BRIEF REVIEW
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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-
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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.
REFERENCES
1. Fischer MJ: Chronic kidney disease and
pregnancy: Maternal and fetal outcomes.
Adv Chronic Kidney Dis 14: 132–145, 2007
2. Smith MC, Moran P, Ward MK, Davison
JM: Assessment of glomerular filtration
rate during pregnancy using the MDRD formula. BJOG 115: 109 –112, 2008
3. Alper AB, Yi Y, Webber LS, Pridjian G, Mumuney AA, Saade G, Morgan J, Nuwayhid
B, Belfort M, Puschett J: Estimation of glomerular filtration rate in preeclamptic patients. Am J Perinatol 24: 569 –574, 2007
4. Rule AD, Larson TS, Bergstralh EJ, Slezak
JM, Jacobsen SJ, Cosio FG: Using serum
creatinine to estimate glomerular filtration
rate: Accuracy in good health and in
chronic kidney disease. Ann Intern Med
141: 929 –937, 2004
5. Eknoyan G, Hostetter T, Bakris GL, Hebert
L, Levey AS, Parving HH, Steffes MW, Toto
R: Proteinuria and other markers of chronic
kidney disease: A position statement of the
National Kidney Foundation (NKF) and the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). Am J
Kidney Dis 42: 617– 622, 2003
6. ACOG practice bulletin: Diagnosis and
management of preeclampsia and eclampsia. Number 33, January 2002. American
College of Obstetricians and Gynecologists.
Int J Gynaecol Obstet 77: 67–75, 2002
7. Waugh JJ, Clark TJ, Divakaran TG, Khan
KS, Kilby MD: Accuracy of urinalysis dipstick techniques in predicting significant
proteinuria in pregnancy. Obstet Gynecol
103: 769 –777, 2004
8. Price CP, Newall RG, Boyd JC: Use of protein:creatinine ratio measurements on random urine samples for prediction of significant proteinuria: A systematic review. Clin
Chem 51: 1577–1586, 2005
9. Rodriguez-Thompson D, Lieberman ES:
Use of a random urinary protein-to-creatinine ratio for the diagnosis of significant
proteinuria during pregnancy. Am J Obstet
Gynecol 185: 808 – 811, 2001
10. Jungers P, Houillier P, Forget D, Labrunie
M, Skhiri H, Giatras I, Descamps-Latscha B:
Influence of pregnancy on the course of
primary chronic glomerulonephritis. Lancet
346: 1122–1124, 1995
Pregnancy for the Nephrologist
19
BRIEF REVIEW
www.jasn.org
11. Hou S: Pregnancy in chronic renal insufficiency and end-stage renal disease. Am J
Kidney Dis 33: 235–252, 1999
12. Sanders CL, Lucas MJ: Renal disease in
pregnancy. Obstet Gynecol Clin North Am
28: 593– 600, vii, 2001
13. Jones DC, Hayslett JP: Outcome of pregnancy in women with moderate or severe
renal insufficiency. N Engl J Med 335: 226 –
232, 1996
14. Imbasciati E, Gregorini G, Cabiddu G,
Gammaro L, Ambroso G, Del Giudice A,
Ravani P: Pregnancy in CKD stages 3 to 5:
Fetal and maternal outcomes. Am J Kidney
Dis 49: 753–762, 2007
15. Kashanizadeh N, Nemati E, Sharifi-Bonab
M, Moghani-Lankarani M, Ghazizadeh S,
Einollahi B, Lessan-Pezeshki M, Khedmat
H: Impact of pregnancy on the outcome of
kidney transplantation. Transplant Proc 39:
1136 –1138, 2007
16. Framarino dei Malatesta M, Rossi M, Rocca
B, Iappelli M, Poli L, Piccioni MG, Gentile T,
Landucci L, Berloco P: Fertility following
solid organ transplantation. Transplantation Proceedings 39: 2001–2004, 2007
17. Blowey DL, Warady BA: Outcome of infants born to women with chronic kidney
disease. Adv Chronic Kidney Dis 14: 199 –
205, 2007
18. Armenti VT, Radomski JS, Moritz MJ,
Gaughan WJ, Hecker WP, Lavelanet A, McGrory CH, Coscia L: Report from the National Transplantation Pregnancy Registry:
Outcomes of pregnancy after transplantation. In: Clinical Transplants 2004, edited
by Cecka JM, Terasaki PI, Los Angeles,
UCLA Immunogenetics Center, 2004, pp
103–114
19. Willis FR, Findlay CA, Gorrie MJ, Watson
MA, Wilkinson AG, Beattie TJ: Children of
renal transplant recipient mothers. J Paediatr Child Health 36: 230 –235, 2000
20. Laube GF, Kemper MJ, Schubiger G, Neuhaus TJ: Angiotensin-converting enzyme
inhibitor fetopathy: Long-term outcome.
