Sun C, Ahmed
A, Kellems RE, Xia Y. Angiotensin II induces soluble fms-Like tyrosine
kinase-1 release via calcineurin signaling pathway in pregnancy. Circ.
Res. 2007;100(1):88-95.
[54] Zheng J, Bird IM, Chen DB, Magness RR. Angiotensin II regulation of
ovine fetoplacental artery endothelial functions: interactions with nitric
oxide. J. Physiol. 2005;565(Pt 1):59-69.
[55] Hanssens M, Keirse MJ, Spitz B, van Assche FA. Angiotensin II levels
in hypertensive and normotensive pregnancies. Br. J. Obstet Gynaecol.
1991;98(2):155-161.
[56] Herse F, Dechend R, Harsem NK, Wallukat G, Janke J, Qadri F, Hering
L, Muller DN, Luft FC, Staff AC. Dysregulation of the circulating and
tissue-based renin-angiotensin system in preeclampsia. Hypertension.
2007;49(3):604-611.
[57] Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jpner
A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H,
Luft FC. Patients with preeclampsia develop agonistic autoantibodies
against the angiotensin AT1 receptor. J. Clin. Invest. 1999;103(7):945-
952.
1994;170(6):1752-7; discussion 1757-9.
[59] Borekci B, Aksoy H, Al RA, Demircan B, Kadanali S. Maternal serum
interleukin-10, interleukin-2 and interleukin-6 in pre-eclampsia and
eclampsia. Am. J. Reprod Immunol. 2007;58(1):56-64.
[60] Al-Othman S, Omu AE, Diejomaoh FM, Al-Yatama M, Al-Qattan F.
Differential levels of interleukin 6 in maternal and cord sera and
placenta in women with pre-eclampsia. Gynecol Obstet Invest.
2001;52(1):60-5.
[61] Guven MA, Coskun A, Ertas IE, Aral M, Zencirci B, Oksuz H.
Association of maternal serum CRP, IL-6, TNF-alpha, homocysteine,
folic acid and vitamin B12 levels with the severity of preeclampsia and
fetal birth weight. Hypertens Pregnancy. 2009;28(2):190-200.
[62] Tosun M, Celik H, Avci B, Yavuz E, Alper T, Malatyaliolu E.
Maternal and umbilical serum levels of interleukin-6, interleukin-8, and
tumor necrosis factor-alpha in normal pregnancies and in pregnancies
complicated by preeclampsia. J. Matern Fetal Neonatal Med. 2010
May 4.
[63] Page NM, Woods RJ, Gardiner SM, Lomthaisong K, Gladwell RT,
Butlin DJ, Manyonda IT, Lowry PJ. Excessive placental secretion of
neurokinin B during the third trimester causes pre-eclampsia. Nature.
2000;405(6788):797-800.
[64] Cackovic M, Buhimschi CS, Zhao G, Funai EF, Norwitz ER, Kuczynski
E, Lockwood CJ, Buhimschi IA. Fractional excretion of tumor necrosis
factor-alpha in women with severe preeclampsia. Obstet Gynecol.
2008;112(1):93-100.
[65] Montagnana M, Lippi G, Albiero A, Salvagno GL, Franchi M, Guidi
GC. Serum pro-inflammatory cytokines in physiological and pre-
eclamptic pregnancies. Gynecol Endocrinol. 2008;24(3):113-6.
[66] Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression
of inflammatory cytokines in placentas from women with preeclampsia.J
Clin. Endocrinol Metab. 2001;86(6):2505-12.
[67] Redman CW, Sargent IL. Pre-eclampsia, the placenta and the maternal
systemic inflammatory response--a review. Placenta. 2003;24 Suppl
A:S21-7.
[68] Kirwan JP, Hauguel-De Mouzon S, Lepercq J, Challier JC, Huston-
Presley L, Friedman JE, Kalhan SC, Catalano PM. TNF-alpha is a
predictor of insulin resistance in human pregnancy. Diabetes.
2002;51(7):2207-13.
[69] Kauma SW, Wang Y, Walsh SW. Preeclampsia is associated with
decreased placental interleukin-6 production. J. Soc Gynecol Investig.
1995;2(4):614-7.
[70] Koga K, Osuga Y, Tajima T, Hirota Y, Igarashi T, Fujii T, Yano T,
Taketani Y. Elevated serum soluble fms-like tyrosine kinase 1 (sFlt1)
level in women with hydatidiform mole. Fertil Steril. 2010;94(1):305-
308.
[71] LaMarca BD, Ryan MJ, Gilbert JS, Murphy SR, Granger JP.
Inflammatory cytokines in the pathophysiology of hypertension during
preeclampsia. Curr. Hypertens Rep. 2007;9(6):480-485.
[72] Daher S, Fonseca F, Ribeiro OG, Musatti CC, Gerbase-DeLima M.
Tumor necrosis factor during pregnancy and at the onset of labor and
spontaneous abortion. Eur. J. Obstet Gynecol Reprod Biol.
1999;83(1):77-79.
1994;170(6):1752-1757.
[74] Vince GS, Starkey PM, Austgulen R, Kwiatkowski D, Redman CW.
Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor
receptors in women with pre-eclampsia. Br. J. Obstet Gynaecol.
1995;102(1):20-25.
[75] Estells A, Gilabert J, Grancha S, Yamamoto K, Thinnes T, Espaa F,
Aznar J, Loskutoff DJ. Abnormal expression of type 1 plasminogen
activator inhibitor and tissue factor in severe preeclampsia. Thromb
Haemost. 1998;79(3):500-508.
[76] Lockwood CJ, Matta P, Krikun G, Koopman LA, Masch R, Toti P,
Arcuri F, Huang ST, Funai EF, Schatz F. Regulation of monocyte
chemoattractant protein-1 expression by tumor necrosis factor-alpha and
interleukin-1beta in first trimester human decidual cells: implications for
preeclampsia. Am. J. Pathol. 2006;168(2):445-452.
[77] Hanssens M, Keirse MJ, Spitz B, van Assche FA. Angiotensin II levels
in hypertensive and normotensive pregnancies. Br. J. Obstet Gynaecol.
1991;98(2):155-161.
[78] Herse F, Dechend R, Harsem NK, Wallukat G, Janke J, Qadri F, Hering
L, Muller DN, Luft FC, Staff AC. Dysregulation of the circulating and
tissue-based renin-angiotensin system in preeclampsia. Hypertension.
2007;49(3):604-611.
[79] Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jpner
A, Baur E, Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H,
Luft FC. Patients with preeclampsia develop agonistic autoantibodies
against the angiotensin AT1 receptor. J. Clin. Invest. 1999;103(7):945-
952.
[80] Stepan H, Faber R, Dornhfer N, Huppertz B, Robitzki A, Walther T.
New insights into the biology of preeclampsia. Biol. Reprod.
2006;74(5):772-776.
[81] Young B, Levin R, Karumanchi A. Pathogenesis of preeclampsia. Ann
Rev. Pathol Mech. 2010;5:173-192.
[82] Roberts JM. Preeclampsia: is there value in assessing before clinically
evident disease? Obstet Gynecol. 2001 Oct;98(4):596-9.
[83] Pijnenborg R, Anthony J, Davey DA, Rees A, Tiltman A, Vercruysse L,
van Assche A. Placental bed spiral arteries in the hypertensive disorders
of pregnancy. Br. J. Obstet Gynaecol. 1991 Jul;98(7):648-55.
[84] Poon LC, Staboulidou I, Maiz N, Plasencia W, Nicolaides KH.
Hypertensive disorders in pregnancy: screening by uterine artery
Doppler at 11-13 weeks. Ultrasound Obstet Gynecol. 2009
Aug;34(2):142-8.
[85] Brodie H, Malinow AM. Anesthetic management of
preeclampsia/eclampsia. Int. J. Obstet Anesth. 1999 Apr;8(2):110-24.
[86] Bombrys AE, Barton JR, Habli M, Sibai BM. Expectant management of
severe preeclampsia at 27(0/7) to 33(6/7) weeks' gestation: maternal and
perinatal outcomes according to gestational age by weeks at onset of
expectant management. Am. J. Perinatol. 2009 Jun;26(6):441-6.
[87] Jamjute P, Ahmad A, Ghosh T, Banfield P. Liver function test and
pregnancy. J. Matern Fetal Neonatal Med. 2009 Mar;22(3):274-83.
[88] McCoy S, Baldwin K. Pharmacotherapeutic options for the treatment of
preeclampsia. Am. J. Health Syst Pharm. 2009 Feb 15;66(4):337-44.
[89] Brown MA, Lowe SA. Current management of pre-eclampsia. Med. J.
Aust. 2009 Jan 5;190(1):3-4.
[90] von Dadelszen P, Menzies J, Gilgoff S, Xie F, Douglas MJ, Sawchuck
D, Magee LA. Evidence-based management for preeclampsia. Front
Biosci. 2007 May 1;12:2876-89.
[91] Magann EF, Bass JD, Chauhan SP, Perry KG Jr, Morrison JC, Martin
JN Jr. Accelerated recovery from severe preeclampsia: uterine curettage
versus nifedipine. J. Soc Gynecol Investig. 1994 Jul-Sep;1(3):210-4.
[92] Churchill D, Beevers GD, Meher S, Rhodes C. Diuretics for preventing
pre-eclampsia. Cochrane Database Syst Rev. 2007 Jan
24;(1):CD004451.
[93] Magpie Trial Follow-Up Study Collaborative Group. The Magpie Trial:
a randomised trial comparing magnesium sulphate with placebo for pre-
eclampsia. Outcome for women at 2 years. BJOG. 2007
Mar;114(3):300-9.
[94] Vijgen S, Koopmans C, Opmeer B, Groen H, Bijlenga D, Aarnoudse J,
Bekedam D, Van Den Berg P, De Boer K, Burggraaff J, Bloemenkamp
K, Drogtrop A, Franx A, De Groot C, Huisjes A, Kwee A, Van Loon A,
Lub A, Papatsonis D, Van Der Post J, Roumen F, Scheepers H, Stigter
R, Willekes C, Mol B, Van Pampus M; for the HYPITAT study group.
An economic analysis of induction of labour and expectant monitoring
in women with gestational hypertension or pre-eclampsia at term
(HYPITAT trial). BJOG. 2010 Sep 14. doi: 10.1111/j.1471-
0528.2010.02710.x.
[95] McElrath TF, Hecht JL, Dammann O, Boggess K, Onderdonk A,
Markenson G, Harper M, Delpapa E, Allred EN, Leviton A; ELGAN
Study Investigators. Pregnancy disorders that lead to delivery before the
28th week of gestation: an epidemiologic approach to classification. Am
J. Epidemiol. 2008 Nov 1;168(9):980-9.
[96] Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for
preventing pre-eclampsia and its complications. Cochrane Database Syst
Rev. 2007 Apr 18;(2):CD004659.
[97] Rath W, Fischer T. The diagnosis and treatment of hypertensive
disorders of pregnancy: new findings for antenatal and inpatient care.
Dtsch Arztebl Int. 2009 Nov;106(45):733-8.


Chapter XIII

Long-Term Consequences
of Preeclampsia

Yoav Yinon, M.D.
*

Department of Obstetrics and Gynecology, Sheba Medical Center,
Tel-Hashomer, Sackler School of Medicine, Tel-Aviv University,
Tel-Aviv, Israel

Introduction

Preeclampsia is a multisystem disorder of pregnancy defined by the
gestational onset of hypertension and proteinuria and is a major cause of both
maternal and perinatal morbidity and mortality [1-3].
Despite the morbidity and mortality associated with preeclampsia, the
etiology of preeclampsia remains unclear; however, endothelial dysfunction is
considered to underlie many of the manifestations of preeclampsia including
hypertension and proteinuria. Recently, circulating antiangiogenic factors
soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng) have
been implicated in the pathogenesis of preeclampsia. Administration of
adenovirus expressing sFlt-1 to pregnant rats cause preeclampsia-like
syndrome, exacerbated by the co-administration of sEng [4, 5]. Moreover, a
rise in sFlt-1 and sEng and a reduction in placental growth factor (PLGF) have

*
Corresponding author: Dr. Yoav Yinon, Department of Obstetrics and Gynecology, Sheba
Medical Center, Tel-Hashomer, Israel 52621; E-mail: yoav.yinon27@gmail.com, Tel- 972-
54-6744141 Fax 972-3-5303168
Yoav Yinon 282
been demonstrated in maternal serum 5 to 10 weeks before the onset of
preeclampsia and are thought to contribute to maternal endothelial dysfunction
[6, 7]. Although many of the clinical and physiological manifestations
associated with preeclampsia resolve soon after delivery, its impact persists
years after pregnancy. Epidemiological studies provide evidence that women
with a history of preeclampsia are more likely to develop cardiovascular
disease later in life. The mechanism linking preeclampsia with future
cardiovascular disease are unknown but may include preexisting risk factors
common to both preeclampsia and cardiovascular disease such as insulin
resistance, obesity, chronic hypertension, renal disease and diabetes[8-10].
However, most women with these risk factors do not develop preeclampsia,
whereas many more women without these risk factors will have preeclampsia.
Endothelial dysfunction is an important indicator for subsequent
cardiovascular disease and is a regular feature in preeclamptic pregnancies.
Several studies have shown reduced maternal endothelial function months to
years after a preeclamptic pregnancy [11-13].
In this chapter we will review the epidemiologic data on the increased risk
of cardiovascular disease after preeclampsia and highlight the role of
endothelial dysfunction in linking preeclampsia to future cardiovascular
disease. We will also try to understand whether the endothelial damage caused
by a preeclamptic pregnancy results in future cardiovascular disease or
whether women who develop preeclampsia have a greater underlying vascular
risk, and pregnancy just unmasks a woman pre-existing risk of future
cardiovascular disease.

