Serum sFlt1 concentration during preeclampsia and mid

trimester blood pressure in healthy nulliparous women

Richard J. Levine, MD, MPH,
a,
*
Cong Qian, MS,
b
Sharon E. Maynard, MD,
c
Kai F. Yu, PhD,
a
Franklin H. Epstein, MD,
d
S. Ananth Karumanchi, MD
d
Division of Epidemiology, Statistics, and Prevention Research, National Institute of Child Health and Human
Development, Department of Health and Human Services, Bethesda, MD
a
; Allied Technology Group, Rockville, MD
b
;
Department of Medicine, University of Massachusetts Medical Center, Worcester, MA
c
; Departments of Medicine,
Obstetrics and Gynecology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA
d
Received for publication May 5, 2005; revised August 30, 2005; accepted October 5, 2005
KEY WORDS
Preeclampsia
Blood pressure
Soluble fms-like
tyrosine kinase 1
sFlt1
Cardiovascular disease
Placental growth
factor
Objective: The purpose of this study was to determine whether serum fms-like tyrosine kinase 1
(sFlt1) concentration during preeclampsia were associated with mid trimester blood pressure,
other maternal characteristics, or pregnancy outcomes.
Study design: We performed a nested case-control study within the Calcium for Preeclampsia
Prevention study cohort. Each woman with preeclampsia (case) was matched to 1 normotensive
control. A total of 120 pairs of women was chosen randomly. Serum concentrations of sFlt1 and
placental growth factor were measured throughout pregnancy, but before labor and delivery. We
focused on data from 40 women with blood specimens that were obtained after the onset of pre-
eclampsia. After logarithmic transformation, we determined mean serum sFlt1 concentrations of
all control specimens within gestational age windows during which case specimens had been ob-
tained after the onset of preeclampsia. Within each of these gestational age windows, we com-
puted an upper bound for the control specimens equal to 2 standard deviations above the
mean. After the onset of preeclampsia, 16 women with log-transformed serum sFlt1 values
greater than the upper bound of the control specimens were considered to have high preeclampsia
serum sFlt1 levels. The 24 other women were considered to have low preeclampsia serum sFlt1
levels.
Results: Women with high or low concentrations of serum sFlt1 during preeclampsia (arithmetic
means, 5746 and 3007 pg/mL, respectively) had similar pregnancy outcomes and similar maternal
characteristics, except for blood pressure at Calcium for Preeclampsia Prevention study enroll-
ment. Systolic and diastolic blood pressure at enrollment at 13 to 21 weeks of gestation were
Supported by intramural salary support from the National Institute of Child Health and Human Development; seed funds from the Departments
of Medicine and the Obstetrics Department Research Foundation of the Beth Israel Deaconess Medical Center; and grants DK64255, DK02825, and
HL079594 from the National Institute of Diabetes, and Digestive and Kidney Diseases and the National Heart Lung and Blood Institute (S.A.K.).
The CPEP trial was supported by the National Institute of Child Health and Development under contracts N01-HD-1-3121 through 3126, N01-HD-
2-3154, and N01-HD-5-3246, with co-funding from the National Heart, Lung, and Blood Institute.
Drs Maynard and Karumanchi are named as coinventors on a pending patent that was led by Beth Israel Deaconess Medical Center for the use
of angiogenesis-related proteins for the diagnosis and treatment of preeclampsia.
* Reprint requests: Richard J. Levine, MD, NIH/NICHD, Building 6100, Room 7B03, Bethesda, MD 20892.
E-mail: LevineRJ@mail.nih.gov
0002-9378/$ - see front matter 2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.10.192
American Journal of Obstetrics and Gynecology (2006) 194, 103441
www.ajog.org
significantly higher in the 24 women with low serum sFlt1 concentrations during preeclampsia
(systolic blood pressure, 114 mm Hg; diastolic blood pressure, 65 mm Hg) than in the 16 women
who had preeclampsia at high serum sFlt1 concentrations (systolic blood pressure, 106 mm Hg;
diastolic blood pressure, 59 mm Hg). Blood pressure at 13 to 21 weeks among the women with
high preeclampsia serum sFlt1 concentrations was identical to the blood pressure among normo-
tensive control subjects. In linear regression analyses of data from all 40 women, both systolic
(P ! .0001) and diastolic (P = .014) blood pressures at enrollment were correlated negatively
with natural logarithm serum sFlt1 concentration after onset of preeclampsia.
