Pregnancy and the Kidney Sharon E. Maynard* and Ravi Thadhani

BRIEF REVIEW
www.jasn.org
Pregnancy and the Kidney
Sharon E. Maynard* and Ravi Thadhani†
*Department of Medicine, Division of Renal Diseases and Hypertension, George Washington University School of
Medicine and Health Sciences, Washington, DC; and †Department of Medicine, Renal Unit, Massachusetts General
Hospital, Harvard Medical School, Boston, Massachusetts
ABSTRACT
Nephrologists are frequently called on to diagnose and treat renal disorders in
pregnant women. In this review, we update recent literature pertinent to pregnancy and renal disease. We initially begin by describing the application of common clinical estimators of GFR and proteinuria in pregnancy and then summarize
recent studies regarding pregnancy in women with chronic kidney disease and the
latest information on the use of common renal medications in pregnancy. In the
final section, we describe advances in our understanding of the pathophysiology of
preeclampsia and the potential clinical implications of these discoveries for screening, prevention, and treatment of preeclampsia.
J Am Soc Nephrol 20: 14 –22, 2009. doi: 10.1681/ASN.2008050493
In recognizing renal disease, measurement of kidney function and proteinuria
are the early standard bearers of subclinical pathology. With the dramatic hormonal and hemodynamic changes of
pregnancy, renal function is altered and
these changes must be considered when
assessing renal function in pregnancy
and in the choice of medications provided through parturition. Renal function and filtration are also affected in
preeclampsia, and recent advances have
greatly expanded our understanding of
the pathophysiologic mechanisms of this
pregnancy-specific renal syndrome.
ASSESSMENT OF GFR AND
PROTEINURIA DURING
PREGNANCY
Estimating GFR in Pregnancy
The physiologic increase in GFR during
pregnancy normally results in a decrease
in concentration of serum creatinine,
which falls by an average of 0.4 mg/dl to a
pregnancy range of 0.4 to 0.8 mg/dl.1
Hence, a serum creatinine of 1.0 mg/dl,
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ISSN : 1046-6673/2001-14
although normal in a nonpregnant individual, reflects renal impairment in a
pregnant woman. The Modification of
Diet in Renal Disease (MDRD) formula,
which estimates GFR using a combination of serum markers and clinical parameters, has become a standard clinical
method to estimate renal function in patients with chronic kidney disease
(CKD). The use of this formula has not
been well studied in the pregnant population, and guidelines on application of
the MDRD formula specifically exclude
interpretation in pregnant women. Creatinine-based formulas developed in
nonpregnant populations are likely to be
inaccurate when applied to pregnant
women. For example, the fall in serum
creatinine during pregnancy reflects not
only the pregnancy-induced increase in
real GFR but also hemodilution resulting
from the 30 to 50% plasma volume expansion by parturition. Perhaps more
important, the MDRD formula systematically underestimates GFR as GFR rises
above 60 ml/min per m2. This inherent
inaccuracy is likely to be more pronounced at the high GFR of pregnancy.
Weight-based formulas, such as Cockroft-Gault, might overestimate GFR because the increased body weight of pregnancy does not typically reflect increased
muscle mass or creatinine production.
In 2007, the accuracy of the MDRD
formula in pregnant women was formally evaluated for the first time in two
prospective studies.2,3 Smith et al.2 compared the performance of the modified
MDRD formula (based on age, serum
creatinine, and gender) with inulin clearance in three groups of women: healthy
pregnant volunteers, women with preeclampsia, and pregnant women with
CKD before pregnancy. Among healthy
pregnant women, creatinine clearance by
24-h urine collection closely approximated GFR by inulin clearance; however,
the MDRD underestimated GFR by ⬎40
ml/min, a degree of bias that is somewhat
higher than observed in nonpregnant
kidney transplant donors with normal
renal function (29 ml/min).4 Among
pregnant women with preeclampsia or
CKD, the MDRD formula performed
slightly better, underestimating GFR by
23.3 and 27.3 ml/min, respectively; however, the average GFR of all three groups
Published online ahead of print. Publication date
available at www.jasn.org.