Preeclampsia and Long-Term
Vascular Complications

Preeclampsia and Future Cardiovascular Disease

In recent years, a growing body of literature has clearly showed a link
between preeclampsia and future vascular disease. An increased future risk of
hypertension, cardiovascular disease, stroke and end-stage renal disease has
been noted in women with a history of preeclampsia [14-21]. In order to
determine the association between preeclampsia and future cardiovascular
disease, a systematic review and meta-analysis including 25 studies was
carried out [14]. Overall, this meta-analysis included 3,488,160 women of
Long-Term Consequences of Preeclampsia 283
whom 198,252 had preeclampsia and over 3 million did not. The relative risk
of later development of hypertension in women after preeclampsia was 3.7
(95% CI 2.7-5.05) compared with women who did not have preeclampsia
(table 1). Analysis according to parity indicated a higher risk of hypertension
after preeclampsia in any pregnancy compared with preeclampsia in the first
pregnancy only[14]. Similarly, women with previous preeclampsia were at
increased risk to develop ischemic heart disease (relative risk of 2.16, 1.86-
2.52) as well as future fatal ischemic heart disease events (relative risk of 2.6,
1.94-3.49) compared to women with no history of preeclampsia. Moreover, the
overall risk of stroke as well as venous thromboembolism in later life was also
increased among women with history of preeclampsia with a relative risk of
1.81 (1.45-2.27) and 1.79 (1.37-2.33) respectively (table 1). However, no
increase in risk of any cancer was found including breast cancer 17 years after
preeclampsia. Overall mortality after preeclampsia was also increased after
14.5 years with a relative risk of 1.49 (95% CI 1.05 to 2.14) [14]. In
accordance with these findings, Shalom et al. have recently reported on
significantly higher rate of chronic hypertension in 2072 patients with previous
preeclampsia compared with 20742 patients without a history of preeclampsia
( 12.5% vs 0.9%; odds ratio of 15.8, 95% CI 12.9-19.3) [22].

Table 1. Preeclampsia and risk of future vascular disease.

Disease Mean follow-up
(years)
Relative risk 95% Confidence
interval
Hypertension [14] 14.1 3.7 2.7-5.05
Ischemic heart
disease[14]
11.7 2.16 1.86-2.52
Stroke[14] 10.4 1.81 1.45-2.27
Thromboembolism[14] 4.7 1.79 1.37-2.33
End-stage renal
disease[19]
26.5 4.7 3.6-6.1

The risk of future vascular disease after preeclampsia seems to be related
to the gestational age at delivery and to the severity of preeclampsia. A
Norwegian population based cohort study has looked at mortality from
cardiovascular causes, cancer and stroke of 626,272 mothers whose first
delivery was registered between 1967 and 1992 with a median follow up of 13
years [16]. They found that women who had preeclampsia had a 1.2 fold
higher long term risk of death (95% CI 1.02-1.37) than women who did not
have preeclampsia, but this risk increased to 2.71 (1.99 to 3.68) in women with
Yoav Yinon 284
preeclampsia and preterm delivery at less than 37 weeks of gestation
compared to women who did not have preeclampsia and whose pregnancies
went to term. Furthermore, the risk of death from cardiovascular causes among
women with preeclampsia and preterm delivery was 8.12 fold higher (4.31 to
15.33) than women without preeclampsia who delivered at term, whereas
women with preeclampsia who delivered at term had only a 1.65 fold ( 1.10 to
2.7) higher risk of cardiovascular death (table 2) [16]. Therefore, women with
a history of early-onset preeclampsia appear to be at a much higher risk of
future cardiovascular disease compared with women who developed late-onset
preeclampsia during their pregnancy. These findings support the idea that the
onset of preeclampsia early and late in pregnancy indicates two different
diseases. There is also evidence for association between the severity of
preeclampsia and future risk of cardiovascular disease. Compared with women
who had a normotensive pregnancy, women who had mild preeclampsia had a
relative risk of future cardiovascular disease of 2 (95% confidence interval
1.83-2.19), women who had moderate preeclampsia had a relative risk of 2.99
(2.51 to 3.58) and those who had severe preeclampsia had a relative risk of
5.36 (3.96 to 7.27)[23].

Table 2. Preeclampsia and cardiovascular mortality according
to gestational age at birth [16]

Gestational age
at birth
Relative risk for
cardiovascular death
95% Confidence
interval
No preeclampsia 37 weeks 1
No preeclampsia 16-36 weeks 2.95 2.12-4.11
Preeclampsia 37 weeks 1.65 1.01-2.7
Preeclampsia 16-36 weeks 8.12 4.3-15.3

As opposed to preeclamptic mothers, the future cardiovascular risk of
fathers of pre-eclamptic pregnancies is not increased. The after mentioned
Norwegian population cohort study also looked at the mortality of fathers of
preeclamptic pregnancies and found that the risk of death from cardiovascular
disease was not higher than the fathers of pregnancies in which preeclampsia
did not occur[16].
To summarize, there is clear evidence for a relation between preeclampsia
and cardiovascular disease in later life, and that this is especially relevant to a
subset of those women who had early-onset preeclampsia requiring preterm
delivery.
Preeclampsia and End-Stage Renal Disease

Preeclampsia is more common in women with underlying renal disease,
especially when associated with chronic hypertension [24]. In a study that was
done more than 30 years ago, when hypertensive pregnant women often
underwent postpartum renal biopsy, glomerular endotheliosis, the classic renal
histology of preeclampsia, was associated with other renal diseases in 24% of
primigravid preeclampsia and 76% of multiparous preeclampsia [25].
Microalbuminuria, which might indicate an underlying renal disease but also
acts as a marker for cardiovascular disease, is more common after
preeclampsia [26, 27]. Bar et al. have found that 58% of women with previous
preeclampsia had microalbuminuria 2-4 months after delivery, and 42% of
them had evidence of microalbuminuria 3-5 years after delivery. There was no
difference in renal function between previous preeclamptic women and
women with previous normal pregnancy, and within the study group the rate
of microalbuminuria was similar among nulliparous and multiparous women
[26]. In order to determine the association between preeclampsia and
subsequent development of end-stage renal disease, Viske et al. have linked
the data from the Medical Birth Registry of Norway of women, who had their
first singleton birth between 1967 and 1991, with data from the Norwegian
Renal Registry. Among women who had been pregnant one or more times,
preeclampsia during the first pregnancy was associated with a relative risk of
end-stage renal disease of 4.7 (95% confidence interval 3.6 to 6.1 (table 1)
[19]. Among women who had been pregnant two or more times, preeclampsia
during the first pregnancy was associated with a relative risk of end-stage renal
disease of 3.2 (95% confidence interval 2.2 to 4.9), and preeclampsia during
the second pregnancy was associated with a relative risk of end-stage renal
disease of 6.7 (95% confidence interval 4.3 to 10.6). Moreover, preeclampsia
during two or three pregnancies was associated with a relative risk of 15.5
(95% confidence interval 7.8 to 30.8). Further analysis showed that having a
low birth-weight infant or preterm infant increased the relative risk of end-
stage renal disease [19].Several mechanisms might explain the association
between preeclampsia and subsequent renal disease. One hypothesis is that
kidney disease and preeclampsia are caused by the same underlying factors
including hypertension, obesity and insulin resistance [28, 29]. A second
possibility is that preeclampsia may exacerbate subclinical kidney disease that
is present before pregnancy or alternatively preeclampsia may cause later
development of renal disease.

Yoav Yinon 286
Low Birth Weight and Future Maternal Cardiovascular Disease

Several studies have shown an inverse relationship between infants' birth
weight and mothers' mortality from cardiovascular disease [30, 31]. In a
longitudinal study, information from birth registry in England of infants born
between 1976-1997 was linked to data from the census and death registration
for the study members. The study found a significant association between
infants' birth weight and mothers' mortality from all causes and from
cardiovascular disease. For mothers whose infants' birth weight was less than
2500 gram, the relative risk for death from all cause was 3.06 (95% CI 2.15-
4.35) and the relative risk for death from cardiovascular disease was 7.05
(95% CI 2.64-18.77) compared to mothers of offspring weighing 3500 gram or
above at birth [30]. Smith et al. have evaluated whether complications of
pregnancy linked with low birth weight are associated with the mother's
subsequent risk of ischemic heart disease by using discharge data on all
singleton first births in Scotland between 1981 and 1985 and linking it to the
mothers' subsequent admissions and deaths. They found that delivering a baby
in the lowest birth weight quintile for gestational age, delivering preterm and
preeclampsia were all associated with an increased risk of admission to
hospital for ischemic heart disease or death from ischemic heart disease during
the subsequent 19 years (table 3) [32]. Delivering a baby less than 2500 gram
resulted in a relative risk of 11.3 (95% CI 3.5-36.1) for death due to ischemic
heart disease compared to women whose offspring's birth weight was 3500
gram or above. Women who had pregnancies complicated by low birth weight
and preeclampsia had a greater risk of future cardiovascular disease compared
to women who had only preeclampsia. Moreover, women who had all three
pregnancy complications including low birth weight infant, preeclampsia and
preterm labor had the highest risk of cardiovascular disease in later life with a
relative risk of 16.1 (95% CI 3.6-72.6) (table 3) [32].

Table 3. Pregnancy complications and risk of death due
to ischemic heart disease [32]

Pregnancy complication Relative
risk
95% Confidence
interval
Lowest birth weight quintile 2.4 1.3-4.4
Lowest birth weight quintile and preeclampsia 3.9 1.3-11.6
Lowest birth weight quintile and preterm labor 6.8 2-22.9
Lowest birth weight quintile, preeclampsia and
preterm labor
16.1 3.6-72.6
Endothelial Dysfunction: The Link
Between Preeclampsia and Future
Cardiovascular Disease

The mechanisms that account for an increased risk of cardiovascular
disease in women with a history of preeclampsia are not yet well understood.
However, it appears that endothelial dysfunction might be the mechanism
linking preeclampsia with future cardiovascular disease.

Figure 1. Measurement of flow-mediated dilatation.
Several studies have showed that endothelial dysfunction is more common
in women with a history of preeclampsia many years after the affected
pregnancy compared to women with previous normal pregnancy [11, 33-35].
Endothelial function is assessed by determining the flow mediated dilatation
(FMD) which is the change in diameter of the brachial artery in response to
post ischemic reactive hyperemia. In order to create post ischemic reactive
hyperemia, a pneumatic cuff is placed at the level of the mid-forearm and is
inflated for 5 minutes followed by deflation which results in post ischemic
reactive hyperemia (figure 1). When the endothelial function is normal,
Yoav Yinon 288
reactive hyperemia leads to vasodilatation of the vessel. Endothelial
dysfunction is defined as FMD less than 4.5% [36]. Assessment of
endothelial-independent vasodilatation is performed by measuring changes in
diameter of the vessel following sublingual administration of glyceryl
trinitrate. Chambers et al. have studied 113 women with previous
preeclampsia, 35 of them with recurrent episodes and 78 with a single episode,
and 48 women with previous uncomplicated pregnancies at least 3 months and
at a median interval of 3 years postpartum. Flow mediated dilatation was
lower in women with previous preeclampsia compared with controls. The
defect was more severe in women with recurrent preeclampsia compared with
a single episode of preeclampsia [33]. In contrast, there were no significant
differences in glyceryl trinitrate-induced, endothelium-independent dilatation
between the 3 groups. Multivariable regression analysis showed that the
relationship between previous preeclampsia and impaired flow-mediated
dilatation was independent of age, BMI, blood pressure, family history of
hypertension, fasting plasma glucose levels and lipid profile. These results
indicated that endothelia function is impaired in women with previous
preeclampsia and cannot be explained maternal risk factors [33]. Similarly,
Germain et al. have also demonstrated significantly decreased endothelium-
dependent vasodilatation among patients with previous preeclampsia
compared with women with previous healthy pregnancies 11 to 27 months
after pregnancy. Among the previous preeclamptic women, 40% exhibited
endothelial dysfunction. Of note, diastolic and mean blood pressures as well as
serum cholesterol were higher in women with previous preeclampsia and a
trend to an inverse correlation was found between serum cholesterol levels and
endothelial-mediated vasodilatation [35].
Arterial stiffness is a key determinant of central aortic pressure and is an
independent predictor of adverse cardiovascular outcomes [37]. Augmentation
index, which is expressed as a percentage of the aortic pulse pressure, is a
measure of the stiffness of the arterial walls, and can be determined
noninvasively using applanation tonometry. Robb et al. have evaluated the
effect of normal pregnancy and preeclampsia on arterial stiffness and found
that augmentation index increased from 24 weeks over the third trimester. In
women with preeclampsia, augmentation index was increased during
pregnancy compared with gestationally matched women with uncomplicated
pregnancies and remained elevated at 7 weeks postpartum[38]. The
aforementioned studies did not differentiate between early and late onset
preeclampsia and did not include patients with isolated intra-uterine growth
restriction (IUGR). Since early-onset preeclampsia and late-onset
preeclampsia are considered by some to be different disease entities[39, 40],
women with a history of preeclampsia in their last pregnancy were studied 6-
24 months postpartum but were divided into early onset (diagnosed before 34
weeks of gestation) and late-onset preeclampsia (diagnosed after 34 weeks of
gestation) [41]. In early-onset disease, under perfusion of the placenta is the
predominant precipitating factor, whereas in late-onset preeclampsia, there is
often minimal or no placental involvement [12, 42]. In addition, this study also
included an interesting group of patients with a history of IUGR without
preeclampsia. All patient with IUGR included in this study had early onset
IUGR and were delivered before 34 weeks of gestation. Flow-mediated
vasodilatation was significantly reduced in women with previous early-onset
preeclampsia and women with previous isolated IUGR compared with women
with previous late-onset preeclampsia and control subjects (3.2% and 2.1%
versus 7.9% and 9.1%, respectively; p<0.0001). In support of the concept that
early and late-onset preeclampsia represent different disease entities, flow-
mediated vasodilatation in women with previous late-onset preeclampsia was
comparable to that in the control group [41]. In addition, 93% and 89% of the
early preeclampsia and IUGR women, respectively, exhibited endothelial
dysfunction defined as FMD<4.5%, whereas only 22% of late preeclamptic
women and 12.5% of the control subjects met the criteria for endothelial
dysfunction (p=0.0024). Similarly, the radial arterial stiffness measured by the
augmentation index was significantly increased only among women with
previous early-onset preeclampsia and women with previous isolated IUGR
but not among the late-onset preeclamptic women, whose augmentation index
values were similar to those of the control subjects [41]. In accordance with
these findings, Khalil et al. reported a significantly higher augmentation index
in early compared with late onset preeclampsia and in severe compared with
mild preeclampsia when patients were studied during pregnancy [43]. These
interesting results suggest that early but not late-onset preeclampsia is
associated with endothelial dysfunction and increased arterial stiffness that
extend beyond pregnancy and might contribute to adverse cardiovascular
outcomes observed mainly in women with previous early-onset preeclampsia.
Women with previous late-onset preeclampsia, however, exhibit normal
physiological vascular profile which explains their relative low risk for future
cardiovascular disease as shown by epidemiological studies [14, 16]. Of
interest, women who had isolated IUGR in their previous pregnancy also
exhibited endothelial dysfunction, which was even more pronounced
compared with early preeclamptic patients. Moreover, in the early
preeclamptic women, those who also had fetal growth restriction had markedly
Yoav Yinon 290
reduced flow-mediated dilatation compared with those without fetal growth
restriction [41]. Similarly, Khalil et al. have showed that augmentation index
during pregnancy was significantly elevated in women with preeclampsia who
also had fetal growth restriction compared with those with preeclampsia
without fetal growth restriction[43]. Therefore, in patients with previous
preeclampsia, the degree of endothelial dysfunction seems to be more severe
in the presence of IUGR, putting these women at higher risk for future