Conclusion: Women with higher mid trimester blood pressure had preeclampsia at lower serum
sFlt1 concentrations. Because higher blood pressure may reflect occult endothelial damage, these
observations may explain increased susceptibility to preeclampsia among women with pre-
existing vascular disease.
2006 Mosby, Inc. All rights reserved.
The hypertensive syndrome of preeclampsia may be
caused by high concentrations of soluble fms-like tyro-
sine kinase 1 (sFlt1) in maternal blood.
1,2
sFlt1, an anti-
angiogenic protein, binds the proangiogenic proteins
vascular endothelial growth factor (VEGF) and placen-
tal growth factor (PlGF), preventing their interaction
with endothelial cell receptors.
2
VEGF is important in
regulating blood pressure and in maintaining the integ-
rity of the glomerular ltration barrier.
2
VEGF signaling
inhibitors have caused hypertension and proteinuria
when administered to patients with cancer who have
been enrolled in antiangiogenic clinical trials.
3
sFlt1
that was administered exogenously to rats reduced the
concentrations of free VEGF and PlGF and produced
a syndrome of hypertension, proteinuria, and glomerular
endotheliosis, which are the classic features of pree-
clampsia.
2
Because the hypertensive syndrome of pree-
clampsia results from generalized maternal endothelial
dysfunction,
4
the disease may be caused by excessive
quantities of sFlt1 in the blood, which induce endothelial
dysfunction by blocking proangiogenic signaling.
Blood pressure at the initiation of prenatal care has
been associated with the risk of subsequent preeclamp-
sia.
5
Higher diastolic blood pressure (DBP) and, in par-
ticular, higher systolic blood pressure (SBP) have been
linked to an elevated risk for preeclampsia in healthy
nulliparous women.
6,7
Increased second trimester mean
arterial pressure also has been associated with the
risk of subsequent preeclampsia among women with
conditions that place them at high risk (pregestational
diabetes mellitus, chronic hypertension, previous pre-
eclampsia, or multifetal gestation).
8
We and others re-
cently have presented evidence that circulating sFlt1
begins to rise during the last 2 months of normal preg-
nancy and that this process is exaggerated in preeclamp-
sia. These data together with the results of laboratory
studies suggest that sFlt1 may play a central role in
the pathogenesis of preeclampsia.
1,2,9,10
However, the
relationship of sFlt1 to the known risk factors for pree-
clampsia is unclear.
We postulate that a threshold exists for sFlt-1 to
cause disease, below which normal pregnancy proceeds
and above which preeclampsia results. Women with risk
factors may represent a group whose threshold has been
lowered, thereby rendering them more vulnerable to the
eects of sFlt-1 and resulting in the maternal hyperten-
sive syndrome at levels not far above those of normal
pregnancy. Blood pressure during early pregnancy may
reect the health of vascular endothelial cells, with
higher blood pressure indicating an endothelium that
is less capable of producing smooth muscle relaxing
factors and more susceptible to damage from circulating
antiangiogenic proteins. Therefore, before performing
the analysis, we hypothesized that, in such persons,
preeclampsia might develop at lower sFlt1 concentra-
tions. To determine whether blood pressure at 13 to 21
weeks of gestation, other maternal characteristics, or
pregnancy outcomes were associated with sFlt1 levels
during preeclampsia, we performed a nested case-control
study within the Calcium for Preeclampsia Prevention
(CPEP) trial with archived serum samples that were
obtained before labor and delivery.
Methods
Participants and specimen collection
The CPEP trial was a randomized, double-blind clinical
trial that was conducted from 1992 to 1995 to evaluate
the eects of daily supplementation with calcium or
placebo on the incidence and severity of preeclamp-
sia.
