Summary of the NHLBI Working Group on Research on
Hypertension During Pregnancy
James M. Roberts, Gail Pearson, Jeff Cutler, Marshall Lindheimer
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Abstract—A Working Group on Research in Hypertension in Pregnancy was recently convened by the National Heart,
Lung, and Blood Institute to determine the state of knowledge in this area and suggest appropriate directions for
research. Hypertensive disorders in pregnancy, especially preeclampsia, are a leading cause of maternal death worldwide
and even in developed countries increase perinatal mortality rates 5-fold. Much has been learned about preeclampsia,
but gaps in the knowledge necessary to direct therapeutic strategies remain. Oxidative stress is a biologically plausible
contributor to the disorder that may be amenable to intervention. Hypertension that antedates pregnancy (chronic
hypertension) bears many similarities to hypertension in nonpregnant women, but the special setting of pregnancy
demands information to guide evidence-based therapy. The recommendations of the Working Group are to attempt a
clinical trial of antioxidant therapy to prevent preeclampsia that is be complemented by mechanistic research to increase
understanding of the genetics and pathogenesis of the disorder. For chronic hypertension, clinical trials are
recommended to direct choice of drugs, evaluate degree of control, and assess implications to the mother and fetus.
Recommendations to increase participation in this research are also presented. (Hypertension. 2003;41:437-445.)
Key Words: hypertension, pregnancy 䡲 preeclampsia 䡲 pregnancy 䡲 research 䡲 oxidative stress 䡲 mortality
T
he hypertensive disorders of pregnancy affect up to 8%
of all gestations and remain major causes of maternal and
neonatal mortality and morbidity in the United States and
worldwide. Most adverse events are attributable directly to
the preeclampsia syndrome, characterized by new-onset hypertension with proteinuria during pregnancy. Women with
chronic hypertension also manifest increased maternal and
neonatal morbidity and mortality. In this setting, these adverse outcomes usually are largely attributable to preeclampsia because preeclampsia is both more common and more
devastating in women with chronic hypertension.
In developed countries, where maternal mortality attributable to preeclampsia has been reduced, the condition primarily affects fetal well-being through intrauterine growth retardation, preterm birth, low birth weight, and perinatal death.
The increased infant morbidity and mortality rates are especially disheartening because at least part of it is attributable to
preterm delivery undertaken to prevent further deterioration
in the fetus and mother.1 In fact, 15% of all preterm births are
indicated early deliveries for preeclampsia. Preterm birth is
associated with increased mortality rates and long-range
neurological disability. Preeclampsia also increases the risk
of intrauterine growth restriction (IUGR). These low-birthweight babies have not only acute problems but more
alarmingly, IUGR may confer a long-term burden in the form
of future cardiovascular risk.2,3
From another public health perspective, it is alarming that
the rate of preeclampsia has increased by 40% between 1990
and 1999,4 probably the result of a rise in the number of older
mothers and multiple births, scenarios that predispose to
preeclampsia. Older maternal age during pregnancy may
contribute to preeclampsia because of an increased frequency
of chronic hypertension.
Because of the clear public health concerns engendered by
hypertensive disorders of pregnancy and the urgency of
providing new directions in research, the National Heart,
Lung, and Blood Institute (NHLBI), with participation from
the National Institute of Child Health and Human Development (NICHD), convened a Working Group on Research on
Hypertension During Pregnancy. The Working Group was
charged with evaluating the current state-of-the-science and
making recommendations for a focused agenda of basic,
clinical, and translational research addressing key issues in
pregnancy-related hypertension. This effort was designed to
complement and be guided by the prior efforts of the NHLBI
to improve treatment of these disorders through recommendations from the National High Blood Pressure Education
Program (NHBPEP).5 The review that follows is based on
Received August 20, 2002; first decision September 8, 2002; revision accepted December 19, 2002.
From the Department of Obstetrics, Gynecology and Reproductive Sciences, Graduate School of Public Health, University of Pittsburgh, and
Magee-Womens Research Institute (J.M.R.), Pittsburgh, Pa; Heart Development, Function and Failure Scientific Research Group, Division of Heart and
Vascular Disease (G.D.P.), and Division of Epidemiology and Clinical Applications (J.A.C.), National Heart, Lung, and Blood Institute/National Institutes
of Health, Bethesda, Md; and Department of Obstetrics & Gynecology and Medicine, Division of Biological Sciences, The Pritzker School of Medicine
(M.D.L.), University of Chicago, Ill.
Correspondence to James M. Roberts, MD, 204 Craft Avenue, Suite 610, Pittsburgh, PA 15213. E-mail [email protected]
© 2003 American Heart Association, Inc.
