American Journal of Obstetrics and Gynecology (2006) 195, 40–9

www.ajog.org

Shared and disparate components of the pathophysiologies

of fetal growth restriction and preeclampsia
Roberta B. Ness, MD, MPH,a,* Baha M. Sibai, MDb

Department of Epidemiology, University of Pittsburgh,a Pittsburgh, PA; Department of Obstetrics and

Gynecology, University of Cincinnati,b Cincinnati, OH

Received for publication March 15, 2005; revised May 25, 2005; accepted July 13, 2005

KEY WORDS Intrauterine growth restriction (IUGR) and preeclampsia differ in their association with maternal
Preeclampsia disease but share a similar placental pathology. Moreover, mothers who have had pregnancies
Fetal growth complicated by preeclampsia or IUGR are at elevated later-life cardiovascular risk. Why, then,
retardation do some women develop IUGR and others develop preeclampsia? In this clinical opinion, based
Placenta on a review of the literature, we hypothesize that both women experiencing preeclampsia and
Metabolic syndrome x IUGR enter pregnancy with some degree of endothelial dysfunction, a lesion that predisposes to
Cytokines shallow placentation. In our opinion, preeclampsia develops when abnormal placentation,
through the mediator of elevated circulating cytokines, interacts with maternal metabolic
syndrome, comprised of adiposity, insulin resistance/hyperglycemia, hyperlipidemia, and
coagulopathy. IUGR develops in the absence of antenatal metabolic syndrome. Among these
women, the baby is affected by shallow placentation but the mother does not develop clinically
apparent disease. This conceptualization provides a testable framework for future etiologic
studies of preeclampsia and IUGR.
Ó 2006 Mosby, Inc. All rights reserved.

Intrauterine growth restriction (IUGR) and pree-
clampsia are pregnancy-specific disorders that have in
common abnormal placental implantation.1,2 Yet the
maternal manifestations of these 2 diseases are pro-
foundly different. Early onset preeclampsia is manifest
by maternal hypertension and proteinuria progressing to
a systemic hypoperfusion of multiple maternal organs,
and often accompanied by subnormal fetal growth3-4;
Funding by AI44151 and AI48909 from the NIAID; HD30367
from NICHD; and HS10592 from AHRQ.
* Reprint requests: Roberta B. Ness, University of Pittsburgh,
Graduate School of Public Health, Room A527, Crabtree Hall, 130
DeSoto Street, Pittsburgh, PA 15261.
E-mail: repro@pitt.edu
IUGR, always involving impairment of fetal growth,
has no appreciable clinical impact on the mother.5 Fetal
growth restriction appears to be accompanied by the
syndrome of preeclampsia when abnormal placentation
interacts with maternal constitutional factors.6 Specifi-
cally, many mothers who develop early onset preeclamp-
sia possess preexisting but subclinical risks for
cardiovascular disease (see details below).7 However,
recent reports show that women who have had an
IUGR baby also experience an elevated risk for later
life ischemic heart disease that is independent of pree-
clampsia and also independent of many potentially
confounding factors, including socioeconomic and be-
havioral factors.8-11 Furthermore, before and after preg-
nancy, women with growth-restricted babies (without

0002-9378/$ - see front matter Ó 2006 Mosby, Inc. All rights reserved.
doi:10.1016/j.ajog.2005.07.049
Ness and Sibai 41