11,12
Healthy nulliparous women with singleton
pregnancies were enrolled between 13 and 21 weeks
of gestation at 5 participating medical centers in the
United States and were followed until 24 hours after
delivery, with the use of a common protocol and iden-
tical data-collection forms. Written informed consent
was obtained from all the participants. Gestational
age was determined by means of ultrasonographic ex-
amination. Serum specimens were requested from the
Levine et al 1035
women before enrollment in the trial, at 26 to 29 weeks
of gestation, at 36 weeks (if they were still pregnant),
and when hypertension or proteinuria was noted. Be-
cause the study reported here used data and specimens
that could not be linked to identiable women, the of-
ce of Human Subjects Research of the National Ins-
titutes of Health granted an exemption from the
requirement for review and approval by the institu-
tional review board.
We recently performed a nested case-control study of
concentrations of angiogenic factors within the CPEP
cohort, using serum specimens that were obtained
throughout gestation, but before labor, from120 normo-
tensive women and 120 women with preeclampsia. We
foundthat high levels of sFlt1 and lowlevels of PlGFwere
present not only at the time of clinical preeclampsia but
also began several weeks before the onset of the disease.
Informationabout the selectionof study subjects has been
published in detail previously.
1
For this study, we used
data from the original nested case-control study but fo-
cused on the 40 women from whom serum specimens
hadbeen obtainedafter the onset of clinical preeclampsia.
Two of these women had O1 specimen obtained during
preeclampsia. To simplify analysis, we used only the rst
specimen after the onset of preeclampsia.
Enrollment blood pressure, preeclampsia, and
small-for-gestational-age infants
Enrollment blood pressure was the standardized blood
pressure measurement that was obtained in the research
clinic on the day of enrollment in the CPEP trial. Blood
pressure was measured with the subject in the sitting
position by a certied examiner who used a standard
mercury sphygmomanometer according to a published
protocol;
12
2 measurements were taken at least 1 minute
apart, and the results were averaged. DBP was deter-
mined by the fth Korotko sound, unless a measure-
ment was zero, in which case the fourth sound was
used.
11,12
Preeclampsia was dened as a DBP of at least
90 mm Hg and proteinuria level of at least 1C (30 mg/
dL) on dipstick testing, each on 2 occasions 4 to 168
hours apart. Detailed denitions have been pub-
lished.
11,12
The time of the onset of preeclampsia was de-
ned as the time of the rst elevated blood pressure or
urinary protein measurement that led to the diagnosis
of preeclampsia. A small-for-gestational-age infant was
dened as an infant whose birth weight was below the
10th percentile according to US tables of birth weight
for gestational age that accounted for race, parity, and
the sex of the infant.
13
Procedures
Assays were performed by a single person (S.E.M.)
who was unaware of pregnancy outcomes. Specimens
were randomly ordered for analysis. Enzyme-linked
immunosorbent assays for sFlt1 and free PlGF were
performed in duplicate, with the use of commercial kits
(R&D Systems, Minneapolis, MN). The minimum de-
tectable doses in the assays for sFlt1 and PlGF were 5
and 7 pg/mL, respectively, with interassay and intra-
assay coecients of variation of 7.6% and 3.3%,
respectively, for sFlt1 and 10.9% and 5.6%, respec-
tively, for PlGF.
Statistical analysis
We determined geometric mean sFlt1 levels of all
control specimens within gestational age windows dur-
ing which case specimens had been obtained after the
onset of preeclampsia (clinical preeclampsia specimens):
at 29 to 32 weeks (21 control and 2 clinical preeclampsia
specimens), 33 to 36 weeks (70 control and 13 clinical
preeclampsia specimens), and 37 to 41 weeks of gesta-
tion (21 control and 25 clinical preeclampsia specimens).
Within each of these gestational age windows, we
computed an upper bound for the control specimens
that was equal to 2 standard deviations above the mean
of sFlt1 concentration after logarithmic (ln) transfor-
mation. Assuming a normal distribution, only 2.5% of
control values should exceed the upper bound. Case
specimens with log-transformed sFlt1 values greater
than the upper bound of the control specimens were
considered to have high preeclampsia sFlt1 levels. Case
specimens with lower sFlt1 values were considered to
have low preeclampsia sFlt1 levels.
Scatter plots were drawn of ln sFlt1 concentration
during preeclampsia versus SBP and DBP at enrollment.