Arch Intern Med Fetal Neonatal Ed 92:
F402–F403, 2007
21. Quan A: Fetopathy associated with exposure to angiotensin converting enzyme inhibitors and angiotensin receptor antagonists. Early Hum Dev 82: 23–28, 2006
22. Alwan S, Polifka JE, Friedman JM: Angiotensin II receptor antagonist treatment during pregnancy. Birth Defects Res A Clin
Mol Teratol 73: 123–130, 2005
23. Cooper WO, Hernandez-Diaz S, Arbogast
PG, Dudley JA, Dyer S, Gideon PS, Hall K,
Ray WA: Major congenital malformations
after first-trimester exposure to ACE inhibitors. N Engl J Med 354: 2443–2451, 2006
24. Danesi R, Del Tacca M: Teratogenesis and
immunosuppressive treatment. Transplant
Proc 36: 705–707, 2004
25. Maynard SE, Min JY, Merchan J, Lim KH, Li
J, Mondal S, Libermann TA, Morgan JP,
20
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
Journal of the American Society of Nephrology
Sellke FW, Stillman IE, Epstein FH,
Sukhatme VP, Karumanchi SA: Excess placental soluble fms-like tyrosine kinase 1
(sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in
preeclampsia. J Clin Invest 111: 649 – 658,
2003
Lu F, Longo M, Tamayo E, Maner W, AlHendy A, Anderson GD, Hankins GDV,
Saade GR: The effect of over-expression of
sFlt-1 on blood pressure and the occurrence of other manifestations of preeclampsia in unrestrained conscious pregnant mice. Am J Obstet Gynecol 196:
396.e1–396.e7, discussion 396.e7, 2007
Gilbert JS, Babcock SA, Granger JP: Hypertension produced by reduced uterine
perfusion in pregnant rats is associated
with increased soluble fms-like tyrosine kinase-1 expression. Hypertension 50: 1142–
1147, 2007
Makris A, Thornton C, Thompson J, Thomson S, Martin R, Ogle R, Waugh R, McKenzie P, Kirwan P, Hennessy A: Uteroplacental
ischemia results in proteinuric hypertension
and elevated sFLT-1. Kidney Int 71: 977–
984, 2007
Bujold E, Romero R, Chaiworapongsa T,
Kim YM, Kim GJ, Kim MR, Espinoza J, Gonçalves LF, Edwin S, Mazor M: Evidence supporting that the excess of the sVEGFR-1
concentration in maternal plasma in preeclampsia has a uterine origin. J Matern
Fetal Neonatal Med 18: 9 –16, 2005
Eremina V, Jefferson JA, Kowalewska J,
Hochster H, Haas M, Weisstuch J, Richardson C, Kopp JB, Kabir MG, Backx PH, Gerber HP, Ferrara N, Barisoni L, Alpers CE,
Quaggin SE: VEGF inhibition and renal
thrombotic microangiopathy. N Engl
J Med 358: 1129 –1136, 2008
Gu Y, Lewis DF, Wang Y: Placental productions and expressions of soluble endoglin,
soluble fms-like tyrosine kinase receptor-1,
and placental growth factor in normal and
preeclamptic pregnancies. J Clin Endocrinol Metab 93: 260 –266, 2007
Venkatesha S, Toporsian M, Lam C, Hanai
J, Mammoto T, Kim YM, Bdolah Y, Lim KH,
Yuan HT, Libermann TA, Stillman IE, Roberts D, D’Amore PA, Epstein FH, Sellke FW,
Romero R, Sukhatme VP, Letarte M, Karumanchi SA: Soluble endoglin contributes
to the pathogenesis of preeclampsia. Nat
Med 12: 642– 649, 2006
Levine RJ, Lam C, Qian C, Yu KF, Maynard
SE, Sachs B, Sibai B, Epstein FH, Romero R,
Thadhani R, Karumanchi SA: Soluble endoglin and other circulating antiangiogenic
factors in preeclampsia. N Engl J Med 355:
992–1005, 2006
Robinson CJ, Johnson DD: Soluble endoglin as a second-trimester marker for preeclampsia. Am J Obstet Gynecol 197: 174
e171– e175, 2007
Rana S, Karumanchi SA, Levine RJ, Ven-
36.
