REPORT of the WORKING GROUP on
RESEARCH on HYPERTENSION DURING PREGNANCY
Meeting Held April 27, 2001
National Heart, Lung, and Blood Institute
[Roster][Resources]
TABLE OF CONTENTS
BACKGROUND Hypertensive disorders of pregnancy,
which affect an estimated five to eight percent of pregnancies in the United
States, contribute significantly to serious complications for both the fetus
and the mother. An important distinction exists between the preeclampsia
syndrome, recognized when elevated blood pressure occurs for the first time
during pregnancy, and preexisting (chronic) hypertension. The two disorders,
although both characterized by high blood pressure, are strikingly different
pathophysiologically and have very different acute and long-range implications
for mother and infant. Gestational hypertension and preeclampsia superimposed
on chronic hypertension are also discussed in the "Definitions" section.
Preeclampsia is the most common hypertensive disorder
during pregnancy, affecting an estimated 5-8% of pregnant women annually in the
United States, and has the greatest effect on maternal and infant outcome.
Chronic hypertension affects an increasing proportion of pregnancies, and
confers significant risk for the development of preeclampsia. Preeclampsia
occurs more frequently and is more severe in women with preexisting
hypertension than in women who are normotensive prior to pregnancy. From a
public health perspective, it is alarming that the rate of preeclampsia has
increased by nearly one-third over the past decade, likely due to a rise in the
number of older mothers and multiple births, scenarios that predispose to
preeclampsia. Older maternal age during pregnancy also contributes to an
increased frequency of chronic hypertension and thus preeclampsia complicating
pregnancy.
Maternal complications acutely can include pulmonary
edema, thrombotic complications, renal failure, and death. Preeclampsia can
evolve into eclampsia, leading to maternal seizures. One specific subset of
signs and symptoms known as the HELLP Syndrome (Hemolysis,
Elevated Liver Enzymes, and Low Platelets) is a
cause of extensive morbidity. In the United States, hypertensive disorders of
pregnancy account for nearly 15 percent of maternal mortality; throughout the
world these conditions are responsible for more than a third of maternal
deaths. The vast majority of these deaths and most infant deaths are due to
preeclampsia and eclampsia, arising either de novo or superimposed on
chronic hypertension. Long-term sequelae may also result. Women with chronic
hypertension have an obvious long-term risk from the persistent hypertension.
However, women with preeclampsia, despite the resolution of the disorder
postpartum, are also at increased risk of cardiovascular disease in later life
compared to women with pregnancies without preeclampsia.
Fetal complications of hypertensive disorders of
pregnancy include growth restriction, prematurity, and stillbirth. In addition,
there is evidence that the intrauterine milieu in a hypertensive pregnancy may,
by mechanisms related to the failure of the fetus to exercise full growth
potential, confer increased risk of cardiovascular events in adult life.
Two millennia ago, Celsus described puerperal
seizures, termed eclampsia. In the late 19th century, it was recognized that
increased blood pressure and proteinuria preceded the seizures. Soon
thereafter, physicians realized that these findings constituted the syndrome of
preeclampsia, which increased maternal and infant mortality and morbidity even
if seizures did not occur. Over the past decade, a great deal of attention has
been focused on understanding the pathophysiology of preeclampsia to assist in
devising therapeutic interventions for subsequent assessment. This has resulted
in a better understanding of the pathophysiological mechanisms, but many
details remain unclear. In addition, clinical trials testing two promising
therapies, calcium supplementation and aspirin, to prevent preeclampsia or
improve its outcome, demonstrated at most minor benefits. Progress has been
limited by the lack of animal models with placental physiology comparable to
humans. In contrast to preeclampsia, in chronic hypertension where prior
knowledge of pathophysiology of the disease in nonpregnant women provides
useful insight to treatment, little work has been done to apply these insights
to therapy for women with hypertension who become pregnant.