A tted regression line that represented the following
equation was included in each plot: Y = b0 C b1 X,
where Y=ln sFlt1 and X=blood pressure. In addition,
a linear regression model was tted for SBP and DBP at
enrollment versus body mass index (BMI) at enrollment,
where Y = blood pressure and X = BMI. A similar
model was tted for SBP and DBP at enrollment versus
gestational age at onset of preeclampsia. Signicance
testing was performed with t-tests for the comparison of
continuous variables and chi-squared tests for compari-
son of categorical variables. Testing for sFlt1, PlGF,
and sFlt1/PlGF was conducted after logarithmic trans-
formation. In all analyses, 2-tailed probability values of
!.05 were considered statistically signicant.
Results
Women with high (n = 16) or low (n = 24) concentra-
tions of sFlt1 during preeclampsia (arithmetic mean
values, 5746 and 3007 pg/mL, respectively) had similar
pregnancy outcomes and similar characteristics at CPEP
enrollment, except for baseline blood pressure (Table I).
Both DBP and especially SBP at enrollment at 13 to 21
weeks of gestation were signicantly higher in the
1036 Levine et al
women with low sFlt1 concentrations during preeclamp-
sia (SBP, 114 mm Hg; DBP, 65 mm Hg) than in the
women with high sFlt1 concentrations. SBP and DBP
at enrollment among women with high sFlt1 concentra-
tions during preeclampsia (SBP, 106 mm Hg; DBP, 59
mm Hg) were identical to those among the 120 normo-
tensive control subjects.
1
Although women with high
sFlt1 concentrations during preeclampsia had lower
BMI than women with low sFlt1 concentrations, the dif-
ference was not statistically signicant.
Besides examining high and low sFlt1 groups on the
basis of an arbitrary cut point, we also determined
whether baseline blood pressure were associated linearly
with sFlt1 concentrations during preeclampsia using the
entire study population. In the 40 women with serum
specimens that were obtained after the onset of pree-
clampsia, higher baseline SBP (P !.0001; R
2
, 0.33) and
DBP (P = .014; R
2
, 0.15) were associated with lower
sFlt1 levels after preeclampsia onset (Figure). There
were, however, no signicant linear relationships be-
tween ln PlGF concentration after preeclampsia onset
and baseline blood pressure in these 40 women; between
ln sFlt1 concentration at enrollment and baseline blood
pressure in all 120 preeclampsia cases or normotensive
Table I Characteristics of cases with high or low sFlt1 concentrations during preeclampsia at enrollment in the CPEP trial or during
subsequent pregnancy and characteristics of their infants
Characteristic
sFlt1 concentration during preeclampsia
High (n = 16) Low (n = 24)
Enrollment
Age (y)* 20.7 G 4.3 20.9 G 4.7
Height (cm)* 161.4 G 7.5 161.8 G 6.5
Weight (kg)* 72.7 G 21.8 77.8 G 23.4
BMI (kg/m
2
)* 27.7 G 7.4 29.6 G 7.7
Gestational age at enrollment (d)* 125.4 G 22.1 127.5 G 17.1
SBP (mm Hg)* 105.9 G 7.6 113.5 G 7.6
y
DBP (mm Hg)* 58.8 G 7.3 65.1 G 8.7
z
Previous pregnancy loss (n) 1 (6.3%) 3 (12.5%)
Current smoker (n) 1 (6.3%) 0
Calcium treatment (n) 6 (37.5%) 10 (41.7%)
Primigravida (n) 15 (93.4%) 21 (87.5%)
Race/ethnicity
White, non-Hispanic (n) 4 (25.0%) 8 (33.3%)
White, Hispanic (n) 5 (31.3%) 4 (16.7%)
Black (n) 5 (31.3%) 12 (50.0%)
Other, unknown (n) 2 (12.5%) 0
Gestational age at enrollment specimen collection (d)* 115.8 G 24.0 117.2 G 18.2
sFlt1 at enrollment (pg/mL)* 899 G 579 728 G 316
PlGF at enrollment (pg/mL)* 113 G 91 109 G 64
sFlt1/PlGF at enrollment* 14.0 G 14.9 9.1 G 6.4
Subsequent pregnancy
Plasma glucose 1 hr after 50 g oral glucose challenge (mg/dL)* 110.1 G 19.6 106.0 G 25.3
Gestational diabetes mellitus (n) 1 (7.7%) 1 (4.4%)
Gestational age at preeclampsia onset (d)* 262.1 G 18.2 260.3 G 24.2
Preeclampsia at !37 wks (n) 6 (37.5%) 9 (37.5%)
Severe preeclampsia (n) 6 (37.5%) 7 (29.2%)
Gestational age at preeclampsia specimen collection (d)* 263.9 G 18.0 262.7 G 23.0
During preeclampsia
sFlt1 (pg/mL)* 5746 G 1017 3007 G 917
x
PlGF (pg/mL)* 122 G 64 188 G 244
sFlt1/PlGF* 69.0 G 53.7 29.6 G 23.4
y
Infant characteristic
Gestational age at delivery (d)* 267.1 G 17.7 267.5 G 19.0
Birth weight (g)* 3129 G 882 3076 G 820
Small for gestational age: !10th percentile (n) 1 (6.3%) 4 (16.7%)
* Data are given as mean G SD.