Correspondence: Dr. Sharon E. Maynard, George
Washington University Medical Faculty Associates,
2150 Pennsylvania Avenue NW, Washington, DC
20037. Phone: 202-741-2283; Fax: 202-741-2285;
E-mail: [email protected]; or Dr. Ravi
Thadhani, Bullfinch 127, Massachusetts General
Hospital, Boston, MA 02114. Phone: 617-724-1207;
Fax: 617-726-2340; E-mail: [email protected]
edu
Copyright 䊚 2009 by the American Society of
Nephrology
J Am Soc Nephrol 20: 14–22, 2009
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was ⬎60 ml/min, a GFR range for which
the MDRD formula is also biased in the
nonpregnant population. Hence, the
bias the authors reported likely represents the inaccuracy of the MDRD equation when applied to any patient with
near-normal renal function, regardless
of whether pregnant.
Alper et al.3 studied GFR estimation
in a cohort of 209 women with preeclampsia. They compared creatinine
clearance by 24-h urine collection, the
Cockroft-Gault formula, and two versions of the MDRD formula. Not surprising, they found the Cockroft-Gault
formula overestimated GFR by approximately 40 ml/min, whereas the MDRD
formulas underestimated GFR (by 19.68
ml/min for the full MDRD and 12.6 ml/
min for the modified MDRD). As in the
study by Smith et al.2, the mean GFR in
their study participants was well over 60
ml/min, a GFR range for which the
MDRD formula is known to be inaccurate. There are no published data on the
accuracy of the MDRD formula in pregnant women with GFR ⬍60 ml/min.
Given these issues, 24-h urine collection
for creatinine clearance remains the gold
standard for GFR estimation in pregnancy.
Estimating Proteinuria during
Pregnancy
The urine protein-to-creatinine ratio
(P:C ratio) has become the preferred
method for the quantification of proteinuria in the nonpregnant population,
because of high accuracy, reproducibility, and convenience when compared
with timed urine collection.5 The quantification of proteinuria in pregnancy is
indicated in at least two clinical situations. The first is monitoring of proteinuria in pregnant women with preexisting
proteinuric kidney disease. In this situation, the assumptions behind use of the
P:C ratio in nonpregnant patients (in effect, steady state with regard to creatinine
production and excretion) would be expected roughly to hold, and the ratio can
and should be used to follow changes in
proteinuria during pregnancy.
The second important indication for
the quantification of proteinuria in pregJ Am Soc Nephrol 20: 14 –22, 2009
nancy is for the diagnosis of preeclampsia. Preeclampsia is defined by the American College of Obstetrics and
Gynecology6 as the new onset of hypertension (BP ⬎140/90) and proteinuria
(ⱖ300 mg protein in a 24-h urine collection) after 20 wk of gestation. Routine
obstetric care includes dipstick protein
testing of a random voided urine sample
at each prenatal visit, a screening method
that has been shown to have a high rate of
false-positive and false-negative results
when compared with 24-h urine protein
measurement.7 Twenty-four-hour urine
collection, although the gold standard
for proteinuria quantification, has several limitations. It is cumbersome for the
patient, it often is inaccurate because of
undercollection, and result availability is
delayed for at least 24 h while the collection is being completed.
The use of the P:C ratio to estimate
24-h protein excretion for the diagnosis
of preeclampsia has been controversial.
Several studies have compared P:C ratio
with 24-h urine collection in this setting,
with discordant conclusions. These studies vary in the study population and the
threshold used to define an abnormal ratio. Nevertheless, a meta-analysis involving 974 pregnant women from 10 studies
showed a pooled sensitivity of 90% and
specificity of 78% using P:C ratio cutoffs
between 0.19 and 0.25, as compared with
the gold standard of 24-h urine protein
excretion (⬎300 mg/d).8 Most misclassifications tended to occur in women with
borderline proteinuria (250 to 400 mg/
d).9 Hence, it is reasonable to use the
urine P:C ratio for the diagnosis of preeclampsia, with 24-h collection undertaken when the result is equivocal.
PREGNANCY IN THE SETTING OF
CKD
The literature on pregnancy in women
with CKD is dominated by single-center,
retrospective, and often uncontrolled
studies with heterogeneous definitions
of kidney disease and of adverse renal
and pregnancy outcomes. Fortunately,
there is good evidence to suggest that
women with only mild renal impair-
BRIEF REVIEW
ment, normal BP, and little or no proteinuria have good maternal and fetal
outcomes, with little risk for accelerated
progression toward ESRD or preterm delivery.10,11 Although few data are available regarding pregnancy outcomes in
specific renal diseases, current consensus
suggests the degree of renal insufficiency,
rather than the underlying renal diagnosis, is the primary determinant of outcome.