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 input 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
basic, clinical and translational research agenda addressing key issues in
pregnancy-related hypertension. The current Working Group was constituted in
part to have overlap with the Working Group that produced the
National High Blood
Pressure Education Program's (NHBPEP/NHLBI) recent
Working
Group Report on High Blood Pressure in Pregnancy (Report of the National
High Blood Pressure Education Program Working Group on High Blood Pressure in
Pregnancy, Am J Obstet Gynecol 2000;183:S1-S22). The current Working Group was
expected to build on this Report, as well as to use other sources of data and
personal expertise to advise the Institute on research priorities in a variety
of areas, such as epidemiological studies, clinical trials, mechanistic
research on the pathophysiology of the various forms of high blood pressure
during pregnancy, and training.
DEFINITIONS Hypertension during pregnancy is
categorized as: preeclampsia/eclampsia, gestational hypertension, the continued
presence of chronic hypertension, and preeclampsia superimposed upon chronic
hypertension. These categories identify disorders with different
epidemiological characteristics, pathophysiology, and risk for mother and baby.
Preeclampsia is defined as a
pregnancy-specific syndrome observed after the 20th week of pregnancy with
systolic blood pressure of >= 140 mm Hg or diastolic blood pressure of >=
90 mmHg, accompanied by significant proteinuria. Previous definitions included
edema as part of the diagnosis, but this has subsequently been dropped as being
too non-specific. Likewise, the criteria of a 30-point change in systolic blood
pressure or a 15-point change in diastolic blood pressure have been eliminated
for the same reason in favor of an absolute blood pressure threshold. As
proteinuria may be a late manifestation, the NHBPEP also advises clinicians
that the disease should be suspected if high blood pressure is accompanied by
symptoms of headache or abdominal pain, or abnormal laboratory tests,
specifically low platelet count and abnormal liver enzymes. In women with
preeclampsia, blood pressure usually returns to baseline within days to weeks
after delivery.
Eclampsia is the occurrence, in a
woman with preeclampsia, of seizures that cannot be attributed to other causes.
Convulsions usually occur after midpregnancy, and may occur postpartum.
Gestational hypertension is defined
as a blood pressure elevation detected for the first time after midpregnancy,
and is distinguished from preeclampsia by the absence of proteinuria. The
category of gestational hypertension is a nonspecific working diagnosis, which
includes women who will proceed to satisfy diagnostic criteria for
preeclampsia, as well as those who never develop proteinuria and whose blood
pressure returns to baseline following pregnancy and women with increased blood
pressure prior to pregnancy masked by the tendency of blood pressure to
decrease in early pregnancy. Gestational hypertension is a working diagnosis
only during pregnancy. If proteinuria develops and the hypertension resolves
after the pregnancy, the diagnosis is changed to preeclampsia. If elevated
blood pressure persists, chronic hypertension is diagnosed. In the absence of
other factors, the diagnosis is termed transient hypertension of
pregnancy.
Chronic hypertension refers to an
elevated blood pressure in the mother that predated the pregnancy. It can also
be diagnosed in retrospect, when preeclampsia or gestational hypertension fail
to normalize after delivery. Chronic hypertension in the mother may not have
been recognized prior to the pregnancy, and may not be under medical control.
At present, there are few therapeutic alternatives for treating pregnant women
with preexisting hypertension. This is particularly important 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 renal failure. The
outcome for mother and infant is worse than for de novo preeclampsia. It is
unknown how treatment of chronic hypertension affects the risk of preeclampsia
and its complications.
STATE-OF-THE-SCIENCE Preeclampsia was the focus
of most of the Working Group's discussion because it is the most common of the
hypertensive disorders of pregnancy, and is associated with the highest rate of
acute maternal and infant mortality and morbidity. However, issues concerning
chronic hypertension in pregnancy also received attention primarily because of
clinical concerns about the lack of evidence-based recommendations for
treatment.