Hypertension is available at http://www.hypertensionaha.org
DOI: 10.1161/01.HYP.0000054981.03589.E9
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March 2003
material presented by Working Group members at the meeting (see Appendix for roster).
Classification of Hypertensive Disorders
of Pregnancy
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Hypertension during pregnancy is categorized as follows:
preeclampsia/eclampsia, gestational hypertension, the continued presence of chronic hypertension, and the superimposition of preeclampsia on chronic hypertension. These categories identify disorders with different epidemiological
characteristics, pathophysiology, and risks for mother and
baby. These categories are summarized below and detailed
further in the NHBPEP report.5
Preeclampsia, a pregnancy-specific syndrome that occurs
after midgestation, is defined by the de novo appearance of
hypertension (systolic blood pressure of ⱖ140 mm Hg or
diastolic blood pressure of ⱖ90 mm Hg), accompanied by
new-onset proteinuria, defined as ⱖ300 mg per 24 hours.
Previous definitions included edema, but this sign is nonspecific and is observed in many normotensive pregnant women.
Thus, edema is no longer considered part of the diagnostic
criteria for preeclampsia. Likewise, previous criteria in which
a rise of 30 mm Hg in systolic pressure and/or 15 mm Hg in
diastolic pressure were considered diagnostic have been
eliminated as too nonspecific, identifying up to 25% of
pregnant women.6 In addition, probably because of this lack
of specificity, it is very difficult to demonstrate an excess of
morbidity in these women.6 As proteinuria may be a late
manifestation of preeclampsia, the NHBPEP advises clinicians to be suspicious when de novo high blood pressure is
accompanied by headache, abdominal pain, or abnormal
laboratory tests, specifically low platelet count and abnormal
liver enzymes, and that it is prudent to treat such patients as
if they have preeclampsia.
Eclampsia occurs when preeclampsia progresses to a
life-threatening convulsive phase. Such convulsions usually
occur after mid-pregnancy or during delivery, but as many as
one third of eclamptic convulsions occur during the first 48
hours of the immediate postpartum period.
Gestational hypertension is defined as de novo hypertension arising after mid-pregnancy and is distinguished from
preeclampsia by the absence of proteinuria. This category is
broad and includes women who later satisfy diagnostic
criteria for preeclampsia and other women with increased
blood pressure before pregnancy but whose true diagnosis is
masked by the tendency of blood pressure to decrease in early
pregnancy. However, in many cases proteinuria never occurs,
the course is relatively benign, and blood pressure normalizes
after delivery, at which time the diagnosis of gestational
hypertension is changed to transient hypertension of
pregnancy.
Chronic hypertension refers to an elevated blood pressure
in the mother that predated the pregnancy. It can be assumed
when elevated blood pressure is detected before midpregnancy and can also be diagnosed in retrospect, when
hypertension fails to normalize 12 weeks after delivery.
Chronic hypertension may not have been recognized before
the pregnancy. At present, there is little consensus on how to
treat pregnant women with preexisting hypertension. The
absence of data to direct medical treatment strategies is
particularly disconcerting because women with chronic hypertension are at increased risk of superimposed preeclampsia
(25% risk), preterm delivery, fetal growth restriction or
demise, abruptio placentae, congestive heart failure, and
acute renal failure. The outcome for mother and infant with
preeclampsia superimposed on existing hypertension is worse
than with de novo preeclampsia. It is uncertain if treatment of
chronic hypertension affects the high risk of this group to
develop preeclampsia and its complications.
Preeclampsia and Chronic Hypertension:
Distinct Disorders
A major discrimination emphasized in the taxonomy of
hypertensive disorders of pregnancy is between preeclampsia
and chronic hypertension. Both disorders are characterized by
increased blood pressure in pregnancy. In preeclampsia,
increased blood pressure is not only of new onset but, in
addition, is an important indicator of an underlying multisystem syndrome. Relatively few of the adverse effects of
preeclampsia are due to increased blood pressure. It is not
surprising that pathological and pathophysiological changes
are different in the two disorders.7 The consequences of
preeclampsia and chronic hypertension also are quite different. Preeclampsia presents acute risks to mother and baby.
Chronic hypertension increases the risk of growth-restricted
infants but its major acute effect on morbidity is secondary to
the increased risk of superimposed preeclampsia. Chronic
hypertension is a well-established cause of cardiovascular
morbidity and mortality, but it is still unclear whether
preeclampsia alone is a cause of later-life cardiovascular
disease.