Moderate to severe CKD results in an
increased risk for pregnancy complications and neonatal morbidity: More than
70% of women who become pregnant
with a serum creatinine ⬎2.5 mg/dl will
experience preterm delivery, and ⬎40%
develop preeclampsia.12,13 Pregnancy
also may result in deterioration in renal
function in some women, although causality has been difficult to establish. In a
landmark 1996 study by Jones and Hayslett,13 women who initiated pregnancy
with a serum creatinine ⬎2.0 mg/dl had
a high (33%) likelihood of an accelerated
decline in renal function during or immediately after pregnancy. A recent
study by Imbasciati et al.14 is the only
study thus far to compare prospectively
the rate of GFR loss before and after
pregnancy in a cohort of women with
stages 3 through 5 CKD. They found the
rate of decline in GFR was not significantly different after delivery compared
with before conception in the entire cohort of women with serum creatinine
⬎1.5 mg/dl; however, an accelerated rate
of GFR loss after delivery was observed in
the subgroup of women with both estimated GFR ⬍40 ml/min per 1.73 m2 and
proteinuria ⬎1 g/d before pregnancy.
This group should be considered especially high risk for both renal loss and
pregnancy complications, and pregnancy should probably be avoided.
Pregnancy after Kidney
Transplantation
Fertility rates increase dramatically after
transplantation in women with endstage kidney disease; therefore, pregnancy is common among young female
transplant recipients. Most evidence suggests that pregnancy after transplantation does not increase risk for loss of graft
Pregnancy for the Nephrologist
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function,15 so long as renal function is
good (creatinine ⬍1.5 mg/dl) and the
patient is on a stable immunosuppressive
regimen. In this situation, rejection rates
are similar to the general transplant population, and there does not seem to be an
increased risk for birth defects.16
Neonatal outcomes in pregnancies
among renal transplantation patients are
generally good. Most adverse neonatal
outcomes are related to a higher rate of
preterm birth (50 to 54%), small for gestational age (33 to 45%), and neonatal
mortality (1 to 3%) as compared with the
general population (12.3, 5, and 0.68%,
respectively).17,18 The highest risk for
preterm birth and small for gestational
age are seen in the setting of maternal
hypertension and impaired baseline renal graft function (creatinine ⬎1.5 mg/
dl).17 Long-term developmental outcomes of surviving infants seem to be
good.19
MEDICATION USE IN
PREGNANCY
Inhibitors of the Renin-AngiotensinAldosterone System
Widely known teratogenic effects of angiotensin-converting enzyme inhibitors
(ACEi) include fetal hypotension, anuria-oligohydramnios, growth restriction, pulmonary hypoplasia, renal tubular dysplasia, neonatal renal failure, and
hypocalvaria. These effects occur with
second- and third-trimester exposure to
ACEi and carry a neonatal mortality rate
as high as 25%.17 Surviving infants have
an increased risk for impaired renal
function and hypertension in childhood
and early adulthood.20 A similar pattern
of fetal anomalies has been reported with
second- and third-trimester exposure to
angiotensin II receptor antagonists.21,22
First-trimester exposure to ACEi was previously considered innocuous, and continuation of ACEi early in the first trimester
was considered safe by many practitioners;
however, the first large epidemiologic
study of first-trimester exposure to ACEi
reported a higher rate of major congenital
abnormalities (primarily cardiovascular
and central nervous system malforma16
tions) compared with unexposed pregnancies (7.1 versus 2.6%).23 Thus, it is now recommended that ACEi and angiotensin
receptor blockers be discontinued before
conception and that patients be educated
regarding the use of appropriate birth control while taking these agents. In addition,
women with inadvertent first-trimester exposure to ACEi or angiotensin receptor
blockers should be evaluated by detailed fetal ultrasound and echocardiography in
midgestation to screen for congenital abnormalities. There are few to no data on
the safety of aldosterone antagonists or renin inhibitors in pregnancy. Given the established teratogenicity of ACEi and the
key role of the renin-angiotensin-aldosterone system in fetal development, the use
of these drugs in pregnancy is generally
contraindicated.