Endothelial Dysfunction and Future
Vascular Disease: Damage
from the Hypertensive Pregnancy
or Pre-Existing Condition?

The mechanism accounting for an increased risk of cardiovascular disease
in women with history of preeclampsia is probably related to endothelial
dysfunction. However, it is still unanswered whether the preeclamptic
pregnancy results in damage to the endothelium leading to future
cardiovascular disease or whether pre-existing endothelial dysfunction
underlies both the predisposition to preeclampsia and later development of
cardiovascular disease (figure 2).

Figure 2. Mechanisms explaining the association between preeclampsia and
It is possible that shared risk factors may jointly predispose to
preeclampsia, endothelial dysfunction and cardiovascular disease. Diabetes
mellitus, chronic hypertension, renal disease and subclinical insulin resistance
predispose women to preeclampsia and elevate the risk of cardiovascular
disease [44-46]. Smith et al. have assessed the physical and biochemical
cardiovascular risk markers in women who had developed preeclampsia in
their previous pregnancy at 1 year postpartum. Women with history of
preeclampsia had increased blood pressure, total cholesterol, higher LDL
cholesterol, triglycerides, increased BMI, fasting insulin HOMA index and
microalbumin/creatinine ratio compared to women with previous
normotensive pregnancies[47]. Of note, patients were not evaluated in this
study before pregnancy, and therefore the authors could not determine whether
cardiovascular risk factors play a role in the pathogenesis of preeclampsia or
whether cardiovascular risk factors are being caused by preeclampsia. In-order
to answer this question, Romundstad et al. have studied the cardiovascular risk
factors before and after pregnancy in women who experienced preeclampsia or
gestational hypertension. They found that nearly half of the elevated
cardiovascular risk factors after pregnancy can be explained by prepregnancy
risk factors, rather than reflecting a direct influence of the hypertensive
disorder in pregnancy[48]. Therefore, pregnancy may be viewed as a stress
test that can reveal subclinical cardiovascular disease phenotypes long before
overt disease[45].
It has become clear in recent years that circulating anti-angiogenic factors
soluble fms-like tyrosine kinase (sFlt-1) and soluble endoglin (sEng) released
from the placenta play a major role in the pathogenesis of preeclampsia. It has
been proposed that in preeclampsia, the placenta produces elevated levels of
sFlt-1, which captures the free VEGF and PLGF, inhibits their action and
causes endothelial dysfunction together with sEng, which inhibits TGF-1
signaling [4, 6, 7]. Adenoviral-mediated over-expression of both sFlt-1 and
sEng caused severe vascular damage, proteinuria and severe hypertension in
rats. Thus, sEng and sFlt-1, two antiangiogenic proteins operating through
separate mechanisms, may combine to produce endothelial dysfunction and
severe preeclampsia [5]. It has been hypothesized that endothelial damage
resulting from maternal exposure to these angiogenic factors during pregnancy
may be the cause of future maternal vascular disease. Although levels of sFlt-1
decline after delivery of the placenta, a persistent and subtle antiangiogenic
milieu may contribute to endothelial dysfunction and an elevated risk of
cardiovascular disease in women with a history of preeclampsia[45]. It has
been showed that monocytes in women with preeclampsia produce elevated
Yoav Yinon 292
levels of sFlt-1 compared to controls [49], and thus the source of sFlt-1 in non-
pregnant women may be peripheral blood mononuclear cells. However,
comparison of circulatory levels of sFlt-1, sEng, VEGF and PLGF 6 to 24
months after delivery between women with previous early-onset preeclampsia
and women with previous normal pregnancy revealed no differences despite
the presence of endothelial dysfunction in women with history of preeclampsia
[41]. Similarly, Germain et al. found similar circulatory levels of sFlt-1 and
VEGF in women with previous severe preeclampsia and women with previous
normal pregnancies 11 to 27 months after pregnancy [35]. In contrast, Wolf et
al. found increased levels of sFlt-1 in women with prior preeclampsia 18
months postpartum, but instead of decreased levels of free VEGF as expected,
they found a trend toward increased free VEGF levels in the preeclamptic
group [50]. Therefore, the basal levels of sFlt-1 appeared to be too low to
influence circulating VEGF, suggesting that sFlt-1 is not likely to play a
clinical significant role in the postpartum state. However, more studies are
needed in order to determine whether antiangiogenic and proangiogenic
molecules contribute to development of cardiovascular disease in women. Of
note, a study on 130 patients with chronic kidney disease showed that sFlt-1
levels were increased in patients with chronic kidney disease compared to
controls, and their serum had antiangiogenic activity attenuated by antibody
against sFlt-1. In addition, sFlt-1 levels were elevated in patients who had a
history of myocardial infarction or stroke [51]. Moreover, high sFlt-1 levels
are also associated with carotid intima-media thickness and progression of
atherosclerosis in hypertensive patients [52]. Interestingly, Noori et al. have
showed that in contrast to the observation during pregnancy, serum PLGF
levels 12 weeks postpartum were higher in women who had a hypertensive
pregnancy compared to women with a previous normotensive pregnancy[53].
PLGF has been shown to stimulate atherosclerotic intimal thickening[54], and
elevated PLGF levels were associated with an increased risk of coronary heart
disease more than 10 years after a baseline test in asymptomatic women[55].
The authors have speculated that the increased risk of cardiovascular disease
after a pregnancy affected by preeclampsia may be partly mediated through
PLGF, which increases atherosclerotic plaque formation[53].
In a very elegant study, Bytautiene et al. have evaluated the long term
effects of preeclampsia on vascular function in a mouse model of sFlt-1
induced preeclampsia. Mice at day 8 of gestation were injected with
adenovirus carrying sFlt-1, and vascular function in the mothers was
investigated 6-8 months after delivery [56]. At 6-8 months postpartum, sFlt-1
blood levels had returned to low levels and were comparable between the sFlt-
1 injected mice and the controls injected with saline. Moreover, there was no
difference in postpartum blood pressure or vascular reactivity between the
groups. Hence, in a mouse model, overexpression of sFlt-1 does not lead to
impaired vascular function after delivery [56]. These findings favor the
hypothesis that the increased risk of cardiovascular disease in women with a
history of preeclampsia is likely the result of preexisting risk factors common
to preeclampsia and cardiovascular disease.
In order to determine whether endothelial function is a preexisting
condition in preeclamptic patients, it is preferable to assess patients during or
even before pregnancy. Savvidou et al. have measured flow-mediated
dilatation at 23-25 weeks of gestation in 86 women, and found that women
who developed preeclampsia, had significantly lower flow-mediated dilatation
than did women who had normal outcome (3.65% vs 8.65%, p<0.0001).
Therefore, it appears that maternal endothelial function is impaired in women
who eventually develop preeclampsia, and it occurs before the development of
the clinical syndrome[57]. The same group has also investigated the
association between serum concentrations of PLGF and sEng with maternal
endothelial dysfunction at 23-25 weeks of gestation[58]. As expected, women
who developed preeclampsia had lower levels of PLGF and higher levels of
sEng as well as significantly lower flow-mediated dilatation compared to
women with normal outcome. However, there was no correlation between the
degree of endothelial dysfunction, as assessed by flow-mediated dilatation,
and serum concentrations of PLGF and sEng [58]. In contrast to the notion that
antiangiogenic factors are directly involved in the maternal endothelial
dysfunction, these findings imply that there is no direct causal relationship
between these factors and the endothelial dysfunction that these women
demonstrate at this stage of pregnancy. In accordance with these findings,
Noori et al. have also demonstrated decreased flow-mediated dilatation at 10-
17 weeks of gestation in women who later developed preeclampsia. Similar to
the aforementioned study, there was no correlation between maternal serum
levels of sFlt-1, sEng or PLGF and brachial artery flow-mediated dilatation at
any time point during pregnancy [53]. Therefore, the evidence in the literature
appears to support the hypothesis that endothelial dysfunction is a pre-existing
condition, and pregnancy unmasks a woman pre-existing risk of
Large population-based prospective studies assessing endothelial function
preconception are required in order to help understanding the causality and
whether endothelial dysfunction is a preexisting condition leading to both
preeclampsia and future cardiovascular disease, or whether preeclampsia itself
Yoav Yinon 294
via antiangiogenic factors may injure the endothelium and thereby increase the
risk of future cardiovascular disease.

Summary

Although the symptoms of preeclampsia resolve over a number of weeks
after delivery, epidemiological data suggest that maternal vascular dysfunction
may persist for years, manifest by increased risk for future development of
hypertension, stroke, coronary artery disease and end-stage renal disease.
Women with early-onset preeclampsia resulting in IUGR have the highest risk
of future cardiovascular disease. Therefore, a woman's obstetric history
becomes an important consideration toward her cardiovascular risk
assessment. It is the role of the obstetrician to highlight the consequences of
pregnancy outcome to the primary care physician as well as the mother, as
these middle-age women with previous preeclampsia, especially if early and
severe, might benefit from adaptation of lifestyle or prophylactic treatment.
Monitoring and controlling weight, hypertension and dyslipidemia may reduce
long-term morbidity and mortality in this group of women.
The mechanism that account for an increased risk of cardiovascular
disease in women with history of preeclampsia is thought to be endothelial
dysfunction, which has been shown to persist in previous preeclamptic women
many years after an affected pregnancy. It is still undetermined whether
preeclampsia itself injure the endothelium, which leads to increased risk of
future cardiovascular disease or whether preexisting endothelial dysfunction
underlies both the predisposition to preeclampsia and the later development of
cardiovascular disease. It has been hypothesized that maternal exposure to
anti-angiogenic factors during a preeclamptic pregnancy results in endothelial
damage, which may lead to future maternal cardiovascular disease. However,
there is conflicting data in the literature regarding the postpartum levels of anti
and pro-angiogenic factors and whether they play a clinically significant role
in the postpartum state. Moreover, a growing body of literature in recent years
indicates that endothelial dysfunction is a preexisting condition leading to both
preeclampsia and cardiovascular disease later in life. Therefore, women who
develop preeclampsia have greater underlying vascular risk. This manifests
during pregnancy in the form of preeclampsia and later in life in the form of
hypertension, stroke and ischemic heart disease. Yet, more large population-
based studies assessing endothelial function prior to conception are needed, in
order to validate this hypothesis.
References

