Research www. AJOG.

org

OBSTETRICS
Maternal C-reactive protein and developmental
programming of atherosclerosis
Antonio Liguori, MD; Francesco P. D’Armiento, MD; Antonio Palagiano, MD; Wulf Palinski, MD; Claudio Napoli, MD, PhD

OBJECTIVE: Maternal hypercholesterolemia during pregnancy en-
hances the susceptibility to atherosclerosis in their offspring by
oxidation-dependent mechanisms. The present study investigated
whether maternal C-reactive protein (CRP) level, which is an indi-
cator of inflammation and cardiovascular risk, or smoking, which
enhances oxidative stress, predict the in utero programming of
atherosclerosis.
STUDY DESIGN: Subsets of patients from the Fate of Early Lesions in
Childhood study (156 normocholesterolemic children) were examined
at autopsy, classified by maternal cholesterol levels during pregnancy.
Maternal CRP level was correlated with maternal cholesterol and aortic
atherosclerosis of children.
RESULTS: CRP level was elevated in hypercholesterolemic mothers
and showed significant correlation with atherogenesis in children in
univariate and multivariate analysis. However, many hypercholester-
olemic mothers did not have elevated CRP levels. Smoking only cor-
related in univariate analysis.
CONCLUSION: CRP level during pregnancy is a predictor of increased
atherogenesis in children of hypercholesterolemic mothers, albeit a weaker
one than maternal cholesterol. In the presence of hypercholesterolemia,
maternal smoking does not further enhance atherogenic programming.
Key words: atherosclerosis, CRP, developmental programming,
inflammation, maternal hypercholesterolemia, oxidative stress

Cite this article as: Liguori A, D’Armiento FP, Palagiano A, Palinski W, Napoli C. Maternal C-reactive protein and developmental programming of
atherosclerosis. Am J Obstet Gynecol 2008;198:281.e1-281.e5.

E xtensive epidemiologic evidence

suggests that in utero conditions in-
fluence the susceptibility to hyperten- cific maternal conditions have been
early atherosclerotic lesions (fatty
streaks) in human fetal aortas,5 and stud-
ies in experimental models with diet-in-
sion, diabetes mellitus, and cardiovascu- identified that program increased sus- duced hypercholesterolemia showed
lar disease later in life.1,2 Although most ceptibility to atherosclerosis in adult off- that the size of these lesions at birth is
epidemiologic studies have focused on spring. One such condition is maternal proportional to the maternal cholesterol
outcome parameters of impaired intra- hypercholesterolemia.3,4 Both tempo- level.6,7 The first indication that maternal
uterine growth (such as small birth- rary hypercholesterolemia during preg- hypercholesterolemia also influences the
weight, which may result from a range of nancy and chronic maternal hypercho- postnatal susceptibility to atherosclerosis
pathogenetically distinct causes), spe- lesterolemia enhance the formation of was provided by the Fate of Early Lesions
in Childhood (FELIC) study, which was an
autopsy study in normocholesterolemic
From the Regional Hospital of Pellegrini and Loreto Crispi Hospital (Dr Liguori); the children.8 Although fetal fatty streaks may
Division of Human Pathology (Dr D’Armiento), 2nd School of Medicine, Federico II
regress partially in the perinatal period,
University; the Division of Obstetrics and Gynecology (Dr Palagiano) and the Division of
Clinical Pathology (Professor Napoli), Department of General Pathology and Excellence
when cholesterol levels are very low, chil-
Research Center on Cardiovascular Diseases, 1st School of Medicine, II University of dren of hypercholesterolemic mothers
Naples, Naples, Italy; and the Department of Medicine (Dr Palinski), University of showed accelerated progression of athero-
California, San Diego, School of Medicine, La Jolla, CA. sclerosis in the aortic arch and abdominal
This study was supported by grants from the Regione Campania and Ministery of University and aorta that could not be explained by con-
Research P.R.I.N. 2006 (C. N.) and National Institutes of Health grants HL067792 and HL56989 ventional risk factors. Although the mech-
(C. N. and W.P.). anisms of in utero programming remain
Received April 26, 2007; accepted Nov. 14, 2007. largely unknown, there is a strong ratio-
Reprints: Prof Claudio Napoli, Department of General Pathology, Division of Clinical Pathology nale to suspect the involvement of inflam-
and Excellence Research Center on Cardiovascular Diseases, 1st School of Medicine, II matory processes that are analogous to
University of Naples, Complesso S. Andrea delle Dame 80138 Naples, Italy.
those promoting atherosclerosis in adults.9
claudio.napoli@unina2.it.
Indeed, plasma and arteries of human and
0002-9378/$34.00 • © 2008 Mosby, Inc. All rights reserved. • doi: 10.1016/j.ajog.2007.11.027
animal offspring of hypercholesterolemic
mothers contain high levels of proinflam-
For Editors’ Commentary, see Table of Contents matory lipid peroxidation products.5-8
Conversely, maternal treatment with an