Immunosuppressive Medications
Calcineurin inhibitors, steroids, and azathioprine are the mainstays of safe immunosuppressive therapy in pregnant transplant recipients. Mycophenolate mofetil
(MMF) has long been avoided in pregnancy on the basis of animal studies suggesting developmental toxicity, malformations, and intrauterine death at therapeutic
dosages. Evidence has continued to build
confirming potentially teratogenic effects
of MMF in human pregnancy, such as fetal
bone marrow suppression and structural
malformations including hypoplastic
nails, shortened fingers, microtia (ear malformations), and cleft lip/palate. Current
guidelines suggest that women who take
MMF and are contemplating pregnancy
should discontinue the medication at least
6 wk before conception. Although there
are few human data on the safety of sirolimus in pregnancy, animal studies suggest teratogenicity, so it, too, should be
avoided.24
RECENT ADVANCES IN
PREECLAMPSIA
Since 2003, evidence has accumulated
supporting the central role of placental
antiangiogenic factors, including soluble
fms-like tyrosine kinase-1 (sFlt1), in the
pathogenesis of preeclampsia (Figure 1).
Journal of the American Society of Nephrology
sFlt1 is a circulating antagonist to both
vascular endothelial growth factor
(VEGF) and placental growth factor
(PlGF) and is overexpressed in the placenta of women with preeclampsia. The
original rat model of sFlt1-induced preeclampsia25 has been reproduced by others.26 Animal models of preeclampsia
based on induction of uteroplacental
ischemia in both rats and primates are
characterized by increased circulating
and placental sFlt1.27,28 In women with
preeclampsia, uterine vein sFlt1 concentration exceeds antecubital vein sFlt1,
confirming a fetoplacental source of excess circulating sFlt1.29 There are now
more than a dozen studies confirming
that circulating levels of sFlt1 and one of
its targets, the proangiogenic PlGF, are
altered several weeks before the onset of
clinical signs and symptoms of preeclampsia—in the case of PlGF, as early as the first
trimester. There is evidence from mouse
models that VEGF is important in maintaining glomerular endothelial cell health
and healing, and its absence induces proteinuria and thrombotic microangiopathy
resembling pathologic glomerular changes
of preeclampsia.30 These diverse findings
support the theory that altered placental
expression of angiogenic factors, induced
or exacerbated by placental ischemia, is a
major contributor to endothelial dysfunction in preeclampsia.
sFlt1 is probably only one of several
circulating factors that contribute to endothelial dysfunction. Soluble endoglin
(sEng), a proteolytic cleavage product of
the TGF-␤ receptor endoglin, seems to
act synergistically with sFlt1; when administered together in pregnant rats,
sFlt1 and sEng produce a syndrome resembling HELLP (hemolysis, elevated
liver enzymes, and low platelets), a severe
preeclampsia variant.31,32 Subsequent human studies confirm that sEng increases in
the circulation before onset of preeclampsia, in a gestational pattern similar to sFlt1,
with levels rising precipitously just before
onset of clinical symptoms.33–35
Angiogenic Factors in High-Risk
Groups
Angiogenic factors provide insight into
the pathophysiology of several estabJ Am Soc Nephrol 20: 14 –22, 2009
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Figure 1. Summary of a current view of pathogenesis for preeclampsia. Placental
dysfunction, triggered by poorly understood mechanisms—including genetic, immunologic, and environmental—plays an early and primary role in the development of preeclampsia. The damaged placenta in turn secretes the antiangiogenic factors, sFlt1 and
sEng, into the maternal circulation. These factors lead to impaired VEGF/PlGF and TGF-␤
signaling, resulting in systemic endothelial cell dysfunction mediated by a variety of
factors, as shown. Endothelial dysfunction, in turn, results in the systemic manifestations
of preeclampsia. HO, heme oxygenase; AT1AA, angiotensin type 1 agonistic autoantibodies; COMT/2ME, catechol-O-methyl-transferase and 2 methoxyestradiol; sFlt1, soluble fms-like tyrosine kinase-1; sEng, soluble endoglin; ET-1, endothelin 1; ROS, reactive
oxygen species; NO, nitric oxide; IUGR, intrauterine growth retardation; HELLP, hemolysis, elevated liver enzymes, low platelets.
lished preeclampsia risk factors. For example, preeclampsia is strongly associated with both first pregnancies and
multiple-gestation pregnancies. Higher
serum sFlt1 levels are observed in both of
these groups, as compared with second
pregnancies and singleton gestations,
respectively.36,37 Similarly, pregnant
women whose fetuses are affected by trisomy 13 (a condition associated with increased preeclampsia risk) have higher
circulating sFlt1 levels as compared with
control subjects,38 possibly as a result of
the extra copy of the sFlt1 gene, which
resides on chromosome 13. Smoking is
associated with both a reduced risk for
preeclampsia39,40 and lower circulating
sFlt1 levels in both pregnant33,41 and
nonpregnant42 individuals, as compared
with nonsmokers. Cigarette smoke extract reduces sFlt1 production by placental cells in vitro.43 The molecular mechanism by which smoking downregulates
sFlt1 (thereby lowering preeclampsia
risk) is unknown, but this response is not
surprising given the known proangioJ Am Soc Nephrol 20: 14 –22, 2009
genic effects of nicotine.44 Nevertheless,
no one recommends smoking during
pregnancy.