The pathology and pathophysiology of chronic hypertension is better understood than that of preeclampsia. For
instance, much of what has been learned from studying the
disorder in nonpregnant populations is relevant to chronic
hypertension in pregnancy. What is lacking for treating
pregnant patients with chronic hypertension is evidencebased therapy directed by such knowledge. On the other
hand, although the past 10 years have witnessed a dramatic
increase in the understanding of preeclampsia as a complex
multisystemic disease, many important facts necessary to
guide therapy remain unknown. Thus the focus of the
Working Group discussion was largely on the need to
increase understanding of preeclampsia to guide future therapy, whereas chronic hypertension was considered from the
perspective of the gaps in evidence necessary to adequately
treat the disorder.
Preeclampsia: Current Concepts
History
Historic perspective is helpful to understand the concepts that
have guided studies of preeclampsia. Eclampsia was described by Celsus in 100 AD as seizures during pregnancy
that abated with delivery,8 and for the ensuing 2000 years,
eclampsia was considered to be a pregnancy-specific seizure
disorder. It was not until the mid-1800s that the similarity of
the edematous eclamptic woman and the dropsic patient with
Bright’s disease (acute glomerulonephritis) stimulated clini-
Roberts et al
cians to determine whether women with eclampsia, like
individuals with Bright’s disease, had protein in their urine.
Protein was indeed present in the urine of eclamptic women.
Furthermore, it was recognized that the proteinuria antedated
the seizures. In another 50 years, it was possible to measure
blood pressure noninvasively. Again, an association of increased blood pressure and eclampsia was recognized, as was
the fact that the hypertension also antedated the seizures.8 It
was soon evident that hypertension and proteinuria during
pregnancy, even without seizures, identified a woman with
the potential for a rapidly progressive life-threatening disorder and a fetus at increased risk for stillbirth. These two
findings of renal dysfunction and hypertension guided research for more than 80 years. It was not until about 10 years
ago that investigators began focusing on the pathophysiology
and multiple systemic manifestations of preeclampsia.
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Epidemiology
Preeclampsia is a disease primarily of first pregnancies and
extremes of maternal age.7 Of interest is the observation that
multigravidas pregnant by a new partner have a risk of
preeclampsia intermediate between that associated with first
pregnancies and subsequent pregnancies with the same partner.9 Because new paternity is also associated with a longer
interpregnancy interval, this finding suggests an immunologic
basis for preeclampsia where the risk is increased by delayed
exposure and/or new paternal antigen.10 This concept is also
supported by the observations that the risk is reduced when
there is a longer period of intercourse with the father before
conception11 and that barrier contraceptives that prevent
exposure to semen increase the risk of preeclampsia.12
Different diagnostic criteria and poor record keeping make
it virtually impossible to compare the frequency of preeclampsia in different populations from routinely collected
data. It is clear that death rates from the disorder are more
common in developing countries; however, this need not
indicate increased disease frequency. Death from preeclampsia is largely preventable by delivery to prevent disease
progression. Thus, increased death rates are primarily a
marker of quality of care rather than disease frequency. There
is a suggestion of a preponderance of preeclampsia in black
women in many nations. Although the disorder appears to be
more common in young women, when the first pregnancy
effect is controlled for, preeclampsia is actually more common in older women.7
Genetics
The epidemiological factors of preeclampsia suggest a genetic basis for the disorder. Preeclampsia is more common in
daughters of preeclamptic women13 and in pregnancies fathered by sons of preeclamptic women,14 suggesting the
involvement of both maternal and fetal genes in the syndrome. Studies of the epidemiological genetics of the disorder
are hampered by the fact that the overt disease only occurs in
women at the time of reproduction. Furthermore, information
from older records frequently is inadequate to establish
family history definitively. Genome-wide searches have begun but as yet have not yielded consistent results. Functionperturbing polymorphisms have been identified for several
candidate genes, but the findings again are inconsistent in
Research on Pregnancy Hypertension
439
different populations.15 In addition, genetic differences have
not been exploited to explain differences in response to
therapy in treatment trials. Genetic markers of the disease
would be useful not only in identifying relevant molecules
but also would facilitate longitudinal studies of pathogenesis.
Pathology and Pathophysiology
The pathophysiology of preeclampsia is appropriately divided into two stages: alterations in placental perfusion (stage
1) and the maternal syndrome (stage 2).