MARCH 2008 American Journal of Obstetrics & Gynecology 281.e1

Research Obstetrics www.AJOG.org

mine lipid parameters and atheroscle-

FIGURE 1
rosis in children has been published.8
CRP levels are significantly greater in the hypercholesterolemic In brief, 156 normocholesterolemic
than in the normocholesterolemic, group of mothers
children, ages 1-14 years, who died of
acute, mostly traumatic, causes and
underwent medicolegal autopsy were
classified into 2 groups, depending ex-
clusively on their mothers’ cholesterol
levels during pregnancy. The latter
were the mean of 3-4 prenatal exami-
nations that were obtained from the
medical records. Total cholesterol had
been determined routinely in all ma-
ternal subjects but not at identical time
points and not by the same laboratory.
Given that the use of mean cholesterol
values compensates for some of this
temporal variability and that they were
also used in the FELIC study, we used
them for all present statistical analysis,
except for the assessment of the corre-
lation between CRP and cholesterol
levels, for which cholesterol data from
the same time point as CRP were used.
Exclusion criteria were preeclampsia,
acute infections, or intrauterine infec-
tions during pregnancy, as far as noted
in medical records. In the FELIC study,
Note that the maternal classification in the FELIC study was based on the average of 3-4 cholesterol maternal records that contain reliable
determinations throughout pregnancy, whereas the total cholesterol data shown here represent cholesterol data could be obtained
corresponding measurements that were obtained during a single prenatal examination. Data from 97 hypercholesterolemic and 59
represent all normo- and hypercholesterolemic mothers (n ⫽ 51 and 87, respectively) for whom age-matched normocholesterolemic
both CRP and cholesterol data were available. mothers. The extent of atherosclerosis
Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.
in all 156 children was determined by
computer-assisted morphometry in 30
antioxidant, vitamin E, prevents athero- humans has not been established. For cross-sections each through the aortic
genic in utero programming.7,10 example, CRP modulates complement arch and abdominal aorta. Maternal
C-reactive protein (CRP), a nonspe- activation,18-20 enhances endothelial in- CRP level and smoking during preg-
cific acute-phase reactant and down- flammation and expression of angioten- nancy (yes/no) were obtained newly
stream biomarker of proinflammatory sin 1 receptors,21,22 and promotes apo- from medical records. However, CRP
cytokines, has gained much attention as ptosis of vascular smooth muscle cells.23 data were far less complete than cho-
a surrogate measure of the inflammation We therefore used specimen and data lesterol data. We therefore chose a sin-
and shows greater predictive power for from the FELIC study to investigate gle time point at which CRP data were
cardiovascular disease than conven- whether maternal CRP level also predicts available for the greatest number of
tional lipid parameters, such as total and developmental programming of athero- subjects and used this for all analyses.
low-density lipoprotein cholesterol or sclerosis in the children. The aim of this Concentrations of CRP in plasma sam-
the low-density lipoprotein/high-den- study was to determine whether mater- ples were obtained with a validated
sity lipoprotein ratio.11-15 CRP level also nal CRP level or smoking were associated high-sensitivity immunoturbidimetric
reflects the rapid changes in plasma cho- with atherosclerosis in the infant. assay on the Hitachi 911 analyzer
lesterol that are achieved by statin treat- (Roche Diagnostics GMBH; Penzburg,
ment16,17 and thus presumably the Germany) with the use of reagents and
reduced pathogenic effects of hypercho- M ATERIALS AND M ETHODS calibrators from Denka Seiken (Ni-
lesterolemia and ensuing oxidative Subjects and study design igata, Japan). Overall, the interassay
stress. Direct pathogenic effects of CRP A detailed description of the design of coefficients of variability at concentra-
on proatherogenic mechanisms have the FELIC study, patient population, tions of 0.90, 3.05, and 13.45 mg/L
also been reported, but their influence in and methods that were used to deter- were 2.78%, 1.56%, and 1.05%, respec-