[1] ACOG practice bulletin. Diagnosis and management of preeclampsia
and eclampsia. Number 33, January 2002. Obstet Gynecol 2002, 99:159-
167.
[2] Berg CJ, Mackay AP, Qin C, Callaghan WM: Overview of maternal
morbidity during hospitalization for labor and delivery in the United
States: 1993-1997 and 2001-2005. Obstet Gynecol 2009, 113:1075-
1081.
[3] MacKay AP, Berg CJ, Atrash HK: Pregnancy-related mortality from
preeclampsia and eclampsia. Obstet Gynecol 2001, 97:533-538.
[4] Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, Libermann
TA, Morgan JP, Sellke FW, Stillman IE, et al: Excess placental soluble
fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial
dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest
2003, 111:649-658.
[5] Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM,
Bdolah Y, Lim KH, Yuan HT, Libermann TA, et al: Soluble endoglin
contributes to the pathogenesis of preeclampsia. Nat Med 2006, 12:642-
649.
[6] Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, Sibai BM,
Epstein FH, Romero R, Thadhani R, Karumanchi SA: Soluble endoglin
and other circulating antiangiogenic factors in preeclampsia. N Engl J
Med 2006, 355:992-1005.
[7] Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF,
Schisterman EF, Thadhani R, Sachs BP, Epstein FH, et al: Circulating
angiogenic factors and the risk of preeclampsia. N Engl J Med 2004,
350:672-683.
[8] Magnussen EB, Vatten LJ, Lund-Nilsen TI, Salvesen KA, Davey Smith
G, Romundstad PR: Prepregnancy cardiovascular risk factors as
predictors of pre-eclampsia: population based cohort study. Bmj 2007,
335:978.
[9] Parretti E, Lapolla A, Dalfra M, Pacini G, Mari A, Cioni R, Marzari C,
Scarselli G, Mello G: Preeclampsia in lean normotensive normotolerant
pregnant women can be predicted by simple insulin sensitivity indexes.
Hypertension 2006, 47:449-453.
[10] Wolf M, Kettyle E, Sandler L, Ecker JL, Roberts J, Thadhani R: Obesity
and preeclampsia: the potential role of inflammation. Obstet Gynecol
2001, 98:757-762.
Yoav Yinon 296
[11] Agatisa PK, Ness RB, Roberts JM, Costantino JP, Kuller LH,
McLaughlin MK: Impairment of endothelial function in women with a
history of preeclampsia: an indicator of cardiovascular risk. Am J
Physiol Heart Circ Physiol 2004, 286:H1389-1393.
[12] Lampinen KH, Ronnback M, Kaaja RJ, Groop PH: Impaired vascular
dilatation in women with a history of pre-eclampsia. J Hypertens 2006,
24:751-756.
[13] Poston L: Endothelial dysfunction in pre-eclampsia. Pharmacol Rep
2006, 58 Suppl:69-74.
[14] Bellamy L, Casas JP, Hingorani AD, Williams DJ: Pre-eclampsia and
risk of cardiovascular disease and cancer in later life: systematic review
and meta-analysis. Bmj 2007, 335:974.
[15] Hannaford P, Ferry S, Hirsch S: Cardiovascular sequelae of toxaemia of
pregnancy. Heart 1997, 77:154-158.
[16] Irgens HU, Reisaeter L, Irgens LM, Lie RT: Long term mortality of
mothers and fathers after pre-eclampsia: population based cohort study.
Bmj 2001, 323:1213-1217.
[17] Kestenbaum B, Seliger SL, Easterling TR, Gillen DL, Critchlow CW,
Stehman-Breen CO, Schwartz SM: Cardiovascular and thromboembolic
events following hypertensive pregnancy. Am J Kidney Dis 2003,
42:982-989.
[18] Ray JG, Vermeulen MJ, Schull MJ, Redelmeier DA: Cardiovascular
health after maternal placental syndromes (CHAMPS): population-based
retrospective cohort study. Lancet 2005, 366:1797-1803.
[19] Vikse BE, Irgens LM, Leivestad T, Skjaerven R, Iversen BM:
Preeclampsia and the risk of end-stage renal disease. N Engl J Med
2008, 359:800-809.
[20] Williams D: Long-term complications of preeclampsia. Semin Nephrol
2011, 31:111-122.
[21] Wilson BJ, Watson MS, Prescott GJ, Sunderland S, Campbell DM,
Hannaford P, Smith WC: Hypertensive diseases of pregnancy and risk of
hypertension and stroke in later life: results from cohort study. Bmj
2003, 326:845.
[22] Shalom G, Shoham-Vardi I, Sergienko R, Wiznitzer A, Sherf M, Sheiner
E: Is preeclampsia a significant risk factor for long-term hospitalizations
and morbidity? J Matern Fetal Neonatal Med 2013, 26:13-15.
[23] McDonald SD, Malinowski A, Zhou Q, Yusuf S, Devereaux PJ:
Cardiovascular sequelae of preeclampsia/eclampsia: a systematic review
and meta-analyses. Am Heart J 2008, 156:918-930.
[24] Williams D, Davison J: Chronic kidney disease in pregnancy. Bmj 2008,
336:211-215.
[25] Fisher KA, Luger A, Spargo BH, Lindheimer MD: Hypertension in
pregnancy: clinical-pathological correlations and remote prognosis.
Medicine (Baltimore) 1981, 60:267-276.
[26] Bar J, Kaplan B, Wittenberg C, Erman A, Boner G, Ben-Rafael Z, Hod
M: Microalbuminuria after pregnancy complicated by pre-eclampsia.
Nephrol Dial Transplant 1999, 14:1129-1132.
[27] McDonald SD, Han Z, Walsh MW, Gerstein HC, Devereaux PJ: Kidney
disease after preeclampsia: a systematic review and meta-analysis. Am J
Kidney Dis 2010, 55:1026-1039.
[28] Joffe GM, Esterlitz JR, Levine RJ, Clemens JD, Ewell MG, Sibai BM,
Catalano PM: The relationship between abnormal glucose tolerance and
hypertensive disorders of pregnancy in healthy nulliparous women.
Calcium for Preeclampsia Prevention (CPEP) Study Group. Am J Obstet
Gynecol 1998, 179:1032-1037.
[29] Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D,
Paul RH: Risk factors for preeclampsia in healthy nulliparous women: a
Human Development Network of Maternal-Fetal Medicine Units. Am J
Obstet Gynecol 1995, 172:642-648.
[30] Smith GD, Harding S, Rosato M: Relation between infants' birth weight
and mothers' mortality: prospective observational study. Bmj 2000,
320:839-840.
[31] Smith GD, Hart C, Blane D, Gillis C, Hawthorne V: Lifetime
socioeconomic position and mortality: prospective observational study.
Bmj 1997, 314:547-552.
[32] Smith GC, Pell JP, Walsh D: Pregnancy complications and maternal risk
of ischaemic heart disease: a retrospective cohort study of 129,290
births. Lancet 2001, 357:2002-2006.
[33] Chambers JC, Fusi L, Malik IS, Haskard DO, De Swiet M, Kooner JS:
Association of maternal endothelial dysfunction with preeclampsia.
Jama 2001, 285:1607-1612.
[34] Evans CS, Gooch L, Flotta D, Lykins D, Powers RW, Landsittel D,
Roberts JM, Shroff SG: Cardiovascular system during the postpartum
state in women with a history of preeclampsia. Hypertension 2011,
58:57-62.
[35] Germain AM, Romanik MC, Guerra I, Solari S, Reyes MS, Johnson RJ,
Price K, Karumanchi SA, Valdes G: Endothelial dysfunction: a link
Yoav Yinon 298
among preeclampsia, recurrent pregnancy loss, and future cardiovascular
events? Hypertension 2007, 49:90-95.
[36] Schroeder S, Enderle MD, Ossen R, Meisner C, Baumbach A, Pfohl M,
Herdeg C, Oberhoff M, Haering HU, Karsch KR: Noninvasive
determination of endothelium-mediated vasodilation as a screening test
for coronary artery disease: pilot study to assess the predictive value in
comparison with angina pectoris, exercise electrocardiography, and
myocardial perfusion imaging. Am Heart J 1999, 138:731-739.
[37] Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L,
Ducimetiere P, Benetos A: Aortic stiffness is an independent predictor
of all-cause and cardiovascular mortality in hypertensive patients.
Hypertension 2001, 37:1236-1241.
[38] Robb AO, Mills NL, Din JN, Smith IB, Paterson F, Newby DE, Denison
FC: Influence of the menstrual cycle, pregnancy, and preeclampsia on
arterial stiffness. Hypertension 2009, 53:952-958.
[39] Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos
E: Placental angiogenic growth factors and uterine artery Doppler
findings for characterization of different subsets in preeclampsia and in
isolated intrauterine growth restriction. Am J Obstet Gynecol 2006,
195:201-207.
[40] Ness RB, Sibai BM: Shared and disparate components of the
pathophysiologies of fetal growth restriction and preeclampsia. Am J
Obstet Gynecol 2006, 195:40-49.
[41] Yinon Y, Kingdom JC, Odutayo A, Moineddin R, Drewlo S, Lai V,
Cherney DZ, Hladunewich MA: Vascular dysfunction in women with a
history of preeclampsia and intrauterine growth restriction: insights into
future vascular risk. Circulation 2010, 122:1846-1853.
[42] Redman CW, Sargent IL: Pre-eclampsia, the placenta and the maternal
systemic inflammatory response--a review. Placenta 2003, 24 Suppl
A:S21-27.
[43] Khalil A, Jauniaux E, Harrington K: Antihypertensive therapy and
central hemodynamics in women with hypertensive disorders in
pregnancy. Obstet Gynecol 2009, 113:646-654.
[44] Laivuori H, Tikkanen MJ, Ylikorkala O: Hyperinsulinemia 17 years
after preeclamptic first pregnancy. J Clin Endocrinol Metab 1996,
81:2908-2911.
[45] Powe CE, Levine RJ, Karumanchi SA: Preeclampsia, a disease of the
maternal endothelium: the role of antiangiogenic factors and
implications for later cardiovascular disease. Circulation 2011,
123:2856-2869.
[46] Wolf M, Sandler L, Munoz K, Hsu K, Ecker JL, Thadhani R: First
trimester insulin resistance and subsequent preeclampsia: a prospective
study. J Clin Endocrinol Metab 2002, 87:1563-1568.
[47] Smith GN, Walker MC, Liu A, Wen SW, Swansburg M, Ramshaw H,
White RR, Roddy M, Hladunewich M: A history of preeclampsia
identifies women who have underlying cardiovascular risk factors. Am J
Obstet Gynecol 2009, 200:58 e51-58.
[48] Romundstad PR, Magnussen EB, Smith GD, Vatten LJ: Hypertension in
pregnancy and later cardiovascular risk: common antecedents?
Circulation 2010, 122:579-584.
[49] Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA,
Karumanchi SA, Thadhani R, Wolf M, Harger G, Markovic N: Extra-
placental expression of vascular endothelial growth factor receptor-1,
(Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells
(PBMCs) in normotensive and preeclamptic pregnant women. Placenta
2005, 26:563-573.
[50] Wolf M, Hubel CA, Lam C, Sampson M, Ecker JL, Ness RB,
Rajakumar A, Daftary A, Shakir AS, Seely EW, et al: Preeclampsia and
future cardiovascular disease: potential role of altered angiogenesis and
insulin resistance. J Clin Endocrinol Metab 2004, 89:6239-6243.
[51] Di Marco GS, Reuter S, Hillebrand U, Amler S, Konig M, Larger E,
Oberleithner H, Brand E, Pavenstadt H, Brand M: The soluble VEGF
receptor sFlt1 contributes to endothelial dysfunction in CKD. J Am Soc
Nephrol 2009, 20:2235-2245.
[52] Shin S, Lee SH, Park S, Kang SM, Chung N, Shim WH, Cho SY,
Manabe I, Jang Y: Soluble fms-like tyrosine kinase-1 and the
progression of carotid intima-media thickness - 24-month follow-up
study. Circ J 2010, 74:2211-2215.
[53] Noori M, Donald AE, Angelakopoulou A, Hingorani AD, Williams DJ:
Prospective study of placental angiogenic factors and maternal vascular
function before and after preeclampsia and gestational hypertension.
Circulation 2010, 122:478-487.
[54] Khurana R, Moons L, Shafi S, Luttun A, Collen D, Martin JF, Carmeliet
P, Zachary IC: Placental growth factor promotes atherosclerotic intimal
thickening and macrophage accumulation. Circulation 2005, 111:2828-
2836.
Yoav Yinon 300
[55] Cassidy A, Chiuve SE, Manson JE, Rexrode KM, Girman CJ, Rimm
EB: Potential role for plasma placental growth factor in predicting
coronary heart disease risk in women. Arterioscler Thromb Vasc Biol
2009, 29:134-139.
[56] Bytautiene E, Lu F, Tamayo EH, Hankins GD, Longo M, Kublickiene
K, Saade GR: Long-term maternal cardiovascular function in a mouse
model of sFlt-1-induced preeclampsia. Am J Physiol Heart Circ Physiol
2010, 298:H189-193.
[57] Savvidou MD, Hingorani AD, Tsikas D, Frolich JC, Vallance P,
Nicolaides KH: Endothelial dysfunction and raised plasma
concentrations of asymmetric dimethylarginine in pregnant women who
subsequently develop pre-eclampsia. Lancet 2003, 361:1511-1517.
[58] Savvidou MD, Noori M, Anderson JM, Hingorani AD, Nicolaides KH:
Maternal endothelial function and serum concentrations of placental
growth factor and soluble endoglin in women with abnormal
placentation. Ultrasound Obstet Gynecol 2008, 32:871-876.

About the Editors

Eyal Sheiner, M.D, Ph.D. is a Professor of Obstetrics and Gynecology at
the Soroka University Medical Center, Ben-Gurion University of the Negev,
Beer-Sheva, Israel. His PhD study at Rush University Medical Center
(Chicago,Il) was supported by a grant from the Fulbright Visiting Scholar
Program of the United States. He serves as Director of the Maternity D
Department and is Program Director of the residency program of the hospital.
In the last decade he has investigated and published extensively in the field of
maternal fetal medicine (contributed more than 370 peer-reviewed articles and
book chapters) and he is the editor of eight books.