Stage 1
There are considerable data to support the theory that the
placenta is the key component of pregnancy that leads to
preeclampsia. Preeclampsia can occur without uterine distention and without a fetus.7 The pregnancy disorder hydatidiform mole, an abnormality in which there is very little fetal
tissue with the products of conception being almost exclusively trophoblastic, is associated with an increased risk of
preeclampsia. It also appears that the feature of the placenta
that leads to preeclampsia is reduced perfusion. The reduced
placental perfusion is primarily due to abnormalities in
implantation and vascular remodeling.7 In normal pregnancy,
the spiral arteries that perfuse the placenta undergo remarkable remodeling, from small muscular arteries in the nonpregnant state to significantly distended vessels16 that have lost
both their smooth muscle and inner elastic lamina layers. This
extensive modification does not occur in preeclampsia. There
may be some superficial remodeling, but it never extends
beyond the decidual lining, whereas in normal pregnancy, the
modified vessels extend into the inner third of the myometrium.17 Thus, many vessels in preeclamptic women undergo
no remodeling, and this results in reduced placental perfusion. There have been enormous increases in the understanding of human trophoblast invasion, its relation to vascular
remodeling, and aberrations that occur in preeclampsia. It is
now evident that these interactions include precisely regulated expression of molecules involved in attachment and
invasion in response to environmental and maternal signals
and that this process is disordered in preeclampsia.18 Several
medical conditions associated with microvascular disease,
such as hypertension, diabetes, and collagen vascular disease,
also increase the risk of preeclampsia, fueling speculation that
impaired placental perfusion may be the common denominator.7 Likewise, obstetric conditions associated with large
placentas (hydatidiform mole, hydropic placentas, and placentas with multiple gestations) all increase the risk of
preeclampsia.19 It is proposed that in these large placentas
there is a relative reduction in placental perfusion. Another
alteration of the spiral arteries in preeclampsia, atherosis,
results in occlusion of the decidual vessels20 reminiscent of
the vascular findings of allograft rejection. This finding
further supports an immunologic component of preeclampsia.21
Stage 2
In women with preeclampsia, blood flow to organs other
than the placenta is reduced, and hemorrhage and necrosis
can occur. In the liver, for example, evidence can be found of
reduced perfusion with secondary necrosis and hemorrhage.8
In the heart, subendocardial necrosis can occur similar to that
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seen in with hypovolemic shock. The explanation for systemically reduced perfusion includes vasoconstriction, microthrombi, and reduced plasma volume secondary to loss of
fluid from the vascular compartment. The vasoconstriction is
not attributable to increased endogenous pressors but rather to
an increased sensitivity to virtually all circulating pressor
agents.22
Preeclampsia also is characterized by activation of the
coagulation cascade. Although consumption of procoagulants
sufficient to be detected by standard testing occurs in only
about 10% of preeclamptic women, sensitive tests of activation of the cascade can be detected in most preeclamptic
women. Thus, platelet size is larger in preeclampsia, indicating increased platelet turnover.23 Other indicators of platelet
activation are also apparent.
Perfusion in preeclampsia is further limited by reduced
plasma volume. Women with preeclampsia have accelerated
loss of protein from the vascular compartment, as indicated
by an increased rate of disappearance of the protein-bound
dye, Evans blue.24
The sequence of events, and thus cause and effect, are
difficult to discern in the overtly ill preeclamptic woman.
Most useful information comes from longitudinal studies in
which women destined to have preeclampsia are examined
before clinically evident disease. These studies reveal that
abnormal activation of coagulation and reduced plasma volume antedate clinically evident preeclampsia.23 Similarly,
some but not all authors have found increased sensitivity to
exogenous pressors weeks before the manifestations of clinically evident preeclampsia.25,26
One pathological change provides particular insight. Renal
biopsy specimens from women with preeclampsia reveal a
change seen in no other form of hypertension. Termed
glomeruloendotheliosis, the lesion consists primarily of enlargement of the glomerulus caused by hypertrophy of endothelial cells.27 This finding was one of the bases for the
hypothesis put forward a decade ago that the diverse pathophysiological changes of preeclampsia could be accounted
for by a common target, the endothelial cell.28 Since that time,
this hypothesis has been extensively tested and largely
supported. Numerous markers of endothelial activation are
present in the circulation of preeclamptic women weeks to
months before clinically evident disease.29 Therefore, hypertension does not appear to be causing the endothelial injury.
Vessels from women with preeclampsia manifest reduced
endothelial-mediated relaxation, and plasma or serum from
preeclamptic women can adversely alter endothelial function
in vitro either with cells in culture or intact vessels.29
Maternal-Fetal Interactions in Preeclampsia
A principal unanswered question is how reduced perfusion of
the placenta can result in the maternal syndrome. One thing
that is quite clear is that the reduced perfusion alone is not
sufficient to explain this linkage. Intrauterine growth restriction is the result of reduced placental perfusion. Yet many
women with growth-restricted infants do not have preeclampsia, and a small percentage of preeclamptic women have large
fetuses. In addition, the implantation defect and failure to
remodel blood vessels that supply the placenta that are
TABLE 1.