37.
38.
39.
40.
41.
42.
43.
44.
45.
46.
katesha S, Rauh-Hain JA, Tamez H,
Thadhani R: Sequential changes in antiangiogenic factors in early pregnancy and risk
of developing preeclampsia. Hypertension
50: 137–172, 2007
Wolf M, Shah A, Lam C, Martinez A, Smirnakis KV, Epstein FH, Taylor RN, Ecker JL,
Karumanchi SA, Thadhani R: Circulating
levels of the antiangiogenic marker sFLT-1
are increased in first versus second pregnancies. Am J Obstet Gynecol 193: 16 –22,
2005
Maynard SE, Moore Simas TA, Solitro MJ,
Rajan A, Crawford S, Soderland P, Meyer
BA: Circulating angiogenic factors in singleton vs multiple-gestation pregnancies.
Am J Obstet Gynecol 198: 200.e201–
200.e207, 2008
Bdolah Y, Palomaki GE, Yaron Y, BdolahAbram T, Goldman M, Levine RJ, Sachs BP,
Haddow JE, Karumanchi SA: Circulating
angiogenic proteins in trisomy 13. Am J
Obstet Gynecol 194: 239 –245, 2006
Conde-Agudelo A, Althabe F, Belizan JM,
Kafury-Goeta AC: Cigarette smoking during pregnancy and risk of preeclampsia: A
systematic review. Am J Obstet Gynecol
181: 1026 –1035, 1999
Hammoud AO, Bujold E, Sorokin Y, Schild
C, Krapp M, Baumann P: Smoking in pregnancy revisited: Findings from a large population-based study. Am J Obstet Gynecol
192: 1856 –1862, discussion 1862–1853,
2005
Lain KY, Wilson JW, Crombleholme WR,
Ness RB, Roberts JM: Smoking during
pregnancy is associated with alterations in
markers of endothelial function. Am J Obstet Gynecol 189: 1196 –1201, 2003
Schmidt-Lucke C, Belgore F, Reinhold D,
Ansorge S, Klein HU, Schmidt-Lucke JA,
Lip GY: Soluble vascular endothelial
growth factor, soluble VEGF receptor Flt-1
and endothelial function in healthy smokers. Int J Cardiol 100: 207–212, 2005
Mehendale R, Hibbard J, Fazleabas A,
Leach R: Placental angiogenesis markers
sFlt-1 and PlGF: Response to cigarette
smoke. Am J Obstet Gynecol 197:
363.e361–363.e365, 2007
Cooke JP, Bitterman H: Nicotine and angiogenesis: A new paradigm for tobacco-related diseases. Ann Med 36: 33–40, 2004
Suwaki N, Masuyama H, Nakatsukasa H,
Masumoto A, Sumida Y, Takamoto N,
Hiramatrsu Y: Hypoadiponectinemia and
circulating angiogenic factors in overweight patients complicated with preeclampsia. Am J Obstet Gynecol 195:
1687–1692, 2006
Levine RJ, Qian C, Maynard SE, Yu KF,
Epstein FH, Karumanchi SA: Serum sFlt1
concentration during preeclampsia and
mid trimester blood pressure in healthy
nulliparous women. Am J Obstet Gynecol
194: 1034 –1041, 2006
J Am Soc Nephrol 20: 14 –22, 2009
www.jasn.org
47. Cudmore M, Ahmad S, Al-Ani B, Fujisawa
T, Coxall H, Chudasama K, Devey LR, Wigmore SJ, Abbas A, Hewett PW, Ahmed A:
Negative regulation of soluble Flt-1 and
soluble endoglin release by heme oxygenase-1. Circulation 115: 1789 –1797, 2007
48. Zenclussen AC, Lim E, Knoeller S, Knackstedt M, Hertwig K, Hagen E, Klapp BF, Arck
PC: Heme oxygenases in pregnancy II:
HO-2 is downregulated in human pathologic pregnancies. Am J Reprod Immunol
50: 66 –76, 2003
49. Barber A, Robson SC, Myatt L, Bulmer JN,
Lyall F: Heme oxygenase expression in human placenta and placental bed: reduced
expression of placenta endothelial HO-2 in
preeclampsia and fetal growth restriction.