Yariv Yogev, M.D. is a Professor of Obstetrics and Gynecology at Helen
Schneider Hospital, Rabin Medical Center, Tel Aviv University, Israel. He
completed his clinical and research fellowship in Maternal Fetal Medicine at
Columbia University and St. Lukes-Roosvelt Hospital in New York. He is the
Director of Obstetrics and Delivery ward in Helen Schneider Hospital for
Women. Prof. Yogev is the President of the Israel Society for Maternal and
Fetal Medicine, vice president of the Israeli Association for Obstetrics and
Gynecology, and the moderator of the diabetes in pregnancy program in the
American Society for Maternal Fetal Medicine (SMFM). He contributed more
than 160 peer-reviewed articles and book chapters.

Index

A
abuse, 259
access, 244, 256
accounting, 3, 117, 290
acetaminophen, 64
acetylation, 113
acid, 45, 78, 117, 159, 175, 212, 240
acidosis, 26
ACTH, 112, 113, 114
acute renal failure, 22, 28
AD, 68, 123, 184, 260, 275, 296, 299, 300
ADAM, 197
adaptation, 3, 40, 139, 265, 294
adaptations, 136
adenosine, 103, 108
adenovirus, 281, 292
adhesion, 61, 159, 164, 169, 170, 182, 266
adipocyte, 128, 146, 150, 153, 155, 159,
160, 161, 164, 181
adiponectin, 77, 102, 128, 129, 130, 133,
136, 137, 138, 139, 142, 143, 145, 146,
147, 148, 149, 150, 153, 154, 155, 157,
159, 160, 161, 162, 163, 164, 176, 177,
179, 181, 182, 183, 184, 185
adipose tissue, 128, 129, 132, 137, 139, 148,
149, 151, 152, 153, 155, 156, 163, 164,
176, 178, 181, 184
adiposity, 94, 137, 152, 179, 180
adjustment, 21, 39, 90, 92
adolescents, 6, 86, 94
adult respiratory distress syndrome, 241
adults, 86, 163
adverse effects, 18, 34, 225, 251, 269
aetiology, 169
Africa, 242, 255
African American women, 246
African-American, 238, 244, 246, 257
age, 6, 10, 15, 24, 33, 36, 38, 49, 63, 78, 81,
99, 100, 104, 107, 140, 167, 171, 199,
226, 232, 238, 243, 244, 266, 271, 284,
288, 294
aggregation, 61, 212
agonist, 117
Alaska, 244
albumin, 81, 117, 224, 232
algorithm, 196
allele, 141, 149, 216
allograft survival, 120, 124
alpha-fetoprotein, 173
ALT, 15, 60, 190, 193
alveolar type II cells, 163
amino, 53, 116, 128, 178
amino acid(s), 53, 116, 128, 178
amniotic fluid, 14, 38, 108, 156, 157, 175,
191, 194, 219, 272, 276, 277
anaesthesiologists, 269
androgen, 181
anemia, 61, 64, 100, 233
anesthesiologist, 247
aneuploidy, 8
angina, 298
Index 304
angiogenesis, 83, 129, 150, 160, 168, 169,
264, 265, 273, 274, 299
angiogenic process, 195
angiotensin converting enzyme, 20, 269
angiotensin II, 37, 39, 152, 192, 194, 263,
264, 267, 268
angiotensin II receptor antagonist, 39
angiotensin receptor antagonist, 20
angiotensin receptor blockers, 36
anorexia nervosa, 130, 163, 164
antibody, 2, 5, 24, 34, 63, 65, 116, 205, 238,
292
anticoagulant, 215
anticonvulsant, 25, 27
antigen, 265, 266
antigen-presenting cell, 265
antihypertensive agents, 20, 30
antihypertensive drugs, 18, 25, 36, 39, 55,
250
anti-inflammatory drugs, 63
antioxidant, 123, 251, 259
antiphospholipid antibodies, 70
antiphospholipid syndrome, 22, 70
aorta, 36
apoptosis, 130, 157, 161, 215
appendicitis, 22
appetite, 128
arginine, 118, 266
arrest, 241
arterioles, 61
artery(ies), 4, 6, 7, 11, 30, 42, 57, 78, 79, 81,
83, 88, 95, 101, 102, 108, 145, 165, 166,
204, 206, 207, 208, 227, 262, 263, 268,
273, 275, 278, 287, 293, 298
arthritis, 63, 120, 156
Asia, 242, 255
aspartate, 27, 53
aspiration, 26, 241
aspiration pneumonia, 241
assessment, 14, 15, 22, 37, 38, 42, 55, 96,
108, 133, 138, 188, 189, 191, 194, 204,
269, 294
assisted reproductive techniques (ART), 99,
103, 104
asthma, 128, 156, 270
asthmatic children, 156
asymptomatic, 22, 292
atherogenesis, 250
atherosclerosis, 96, 129, 142, 155, 292
atherosclerotic plaque, 292
atrophy, 158
autoantibodies, 267, 276, 278
autoimmune disease, 63, 195
autoimmune diseases, 195
avoidance, 38, 246
awareness, 246
B
bacteria, 62
base, 9, 13, 36, 259
basic research, 199
BD, 256, 272, 277
beneficial effect, 33
benefits, 7, 16, 17, 26, 212, 213, 214, 217,
226, 232
benign, 29, 112
beta blocker, 251, 269
bilateral, 197
bilirubin, 22, 191, 194
binding globulin, 90
bioassay, 113, 114
bioinformatics, 200, 206
biological activity(ies), 114, 119, 129, 130
biological media, 246
biomarkers, 4, 195, 196, 198, 203, 205
biopsy, 60, 285
biosynthesis, 122
birth weight, 32, 53, 54, 79, 80, 84, 149,
158, 177, 213, 216, 217, 276, 286, 297
births, 3, 24, 54, 84, 99, 175, 229, 246, 286,
297
birthweight, 80, 154
black women, 243, 246
bleeding, 19, 23
blindness, 11, 46
blood, 2, 6, 8, 9, 11, 12, 13, 15, 17, 18, 19,
20, 22, 24, 31, 32, 33, 34, 35, 36, 37, 38,
39, 44, 45, 51, 54, 55, 61, 71, 72, 75, 83,
84, 85, 89, 94, 95, 112, 113, 114, 115,
Index 305
120, 122, 133, 136, 141, 142, 149, 153,
154, 158, 160, 166, 176, 177, 181, 185,
188, 189, 191, 192, 194, 195, 197, 199,
207, 208, 224, 225, 226, 227, 232, 235,
236, 240, 241, 246, 247, 254, 258, 261,
264, 266, 267, 268, 269, 270, 271, 288,
291, 292
blood flow, 17, 37, 45, 51, 115, 227, 236
blood pressure, 2, 8, 9, 12, 13, 17, 18, 19,
20, 24, 31, 32, 33, 34, 35, 36, 37, 38, 39,
44, 54, 55, 71, 72, 83, 84, 85, 89, 94, 95,
115, 149, 154, 160, 166, 185, 188, 189,
191, 192, 194, 195, 197, 199, 207, 208,
225, 226, 235, 240, 246, 247, 254, 258,
261, 264, 267, 268, 269, 270, 271, 288,
291, 293
blood pressure reduction, 246
blood smear, 11, 15, 22, 61
blood transfusion, 241, 246
blood transfusions, 241
blood urea nitrogen, 34
blood vessels, 115, 264
body composition, 176
body fat, 133
body mass index (BMI), 86, 90, 91, 92, 97,
98, 100, 132, 133, 136, 137, 138, 139,
140, 173, 175, 182, 183, 191, 194, 195,
288, 291
body weight, 152, 155
bonds, 161
bone, 128
bradycardia, 25, 248
brain, 8, 11, 53, 65, 113, 115, 116, 117, 182,
254
brain damage, 11
breast cancer, 283
breast milk, 20, 39, 184
breastfeeding, 20
C
caesarean section, 268
caffeine, 192, 193
calcium, 6, 7, 18, 20, 27, 28, 39, 43, 47, 63,
79, 192, 195, 197, 206, 224, 225, 226,
227, 228, 229, 230, 231, 232, 233, 234,
235, 236, 247, 250, 251, 258, 269
calcium channel blocker, 18, 20, 28, 39,
247, 251, 269
cancer, 21, 49, 260, 265, 283, 296
cancer therapy, 274
capillary, 10, 199
capsule, 13
carbohydrate(s), 96, 136
carbohydrate metabolism, 178
cardiac arrest, 270
cardiac output, 9
cardiomyopathy, 39
cardiovascular disease(s), 20, 21, 49, 128,
130, 155, 158, 198, 201, 205, 253, 260,
282, 284, 285, 286, 287, 289, 290, 291,
293, 294, 296, 299
cardiovascular function, 300
cardiovascular morbidity, 18, 104, 106, 253
cardiovascular risk, 21, 49, 94, 165, 284,
291, 294, 295, 296, 299
Caribbean, 3, 242, 255
Caucasian population, 149
causal relationship, 293
causality, 6, 293
CD30, 171
CDC, 239
cDNA, 153, 158
cell differentiation, 152
cell line(s), 118, 121
cell surface, 264
central nervous system (CNS), 11, 13, 25,
27, 63, 131
cerebral arteries, 24
cerebral edema, 11
cerebral hemorrhage, 13, 15, 17, 19, 28, 32,
45, 242, 246
cerebrovascular disease, 253
cervix, 16, 26, 28, 31
cesarean section, 9, 26, 100, 104, 116
channel blocker, 18, 20, 36, 47, 251
chemical(s), 120, 121, 220, 267
chemokines, 182
chicken, 272
childhood, 62, 156, 162, 224
Index 306
children, 56, 86, 94, 176
cholestasis, 13
cholesterol, 178, 288, 291
choline, 116, 117
chorionic gonadotropin, 112, 263
choroid, 273
chromosome, 205
chronic hypertension (CHTN), 1, 2, 3, 6, 7,
12, 19, 20, 29, 31, 32, 33, 34, 36, 38, 39,
55, 71, 72, 84, 87, 92, 189, 191, 194,
238, 239, 240, 243, 250, 252, 253, 262,
282, 283, 285, 291
chronic kidney disease (CKD), 292, 299
chronic renal failure, 275
cigarette smoking, 263
circulation, 9, 88, 101, 108, 113, 117, 119,
123, 129, 132, 142, 184, 215, 264, 267
classification, 188, 189, 200, 207, 279
cleavage, 118, 159
clinical application, 158, 200
clinical diagnosis, 25, 165
clinical presentation, 22, 82, 131, 140
clinical symptoms, 60, 199, 224, 268
clinical syndrome, 25, 293
clinical trials, 17, 23, 213, 215, 234, 259
cloning, 114, 153, 158
clonus, 190, 193
coagulation profile, 269
coagulopathy, 8, 28, 60, 241
coarctation, 36
collagen, 5, 32, 36, 130, 153, 158, 163
coma, 2, 24, 25
combination therapy, 217, 218
complement, 23, 34, 40, 62, 63, 68, 69, 130,
159, 160
complexity, 199, 207
compliance, 188
complications, vii, 5, 11, 12, 15, 16, 23, 28,
30, 31, 34, 35, 38, 40, 45, 49, 54, 60, 69,
70, 72, 79, 80, 81, 86, 97, 98, 102, 103,
104, 106, 109, 128, 131, 132, 136, 173,
175, 203, 213, 217, 219, 220, 226, 229,
232, 233, 234, 237, 239, 240, 241, 244,
246, 247, 249, 256, 257, 259, 260, 263,
279, 286, 296, 297
computed tomography, 52, 60
conception, 33, 34, 36, 63, 64, 75, 86, 89,
137, 224, 294
congenital malformations, 98
congestive heart failure, 270
consensus, 17, 22, 34, 38, 119, 142, 179,
193
consumption, 45, 60, 224, 234, 259
contamination, 116
control group, 136, 142, 289
controlled studies, 5, 42, 174, 234, 272
controlled trials, 27, 35, 218, 219, 226, 233,
248, 251
controversial, 6, 21, 26, 33, 37, 38, 40, 215,
250
controversies, 43, 50, 66, 72, 73
convulsion, 23, 26, 27
coronary artery disease, 160, 162, 294, 298
coronary heart disease, 292, 300
correlation(s), 54, 88, 90, 92, 129, 130, 137,
138, 154, 169, 199, 266, 288, 293, 297
corticosteroid therapy, 50
corticosteroids, 16, 27, 30, 269
corticotropin, 111, 113, 114, 122
cortisol, 114
cost, 32, 196
cotyledon, 267
counseling, 30, 33
creatinine, 9, 10, 12, 15, 30, 34, 81, 82, 189,
197, 206, 240, 269, 291
CRF, 113, 114, 118, 119, 122
cross-sectional study, 137, 138, 146
CRP, 133, 154, 197, 276
CT, 56, 60, 151, 205
culture, 34, 152
culture medium, 205
cure, 268
cyanide poisoning, 19
cyanosis, 190, 193, 240
cysteine, 153
cytokines, 136, 151, 157, 170, 171, 176,
179, 181, 182, 212, 262, 263, 265, 266,
272, 276, 277
Index 307
D
data set, 246
database, 229
DBP, 195
deaths, 26, 237, 238, 241, 242, 243, 244,
246, 254, 257, 286
decision-making process, 9
deficiency, 152, 234
dendritic cell, 265, 272