Risk Factors for Preeclampsia
Hypertension
Collagen vascular disease
Obesity
Black race
Insulin resistance
Diabetes
Increased circulating testosterone
Thrombophillias
characteristic of preeclampsia also are present in pregnancies
with growth restriction30 and in one-third of pregnancies
ending in spontaneous preterm birth.31 This has led some to
the postulate that the reduced perfusion must interact with
maternal factors to result in the maternal syndrome. These
factors are posited to be genetic, behavioral, or environmental. As this list is assembled, it is interesting that there these
factors and those predisposing to cardiovascular disease in
later life are quite similar (Table 1).
Relation of Preeclampsia to Cardiovascular Disease
In addition to the shared risk factors, a relation between
preeclampsia and the atherosclerotic and hypertensive cardiovascular diseases has been noted for some time. Early studies
suggesting that preeclampsia caused cardiovascular disease
were compromised by poor diagnostic criteria and inappropriate controls. In the early 1930s, Chesley32 began a masterful follow-up study of women with eclampsia. He chose
women with eclampsia to increase diagnostic specificity. He
followed these women for 47 years and concluded that
eclampsia (and by extension, preeclampsia) did not cause
later cardiovascular disease. This conclusion was based on
findings from women with eclampsia in their first pregnancy.
At long-term follow-up, these women had no excess of
hypertension or cardiovascular disease compared with a
control group matched for age, race, and socioeconomic
status but with unknown pregnancy history. However,
women who had eclampsia in pregnancies other than the first
had a striking increase in hypertension in later life. He
concluded that preeclampsia did not cause later cardiovascular disease but that preeclampsia in later pregnancies was
caused by preexisting (subclinical) cardiovascular disease.
Sibai et al33 followed women with severe preeclampsia rather
than eclampsia with similar findings. Women with severe
preeclampsia in only their first pregnancy did not have an
increased risk of later life hypertension, whereas women with
preeclampsia in later pregnancies had increased risk. Fisher
and Lindheimer34 expanded these findings in a follow-up
study of women with renal biopsy diagnosis of preeclampsia.
In their study, women with preeclampsia were compared with
women who had been pregnant and did not have preeclampsia. There was no excess of hypertension or other cardiovascular diseases in women with renal biopsy evidence of
preeclampsia when compared with the general female population. However, women who had pregnancy without preeclampsia had a lower incidence of cardiovascular disease
than the general population. In other studies, women who
Roberts et al
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have had preeclampsia years previously manifest many risk
factors for cardiovascular disease including dyslipidemia,
insulin resistance, and blunted endothelial relaxation.35–37
The data would tend to support the concept that the same
factors that predispose to preeclampsia also predispose to
cardiovascular disease in later life.
There are other similar findings in preeclampsia and
atherosclerotic cardiovascular disease. Preeclampsia is characterized by a dyslipidemia identical to that predisposing to
cardiovascular disease. Increased triglycerides, increased
LDL and reduced HDL cholesterol, and an increased prevalence of small dense LDL all are present in women with
preeclampsia.38 Furthermore, there is an exaggerated activation of the inflammatory response in preeclampsia compared
with normal pregnancy.39 Markers of inflammation antedate
clinically evident preeclampsia,40 and the endothelium appears to be an important pathogenetic target in preeclampsia,
as it is in atherosclerosis.29
These similarities have suggested that the disorders may
share a common pathophysiology. The oxidation hypothesis
of atherosclerosis proposes that inflammatory activation of
endothelium and circulating blood cells generate free radicals. The impact of these reactive oxygen species is increased
by the dyslipidemia of atherosclerosis. Small dense LDL
particles have preferential access to the subendothelial space,
where they are sequestered from circulating antioxidants. In
addition, these lipoprotein variants are inherently more easily
oxidized. The oxidized LDL generated acts on endotheliumaltering function and upregulating VCAM, leading to recruitment of monocytes. These cells take up the oxidized LDL
with the eventual formation of the fatty streak and atheromatous plaque.41
Oxidative Stress in Preeclampsia
Oxidative stress has been proposed as the linkage between the
two stages of preeclampsia.42 The oxidative stress hypothesis
proposes that hypoxia at the fetal-maternal interface results in
the generation of free radicals that may lead to oxidative
stress dependent on the maternal constitution. Abundant
evidence of oxidative stress in blood and tissues of women
with preeclampsia support the hypothesis (Table 2).38 Further
support comes from a small study in which antioxidants were
administered from early gestation to women at high risk of
preeclampsia. The goal of the study was to determine if
prophylactic antioxidants could prevent evidence of endothelial activation, as measured by soluble PAI-1, a marker of
endothelial activation. The ratio of PAI-1 (made by endothelium) to PAI-2 (made by placenta) was reduced in the women
receiving antioxidants. In addition, and even more important
from a clinical standpoint, the frequency of preeclampsia was
reduced in the treated women.43 This study, although encouraging, was quite small, and thus the efficacy and safety of
antioxidant treatment for the infant require confirmation in
larger studies.