Several preeclampsia risk factors—including chronic hypertension, diabetes,
and obesity—are related to underlying
maternal endothelial dysfunction. These
women may be more susceptible to the
adverse endothelial effects of antiangiogenic factors. If so, then preeclampsia
would be expected to develop at a lower
threshold of circulating sFlt1 in women
with these maternal endothelial risk factors compared with previously healthy
women. Indeed, sFlt1 levels are lower
in obese women with established preeclampsia as compared with normalweight women with preeclampsia.45
Similarly, women with preeclampsia in
association with relatively low levels of
circulating sFlt1 were found to have
higher BP at booking (13 to 20 wk gestation) compared with women with
high-sFlt1 preeclampsia,46 suggesting
subclinical endothelial dysfunction
may result in a lower sFlt1 threshold
BRIEF REVIEW
for the development of preeclampsia.
Whether other vascular risk factors,
such as chronic hypertension and diabetes, have a similar pattern remains to
be seen.
The molecular pathways affecting
sFlt1 and sEng expression and how these
might relate to other theories of the
pathogenesis of preeclampsia are just
emerging. Heme oxygenase (HO), an anti-inflammatory enzyme with antioxidant properties, attenuates VEGF-induced sFlt1 expression.47 Diminished
HO activity has been observed in women
with preeclampsia48,49 and mediates increased placental sFlt1 and sEng expression. This observation suggests a
potential therapeutic use of statins in
preeclampsia, because these agents upregulate HO-1 and decrease VEGFinduced sFlt1 release from placental
villous explants47; however, adverse fetal
effects will first need to be excluded in
clinical trials, a critical standard for any
novel preeclampsia therapy.
A potential role for agonistic autoantibodies to the angiotensin AT1 receptor
(AT1-AA) in the pathogenesis of preeclampsia has developed in recent years.
Elevations in circulating levels of AT1-AA
in women with preeclampsia were first described in 199950 and posited to mediate
the enhanced vascular reactivity to angiotensin II and possibly the endothelial dysfunction that are characteristic of preeclampsia. Although subsequent work
has shown these autoantibodies are not
specific for preeclampsia, there remains
significant experimental evidence to suggest they may play an important pathogenic role. AT1-AA are linked to oxidative stress and decreased trophoblast
invasion,51 and circulating levels increase
in a transgenic mouse model of preeclampsia.52 AT1 receptor autoantibodies stimulate trophoblast sFlt1 production in vitro and therefore may mediate
excess sFlt1 production by the placenta
in preeclampsia53; however, AT1-AA
have not been temporally correlated to
the clinical phenotype of preeclampsia in
large clinical studies.
Recently, deficiency of placental enzyme
catechol-O-methyl-transferase (COMT)
and 2-methoxyestradiol (2-ME) was also
Pregnancy for the Nephrologist
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associated with preeclampsia.54 Mice deficient in COMT develop preeclampsialike signs and symptoms that are rescued
by exogenous therapy with 2-ME, possibly
through inhibition of hypoxia-inducible
factor 1-␣ and downstream targets such
as sFlt1. The investigators also demonstrated that human placenta obtained
from patients with preeclampsia are deficient in COMT, which is accompanied
by low circulating levels of 2-ME. More
work is needed to understand the precise
role of COMT during normal and abnormal pregnancies.
Screening for Preeclampsia
The ability to detect preeclampsia before
the onset of hypertension, proteinuria,
and other overt manifestations of disease
will probably be the first application of
angiogenic factors in the clinical management of preeclampsia. To date, more
than a dozen independent studies have
verified significant changes in PlGF,
sFlt1, or sEng before the onset of preeclampsia.33,35,55– 69 Changes in PlGF are
seen by the first trimester,67– 69 whereas
reproducible alterations in sFlt1 and
sEng are observed in the mid to late second trimester onward. PlGF is excreted
in the urine at lower levels in preeclampsia, and measurement of urinary PlGF
may have a role in preeclampsia screening70 or diagnosis.71–73 Combining these
three biomarkers into a single angiogenic
index33,55,65 or with uterine artery Doppler74 –77 may be more predictive than any
single marker.