y
P ! .01.
z
P ! .05.
x
Statistical testing inappropriate.
Levine et al 1037
control subjects; or between baseline blood pressure in
the 40 cases with blood specimens that were obtained
during preeclampsia and gestational age at onset of
preeclampsia.
Because obesity is an important risk factor for pree-
clampsia and is known to be associated with increased
blood pressure, we examined the relationship of BMI to
blood pressure at enrollment and to angiogenic factor
concentrations during preeclampsia. Among the women
with specimens that were obtained during preeclampsia,
those who were of normal weight or who were under-
weight (BMI, !25 kg/m
2
; n = 13) did not dier signif-
icantly from those who were obese (BMI, R30 kg/m
2
;
n = 12) or who were extremely obese (BMI, R40 kg/m
2
;
n = 5) with respect to blood pressure at enrollment or
sFlt1 or PlGF concentrations during preeclampsia
(Table II). Among all normotensive control subjects,
but not among all preeclampsia cases, a higher BMI
was correlated with increased baseline SBP (b1 = 0.59;
P ! .0001) and DBP (b1 = 0.21; P = .057).
Comment
Preeclampsia is a complex disorder that is characterized
by widespread endothelial dysfunction. Placental fac-
tors, such as sFlt1, appear to be important mediators of
this endothelial dysfunction. Moreover, disorders that
aect vascular endothelial health (such as diabetes
mellitus and hypertension) are known risk factors for
preeclampsia. Ness and Roberts
14
have proposed that
the endothelium is the point of convergence of maternal
and placental causes of preeclampsia and that the fac-
tors that are associated with increased maternal risk
for preeclampsia can have direct eects on endothelial
integrity. We hypothesized that women with poor endo-
thelial health will have higher mid trimester blood pres-
sure and will be susceptible to the development of
preeclampsia at lower sFlt1 concentrations than women
whose endothelium is relatively healthy. To test this hy-
pothesis, we searched for dierences in baseline clinical
characteristics in 24 women who had preeclampsia at
relatively low sFlt1 levels as compared with 16 women
who had preeclampsia at high sFlt1 levels. We found
that women who had preeclampsia at low sFlt1 levels
had signicantly higher baseline blood pressure (mean,
18 weeks of gestation) than women who had preeclamp-
sia at high sFlt1 levels. The baseline blood pressures of
normotensive control subjects and of women with high
sFlt1 concentrations during preeclampsia were identical.
Results of the 2-groupcomparisonwere conrmedamong
all 40 women by linear regressions of ln sFlt1 concentra-
tion during preeclampsia on baseline SBP and DBP.
These showed that, as baseline blood pressure increased,
ln sFlt1 concentration during preeclampsia decreased.
Dierences in pregnancy outcomes were not observed
between women with preeclampsia who had high or low
sFlt1 concentrations. Although the inability to detect
dierences could be due to the limited size of the
population under study, we believe that the severity of
preeclampsia depends not only on sFlt1 concentration
but also on the interaction of angiogenic imbalance and
pre-existing vascular endothelial health, as reected by
mid trimester blood pressure. Angiogenic imbalance
itself is determined by the relative proportions of several
angiogenic factors. Contrary to expectation, there was
no relationship between baseline blood pressure and
PlGF concentration after onset of preeclampsia. This
might have been due to the small sample size, laboratory
variability, or other unmeasured angiogenic factors.