281.e2 American Journal of Obstetrics & Gynecology MARCH 2008

www. AJOG.org
FIGURE 2
Maternal plasma cholesterol
level correlates with maternal
CRP level during pregnancy
Data represent all mothers for whom both data
were available at the same time point (n ⫽ 89).
In contrast to all other analyses, cholesterol
levels that were obtained at the same time point
as CRP level were used instead of mean cho-
lesterol levels.
Liguori. Maternal CRP and atherosclerosis. Am J Obstet
Gynecol 2008.
tively. This assay had a sensitivity of
0.025 mg/L.
We initially compared CRP levels be-
tween the 2 maternal groups defined in
the Lancet study. For further analyses (in
FIGURE 3
Atherosclerosis progresses
much faster in children
of mothers who were
hypercholesterolemic
during pregnancy
Examples shown are the cumulative areas of
atherosclerotic lesions in 30 cross-sections
through the aortic arch (n ⫽ 97 and 59 for
children of hyper- and normocholesterolemic
mothers, respectively).8
Liguori. Maternal CRP and atherosclerosis. Am J Obstet
Gynecol 2008.
particular, multiple regression analysis
of the correlation between maternal CRP
level, smoking, and total cholesterol with
offspring atherosclerosis), data from
both groups were combined and ana-
lyzed together, and actual maternal cho-
lesterol levels were used. Case numbers
for each analysis vary, because not all
maternal records contained all of the pa-
rameters that were assessed.
Statistical analysis
Maternal total cholesterol and CRP lev-
els were compared by unpaired t test and
linear correlation. The cumulative lesion
areas in the aortic arch and abdominal
aorta are correlated highly and were con-
densed into a single parameter, with the
use of principal-components analysis of
log-transformed lesion sizes. The first
principal component accounted for
more than 98.5% of the variation of the
data (Eigen value, 1.97). We then per-
formed multiple stepwise linear regres-
sion analysis with maternal risk factors,
using pooled data from children of both
normocholesterolemic and hypercho-
lesterolemic mothers. The criteria to be
entered into the stepwise model were an
enter value of 0.05 and an elimination
value of 0.10. From the resultant model,
we tested individual covariates with
Bonferroni-adjusted criteria for signifi-
cance. P ⬍ .05 was considered signifi-
cant. All statistical evaluations were per-
formed with SPSS statistical software (v
13; SPSS Inc, Chicago, IL). Data are re-
ported as means ⫾ SEM.
The FELIC study and its present ex-
tension were approved by the human
ethics committee of the University of
Naples and the University of California,
San Diego. Informed consent was ob-
tained from all participating mothers.
R ESULTS
By definition, maternal cholesterol levels
in the second to third trimester of preg-
nancy were significantly greater in the
hypercholesterolemic than the normo-
cholesterolemic maternal group (194.9
⫾ 2.9 mg/dL vs 279.9 ⫾ 3.4 mg/dL; P ⬍
.000001). Maternal CRP levels were also
much greater in hypercholesterolemic
mothers (6.93 ⫾ 0.36 mg/dL vs 4.68 ⫾
MARCH 2008 American Journal of Obstetrics & Gynecology
Obstetrics Research
0.14 mg/dL; P ⬍ .000001; Figure 1). In-
terestingly, less than one-half of the hy-
percholesterolemic mothers had sub-
stantially elevated CRP levels (⬎ 8
mg/dL).
The correlation between maternal
CRP and plasma cholesterol levels in a
subset of mothers (n ⫽ 89) for which
both values could be obtained from
medical records of the same prenatal ex-
amination is shown in Figure 2. The per-
centage of mothers who smoked during
pregnancy was much greater in the hy-
percholesterolemic group than in the
normocholesterolemic group (58.6% vs
38.5%), whereas the average number of
cigarettes per day per smoker was simi-
lar. CRP also correlated significantly
with maternal smoking in univariate
analysis (R2 ⫽ 0.223; P ⬍ .0005). When
CRP level was used as a dependable pa-
rameter in multivariate analysis, both
maternal plasma cholesterol level and
smoking remained significant (R2 ⫽
0.408; P ⬍ .0005; standardized beta val-
ues 0.468 and 0.370, respectively).
The FELIC study had indicated a
strong correlation of atherosclerosis
with age (Figure 3), which must be kept
in mind when assessing correlations of
maternal factors with non–age-cor-
rected atherosclerosis data, such as the
composite measure of atherosclerosis in
the arch and abdominal aorta of chil-
dren. Nevertheless, in addition to factors
previously established as significant (ie,
the age of the child [R2 ⫽ 0.536; P ⬍
.0005], the maternal group [R2 ⫽ 0.368;
P ⬍ .0005], and maternal cholesterol
level [R2 ⫽ 0.343; P ⬍ .0005]), maternal
CRP level (R2 ⫽ 0.173; P ⬍ .0005; Figure
4) and maternal smoking (R2 ⫽ 0.084; P
⬍ .001) showed significant correlation
with offspring atherosclerosis in univar-
iate analysis.
Significant parameters (child age, ma-
ternal total cholesterol, CRP, and smok-
ing) were then included in a stepwise
multiple regression analysis. Note that,
in contrast to the FELIC study, we used
the single maternal cholesterol value that
was measured at the same time as CRP
level, instead of the (highly correlated)
maternal group, which was defined by
the average maternal cholesterol level
during multiple prenatal examinations.
281.e3
Research Obstetrics www.AJOG.org