FASEB J 15: 1158 –1168, 2001
50. Wallukat G, Homuth V, Fischer T, Lindschau C, Horstkamp B, Jupner A, Baur E,
Nissen E, Vetter K, Neichel D, Dudenhausen JW, Haller H, Luft FC: Patients with
preeclampsia develop agonistic autoantibodies against the angiotensin AT1 receptor. J Clin Invest 103: 945–952, 1999
51. Xia Y, Wen H, Bobst S, Day MC, Kellems
RE: Maternal autoantibodies from preeclamptic patients activate angiotensin receptors on human trophoblast cells. J Soc
Gynecol Investig 10: 82–93, 2003
52. Dragun D, Muller DN, Brasen JH, Fritsche
L, Nieminen-Kelha M, Dechend R,
Kintscher U, Rudolph B, Hoebeke J, Eckert
D, Mazak I, Plehm R, Schonemann C, Unger T, Budde K, Neumayer HH, Luft FC,
Wallukat G: Angiotensin II type 1-receptor
activating antibodies in renal-allograft rejection. N Engl J Med 352: 558 –569, 2005
53. Zhou CC, Ahmad S, Mi T, Abbasi S, Xia L,
Day MC, Ramin SM, Ahmed A, Kellems RE,
Xia Y: Autoantibody from women with preeclampsia induces soluble Fms-like tyrosine kinase-1 production via angiotensin
type 1 receptor and calcineurin/nuclear
factor of activated T-cells signaling. Hypertension 51: 1010 –1019, 2008
54. Kanasaki K, Palmsten K, Sugimoto H, Ahmad S, Hamano Y, Xie L, Parry S, Augustin
HG, Gattone VH, Folkman J, Strauss JF,
Kalluri R: Deficiency in catechol-O-methyltransferase and 2-methoxyoestradiol is associated with pre-eclampsia. Nature 453:
1117–1121, 2008
55. Moore Simas TA, Crawford SL, Solitro MJ,
Frost SC, Meyer BA, Maynard SE: Angiogenic factors for the prediction of preeclampsia in high-risk women. Am J Obstet
Gynecol 197: 244.e1–244.e8, 2007
56. Su YN, Lee CN, Cheng WF, Shau WY,
Chow SN, Hsieh FJ: Decreased maternal
serum placenta growth factor in early second trimester and preeclampsia. Obstet
Gynecol 97: 898 –904, 2001
57. Tjoa ML, van Vugt JM, Mulders MA, Schutgens RB, Oudejans CB, van Wijk IJ: Plasma
placenta growth factor levels in midtrimes-
J Am Soc Nephrol 20: 14 –22, 2009
58.
59.
60.
61.
62.
63.
64.
65.
66.
67.
68.
ter pregnancies. Obstet Gynecol 98: 600 –
607, 2001
Taylor RN, Grimwood J, Taylor RS, McMaster MT, Fisher SJ, North RA: Longitudinal
serum concentrations of placental growth
factor: Evidence for abnormal placental angiogenesis in pathologic pregnancies.
Am J Obstet Gynecol 188: 177–182, 2003
Polliotti BM, Fry AG, Saller DN, Mooney
RA, Cox C, Miller RK: Second-trimester maternal serum placental growth factor and
vascular endothelial growth factor for predicting severe, early-onset preeclampsia.