It remains to be seen whether angiogenic biomarkers will be sensitive and specific enough for widespread clinical use.
For example, alterations in angiogenic factors are associated with normotensive
pregnancies complicated by intrauterine
growth restriction (IUGR).58,78 – 81 Angiogenic factor changes in IUGR are less pronounced than those seen in preeclampsia
and (with the exception of sEng33) have not
been observed in second- and early thirdtrimester samples,33,58,63,82 so this overlap
may not be relevant for an early preeclampsia screening test. An international, prospective cohort study of angiogenic biomarkers for preeclampsia
screening, sponsored by the World
18
Health Organization and with a recruitment goal of 10,000 women, is ongoing
(http://www.crep.com.ar/plgf/) and will
help clarify many of these controversies.
In addition to screening and diagnosis
before the onset of clinical symptoms,
angiogenic factors may prove useful in
distinguishing preeclampsia from other
hypertensive disorders of pregnancy,
such as gestational hypertension and
chronic hypertension.83,84
Placental protein-13 (PP-13) has also
emerged as an early biomarker for preeclampsia and other disorders related to
inadequate placentation. PP-13 is a placenta-specific protein that is involved in
normal implantation and placental vascular development. First-trimester circulating maternal serum levels of PP-13
are significantly lower in women who go
on to develop preeclampsia, IUGR, and
preterm birth. Some early studies suggested excellent prediction of preeclampsia
by first-trimester serum PP-13,85 although
other work suggested PP-13 is a robust
biomarker only for early-onset disease
and is less useful for preeclampsia occurring closer to term.86 Combining firsttrimester PP-13 serum screening with
uterine artery Doppler may further improve
prediction.87 Mutations in LGALS13, the
gene encoding PP-13, have been detected
in cases of preeclampsia.88 This polymorphism may result in production of a
shorter splice variant of PP-13 that is not
detected by conventional assays, contributing to low circulating levels and decreased local activity of PP-13 in some
cases of preeclampsia.
A screening tool for preeclampsia will
have the greatest impact on clinical outcomes when effective prevention or
treatment becomes available. To date, no
effective prevention is available for preeclampsia, and management is supportive, with delivery of the neonate the only
definitive treatment. Nevertheless, early
diagnosis of preeclampsia with angiogenic biomarkers is likely to improve
clinical outcomes using interventions
currently at hand. For example, intensive
monitoring of screen-positive patients
will allow for timely intervention with
antihypertensive medications, bed rest,
magnesium for seizure prophylaxis, ste-
Journal of the American Society of Nephrology
roids for fetal lung maturity, and expedient delivery (when appropriate). The effect of screening on clinical outcomes
using these methods will need to be
proved. The greatest potential impact of
screening and early diagnosis will depend on new treatment or prevention
strategies for preeclampsia, based on altering the placental production or endothelial effects of angiogenic factors. Interventions that allow delivery to be
safely postponed as little as 1 wk have the
potential to improve neonatal outcomes
significantly in preeclampsia.89 Such
treatments are further on the horizon but
hold the greatest hope for the transformation of our care of women with preeclampsia.
PREVENTION AND TREATMENT
OF PREECLAMPSIA
Several medications and new therapies
may play a role in the management of
preeclampsia.
Aspirin
The theoretical benefits of aspirin are
based on prominent alterations in prostacyclin-thromboxane balance in preeclampsia. Aspirin for the prevention of
preeclampsia has been extensively studied. Dozens of trials have produced
mixed results, culminating in three large
randomized, controlled trials, with a cumulative enrollment of 12,000 high-risk
women in the mid-1990s.90 –92 All three
studies found a small, nonsignificant
trend toward a lower incidence of preeclampsia in the aspirin-treated groups.