dicted 68% of the atherosclerosis (P ⬍ atherogenesis in children, both in uni-

FIGURE 4
.0005). variate and multiple regression analysis.
Maternal CRP level correlates
However, CRP level was a lesser indica-
with atherosclerosis
in the child C OMMENT tor of atherogenic programming than
Evidence from both human studies and maternal cholesterol level. A low beta
experimental models indicates that ma- factor of maternal CRP also makes it un-
ternal hypercholesterolemia programs likely that the postulated atherogenic ef-
increased susceptibility to atherosclero- fects of CRP contribute substantially to
sis later in life.5,7,8,24-27 Unfortunately, in utero programming. It is tempting to
maternal hypercholesterolemia is not conclude that CRP level merely reflects
determined routinely during pregnancy the inflammation that is concomitant
in most Western countries, with the no- with hypercholesterolemia. On the other
table exception of Italy, where it is part of hand, elevated CRP level is not specific
the standard clinical laboratory tests that for atherosclerosis, and CRP levels may
are performed during prenatal examina- be confounded by a number of unrelated
Atherosclerosis that is indicated as the log- tions.28 Although the mechanisms of conditions, such as maternal infections,
transformed first component was determined developmental programming remain that may not affect in utero program-
from mean cross-sectional lesion areas that largely unknown, they are clearly depen- ming. Elevated CRP levels may be a ret-
were measured in the aortic arch and abdominal dent on oxidative stress, which is raised rospective indicator of postnatal athero-
aorta. Note that atherosclerosis was not cor- both by maternal hypercholesterolemia genic risk, where cholesterol levels were
rected for the age of the children and therefore and smoking.3,5-7,10,29-33 Oxidative not determined, and may prompt cho-
shows considerable variability. Data reflect all stress affects the expression of many
mother/child pairs for whom maternal CRP level
lesterol determination, if detected before
genes that influence recruitment, differ-
was known (n ⫽ 136). or during pregnancy.
entiation, and secretory activity of mac-
Liguori. Maternal CRP and atherosclerosis. Am J Obstet Maternal smoking, which may induce
Gynecol 2008.
rophages and T cells; conversely,
atherogenic programming in normo-
increased inflammation promotes oxi-
cholesterolemic animals,30 also corre-
dative stress. It was tempting therefore to
As shown in the Table, CRP level re- assume that, in the absence of cholesterol lated with atherosclerosis in children but
mained significant in the multiple re- data, elevated maternal levels of CRP, lost significance when assessed together
gression analysis but showed a low beta which is a marker of inflammation, with maternal hypercholesterolemia.
factor. Smoking was not significant. Al- might be a surrogate indicator of the ath- This suggests that oxidative stress– ensu-
though maternal cholesterol level had a erosclerosis risk of children. The present ing hypercholesterolemia by itself is
higher correlation than CRP level for results indeed establish that maternal more than enough to trigger atherogenic
childhood atherosclerosis, when choles- CRP level that is measured during the programming in the fetus and that
terol was removed from the multiple re- late second/early third trimester is ele- smoking does not further enhance it suf-
gression analysis, the age of the child and vated in hypercholesterolemic mothers ficiently to become an independent
maternal CRP level together still pre- and that it correlates with the extent of predictor.