Although by design all study subjects were normoten-
sive at CPEP enrollment, we suggest that increased
baseline blood pressure may reect subtle impairment
of endothelial health. If insulin resistance, inammatory
cytokines, hyperhomocysteinemia, dyslipidemia, or other
factors have damaged vascular endothelium and result in
Figure A, Scatter plot of ln sFlt1 (picograms per milliliter)
after the onset of preeclampsia and SBP (millimeters of mer-
cury) at CPEP enrollment (13-21 weeks of gestation). The
slope of the regression line is signicantly dierent from zero
(P ! .0001; R
2
, 0.33). B, Scatter plot of ln sFlt1 (picograms
per milliliter) after onset of preeclampsia and DBP (millimeters
of mercury) at CPEP enrollment (13-21 weeks of gestation).
The slope of the regression line is signicantly dierent from
zero (P = .014; R
2
, 0.15).
1038 Levine et al
small increases in blood pressure, lower levels of sFlt1 or
other antiangiogenic factors may be sucient to trigger
preeclampsia. Indeed, Yogev et al
15
have demonstrated
that the rate of preeclampsia is inuenced by the severity
of gestational diabetes mellitus, a condition that is associ-
ated with dysfunction of the vascular endothelium, and
that optimizing glucose control during pregnancy may
decrease the rate. Hyperglycemia is known to attenuate
endothelium-dependent vasodilation and to increase vas-
cular tone.
16-18
Moreover, both experimental and clinical
data suggest a synergistic interaction between insulin
resistance and endothelial dysfunction.
19,20
BMI was associated signicantly with blood pressure
at CPEP enrollment only among normotensive control
subjects. Although we believe that the consequences of
obesity are injurious to vascular endothelial cells, in
women who had preeclampsia BMI was not signi-
cantly related to either baseline blood pressure or to the
level of sFlt1 during preeclampsia. Nevertheless, we note
that the mean BMI was almost 2 units higher in the low
preeclampsia sFlt1 group (Table I) and that women who
were obese (sFlt1, 3821 pg/mL) or extremely obese
(sFlt1, 4194 pg/mL) had lower sFlt1 concentrations dur-
ing preeclampsia (Table II) than women who were of
normal weight or who were underweight (sFlt1, 5029
pg/mL). Although obesity is associated with factors
that may injure vascular endothelium, even among con-
trol subjects, where the relationship of BMI to baseline
SBP was highly statistically signicant, BMI accounted
for only 16% of the variance of SBP. We believe that,
in the preeclampsia cases, other factors that aect base-
line blood pressure and sFlt1 levels during preeclampsia
may have obscured the eects of BMI.
Many studies have documented the relationship of
blood pressure throughout pregnancy to the risk of
subsequent preeclampsia.
5-8,21-27
An elevation in blood
pressure may reect either subclinical preeclampsia be-
fore the onset of hypertension and proteinuria or rather
may be a marker for preeclampsia risk.
8
Supporting the
possibility that higher blood pressure indicates already
established disease is the fact that, in many instances
of women with preeclampsia, the transformation of
the uteroplacental arterial bed to a low-resistance, low-
pressure, high-ow system normally complete by 20
weeks of gestation does not occur.
7
Because a portion
of the reduction in blood pressure that occurs in preg-
nancy has been attributed to hemodynamic changes
which accompany remodeling of the uteroplacental arte-
rial bed, failure of uteroplacental arterial remodeling
might account for the increased blood pressure noted
long before the onset of hypertension and proteinuria
in women who have preeclampsia. In this study, women
with high preeclampsia sFlt1 concentrations did not
have increased blood pressure at 13 to 21 weeks of ges-
tation. This observation is dicult to reconcile with the
explanation given earlier, unless uteroplacental vascular
remodeling failed to occur only in women with low pre-
eclampsia sFlt1 concentrations or if elevated blood pres-
sure in women who were destined to have preeclampsia
were produced by an altogether dierent mechanism.
Moreover, Xiong et al
28,29
and others
30
have pointed
out that most women with preeclampsia are delivered
of infants of appropriate or even increased weight for
gestation, which suggests the presence of normal utero-
placental vasculature in most women with preeclampsia.