Obstet Gynecol 101: 1266 –1274, 2003
Levine RJ, Maynard SE, Qian C, Lim KH,
England LJ, Yu KF, Schisterman EF,
Thadhani R, Sachs BP, Epstein FH, Sibai
BM, Sukhatme VP, Karumanchi SA: Circulating angiogenic factors and the risk of
preeclampsia. N Engl J Med 350: 672– 683,
2004
Hertig A, Berkane N, Lefevre G, Toumi K,
Marti HP, Capeau J, Uzan S, Rondeau E:
Maternal serum sFlt1 concentration is an
early and reliable predictive marker of preeclampsia. Clin Chem 50: 1702–1703, 2004
Krauss T, Pauer HU, Augustin HG: Prospective analysis of placenta growth factor
(PlGF) concentrations in the plasma of
women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy 23: 101–111, 2004
Bersinger NA, Odegard RA: Second- and
third-trimester serum levels of placental
proteins in preeclampsia and small-for-gestational age pregnancies. Acta Obstet Gynecol Scand 83: 37– 45, 2004
Park CW, Park JS, Shim SS, Jun JK, Yoon
BH, Romero R: An elevated maternal
plasma, but not amniotic fluid, soluble fmslike tyrosine kinase-1 (sFlt-1) at the time of
mid-trimester genetic amniocentesis is a
risk factor for preeclampsia. Am J Obstet
Gynecol 193: 984 –989, 2005
Kim SY, Ryu HM, Yang JH, Kim MY, Han JY,
Kim JO, Chung JH, Park SY, Lee MH, Kim
do J: Increased sFlt-1 to PlGF ratio in women
who subsequently develop preeclampsia. J
Korean Med Sci 22: 873–877, 2007
Vatten LJ, Eskild A, Nilsen TI, Jeansson S,
Jenum PA, Staff AC: Changes in circulating
level of angiogenic factors from the first to
second trimester as predictors of preeclampsia. Am J Obstet Gynecol 196:
239.e1–239.e6, 2007
Tidwell SC, Ho HN, Chiu WH, Torry RJ,
Torry DS: Low maternal serum levels of
placenta growth factor as an antecedent of
clinical preeclampsia. Am J Obstet Gynecol 184: 1267–1272, 2001
Thadhani R, Mutter WP, Wolf M, Levine RJ,
Taylor RN, Sukhatme VP, Ecker J, Karumanchi SA: First trimester placental growth
factor and soluble fms-like tyrosine kinase 1
and risk for preeclampsia. J Clin Endocrinol
Metab 89: 770 –775, 2004
BRIEF REVIEW
69. Smith GC, Crossley JA, Aitken DA, Jenkins
N, Lyall F, Cameron AD, Connor JM, Dobbie R: Circulating angiogenic factors in
early pregnancy and the risk of preeclampsia, intrauterine growth restriction, spontaneous preterm birth, and stillbirth. Obstet
Gynecol 109: 1316 –1324, 2007
70. Levine RJ, Thadhani R, Qian C, Lam C, Lim
KH, Yu KF, Blink AL, Sachs BP, Epstein FH,
Sibai BM, Sukhatme VP, Karumanchi SA:
Urinary placental growth factor and risk of
preeclampsia. JAMA 293: 77– 85, 2005
71. Buhimschi CS, Magloire L, Funai E, Norwitz
ER, Kuczynski E, Martin R, Richman S,
Guller S, Lockwood CJ, Buhimschi IA: Fractional excretion of angiogenic factors in
women with severe preeclampsia. Obstet
Gynecol 107: 1103–1113, 2006
72. Buhimschi CS, Norwitz ER, Funai E, Richman S, Guller S, Lockwood CJ, Buhimschi
IA: Urinary angiogenic factors cluster hypertensive disorders and identify women
with severe preeclampsia. Am J Obstet Gynecol 192: 734 –741, 2005
73. Aggarwal PK, Jain V, Sakhuja V, Karumanchi SA, Jha V: Low urinary placental growth
factor is a marker of pre-eclampsia. Kidney
Int 69: 621– 624, 2006
74. Espinoza J, Romero R, Nien JK, Gomez R,
Kusanovic JP, Goncalves LF, Medina L, Edwin S, Hassan S, Carstens M, Gonzalez R:
Identification of patients at risk for early
onset and/or severe preeclampsia with the
use of uterine artery Doppler velocimetry
and placental growth factor. Am J Obstet
Gynecol 196: 326.e1–326.e13, 2007
75. Stepan H, Unversucht A, Wessel N, Faber
R: Predictive value of maternal angiogenic
factors in second trimester pregnancies
with abnormal uterine perfusion. Hypertension 49: 818 – 824, 2007
76. Muller PR, James AH, Murtha AP, Yonish B,
Jamison MG, Dekker G: Circulating angiogenic factors and abnormal uterine artery
Doppler velocimetry in the second trimester. Hypertens Pregnancy 25: 183–192,
2006
77. Crispi F, Llurba E, Dominguez C, MartinGallan P, Cabero L, Gratacos E: Predictive
value of angiogenic factors and uterine artery Doppler for early- versus late-onset
pre-eclampsia and intrauterine growth restriction. Ultrasound Obstet Gynecol 31:
303–309, 2007
78. Shibata E, Rajakumar A, Powers RW, Larkin
RW, Gilmour C, Bodnar LM, Crombleholme WR, Ness RB, Roberts JM, Hubel
CA: Soluble fms-like tyrosine kinase 1 is
increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: Relationship to circulating placental growth factor. J Clin
Endocrinol Metab 90: 4895– 4903, 2005
79. Stepan H, Kramer T, Faber R: Maternal
plasma concentrations of soluble endoglin
in pregnancies with intrauterine growth re-
Pregnancy for the Nephrologist
21
BRIEF REVIEW
80.