Implications of Current Scientific Knowledge
The current knowledge about preeclampsia has important
implications. The interaction of reduced placental perfusion
with numerous maternal factors indicates that various causal
factors may have different degrees of importance among
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TABLE 2.
441
Evidence of Oxidative Stress in Preeclampsia
Circulating markers
Nonlipid markers
Antibodies to LDL62
Ascorbate oxidizing activity63
Increased nitrosothiols64
Lipid markers
Lipid oxidation products38
Antibodies to oxidized LDL62
In systemic maternal tissues
Increased nitrotyrosine residues in blood vessels65
Activated neutrophils and monocytes66
In decidua
Atherosis with lipid-laden macrophages20
Increased lipid peroxides67
Increased isoprostanes (8 iso PGF2␣)68
Protein carbonyls69
In placenta
Nonlipid markers
Increased xanthine oxidase in invading trophoblast cells70
Increased nitrotyrosine resides in fetal blood vessel71
Antioxidants
Reduced superoxide dismutase70,72
Reduced glutathione peroxidase73
Lipid markers
Increased malondialdehyde74
Increased lipid peroxides73
Protein carbonyls69
individuals. Although this increases the complexity of the
scientific endeavor, it raises the possibility that specific
causes in specific women may be treatable. The similarities to
the pathophysiology of cardiovascular disease in later life are
intriguing. It is likely that the study of both disorders might
provide complementary insights. There is abundant evidence
that the pathophysiological changes of preeclampsia are
present long before the clinical presentation of the disorder,
which probably explains why all management of overt
preeclampsia other than delivery is only palliative. This
indicates that future successful therapies will require the
institution of therapy before clinically evident disease.44
Thus, predictors of preeclampsia with high sensitivity and
moderate specificity will be useful initially in the conduct of
clinical trials and perhaps eventually for therapy.23
Gaps in Understanding
Although the understanding of preeclampsia has grown enormously, it is important to point out that several postulates,
including the linkage of the two stages of preeclampsia by
oxidative stress, remain hypotheses requiring further testing.
If oxidative stress provides this linkage, how do the evanescent free radicals formed in the intervillous space result in
systemic endothelial activation? There are numerous candidates proposed as intermediaries in this process, including
stable products of lipid peroxidation (eg, malondialdehyde),
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and neutrophils or monocytes activated directly in the intervillous space or by material (placental fragments or cytokines) from the hypoxic placenta. Furthermore, the identification of angiotensin antibodies with the capability to activate
NADPH oxidase with subsequent free radical formation in
women with preeclampsia suggests a very different origin for
oxidative stress.45 In addition, the role of oxidative stress,
although attractive, can only be shown to be causally important by the demonstration in clinical trials that preventing
oxidative stress prevents preeclampsia. It must be borne in
mind that preeclampsia has been characterized as the “disease
of theories,” none of which has stood the test of time.46
Indeed, although this review has stressed a current and very
plausible hypothesis, it would be remiss not to summarize
other postulates under consideration. These include abnormalities in the mother’s circulatory adaptations to pregnancy,47,48 maternal endothelial dysfunction secondary to cytokines,49 altered autocoid systems,50 vitamin and mineral
deficiencies,51 infectious agents similar to those linked to
atherosclerosis,52 impairment of the normal barriers against
the importation of fetal and trophoblastic material into the
maternal circulation,53 and a combination of these factors
with those described in detail above. This emphasizes the
value and need for clinical trials that incorporate mechanistic
studies to increase understanding further.
The relation of preeclampsia to long-range cardiovascular
disease has important implications. Women who have had
preeclampsia have increased risk of cardiovascular disease in
later life compared with women who have had normal
pregnancies. This has been interpreted as indicating similar
risk factors for preeclampsia and later life cardiovascular
disease. However, the nature of this relation remains to be
established, and data on women who have been examined
before, during, and after a preeclamptic pregnancy do not
exist. The alternative possibility that preeclampsia leads to
cardiovascular disease in later life or even that normal
pregnancy has a beneficial long-range cardiovascular effect
cannot be excluded based on current data. The public health
implications of these possibilities are quite different and merit
careful consideration.