We believe that elevated mid trimester blood pressure
indicates an increased risk for preeclampsia because of
pre-existing endothelial cell damage. This increases
blood pressure and preeclampsia risk by reducing the
production of vasodilators and/or increasing production
of vasoconstrictors.
31
Women who have had preeclampsia may be at a
higher risk of the development of the metabolic syn-
drome
32
and subsequent cardiovascular disease.
33-35
This increased risk may not be due to the eects of pre-
eclampsia itself, but instead may reect the fact that
women with vascular risk factors are more likely to
have preeclampsia. If so, we speculate that the increased
risk of cardiovascular disease might be limited to the
subgroup of women with elevated mid trimester blood
pressure, who experience preeclampsia at low sFlt1
levels, because these are the women with impaired base-
line endothelial health.
In summary, SBP and DBP at 13 to 21 weeks of
gestation in women with high sFlt1 concentrations
during preeclampsia were identical to those of normo-
tensive control subjects. Mid trimester blood pressure
was elevated in the women with low preeclampsia sFlt1
concentrations. This suggests that, among the spectrum
of women who have preeclampsia, there are those
Table II Blood pressure at CPEP enrollment and angiogenic protein concentration during preeclampsia among women who were of
normal weight or who were underweight (BMI, !25 kg/m
2
), obese (BMI, R30 kg/m
2
), or extremely obese (BMI, R40 kg/m
2
)
Characteristic BMI, !25 kg/m
2
(n = 13) BMI, R30 kg/m
2
(n = 12) BMI, R40 kg/m
2
(n = 5)
SBP at enrollment (mm Hg) 110.8 G 8.1 108.3 G 11.4 112.2 G 10.9
DBP at enrollment (mm Hg) 62.2 G 9.8 61.8 G 7.2 64.0 G 5.1
sFlt1 during preeclampsia (pg/mL) 5029 G 1917 3821 G 1611 4194 G 1714
PlGF during preeclampsia (pg/mL) 127 G 65 124 G 99 93 G 41
sFlt1/PlGF during preeclampsia 55.4 G 47 51.9 G 53 71.9 G 77
Data are given as mean G SD; group comparisons were not statistically signicant.
Levine et al 1039
women with a healthy endothelium in whom preeclamp-
sia is almost entirely due to circulating placental factors
and who require high concentrations of sFlt1 to produce
disease and those women who are predisposed to vas-
cular disease who have preeclampsia subsequent to
exposure to released placental factors at modest con-
centrations. We believe that small elevations of blood
pressure during the early mid trimester may be the
consequence of underlying occult vascular damage. We
predict that preeclampsia may occur at even lower sFlt1
concentrations in women with pregestational hyperten-
sion or diabetes mellitus who clearly enter pregnancy
with pre-existing vascular disease.
36
These ndings also
raise the possibility that alterations in sFlt1 may be
more useful for the diagnosis and prediction of pree-
clampsia in women who lack the traditional risk factors
for the development of the disease.
Acknowledgments
We thank the CPEP Study group who assembled the
database and specimen repository that was used here
and the patients who took part in the study. The
following were members of the CPEP Study group:
University of Alabama at Birmingham: J. C. Hauth, R.
Goldenberg, B. S. Stofan; University of New Mexico at
Albuquerque: L. B. Curet, G. M. Joe, V. Dorato;
University of Tennessee at Memphis: B. M. Sibai, S. A.
Friedman, B. M. Mercer, T. Carr; Case Western Re-
serve University at MetroHealth Medical Center, Cleve-
land: P. M. Catalano, A. S. Petrulis, L. Barabach;
Oregon Health Sciences University, Portland: C. Mor-
ris, S.-L. Jacobson, K. McCracken; The EMMES Cor-
poration, Rockville: J. R. Esterlitz, M. G. Ewell, D. M.
Brown; National Institute for Child Health and Human
Development: R. J. Levine, R. DerSimonian, J. D.
Clemens, M. A. Klebano, E. G. Raymond, J. G.
Rigau-Perez, H. Shifrin; National Heart, Lung and
Blood Institute: J. A. Cutler, D. E. Bild; and the Data
Safety and Monitoring Board: M. Lindheimer, C. Begg,
T. Chalmers, M. Druzin, R. Sokol.
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