81.
82.
83.
84.
85.
86.
87.
88.
22
www.jasn.org
striction. J Clin Endocrinol Metab 92:
2831–2834, 2007
Wallner W, Sengenberger R, Strick R, Strissel PL, Meurer B, Beckmann MW, Schlembach D: Angiogenic growth factors in maternal and fetal serum in pregnancies
complicated by intrauterine growth restriction. Clin Sci (Lond) 112: 51–57, 2007
Yinon Y, Nevo O, Xu J, Many A, Rolfo A,
Todros T, Post M, Caniggia I: Severe intrauterine growth restriction pregnancies
have increased placental endoglin levels.
Am J Pathol 172: 77– 85, 2008
Wathen KA, Tuutti E, Stenman UH, Alfthan H, Halmesmaki E, Finne P, Ylikorkala
O, Vuorela P: Maternal serum-soluble
vascular endothelial growth factor receptor-1 in early pregnancy ending in preeclampsia or intrauterine growth retardation. J Clin Endocrinol Metab 91: 180 –
184, 2006
Salahuddin S, Lee Y, Vadnais M, Sachs BP,
Karumanchi SA, Lim KH: Diagnostic utility
of soluble fms-like tyrosine kinase 1 and
soluble endoglin in hypertensive diseases
of pregnancy. Am J Obstet Gynecol 197:
28.e1–28.e6, 2007
Masuyama H, Suwaki N, Nakatsukasa H,
Masumoto A, Tateishi Y, Hiramatrsu Y: Circulating angiogenic factors in preeclampsia, gestational proteinuria, and preeclampsia superimposed on chronic
glomerulonephritis. Am J Obstet Gynecol
194: 551–556, 2006
Chafetz I, Kuhnreich I, Sammar M, Tal Y,
Gibor Y, Meiri H, Cuckle H, Wolf M: Firsttrimester placental protein 13 screening for
preeclampsia and intrauterine growth restriction. Am J Obstet Gynecol 197: 35.e1–
35.e7, 2007
Romero R, Espinoza J, Edwin S, Chefetz I,
Sammar M, Meiri H, Tal Y, Kuhnreich I,
Cuckle H: Assessment of first trimester maternal serum PP13 in early vs. term sever
preeclampsia. Am J Obstet Gynecol
195[Suppl 1]: S133, 2006
Nicolaides KH, Bindra R, Turan OM, Chefetz
I, Sammar M, Meiri H, Tal J, Cuckle HS: A
novel approach to first-trimester screening
for early pre-eclampsia combining serum
PP-13 and Doppler ultrasound. Ultrasound
Obstet Gynecol 27: 13–17, 2006
Sammar M, Stalk M, Gebhardt S, Pick-Golan E, Meiri H, Huppertz B, Hillerman R:
89.
90.
91.
92.
93.
94.
95.
96.
97.