deoxyribonucleic acid, 64
depression, 270
detectable, 215
detection, 16, 39, 72, 81, 106, 195, 196,
204, 205
developed countries, 24, 241, 242, 252
developing countries, 3, 24, 240, 241
diabetes, vii, 19, 21, 36, 49, 73, 88, 89, 92,
112, 129, 130, 151, 153, 154, 155, 160,
164, 192, 195, 212, 224, 252, 262, 282
diabetic patients, 159, 160, 162
diagnostic criteria, 3, 9, 39, 40, 224
dialysis, 62
diarrhea, 62
diastolic blood pressure, 8, 12, 22, 28, 44,
52, 90, 190, 192, 193, 195, 225, 239
diastolic pressure, 2, 8, 17, 32, 35, 36
diet, 92, 163, 225, 250, 258
dietary intake, 192, 195
differential diagnosis, vii, 24, 59
discomfort, 86
discordance, 244, 257
discrimination, 230
disease progression, 51, 191, 194
diseases, 22, 55, 87, 185, 192, 198, 212,
284, 285, 296
disorder, 2, 3, 5, 32, 55, 62, 64, 75, 86, 95,
131, 169, 218, 223, 253, 254, 256, 260,
261, 262, 281, 291
disseminated intravascular coagulation, 22
distribution, 74, 77, 137, 138, 145, 149, 150,
161, 178, 215
diuretic, 39, 250, 251
diversity, 130
DNA, 196, 205
DOI, 43, 204
dosing, 247, 249
double blind study, 259
double-blind trial, 227
down-regulation, 124
drawing, 6
drug abuse, 25
drug therapy, 47, 233, 259
drugs, 20, 27, 34, 35, 36, 37, 39, 120, 121,
130, 218, 219, 220, 249, 251, 269
dyslipidemia, 131, 160, 294
E
echocardiogram, 34
edema, 2, 7, 8, 9, 13, 22, 62, 115, 235, 240,
241, 250, 261
egg, 100, 272
EKG, 34
elevated liver enzymes, 49, 50, 51, 60, 64,
66, 68, 85, 104, 168, 172, 190, 193, 201,
211, 241, 244, 256
embolism, 20, 242
emergency, 19, 68, 241, 246
encephalitis, 25
encephalopathy, 25, 32, 35, 38, 52, 241
encoding, 159, 267
end stage renal disease, 62
endocrine, 112, 121, 127, 150, 155, 158
endocrinology, 118
endothelial cells, 27, 61, 130, 160
endothelial dysfunction, 3, 8, 40, 74, 87, 94,
102, 167, 178, 215, 267, 281, 282, 287,
289, 290, 291, 293, 294, 295, 297, 299
endothelial NO synthase, 264
endothelial-cell dysfunction., 223
endothelium, 31, 68, 264, 288, 290, 294,
298
end-stage renal disease, 254, 260, 282, 285,
294, 296
energy, 128, 151, 178
environmental effects, 43
environmental factors, 21
enzyme(s), 21, 36, 37, 39, 63, 121, 152,
160, 192, 193, 194, 212, 216, 265
Index 308
enzyme inhibitors, 36, 39, 192, 194
enzyme-linked immunosorbent assay, 160
epidemic, 94, 100, 243
epidemiologic, 74, 279, 282
epidemiology, vii
epigastric pain, 10, 13, 16, 22, 25, 189, 190,
193, 261, 268
epilepsy, 2, 25
epitopes, 115
estrogen, 77
ethnic groups, 244, 245
ethnicity, 232, 238, 243, 257
etiology, 10, 34, 88, 212, 223, 224, 281
evidence, 4, 5, 7, 11, 17, 18, 20, 21, 29, 30,
34, 39, 43, 45, 46, 71, 74, 75, 80, 98,
115, 119, 128, 132, 136, 137, 139, 142,
148, 150, 157, 169, 188, 195, 232, 234,
235, 249, 262, 267, 282, 284, 285, 293
exclusion, 92
excretion, 4, 9, 12, 15, 142, 146, 266, 276
exercise, 7, 162, 163, 298
experimental autoimmune
encephalomyelitis, 156
exposure, 88, 247, 291, 294
extracts, 113, 115, 118
F
false negative, 30
false positive, 30, 195, 196
family history, 5, 22, 33, 288
fasting, 89, 90, 133, 138, 288, 291
fasting glucose, 90
fat, 10, 45, 133, 136, 137, 146, 151, 152,
153, 159, 178, 179, 182
fatty acids, 132, 175, 178, 234, 250, 259
fertilization, 104
fetal demise, 104
fetal distress, 48, 270
fetal growth, 11, 13, 14, 16, 17, 19, 32, 33,
37, 38, 40, 46, 47, 56, 79, 102, 136, 169,
177, 181, 185, 190, 191, 194, 213, 215,
240, 289, 298
fetus, 8, 15, 18, 22, 23, 25, 26, 29, 32, 34,
35, 36, 38, 63, 112, 113, 114, 150, 224,
225
fever, 60, 61
fibrin, 10, 74
fibrinogen, 11, 45
filtration, 10, 115, 118
financial, 200, 204
Finland, 253
fish, 234, 250, 259
fish oil, 234, 250, 259
fitness, 128
fluid, 37, 89, 183, 269
fluid balance, 269
folic acid, 276
Food and Drug Administration, 7, 43, 232,
234
food intake, 155
formation, 11, 118, 123, 124, 160, 164, 225,
292
fragments, 115, 116
free radicals, 27
functional activation, 157
G
gallbladder disease, 22
gastroenteritis, 22
gastrointestinal bleeding, 61
gel, 115, 118
gene expression, 151, 152, 181, 267
generalized tonic-clonic seizure, 25
genes, 5, 62, 88, 112, 114, 185
genetic background, 121
genetic factors, 269
genetic predisposition, 75
genome, 205
genotype, 141, 148, 149
gestation, 2, 3, 4, 5, 7, 8, 12, 14, 16, 17, 19,
21, 24, 25, 26, 28, 29, 30, 32, 38, 39, 46,
64, 71, 74, 77, 78, 81, 86, 87, 89, 99,
100, 107, 108, 131, 132, 133, 136, 138,
139, 140, 142, 145, 146, 149, 154, 167,
177, 179, 180, 184, 188, 195, 199, 200,
201, 206, 208, 212, 213, 217, 227, 239,
Index 309
240, 252, 262, 266, 278, 279, 283, 289,
292, 293
gestational age, 2, 4, 15, 17, 19, 23, 24, 28,
29, 46, 73, 76, 77, 78, 79, 81, 86, 87, 92,
93, 106, 133, 136, 137, 146, 149, 168,
169, 171, 177, 196, 199, 204, 214, 216,
217, 227, 230, 253, 268, 278, 283, 284,
286
gestational diabetes, 39, 86, 89, 96, 98, 100,
104, 154, 174, 177, 178, 236
gestational hypertension (GHTN), 2, 6, 8,
12, 24, 29, 30, 31, 43, 46, 48, 53, 54, 71,
72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,
83, 84, 85, 86, 87, 89, 90, 91, 92, 93, 94,
95, 100, 102, 106, 142, 145, 169, 174,
189, 191, 193, 194, 199, 208, 238, 243,
250, 255, 279, 291, 299
gland, 113
glucocorticoid, 23, 151
glucocorticoids, 64
glucose, 21, 34, 87, 89, 90, 128, 130, 133,
138, 150, 153, 154, 159, 161, 162, 163,
174, 177, 178, 288, 297
glucose tolerance, 133, 159, 161, 162, 163,
174, 177, 297
glucose tolerance test, 133
glutamate, 27
glycerol, 116
glycine, 116, 164
glycosylation, 119, 164
growth, 3, 4, 11, 15, 23, 29, 30, 33, 37, 38,
42, 46, 54, 56, 57, 63, 79, 82, 83, 88, 95,
96, 100, 101, 102, 103, 128, 140, 152,
159, 165, 166, 167, 168, 177, 181, 191,
193, 194, 196, 197, 204, 209, 213, 215,
219, 233, 240, 259, 263, 264, 268, 269,
273, 274, 275, 281, 288, 298, 299, 300
growth factor, 4, 57, 83, 88, 96, 101, 128,
140, 152, 165, 166, 167, 168, 181, 196,
197, 204, 215, 264, 268, 273, 274, 275,
281, 298, 299, 300
guidance, 17
guidelines, 17, 98, 188, 189, 191, 193, 194,
195, 200, 202, 213, 246, 257
H
haemostasis, 212
haplotypes, 83, 141
headache, 2, 13, 22, 25, 29, 86, 189, 190,
193, 240, 248
health, vii, 86, 94, 112, 226, 237, 296
health care, vii
health condition, 237
heart disease, 20, 175, 253, 283, 286, 294
heart failure, 10, 32, 35
heart rate, 25, 28, 53, 115, 160, 198, 207,
208, 209
hematocrit, 11, 269
hematoma, 22
hematuria, 61, 62
hemoglobin, 269
hemolytic anemia, 64
hemolytic uremic syndrome, 13, 67, 68, 69
hemorrhage, 3, 10, 11, 21, 25, 28, 51, 73,
100, 237, 241, 242, 246, 256
hemorrhagic stroke, 241, 254
hemostasis, 252
hepatic failure, 61, 241
hepatitis, 22
hepatitis a, 13
hepatocytes, 60
heterogeneity, 226, 254
high blood pressure, 9, 35, 36, 41, 47, 226,
227
high density lipoprotein, 132
high-risk women, 43, 103, 252
histidine, 197, 206
histocompatability, 88
histology, 285
history, 5, 20, 21, 23, 34, 51, 63, 73, 89,
100, 175, 195, 196, 198, 199, 211, 215,
216, 228, 232, 252, 253, 254, 262, 282,
284, 287, 289, 290, 291, 293, 294, 296,
297, 298, 299
HLA, 88, 103
HM, 167, 178, 299
homeostasis, 128, 138, 169, 274
homocysteine, 276
Index 310
hormone(s), 90, 112, 122, 124, 130, 132,
154, 158, 159, 161, 176, 178, 273
hospitalization, 249, 295
host, 117, 120
human, 56, 88, 112, 113, 114, 116, 118,
119, 120, 122, 123, 124, 128, 129, 130,
131, 136, 150, 151, 152, 153, 154, 155,
157, 158, 160, 164, 168, 175, 176, 177,
179, 196, 205, 215, 220, 223, 264, 265,
267, 271, 272, 273, 274, 277
human chorionic gonadotropin, 196
human leukocyte antigen, 88
human milk, 220
Hunter, 167, 171, 175
hyaline membrane disease, 46
hydatid mole, 121
hydatidiform mole, 277
hydrogenase, 61
hydrops, 44, 167
hyperbilirubinemia, 60, 61, 64
hypercholesterolemia, 132, 175
hyperemia, 287
hyperfiltration, 273, 275
hyperinsulinemia, 87, 89, 93, 159, 161
hyperlipidemia, 136
hypertension (HTN), 1, 2, 3, 5, 7, 8, 9, 12,
13, 14, 17, 18, 19, 20, 21, 23, 26, 28, 29,
30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40,
43, 44, 47, 48, 52, 54, 55, 56, 57, 59, 60,
62, 63, 71, 72, 73, 75, 76, 78, 79, 80, 81,
82, 83, 85, 87, 88, 89, 90, 91, 93, 94, 95,
96, 97, 104, 114, 119, 129, 131, 142,
145, 160, 167, 172, 174, 175, 183, 189,
190, 191, 193, 194, 195, 198, 199, 200,
201, 202, 205, 207, 208, 219, 224, 226,
232, 233, 234, 235, 237, 238, 239, 240,
242, 243, 244, 245, 246, 247, 248, 249,
250, 252, 253, 254, 256, 257, 258, 259,
264, 268, 271, 272, 277, 281, 282, 285,
288, 291, 294, 295, 296
hypertriglyceridemia, 132, 162
hyperuricemia, 10, 45
hyperventilation, 25
hypoglycemia, 37, 60, 61
hypotension, 18, 20, 28, 48, 248, 270
hypothalamus, 113
hypothesis, 75, 101, 116, 172, 235, 265,
275, 285, 293, 294
hypoxemia, 38, 88
hypoxia, 25, 26, 101, 180, 219, 220, 262,
263, 265, 266, 268, 270, 272
I
iatrogenic, 3, 10, 12
ID, 205
identical twins, 103
identification, 117, 200, 208, 224
identity, 111, 114, 116
idiopathic, 22
idiopathic thrombocytopenic purpura, 22
IL-8, 164, 219
immune response, 69, 112, 128, 131, 158,
265
immune system, 102, 112, 120, 121
immunity, 108, 120, 151, 171
immunoglobulin(s), 115, 118
immunomodulation, 120
immunomodulatory, 124
immunoreactivity, 117, 118, 166
immunosuppression, 70, 158
immunosuppressive drugs, 70, 121
impairments, 150
imprinting, 88
in utero, 227
in vitro, 113, 123, 130, 267, 272
in vivo, 113, 114, 116, 151
incidence, 3, 5, 6, 7, 20, 21, 22, 24, 32, 35,
40, 52, 55, 60, 61, 65, 81, 85, 86, 93, 99,
100, 103, 104, 213, 215, 224, 225, 226,
232, 238, 241, 243, 244, 246, 250, 251,
252, 253, 254, 261
India, 26, 207, 241, 243
Indians, 225
indirect effect, 224
individuals, 129, 137, 152
induction, 16, 19, 26, 27, 46, 53, 120, 130,
164, 267, 279
industrialized countries, 242
infancy, 62, 177
Index 311
infants, 29, 39, 92, 99, 213, 216, 286, 297
infarction, 21, 48, 198, 246
infection, 25, 43, 62, 68, 120, 157, 237, 242
infertility, 100
inflammation, 10, 88, 89, 102, 125, 132,
150, 151, 152, 153, 156, 157, 163, 169,