Today, the pathophysiology of preeclampsia is
increasingly well-understood, but the etiology, early predictive markers, and
means of effective prevention remain elusive. Preeclampsia is a
pregnancy-specific syndrome in which there is increased vascular responsiveness
to vasoconstrictor stimuli and activation of the coagulation cascade. The
initial insult appears to be reduced placental perfusion frequently due to
abnormal implantation of the blastocyst and abnormal remodeling of the maternal
vessels that supply the intervillous space. These phenomena lead to decreased
perfusion of the placenta and are considered by some to represent stage one of
a two-stage process. Stage two refers to development of the maternal and fetal
syndrome of preeclampsia. At present, the link between stages is not clear. It
is evident that reduced placental perfusion does not always result in the
maternal syndrome, and that maternal factors also are required. Genetic
polymorphisms, fetal signals, and increased hypoxia at the maternal fetal
interface likely play a role in the interaction of reduced placental perfusion
and the maternal constitution to generate the preeclampsia syndrome. Many of
these predisposing maternal factors are also risk factors for cardiovascular
disease in later life. For example, coagulation abnormalities, dyslipidemia,
increased inflammatory markers, and evidence of oxidative stress and
endothelial activation are associated with increased cardiovascular disease
risk, and also are detectable in women who develop preeclampsia, occurring
before the overt clinical symptoms appear.
Areas of opportunity for research on hypertension
during pregnancy were identified by the working group. A summary of key points
in each of these areas follows:
Genetics. Differences in the frequency, timing,
and severity of preeclampsia among populations, as well as evidence of
heritability, suggest a role for genetic influence. The principal gap is in
understanding the genetic heterogeneity that appears to be present. Genetic
polymorphisms that may occur more frequently in preeclamptic women include
angiotensinogen, Factor V Leiden, methylene tetrahydrofolate reductase, and
lipoprotein lipase. These polymorphisms do not appear to be related to
preeclampsia in all populations. Genome-wide search strategies are premature
and would be compromised if they are based on retrospective diagnosis of
preeclampsia from historical medical charts. Understanding the genetic
diversity could lead to a role for pharmacogenetic research, as well as to
identification of a subset of women with preeclampsia who may be at increased
risk for cardiovascular disease in the future.
Hemodynamics. One of the barriers to advances
in preeclampsia research is that the available knowledge about normal and
abnormal hemodynamics in pregnancy is largely descriptive. Newer noninvasive
techniques that measure components of the pulsatile arterial load including
compliance, as well as techniques to assess markers of endothelial function,
have only sporadically been applied in pregnancy. For example, very little is
known about the hemodynamics of women with chronic hypertension who become
pregnant. Because 25% of these women, compared to about 5% of non-hypertensive
women, develop preeclampsia, this information should be obtained. Another need
would be to characterize the hemodynamic parameters of women with type 1 and
type 2 diabetes, who also are at increased risk of preeclampsia.
Immunology and Inflammatory Responses in Pregnancy
and Preeclampsia. T-cell activation occurs in preeclampsia, and study of
the maternal-fetal interface should provide additional information not only
about normal pregnancy but also about pregnancies complicated by hypertensive
disorders. Some women with preeclampsia also have autoimmune disorders. There
are several promising animal models that suggest a role for inflammation in the
pathogenesis of preeclampsia. There is evidence of activation of the
inflammatory response in pregnancy that is further increased in preeclampsia.
Researchers have thus been led to consider inflammatory markers both as
important in the epidemiology of preeclampsia, and as a potential link between
preeclampsia and future cardiovascular disease. For example, cytokines such as
TNF-alpha are significantly increased in preeclampsia. Animal models may
provide a means of testing hypotheses about inflammation, but because of
differences in placentation across species, will not provide a definitive
explanation of preeclampsia. Shedding of placental cells in the maternal
circulation may also play a role in inducing inflammation. The surface of the
placenta normally sheds, like skin, into the maternal circulation, a process
stimulated by hypoxia and mediated by apoptosis.
Long-range Implications of Preeclampsia for Mother
and Infant. Women with preeclampsia are at increased risk of cardiovascular
disease compared to women who have pregnancies without preeclampsia.
Epidemiological studies indicate that this likely is the result of common risk
factors for preeclampsia and cardiovascular disease rather than preeclampsia
causing cardiovascular disease. Most of the risk factors for preeclampsia
(e.g., race, dyslipidemia, obesity, diabetes, hypertension, and elevated
homocysteine) are also risk factors for cardiovascular disease. Likewise, many
of the pathophysiological features of preeclampsia (e.g., dyslipidemia,
inflammatory and endothelial activation, insulin resistance) are features of
cardiovascular disease. There is increasing evidence that women who have
recovered from preeclamptic pregnancies manifest cardiovascular and metabolic
differences compared to women who have had normal pregnancies. It is possible
that the normal changes of pregnancy sensitize certain women to insults that
would require years to manifest effects in the absence of pregnancy.