TABLE
Stepwise linear regression analysis with the use of a composite measure of atherosclerosis
in the aortic arch and abdominal aorta as outcome parameter and factors
that were correlated significantly with it in univariate analysis as predictors
Standard error of Significance of Standardized Significance
Model R2 the estimate modela coefficient (beta) of covariatea
1. Age of child 0.489 0.688 .0005 0.699 .0005
................................................................................................................................................................................................................................................................................................................................................................................
2. Age of child 0.872 0.343 .0005 0.732 .0005
................................................................................................................................................................................................................................................................................................................................................................................
Maternal cholesterol 0.622 .0005
................................................................................................................................................................................................................................................................................................................................................................................
3. Age of child 0.884 0.331 .0005 0.740 .0005
................................................................................................................................................................................................................................................................................................................................................................................
Maternal cholesterol 0.562 .0005
................................................................................................................................................................................................................................................................................................................................................................................
Maternal CRP 0.116 .009
................................................................................................................................................................................................................................................................................................................................................................................
Maternal cholesterol level, age of child, and atherosclerosis, 156 patients; maternal smoking, 154 patients; maternal CRP level, 136 patients.
a
Probability value.
Liguori. Maternal CRP and atherosclerosis. Am J Obstet Gynecol 2008.

281.e4 American Journal of Obstetrics & Gynecology MARCH 2008

www.AJOG.org
Limitations include the retrospective
nature of the FELIC study and the ensu-
ing need to rely on medical records for
maternal data during pregnancy. The
fact that these data were generated by a
number of different clinical laboratories
over a 14-year period may have increased
variability. The retrospective nature of
the study also made it impossible to sup-
plement maternal data during preg-
nancy by measurements of other li-
poproteins, in particular high-density
lipoprotein, parameters of oxidative
stress (to validate smoking history), and
other parameters of inflammation, such
as isoprostanes or antibody titers to oxi-
dation-specific epitopes. In particular,
uterine infections or general infections
and other conditions that raise CRP level
may not have been documented in
maternal medical records, and their con-
founding effect may have been underes-
timated. Furthermore, not all parame-
ters were available in all of the 156
mothers and their children, which re-
duced the power of the analysis. Finally,
the incidence of other maternal condi-
tions that potentially affect oxidative
stress, such as maternal diabetes melli-
tus, was too low to yield reliable data for
CRP. Ideally, the association of maternal
risk factors with atherogenic program-
ming and coronary heart disease should
be assessed in prospective studies, but
such studies would have to be very large
and span at least 4 decades for cardiovas-
cular outcomes (lesser periods, if surro-
gate measures of atherosclerosis are
considered). f J Med 2002;347:1557-65.
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281.e5