170, 212, 219, 220, 262, 270, 295
inflammatory bowel disease, 128, 156
inflammatory mediators, 152, 267
inheritance, 103
inhibition, 27, 83, 120, 212, 268, 273
inhibitor, 23, 39, 69, 128, 140, 152, 180,
264, 265, 275, 277
initiation, 35, 246, 250
injure, 294
injury, 10, 13, 20, 28, 45, 61, 62, 67
innate immunity, 265
insulin, 21, 77, 87, 89, 90, 93, 94, 96, 128,
129, 130, 131, 132, 133, 136, 138, 142,
146, 150, 151, 152, 153, 154, 155, 159,
161, 162, 163, 164, 174, 175, 176, 177,
178, 180, 181, 183, 184, 196, 252, 267,
277, 282, 285, 291, 295, 299
insulin resistance, 77, 87, 89, 90, 93, 94, 96,
128, 129, 130, 131, 132, 133, 136, 138,
142, 146, 150, 151, 152, 153, 154, 155,
159, 161, 163, 174, 175, 176, 181, 184,
277, 282, 285, 291, 299
insulin sensitivity, 89, 90, 133, 138, 161,
176, 180, 183, 184, 295
integrins, 170
integrity, 9
intensive care unit, 104, 106
interferon, 156
interleukin-8, 164, 276
International Classification of Diseases, 238
intervention, 92, 93, 150, 224, 226, 247
intima, 292, 299
intoxication, 44
intracellular calcium, 224
intra-uterine growth restriction (IUGR),
100, 191, 193, 194, 288, 294
intrauterine growth retardation, 177, 274
intravenous fluids, 38
intravenously, 18, 27, 28, 247, 270
intron, 148, 149
involution, 121
ions, 116
IP-10, 169
Ireland, 202
iron, 235
ischaemic heart disease, 175, 297
ischemia, 8, 10, 88, 101, 114, 121, 160, 198,
212, 262, 263, 266, 268, 270, 272
J
jaundice, 60
joints, 63
K
kidney(s), 8, 10, 19, 62, 63, 65, 67, 87, 131,
142, 146, 191, 194, 285, 292, 297
knots, 74
L
laboratory studies, 61, 62
laboratory tests, 6, 34, 269
lactate dehydrogenase, 11, 15, 190
lactation, 20, 56
lactic acid, 269
larynx, 21
later life, 49, 55, 260, 283, 284, 286, 296
Latin America, 3, 242, 255
LDL, 160, 291
lead, 9, 12, 18, 21, 23, 24, 28, 40, 103, 118,
188, 195, 198, 246, 253, 262, 266, 269,
279, 293, 294
leptin, 77, 128, 129, 132, 133, 134, 136,
139, 140, 141, 142, 150, 152, 153, 154,
155, 156, 157, 158, 163, 175, 176, 177,
179, 180, 181, 182, 183, 185, 198
lesions, 10, 25, 63, 215, 254, 260
leukocytes, 170
lifestyle changes, 155
lipid metabolism, 5, 128, 131, 150, 163, 177
lipids, 21, 136, 163
Index 312
lipolysis, 146
liver, 2, 8, 10, 11, 13, 15, 19, 22, 29, 39, 45,
49, 50, 51, 60, 61, 63, 64, 65, 66, 67, 68,
85, 104, 114, 115, 131, 168, 172, 190,
191, 193, 194, 201, 211, 241, 244, 256,
261
liver disease, 66, 67
liver enzymes, 2, 22, 39, 49, 50, 51, 60, 64,
66, 68, 85, 104, 168, 172, 190, 191, 193,
194, 201, 211, 241, 244, 256
liver failure, 66
liver function tests, 261
liver transplant, 61
liver transplantation, 61
loci, 149, 159
longitudinal study, 132, 133, 136, 137, 139,
168, 176, 179, 180, 286
low platelet count, 49, 50, 66, 172, 241,
242, 244
low risk, 33, 289
Luo, 205
lupus, 22, 63, 64, 69, 70
lymphoid, 158
lysine, 116, 164
M
macrophages, 155, 157, 159, 265, 266, 267
magnesium, 23, 27, 28, 52, 53, 224, 238,
244, 248, 258, 260, 269, 279
magnetic resonance imaging, 45, 51, 60
majority, 89, 131, 140, 212
mammalian brain, 113
mammals, 152
man, 164
management, 1, 3, 4, 15, 16, 17, 18, 22, 23,
26, 32, 33, 38, 40, 41, 43, 45, 46, 47, 48,
50, 53, 57, 66, 67, 69, 70, 93, 188, 189,
191, 198, 200, 201, 202, 203, 224, 238,
246, 248, 255, 269, 270, 278, 279, 295
manipulation, 131, 249, 250
mass, 91, 97, 98, 123, 133, 137, 140, 173,
175, 178, 179, 182, 183, 194, 195, 262
mass spectrometry, 116, 117
maternal care, 195
matrix, 152
matter, 254
MB, 201, 256, 271, 275
MCP, 164
MCP-1, 164
mean arterial pressure, 47, 204
measurement(s), 4, 7, 12, 71, 83, 86, 115,
120, 133, 188, 195, 196, 198, 200, 208,
229
mechanical ventilation, 241, 246
media, 202, 292, 299
median, 21, 78, 91, 137, 138, 142, 145, 146,
147, 148, 253, 283, 288
medical, 85, 230, 238, 241, 262
medication, 34, 38, 39, 55, 247
medicine, vii, 164, 205, 247
mellitus, 5, 39, 89, 92, 98, 130, 178, 224,
236
membranes, 63, 116, 157
meningitis, 25
mercury, 188, 192
messages, 112
messenger RNA, 124
meta-analysis, 6, 7, 35, 43, 49, 69, 70, 82,
92, 98, 132, 213, 219, 220, 226, 233,
234, 247, 249, 251, 252, 253, 258, 259,
260, 282, 296, 297
metabolic, 127, 129, 136, 179, 205, 236
metabolic changes, 136
metabolic disorder, 25, 150
metabolic disorders, 25, 150
metabolic pathways, 196
metabolic syndrome, 10, 89, 128, 132, 136,
150, 153, 155, 158, 159, 160, 163, 176
metabolism, 45, 112, 128, 136, 175, 178,
212
metabolites, 198
metabolized, 265
metalloproteinase, 64
methodology, 199
methyl groups, 116
mice, 49, 120, 130, 151, 155, 156, 157, 158,
159, 263, 293
microangiopathic hemolytic anemia, 22, 61,
240
Index 313
microcirculation, 61
microparticles, 82
migration, 273
mild hypertensive, 35, 36
miscarriage, 100, 120
miscarriages, 213
mitogen, 264
MMPs, 215
models, 27, 152, 195, 196
modifications, 117, 131, 164
mole, 112, 262
molecular weight, 160, 161, 162, 163, 164,
184, 215, 220, 260
molecules, 101, 128, 131, 159, 169, 170,
182, 265, 292
monoclonal antibody, 63
monocyte chemoattractant protein, 128, 277
moratorium, 48
morbidity, vii, 1, 5, 16, 17, 19, 22, 26, 29,
30, 33, 35, 50, 60, 62, 65, 66, 79, 100,
104, 132, 223, 225, 226, 238, 246, 255,
256, 261, 281, 294, 295, 296
mortality, vii, 1, 3, 16, 23, 26, 28, 30, 32,
41, 50, 54, 60, 62, 65, 66, 79, 80, 84,
100, 103, 106, 132, 165, 175, 196, 213,
223, 226, 237, 238, 240, 241, 242, 246,
252, 253, 254, 255, 256, 257, 261, 269,
281, 283, 284, 286, 294, 295, 296, 297,
298
mortality rate, 28, 60, 62, 196, 226, 246
motif, 64
MR, 159, 162, 165, 167, 168, 169, 180
MRI, 60
mRNA, 137, 153, 156, 184, 266, 267
mucoid, 62
multiple regression analyses, 138
multiple sclerosis, 128, 156
multivariate analysis, 173
mutation(s), 62, 68, 130, 164, 218, 264
myasthenia gravis, 28
myocardial infarction, 292
myocardial ischemia, 48
myocardium, 9
N
National Academy of Sciences, 123
National Health and Nutrition Examination
Survey (NHANES), 86
National Institutes of Health, 41
natural killer cell, 88
nausea, 16, 22, 60, 61
necrosis, 11, 154, 170, 171, 272, 276, 277
nematode, 117, 120, 124, 125
neonates, 129, 167
nephritis, 63, 64, 69, 70
nervous system, 19, 63
neural connection, 112
neural network, 207
neuroimaging, 25
neurokinin, 115, 122, 123, 124, 276
neurons, 123
neuropeptides, 118
nitric oxide, 7, 263, 265, 273, 275
nitric oxide synthase, 263, 265, 273, 275
nonsmokers, 6
nuclei, 60
nulliparity, 22, 100
nursing, vii
nutrient(s), 114, 235
O
obesity, vii, 5, 86, 87, 89, 90, 91, 92, 93, 94,
97, 100, 128, 130, 131, 132, 146, 149,
150, 151, 152, 153, 154, 155, 158, 159,
162, 163, 171, 173, 174, 175, 178, 238,
243, 282, 285
occlusion, 10
oedema, 123
oil, 7, 233, 250, 259
oligomers, 129, 130, 161
opportunities, 254
optic nerve, 11
optimism, 225
organ, 8, 10, 13, 22, 30, 33, 35, 36, 63, 65,
67, 88, 121, 127, 131, 150, 155, 158,
192, 195, 261
Index 314
organs, 63, 65
overlap, 12
overweight, 86, 87, 91, 92, 94, 137, 138,
139, 160, 172, 173, 179, 183, 184
overweight adults, 86
oxidation, 159
oxidative stress, 10, 101, 102, 115, 169,
170, 267, 272
oxygen, 25, 26, 88, 269
P
Pacific, 244, 257
pain, 10, 13, 16, 22, 25, 29, 60, 61, 189,
190, 193, 240, 261, 268
palpation, 22
palpitations, 248
pancreatitis, 13, 60
paradigm shift, 47, 256
parallel, 267
parasite, 112
parasites, 111, 117
parathyroid, 224
parents, 244
parity, 107, 139, 140, 283
partial thromboplastin time, 11
participants, 91, 133
patents, 196, 204
pathogenesis, vii, 41, 42, 70, 74, 75, 89, 95,
101, 102, 103, 107, 145, 155, 165, 168,
172, 198, 200, 212, 215, 223, 262, 267,
268, 270, 281, 291, 295
pathology, 11, 102, 115, 262
pathophysiological, 102, 168, 265
pathophysiology, 75, 96, 101, 102, 103,
128, 129, 136, 142, 150, 152, 165, 272,
273, 277
pathways, 128, 129, 152, 157, 161
PCR, 141
peptide(s), 89, 96, 111, 112, 113, 115, 116,
117, 118, 119, 120, 121, 122, 123, 124,
182
percentile, 13, 216, 217
perfusion, 8, 11, 17, 18, 24, 40, 100, 115,
208, 262, 266, 289, 298
perinatal, vii, 1, 17, 19, 23, 28, 29, 30, 32,
33, 34, 36, 43, 46, 49, 50, 51, 52, 54, 55,
59, 65, 67, 79, 80, 84, 93, 94, 97, 98,
103, 188, 203, 213, 219, 223, 226, 229,
252, 256, 278, 281
perinatal morbidity, vii, 1, 29, 30, 65, 223,
281
periodicity, 194
periodontal, 6
periodontal disease, 6
peripheral blood, 167, 170, 292, 299
peripheral blood mononuclear cell, 167,
292, 299
permeability, 8, 273
permission, 147, 148
PET, 62, 71, 72, 73, 74, 75, 76, 77, 78, 79,
80, 81
petechiae, 11
pH, 38
phenotype, 263
phenotypes, 87, 159, 291
phenytoin, 27, 52, 249, 258, 270
photophobia, 25
physical activity, 43, 92, 93
physicians, 17
physiology, 152, 158, 178, 181
pilot study, 52, 215, 220, 298
pioglitazone, 163
pituitary gland, 112, 113, 114
placebo, 27, 43, 50, 51, 52, 53, 70, 163, 217,
225, 226, 227, 248, 251, 252, 258, 260,
279
placenta, 4, 8, 11, 16, 22, 26, 28, 29, 32, 33,
36, 68, 70, 74, 88, 101, 103, 104, 105,
106, 107, 111, 112, 113, 114, 115, 116,
117, 119, 120, 121, 123, 124, 129, 136,
139, 140, 142, 158, 166, 167, 170, 176,
179, 181, 213, 215, 217, 220, 246, 263,
264, 265, 267, 268, 272, 273, 274, 276,
277, 289, 291, 298
placenta previa, 104, 106, 246
placental abruption, 15, 19, 23, 25, 40, 68,
79, 104, 106, 240, 268, 270
placental hormones, 77
plasma levels, 141, 155, 181
Index 315
plasma proteins, 129
plasminogen, 128, 140, 152, 180, 277
platelet activating factor, 117, 119
platelet aggregation, 27, 223
platelet count, 23, 191, 193, 194, 233, 268,
269
platelets, 13, 49, 50, 51, 60, 61, 64, 68, 75,
85, 118, 123, 168, 190, 201, 211, 212,
213, 252, 256, 261
plexus, 273
polycythemia, 100
polymerase, 149
polymerase chain reaction, 149
polymorphism, 75, 141, 149, 159, 183
polymorphisms, 141, 148, 149, 159, 183,
185, 264
polypeptides, 124
polysaccharide, 117, 119
poor implantation, 111, 114, 115
portal vein, 123
potential benefits, 35
poverty, 244
precipitation, 10
prediction models, 197
preeclamptic pregnancy, 44, 207, 282, 290,