Journal of the American Society of Nephrology
RNA splicing and DNA polymorphism
leading to two shorter sub-forms of
placenta protein 13 in preeclampsia. Am J
Obstet Gynecol 195[Suppl 1]: S141, 2006
Habli M, Levine RJ, Qian C, Sibai B: Neonatal
outcomes in pregnancies with preeclampsia
or gestational hypertension and in normotensive pregnancies that delivered at 35, 36,
or 37 weeks of gestation. Am J Obstet Gynecol 197: 406.e1–406.e7, 2007
Low-dose aspirin in prevention and treatment of intrauterine growth retardation
and pregnancy-induced hypertension. Italian study of aspirin in pregnancy. Lancet
341: 396 – 400, 1993
Caritis S, Sibai B, Hauth J, Lindheimer MD,
Klebanoff M, Thom E, VanDorsten P,
Landon M, Paul R, Miodovnik M, Meis P,
Thurnau G: Low-dose aspirin to prevent
preeclampsia in women at high risk. National Institute of Child Health and Human
Development Network of Maternal-Fetal
Medicine Units. N Engl J Med 338: 701–
705, 1998
CLASP: A randomised trial of low-dose
aspirin for the prevention and treatment
of pre-eclampsia among 9364 pregnant
women. CLASP (Collaborative Low-dose
Aspirin Study in Pregnancy) Collaborative
Group. Lancet 343: 619 – 629, 1994
Askie LM, Duley L, Henderson-Smart DJ,
Stewart LA: Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of
individual patient data. Lancet 369: 1791–
1798, 2007
Duley L, Henderson-Smart DJ, Knight M,
King JF: Antiplatelet agents for preventing
pre-eclampsia and its complications. Cochrane Database Syst Rev (2): CD004659,
2007
Poston L, Briley AL, Seed PT, Kelly FJ,
Shennan AH: Vitamin C and vitamin E in
pregnant women at risk for pre-eclampsia
(VIP trial): Randomised placebo-controlled
trial. Lancet 367: 1145–1154, 2006
Spinnato JA II, Freire S, Pinto e Silva JL,
Cunha Rudge MV, Martins-Costa S, Koch
MA, Goco N, Santos CdB, Cecatti JG,
Costa R, Ramos JG, Moss N, Sibai BM:
Antioxidant therapy to prevent preeclampsia: A randomized controlled trial. Obstet
Gynecol 110: 1311–1318, 2007
Rumbold AR, Crowther CA, Haslam RR,
Dekker GA, Robinson JS: Vitamins C and E
98.
99.
100.
101.
102.
103.
104.
105.
and the risks of preeclampsia and perinatal
complications. N Engl J Med 354: 1796 –
1806, 2006
Hofmeyr GJ, Atallah AN, Duley L: Calcium
supplementation during pregnancy for
preventing hypertensive disorders and related problems. Cochrane Database Syst
Rev 3: CD001059, 2006
Villar J, Abdel-Aleem H, Merialdi M, Mathai
M, Ali MM, Zavaleta N, Purwar M, Hofmeyr
J, Nguyen TN, Campodonico L, Landoulsi
S, Carroli G, Lindheimer M: World Health
Organization randomized trial of calcium
supplementation among low calcium intake pregnant women. Am J Obstet Gynecol 194: 639 – 649, 2006
Wen SW, Chen X-K, Rodger M, Rennicks
White R, Yang Q, Smith GN, Sigal RJ, Perkins SL, Walker MC: Folic acid supplementation in early second trimester and the risk
of preeclampsia. Am J Obstet Gynecol
198: 45.e41– 45.e47, 2008
Li Z, Zhang Y, Ying Ma J, Kapoun AM,
Shao Q, Kerr I, Lam A, O’Young G, Sannajust F, Stathis P, Schreiner G, Karumanchi SA, Protter AA, Pollitt NS: Recombinant vascular endothelial growth factor
121 attenuates hypertension and improves
kidney damage in a rat model of preeclampsia. Hypertension 50: 686 – 692,
2007
Savvidou MD, Hingorani AD, Tsikas D,
Frolich JC, Vallance P, Nicolaides KH: Endothelial dysfunction and raised plasma
concentrations of asymmetric dimethylarginine in pregnant women who subsequently develop pre-eclampsia. Lancet
361: 1511–1517, 2003
Speer PD, Powers RW, Frank MP, Harger
G, Markovic N, Roberts JM: Elevated asymmetric dimethylarginine concentrations
precede clinical preeclampsia, but not
pregnancies with small-for-gestational-age
infants. Am J Obstet Gynecol 198: 112.e1–
112.e7, 2008
Meher S, Duley L: Nitric oxide for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev (2):
CD006490, 2007
Facchinetti F, Saade GR, Neri I, Pizzi C,
Longo M, Volpe A: L-arginine supplementation in patients with gestational hypertension: A pilot study. Hypertens Pregnancy 26: 121–130, 2007
J Am Soc Nephrol 20: 14 –22, 2009