The long-term implications of preeclampsia for the
offspring is another area about which little is known. Preeclampsia is
associated with an increased risk of fetal growth retardation, but many
children born to women with preeclampsia are appropriate for gestational age,
and still others are large for gestational age. It is possible that the
long-range outcome of even the growth restricted infants of preeclamptic
infants is not the same as that of the usual growth-restricted infant.
Metabolism. Pregnancy is a hypermetabolic
state, with cholesterol and triglyceride concentrations rising up to
three-fold. In women with preeclampsia, these increases are further
exaggerated. Conversely, homocysteine normally decreases in pregnancy, but the
decrease is only half as great in preeclampsia. The coagulation cascade also is
altered in pregnancy, and further deranged in preeclampsia. Many of the
features of preeclampsia mimic the insulin resistance or metabolic syndrome,
and insulin resistance is a prominent feature of preeclampsia. These findings
provide evidence of a link between preeclampsia and future cardiovascular
disease, although the direction of causation is unclear at present.
Nutrition/Physical Activity. Little information
is available about diet and nutritional supplements and hypertensive disorders
of pregnancy. Calcium supplementation has been reported to reduce the frequency
of preeclampsia in South American populations with decreased calcium intake,
but was not successful in a U.S. trial supported by NICHD and NHLBI. Further,
standard tools for assessing nutritional status, such as food frequency
questionnaires, have not been validated in pregnancy. Such instruments should
be validated independently during each trimester of pregnancy as changes in
standard serum biomarkers occur throughout gestation. Once validated, food
frequency questionnaires in combination with serum markers, obtained
prospectively, would minimize the inherent measurement errors of each and might
identify specific populations at risk. Although physical activity is a
well-known predictor of future cardiovascular risk, it has thus far received
minimal attention in preeclampsia.
Oxidative Stress in Preeclampsia. An intriguing
hypothesis is that the decreased placental perfusion characteristic of
preeclampsia leads to placental hypoxia, that in conjunction with maternal
constitution results in the generation of oxidative stress. The role of
oxidative stress as the linkage of the two stages of preeclampsia is further
supported by abundant evidence of oxidative stress in blood and tissues of
women with preeclampsia. Furthermore, a small trial of antioxidant therapy
(1,000 mg vitamin C and 400 IU of vitamin E) resulted in a reduced incidence of
preeclampsia when begun at 22 weeks gestation in women at high risk for the
syndrome. Thus, the closest thing to a treatment target in the field is
anti-oxidant therapy based on this collection of hypotheses and data. However,
effectiveness in large populations and, even more importantly, safety for the
fetus, are not established.
Resources. Animal models are of limited benefit
because of significant differences in placentation among mammals, as well as
differences in length of gestation and perhaps even posture between mammalian
models and humans. Animal models are useful for generation and testing of
hypotheses, but it was agreed that definitive hypothesis-testing would require
clinical studies in well-characterized populations of women before, during, and
after pregnancy. It is currently assumed that cardiovascular differences
between women who have had normal pregnancies and those who have had
pregnancies complicated by preeclampsia indicate changes that antedated the
pregnancy. This can only be differentiated from the alternative explanations
that these are residual effects of preeclampsia or that normal pregnancy has a
long-term beneficial cardiovascular effect by data accumulated in a subset of
women prior to a preeclamptic pregnancy. Normative data on placental vascular
biology and on hemodynamic alterations in pregnancy are also required as a
baseline for subsequent study of alterations due to preeclampsia. Many
hypotheses about prevention and future cardiovascular risk require longitudinal
cohort studies over a decade or more. In addition to clinical resources for
research, there is not a sufficient number of basic or clinical scientists
adequately trained to participate in this research.
Treatment of Chronic Hypertension in Pregnancy
. Chronic hypertension during pregnancy is increasing in importance as the
proportion of pregnancies to older women increases. This condition is now
expected to affect at least 5% of pregnancies annually in the United States.