A comprehensive meta-analysis published in 2004, subsequently reinforced
by a second meta-analysis in 2007, combined randomized, controlled trial data
on ⬎32,000 women of varying risk status
from 31 trials. Both meta-analyses suggested a small but significant overall benefit, with a relative risk for preeclampsia
of 0.81 to 0.90 for aspirin-treated patients.93,94 A small reduction in the risk
for early preterm birth was also observed
in both analyses. Low-dosage aspirin
seems to be safe: Early concerns of an increased risk for postpartum hemorrhage
J Am Soc Nephrol 20: 14 –22, 2009
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have clearly been assuaged. Given the
small but significant protective effect, aspirin prophylaxis should be considered
as primary prevention for preeclampsia,
especially for women who are at high
baseline risk and for whom the absolute
risk reduction will be greatest.
renal damage.101 Other strategies that may
be explored include the use of placental
growth factor; mAbs to sFlt1 or sEng;
small-molecule inhibitors of sFlt1 or sEng
action; or agents that enhance endogenous
VEGF, PlGF, or TGF-␤ production.
L-Arginine
Antioxidants
Nutritional supplements, including antioxidants, calcium, and folic acid, all have
been proposed as offering protection from
preeclampsia. Unfortunately, none have
proved effective in randomized, controlled
trials. The use of antioxidants has garnered
particular enthusiasm in the past several
years, fueled in part by research suggesting
a major role for oxidative stress in the
pathogenesis of preeclampsia; however,
three large randomized, controlled trials of
vitamin C and E supplementation, with
sample sizes ranging from 700 to 2400
women, showed no benefit in high-risk95,96
or in healthy, nulliparous women.97 A
larger trial sponsored by the National Institutes of Health Maternal-Fetal Medicine
Units Network, with anticipated enrollment of 10,000 low-risk women, is ongoing; however, the current data do not support the routine use of antioxidants for the
prevention of preeclampsia.
Calcium and Folic Acid
Calcium supplementation is not effective
in women with normal or high baseline
calcium intake but may be beneficial in
populations with low (⬍600 mg/d) dietary calcium intake.98,99 Folic acid has
been suggested to be protective by observational data,100 but no randomized,
controlled trials are yet available to support this claim.
Another potential treatment strategy for
preeclampsia capitalizes on the role of
nitric oxide (NO) in the pathogenesis of
disease. The endothelial protective effect
of VEGF and PlGF in normal pregnancy
is mediated by NO, and impaired NO
synthesis may contribute to endothelial
dysfunction in preeclampsia. Women
with preeclampsia have high circulating
levels of asymmetric dimethylarginine,
an endogenous inhibitor of NO synthase, even before the clinical onset of
disease.102,103 Hence, NO donors or precursors, such as L-arginine, might be effective for the prevention or treatment of
preeclampsia. Although clinical studies
thus far have been too small to show a
conclusive benefit,104 pilot data suggested L-arginine may prolong pregnancy and reduce BP in women with gestational hypertension.105 Larger studies
are needed to determine whether L-arginine or other interventions aimed at restoring endothelial NO activity are safe
and effective for preeclampsia.
There remain significant challenges to
the development of new treatments for
preeclampsia, and it is unclear whether
these novel therapies will prove to be safe
and effective. Nevertheless, it is exciting
to witness advances in our understanding of the pathophysiology of preeclampsia that have the potential finally
to lead to treatment options for this challenging disease.
Angiogenic Therapies
Endothelial damage in preeclampsia is
mediated, at least in part, by disruptions
in balance between proangiogenic
(VEGF, PlGF, and TGF-␤) and antiangiogenic (sFlt1 and sEng) circulating factors. Given this, interventions that seek
to reestablish angiogenic balance hold
promise for the prevention or treatment
of preeclampsia. In a rat model of sFlt1induced preeclampsia, recombinant
VEGF-121 ameliorated hypertension and
J Am Soc Nephrol 20: 14 –22, 2009
ACKNOWLEDGMENTS
S.E.M. is supported by the Charles E.
Culpeper Scholarship in Medical Sciences.
R.T. is supported by grant DK67397 from the
National Institutes of Health.
DISCLOSURES
S.E.M. is a co-inventor on a patent filed on behalf
of Beth Israel Deaconess Medical Center for the use
BRIEF REVIEW
of angiogenesis-related proteins for the diagnosis
and treatment of preeclampsia. R.T. is a co-inventor on patents filed on behalf of the Massachusetts
General Hospital and licensed to multiple diagnostic
companies for the use of proteins including angiogenesis-related proteins for the diagnosis of preeclampsia. R.T. also serves as a consultant to the following
diagnostic companies pursuing preeclampsia tests:
Abbott Diagnostics, Beckman Coulter, Roche Diagnostics, and Ortho Clinical Diagnostics.
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