Management of Chronic Hypertension
As women in developed countries delay childbirth, the impact
of chronic hypertension will increase because the prevalence
of hypertension increases with age. It is likely that in the near
future, as many as 5% of women who become pregnant will
have preexisting hypertension. Clinicians do not have sufficient evidence to know which pharmacological therapy is
best, when to begin treatment, how vigorously to treat, or
whether to stop treatment and hope that the hypotensive
effect of normal pregnancy will be enough to control blood
pressure. The only trial for treatment of hypertension during
pregnancy with adequate infant follow-up (7.5 years) was
performed over 25 years ago with a drug (alpha-methyldopa)
now rarely used in nonpregnant patient.54,55 Past clinical trials
also have not supported a beneficial effect on pregnancy
outcome of treating mild hypertension. There has been no
reduction in perinatal mortality, placental abruption, or superimposed preeclampsia.56,57 All of these trials are subject to
criticism, including small numbers, starting the drug too late
in pregnancy, or flawed study design. Nonetheless, no other
data are available. Because of the unknown long-term effects
on the infant of any treatment, these studies have led to
recommendations to treat only on the basis of blood pressure
sufficiently elevated to pose potential acute risk to the
mother.5 Whether this is the appropriate strategy is not clear.
Small and frequently poorly designed studies have recently
suggested that therapy of mildly elevated blood pressure may
prevent progression to preeclampsia.58,59 Even for women
with blood pressure elevation sufficient to justify therapy for
their own benefit, it is not clear whether treatment is beneficial or detrimental for the fetus. In several studies, treatment
of hypertensive women resulted in an increased risk of
growth restriction in their infants.60 It is not known whether
this is the inevitable consequence of lowering blood pressure
during pregnancy or whether it is due to excessive blood
pressure decreases or to specific drugs.
Dietary and other lifestyle changes have been shown in
nonpregnant women to substantially lower blood pressure in
the short term, both in hypertensive and nonhypertensive
individuals. For example, in the Dietary Approaches to Stop
Hypertension (DASH)–Sodium Study, the combination of the
DASH diet and lower sodium intake (65 mmol/24-hour
urinary excretion) reduced systolic blood pressure by
11.5 mm Hg in hypertensive over 4 weeks, compared with a
typical American diet.61 Whether such blood pressure reduction can be achieved safely in hypertensive pregnant women
is not known and should be evaluated.
These questions can only be resolved with well-designed,
relatively long-term clinical trials. Pharmaceutical companies
have not been eager to test drugs in this small market with a
high potential for litigation. These studies nonetheless must
be carried out.
Recommendations for Research
Specific recommendations were developed by Working
Group members and assigned priorities by using standard
techniques for obtaining group consensus. In developing
recommendations, the Working Group considered the merits
of competing scientific questions, the maturity of hypotheses
for clinical testing, and the availability of scientific resources.
The research questions deemed to be of the highest priority
and the proposed scientific strategies are summarized below.
How Does Preeclampsia Develop, and Does It Confer
Future Cardiovascular Risk?
It is accepted that abnormal implantation of the blastocyst and
abnormal placental bed remodeling or other causes of reduced placental perfusion are prerequisites for preeclampsia,
but the mechanistic links between this step and the development of preeclampsia many weeks later are not known.
Moreover, little work is currently being done in this area.
Mechanistic studies should be encouraged, both independently and as part of ongoing or future longitudinal studies to
determine the cell biology and physiology that links reduced
placental perfusion to the maternal syndrome of preeclampsia. Studies could focus on basic pathological mechanisms,
the natural history of vascular changes in pregnancy, perfu-
Roberts et al
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sion of the placental vasculature, inflammatory responses,
and placental vasculopathy.
Other components of the linkage are the maternal factors
that result in a particular woman having preeclampsia in the
setting of reduced placental perfusion. Many such characteristics are also risk factors for atherosclerotic and hypertensive
cardiovascular disease. Fundamental studies of this topic
should also provide insight into pathophysiological similarities and differences between preeclampsia and cardiovascular
disease that could be useful in understanding both disorders.
Studies exploring mechanisms by which maternal factors
predispose to preeclampsia should be encouraged. A related
question is whether, once preeclampsia occurs, the woman is
at increased risk for future cardiovascular disease. Although
this seems to be the case, causality has not been demonstrated. It would be equally plausible to hypothesize that the
factors that confer excess risk contribute to the development
of preeclampsia in the first place. This can only be resolved
by a prospective observational study in a cohort that will span
preconception to post pregnancy. In this context, markers of
cardiovascular risk (eg, genetic, biochemical, and physiological markers) could be measured serially. A long-term observational study could advance the field significantly by linking
outcomes to multiple exposures in temporal sequence.