294
prematurity, 3, 40, 60, 62, 69, 79
preparation, iv, 123
preterm delivery, 12, 16, 23, 29, 37, 46, 63,
104, 213, 226, 252, 283, 284
preterm infants, 16
prevalence rate, 246
prevention, vii, 3, 6, 7, 15, 23, 26, 27, 33,
43, 52, 57, 69, 79, 172, 188, 191, 200,
212, 213, 214, 217, 218, 219, 220, 221,
228, 233, 234, 235, 248, 249, 250, 251,
252, 258, 259, 260, 269, 271
principles, 155
probability, 90
prodrome, 62
progesterone, 7, 77
prognosis, 42, 49, 51, 54, 82, 175, 201, 218,
260, 297
pro-inflammatory, 130, 131, 157, 171, 276
proliferation, 124, 157
proline, 118
prophylactic, 52, 195, 215, 216, 294
prophylaxis, 31, 41, 52, 215, 243, 248, 252,
259
propranolol, 20
prostaglandins, 176, 272, 275
protection, 27, 114, 120, 149
protein kinase C, 124
proteins, 9, 108, 111, 115, 117, 120, 121,
122, 128, 168, 195, 196, 198, 205, 291
proteinuria, 2, 3, 7, 8, 12, 13, 21, 22, 28, 30,
31, 34, 37, 39, 40, 44, 59, 62, 63, 71, 72,
75, 81, 82, 86, 131, 165, 167, 183, 185,
189, 190, 191, 193, 194, 235, 239, 240,
248, 261, 264, 281, 291, 295
proteome, 49, 205
proteomics, 123
prothrombin, 11
puerperium, 24, 48, 69, 70, 270
pulmonary edema, 9, 10, 18, 22, 23, 38, 39,
45, 190, 193, 194, 241
purification, 114, 116
purpura, 68
Q
quality of life, 254
quantification, 196
quartile, 145
questioning, 30
R
race, 5, 100, 238
racial differences, 246
Ramadan, 50, 51
reactivity, 101, 263, 273, 293
reading, 111
Receiver Operating Characteristic (ROC),
231
receptors, 27, 87, 88, 115, 119, 123, 128,
129, 153, 161, 163, 168, 171, 179, 264,
273, 277
recognition, 102
Index 316
recommendations, 13, 37, 97, 191, 250
recovery, 60, 65, 279
recruiting, 265
recurrence, 5, 20, 26, 73, 74, 82, 87, 95,
103, 211, 212, 213, 216, 217, 253
reduced maternal endothelial function, 282
reflexes, 269, 270
Registry, 67, 285
regression, 51, 121, 203, 288
regression analysis, 288
regression model, 203
rejection, 88, 111, 265
relevance, 120, 254
remission, 63, 120
remodelling, 263
renal dysfunction, 19, 61, 79, 262, 266
renal failure, 10, 15, 19, 23, 32, 35, 38, 60,
94, 241, 254
renin, 262, 267, 270, 275, 278
reproduction, 70, 175
reproductive age, 86, 131
requirements, 178, 196
researchers, 92, 101, 102, 200, 225
residues, 164
resistance, 9, 87, 88, 89, 90, 94, 102, 108,
118, 133, 138, 174, 223, 227
resolution, 31, 60, 103, 109, 156
resource availability, 28
respiration, 19
respiratory arrest, 28
respiratory distress syndrome, 16
respiratory rate, 269
response, 3, 18, 40, 44, 101, 103, 120, 123,
128, 131, 132, 146, 150, 152, 160, 162,
170, 177, 199, 212, 223, 247, 262, 263,
266, 272, 277, 287, 298
responsiveness, 177
retardation, 23
reticulum, 117
retinal detachment, 11
retinal ischemia, 11
retinol, 128, 154
retinopathy, 32, 36
rheumatoid arthritis, 120, 128
risk assessment, 168
risk factors, 3, 5, 6, 24, 29, 34, 40, 49, 73,
77, 82, 87, 88, 100, 106, 142, 146, 155,
160, 162, 173, 174, 199, 203, 223, 224,
238, 252, 254, 260, 282, 288, 291, 293
rituximab, 62
rosiglitazone, 161
S
safety, 19, 37, 63
saturation, 269
savings, 204
scope, 33, 88, 94, 136
secrete, 112, 129
secretion, 116, 119, 122, 124, 128, 129, 130,
133, 142, 148, 152, 164, 224, 263, 265,
266, 276
sedative, 27, 36
sediment, 63
seizure, 25, 26, 31, 243, 248, 269, 270
selectivity, 9
sensitivity, 8, 72, 75, 78, 83, 90, 96, 129,
133, 139, 177, 195, 197, 199, 206, 207,
208, 224, 230, 267
sepsis, 60, 157, 170
serine, 212
serum, 4, 10, 11, 22, 28, 34, 40, 56, 61, 83,
96, 101, 108, 117, 120, 130, 136, 138,
139, 140, 145, 146, 147, 149, 153, 160,
162, 163, 166, 167, 171, 173, 175, 176,
177, 179, 180, 181, 182, 183, 184, 204,
206, 224, 230, 232, 240, 266, 269, 271,
274, 276, 277, 281, 288, 292, 293, 300
serum albumin, 117, 120
sex, 90
showing, 31, 79, 105, 267
side effects, 18, 39, 53, 123, 249, 270
signal transduction, 161, 224
signaling pathway, 160, 275
signalling, 151, 264, 265, 267
signals, 116, 117, 275
signs, 2, 8, 11, 12, 14, 22, 29, 35, 37, 38, 60,
65, 86, 139, 190, 193, 270
skeletal muscle, 130, 163
skin, 63, 113, 121, 199
Index 317
smoking, 195, 272
smooth muscle, 224, 267
smooth muscle cells, 267
SNP, 149, 159
socioeconomic status, 238
sodium, 10, 23, 37, 87, 89, 94, 191, 194,
250, 258
SP, 122, 124, 163, 203, 204, 207, 279
specialists, 34
species, 113, 119
spectroscopy, 117
sphygmomanometer, 188, 192
spontaneous abortion, 277
spontaneous pregnancy, 104
SS, 170, 171, 203
stabilization, 22, 28, 60
standardization, 200
starvation, 158
state(s), 89, 90, 96, 101, 102, 130, 131, 132,
137, 160, 174, 196, 229, 292, 294, 297
stem cells, 121
steroids, 16
stillbirth, 15, 17, 42, 100
stimulation, 25, 136, 160, 268, 273
stimulus, 263
stomach, 21
stratification, 200
stress, 151, 194, 259, 265, 291
stress test, 194, 291
stroke, 11, 20, 31, 35, 36, 52, 55, 241, 246,
250, 253, 254, 282, 283, 292, 294, 296
structure, 117, 160, 161, 163
subgroups, 35, 76, 142, 214, 244, 257
substitution, 164, 247
sulfate, 23, 26, 27, 28, 31, 41, 52, 53, 238,
244, 248, 258, 269
Sun, 157, 184, 205, 275
supplementation, 7, 43, 192, 195, 224, 225,
226, 227, 228, 232, 233, 234, 235, 236,
250, 251, 258, 259
suppression, 161
surfactant, 163
surveillance, 30, 31, 38, 54, 83, 94, 111,
117, 120, 121, 201, 202, 257, 268
survival, 16, 33, 104, 105, 112, 117, 120,
168
susceptibility, 149, 156, 175
swelling, 10
symptoms, 2, 3, 8, 12, 22, 30, 31, 39, 61, 64,
65, 86, 109, 111, 112, 114, 115, 119,
139, 262, 270, 294
syndrome, 2, 3, 5, 8, 10, 12, 15, 16, 21, 22,
23, 24, 25, 28, 34, 49, 50, 51, 52, 54, 61,
62, 64, 65, 66, 68, 69, 70, 75, 85, 86, 89,
94, 96, 100, 104, 106, 113, 119, 131,
162, 163, 166, 168, 171, 172, 174, 179,
189, 190, 193, 201, 211, 215, 220, 238,
240, 241, 256, 261, 265, 270, 281
synergistic effect, 262
synovial fluid, 156
synthesis, 121, 265, 267, 275
systemic change, 267
systemic lupus erythematosus, 13, 69, 70,
238
systolic blood pressure, 8, 28, 32, 47, 86,
138, 193, 195, 225, 242, 256
systolic pressure, 2, 17, 35, 36, 149
T
target, 8, 18, 33, 150, 192, 195, 273
target organs, 8
techniques, 99, 114
technology, 104, 109
tendon, 270
testing, 14, 34, 38, 191
testis, 117
TGF, 273, 291
therapy, 15, 17, 18, 19, 20, 26, 27, 30, 31,
34, 35, 36, 37, 39, 53, 62, 70, 82, 155,
164, 212, 214, 216, 218, 234, 243, 247,
249, 250, 251, 257, 273, 298
thiazolidinediones, 161
threonine, 118
thrombin, 170
thrombocytopenia, 2, 13, 14, 15, 19, 29, 39,
50, 60, 61, 63, 64, 190, 193, 240
thrombocytopenic purpura, 13, 22, 25, 61,
64, 67, 68, 70
Index 318
thrombosis, 5, 11, 65, 215
thrombus, 118, 124
thyroid, 89, 112, 183
time frame, 26
tissue, 10, 101, 102, 103, 113, 116, 117,
121, 127, 129, 137, 139, 150, 152, 155,
158, 160, 205, 266, 273, 275, 277, 278
TNF, 128, 151, 152, 154, 157, 170, 198,
212, 219, 266, 267, 276, 277
TNF-alpha, 151, 152, 154, 157, 170, 219,
266, 276, 277
tobacco, 192, 193
tonic, 25
tonic-clonic seizures, 25
tonometry, 288
total cholesterol, 291
total energy, 178
toxicity, 28, 249
toxin, 62
training, vii, 163
transaminases, 10, 62, 191, 194
transduction, 129
transformation, 83, 88
transforming growth factor, 180
transfusion, 23, 100
transplant, 88, 121
trauma, 26
treatment, 15, 17, 18, 22, 23, 26, 28, 33, 34,
35, 36, 46, 47, 48, 50, 51, 52, 56, 59, 60,
62, 65, 66, 67, 69, 70, 75, 116, 120, 130,
162, 163, 172, 188, 193, 195, 196, 200,
215, 220, 225, 233, 248, 250, 252, 254,
258, 262, 268, 269, 270, 278, 279, 294
trial, 17, 26, 27, 41, 46, 47, 48, 50, 51, 52,
53, 56, 79, 91, 155, 159, 215, 216, 218,
220, 225, 226, 233, 234, 235, 236, 247,
248, 250, 251, 252, 258, 260, 270, 279
triglycerides, 133, 178, 291
trypsin, 118
tumor(s), 112, 121, 128, 150, 151, 157, 171,
271, 272, 273, 276, 277
tumor necrosis factor, 128, 150, 151, 157,
171, 271, 272, 276, 277
twin anemiapolycythemia sequence
(TAPS), 100
twin reversed arterial perfusion sequence
(TRAP), 100
twins, 101, 102, 103, 104, 105, 108
type 2 diabetes, 150, 154, 159, 161, 162
tyrosine, 4, 88, 101, 107, 167, 197, 204,
264, 274, 275, 277, 281, 291, 295, 299
U
ulcerative colitis, 156
ultrasonography, 60, 178
ultrasound, 42, 56, 103, 191, 194, 198, 200,
227
umbilical cord, 217
uric acid, 10, 14, 15, 40, 63, 83, 240, 269
uric acid levels, 78, 79, 81, 169
urinalysis, 34
urinary tract, 6
urinary tract infection, 6
urine, 6, 9, 10, 12, 13, 28, 30, 34, 63, 72, 82,
86, 189, 190, 193, 197, 269, 270, 271
uterus, 115, 121, 265
V
variables, 162, 180, 196, 197, 199
variations, 199
vascular cell adhesion molecule, 169
vascular endothelial growth factor (VEGF),
75, 101, 224
vascular wall, 155
vasculature, 247
vasculitis, 25
vasoconstriction, 9, 212, 224, 269
vasodilation, 227, 263, 273, 275, 298
vasodilator, 123, 263, 273, 275
vasomotor, 123
vasopressin, 113, 122
vasospasm, 24, 212, 252
vein, 65, 267
velocity, 102, 108, 200, 208
vessels, 27, 65, 88, 115
visceral adiposity, 151
vision, 11, 13, 25, 254
Index 319
vitamin B1, 276
vitamin B12, 276
vitamin C, 6, 7, 43, 234, 251
vitamin D, 205, 258
vitamin E, 7
vitamins, 251
vomiting, 16, 22, 60, 190, 193, 261, 268
W
water, 179
wavelet, 206
weakness, 270
weight control, 224
weight gain, 9, 89, 93, 97, 98, 177
weight loss, 151, 155, 159, 161, 162
weight reduction, 93, 129, 130, 161
well-being, 17, 30
white matter, 254
World Health Organization (WHO), 41, 52,
56, 73, 86, 94, 95, 165, 188, 189, 190,
191, 192, 193, 195, 202, 226, 234, 235,
238, 242, 256
worldwide, 2, 100, 131, 223, 237, 242, 252,
254
Y
young women, 6, 33, 149

Controversias en Preeclampsia

Diunggah oleh

Informasi Dokumen

Deskripsi Asli:

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Controversias en Preeclampsia

Diunggah oleh

Hak Cipta:

Format Tersedia

OBSTETRICS AND GYNECOLOGY ADVANCES

Corresponding author: Eyal Sheiner MD, PhD, Email: sheiner@bgu.ac.il

Correspondence: Roberto Romero, MD, D(Med)Sci, Perinatology Research Branch,

Corresponding authors Email: irebelo@ff.up.pt

Anda mungkin juga menyukai