This is a significant public health problem because of the high risk it confers
for preeclampsia, and the increased complication rate for mother and fetus when
preeclampsia is superimposed on chronic hypertension. In addition,
recommendations for treatment of women with chronic hypertension who then
become pregnant are based on very little evidence, and have not changed in
recent years. The uncertainty includes the utility of non-pharmacological
approaches, the choice of drugs, and appropriate blood pressure goals. The
preferred approach in the obstetrical community is to substitute
alpha-methyldopa, an agent known to be safe in pregnancy, for the
antihypertensive therapy prescribed prior to the pregnancy. This decision is
due to the fact that alpha-methyldopa is the only hypertensive agent with
follow-up safety data in infants. The almost complete absence of data on which
to base treatment decisions in this growing group of women, and the difficulty
this poses for obstetricians, was emphasized.
RECOMMENDATIONS In developing recommendations,
Working Group members first discussed a number of issues that were viewed as
barriers to research progress. In general, although a great deal has been
learned about the pathophysiology of preeclampsia and other hypertensive
disorders in pregnancy in the past decade, much remains unclear. First, the
cardiovascular physiology and placental biology of normal pregnancy are not
completely understood, so departures from normal may not be fully appreciated
or assessed. Second, in order to advance understanding of the antecedents of
preeclampsia, a prospectively collected, well-characterized population is
required. Much of the clinical work done to date has relied on retrospective
definitions of preeclampsia, with all the inherent difficulties of precision
and accuracy this engenders. Third, mechanistic studies linking abnormal
implantation to the maternal syndrome of preeclampsia, as well as linking
preeclampsia and future cardiovascular risk are lacking. Fourth, the treatment
of chronic hypertension in pregnancy, particularly as a potential means of
preventing superimposed preeclampsia, has not been evaluated systematically.
Finally, there are few obstetrician/gynecologists trained in rigorous clinical
research, and even fewer formal training programs.
Specific recommendations were developed from the
written materials prepared by Working Group members in advance of the meeting,
as well as from the vigorous discussion that occurred at the meeting. After the
recommendations were summarized, priorities were assigned 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 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, perfusion of the placental vasculature, inflammatory responses, and
placental vasculopathy.
Other components of the linkage are the maternal
factors that result in a particular woman developing preeclampsia in the
setting of reduced placental perfusion. Many such characteristics are also risk
factors for later life cardiovascular disease. Fundamental studies of this
topic also provide insight into pathophysiological similarities and differences
between preeclampsia and later life 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 postpregnancy. In this
context, markers of cardiovascular risk (e.g., 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
seven to ten years postpartum, 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 postpartum 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 alpha methyldopa, based on a single study completed many years ago that
had long-term follow up of the offspring to demonstrate fetal safety. Although
some antihypertensives such as angiotensin-converting enzyme (ACE) inhibitors
are contraindicated in pregnancy, there are a number of alternate
antihypertensive agents that should be studied. A prospective study of
antihypertensives in pregnancy should be conducted to evaluate blood pressure
control, fetal growth and safety, and genetic variation in response to
therapy.
Will anti-oxidant therapy safely prevent
preeclampsia? Treatment and prevention trials have been disappointing to
date. However, several recent studies have suggested causal links between
oxidative stress, depletion of vitamin C, low levels of the endogenous
vasodilator nitric oxide, and the development of preeclampsia, suggest that
there may be a role for anti-oxidant vitamins in the prevention of
preeclampsia. A clinical trial should be undertaken testing the hypothesis
that anti-oxidant vitamins can reduce the risk of preeclampsia, reduce maternal
and fetal mortality, and increase birthweight. Such a trial, and all other
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. A protocol for a similar
trial has been developed in the National Institute of Child Health and Human
Development's (NICHD) Maternal-Fetal Medicine Units Network and the possibility
of a collaborative arrangement of the NHLBI with NICHD in conducting such a
trial should be explored. It might be effective to utilize this same resource
for a study for the treatment of preexisting hypertension in pregnancy.
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.
SUMMARY
The hypertensive disorders of pregnancy collectively
represent a significant public health problem in the United States and
throughout the world. Although great strides have been made in understanding
these clinical conditions, a great deal remains to be done. The Working Group's
recommendations represent the next steps toward achieving the goal of
understanding and preventing complications of hypertension and preeclampsia
during pregnancy.
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