Women with both normal and hypertensive pregnancies
would be included and would be followed from preconception to 7 to 10 years after delivery at a minimum. This study
could make the important distinction of whether the abnormalities in cardiovascular function that can be identified
several years after preeclampsia occurred before the pregnancy and are thus risk factors or occur only after delivery
and thus are residua of the preeclampsia syndrome.
How Should Chronic Hypertension in Pregnancy Be Treated?
Women with chronic hypertension who become pregnant are
treated with ␣-methyldopa, based on a single study completed
many years ago that had long-term follow-up of the offspring
to demonstrate fetal safety of the treatment. Although some
antihypertensive agents such as ACE inhibitors are contraindicated in pregnancy, there are a number of alternate antihypertensive agents that should be studied. A clinical trial of
antihypertensive treatment in pregnancy should be conducted
to evaluate blood pressure control, fetal growth and safety,
and genetic variation in response to therapy.
Will Antioxidant Therapy Safely Prevent Preeclampsia?
Treatment and prevention trials have been disappointing to
date. However, several recent studies that have suggested
causal links between oxidative stress, depletion of vitamin C,
low levels of the endogenous vasodilator nitric oxide, and the
development of preeclampsia indicate that there may be a role
for antioxidant vitamins in the prevention of preeclampsia. A
clinical trial should be undertaken testing the hypothesis that
antioxidant vitamins can reduce the risk of preeclampsia,
reduce maternal and fetal mortality rates, and increase birth
weight. Such clinical trials also should incorporate study of
biomarkers and other measures of risk factors and determine
predictors and early pathophysiological changes of preeclampsia in low-risk and high-risk populations.
Research on Pregnancy Hypertension
443
How Should Research Capabilities Be Developed?
Career development programs should be encouraged to enhance the research capabilities of scientists interested in
hypertensive disorders of pregnancy. A major goal of career
development programs should be to increase the involvement
of scientists with diverse research backgrounds and capabilities in the study of hypertensive disorders of pregnancy. A
focused effort would improve the skills of individuals working in this area and bring new researchers and skills to bear on
the study of hypertensive disorders of pregnancy.
Appendix
Roster: Working Group, High Blood Pressure
in Pregnancy
Chair: James M. Roberts, MD, Director, Magee-Women’s Research
Institute, and Professor and Vice Chair (Research), Department of
Obstetrics, Gynecology and Reproductive Sciences, University of
Pittsburgh. Members: Phyllis August, MD, Professor of Medicine,
Obstetrics and Gynecology, Chief, Hypertension Division, Weill
Medical College of Cornell University; Matthew W. Gillman, MD,
S.M., Associate Professor, Department of Ambulatory Care and
Prevention, Harvard Medical School/Harvard Pilgrim Health Care;
Marshall Lindheimer, MD, Professor, Departments of Obstetrics and
Gynecology and Medicine, The Pritzker School of Medicine, University of Chicago; Leslie Myatt, PhD, Professor of Obstetrics and
Gynecology, University of Cincinnati, College of Medicine;
Christopher W.G. Redman, M.A., M.B., Bchir, Nuffield Department
of OB/Gyn, Headington, Oxford; Baha Sibai, MD, Professor and
Chairman, Department of Ob/Gyn, University of Cincinnati College
of Medicine; Kenneth Ward, MD, Professor, Obstetrics and Gynecology and Human Genetics, University of Utah; Michelle Williams,
ScD, Professor of Epidemiology, Department of Epidemiology,
University of Washington; Representative, NHLBI Public Interest
Organization: Anne E. Garrett, Executive Director, Preeclampsia
Foundation.
NIH Staff
Jeffrey Cutler, MD, NHLBI; Mark Klebanoff, MD, MPH, NICHD;
Gail Pearson, MD, ScD, NHLBI; Edward Roccella, PhD, MPH,
NHLBI; Catherine Spong, MD, NICHD; Paul Velletri, PhD, NHLBI;
Carole Webb, MSN, NHLBI.
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Summary of the NHLBI Working Group on Research on Hypertension During Pregnancy
James M. Roberts, Gail Pearson, Jeff Cutler and Marshall Lindheimer
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Hypertension. 2003;41:437-445; originally published online February 10, 2003;
doi: 10.1161/01.HYP.0000054981.03589.E9
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