preeclampsia) are more likely to experience elevated

blood pressure.12-14 These and other recent findings
suggest that maternal susceptibility to cardiovascular
risk is not unique to preeclamptic mothers with growth
restricted babies. Why, then, do women with IUGR not
develop preeclampsia?
In this review of existing literature, we hypothesize
that both IUGR and preeclampsia arise from a maternal
predisposition to endothelial dysfunction, which con-
tributes to shallow placental implantation and results in
later-life elevations in maternal cardiovascular disease.
During the affected pregnancy, our review of the liter-
ature documents a chain of pathophysiologic changes
arising from an endothelial-induced placental abnor-
mality. We posit that this involves release of placental
cytokines that interact with a maternal metabolic syn-
drome, elements of which include adiposity, insulin
resistance/hyperglycemia, hyperlipidemia, coagulopa-
thies, and maternal inflammatory mediators, to produce
the accelerated disease state of preeclampsia. Possibly,
infection may also accelerate cytokine release.15,16 Ab-
sence of maternal metabolic syndrome or other exoge-
nous inflammatory triggers, we hypothesize, precludes
the mother from developing appreciable maternal pa-
thology (Figure). This clinical opinion (the details of
which are presented in the sections to follow) extends
existing theories of the pathogenesis of preeclampsia4 by
suggesting a key role for maternal endothelial dysfunc-
tion, is coherent with emerging data on IUGR,8-11 and
provides a unifying pathophysiologic model for pree-
clampsia and IUGR.
From the outset, we note that this discussion focuses
on the specific subset of IUGR that derives from
placental/maternal causes and the subset of preeclamp-
sia that results in growth-restricted babies.17 This rep-
resents about three quarters of pregnancies complicated
by IUGR and many of the preeclamptic pregnancies
occurring early in gestation (eg, before 35 weeks).18
Evidence for endothelial dysfunction in
IUGR and preeclampsia
Preexisting conditions that often involve endothelial
dysfunction are common to IUGR and preeclampsia.
These include hypertension,19,20 renal disease, systemic
lupus erythematosus,21,22 and older age.23 The relation-
ships between these cardiovascular risk conditions and
preeclampsia or IUGR are generally strong (associations
often in the range of 2- to 8-fold); involve dose-response
relationships between severity of preexisting disease and
pregnancy-related risk; and demonstrate a temporality
whereby the cardiovascular risk conditions precede
pregnancy-specific disease.19-24 All of this suggests that
cardiovascular risk conditions that often involve
endothelial dysfunction predispose to IUGR/preeclamp-
sia.25,26 Further support for this view lies in the obser-
Figure Schematic of Proposed Pathogenesis of IUGR and
Preeclampsia.
vation that family history of hypertension, coronary
heart disease, and stroke elevates preeclampsia risk.27,28
During pregnancy, accelerated endothelial dysfunc-
tion is a central feature of both preeclampsia and IUGR.
Endothelial activators such as vascular cellular adhesion
molecule-1 (VCAM), intercellular adhesion molecule-1
(ICAM), endothelin-1, cellular fibronectin, and E-selectin
are elevated in the maternal serum and plasma of women
with both conditions,29-36 although activator levels in
preeclampsia exceed those observed in IUGR. Markers of
endothelial dysfunction are evident months before the
clinical recognition of preeclampsia.30 At 23 to 25 weeks
of pregnancy, both women with IUGR and preeclampsia
are more likely to demonstrate impaired uterine artery
Doppler waveforms37 and (compared with women with
normal uterine artery Doppler results) to experience
reduced flow mediated dilation of the brachial artery.26
The reductions in brachial artery dilation were greater for
women with preeclampsia than IUGR. This suggests that
endothelial dysfunction may precede both preeclampsia
and IUGR, albeit the degree of endothelial dysfunction
may be greater in preeclampsia.
Women with preeclampsia have demonstrable endo-
thelial dysfunction postpartum, as measured by nonin-
vasive plethysmography and ultrasound.38,39 Moreover,
the high prevalence of later hypertension and cardio-
vascular disease among women with previous preeclamp-
sia speaks to their tendency to ultimate endothelial
disease.8,40-44
Mothers who have had an IUGR baby also appear to
be at elevated risk for later ischemic heart disease. This
42
risk is independent of preeclampsia and also indepen-
dent of many potentially confounding factors, including
socioeconomic and behavioral factors.8-11 More specif-
ically, older women who report having had a growth-
restricted baby are more likely to demonstrate elevated
blood pressure and higher insulin resistance scores.14
Thus, in preeclampsia, and perhaps to a lesser degree
in IUGR, endothelial dysfunction–related conditions
precede affected pregnancies; markers of endothelial
dysfunction are apparent early in pregnancy; and hyper-
tension is more common after pregnancy. Although
other factors may contribute to the endothelial impair-
ment characteristic of pregnant women with both syn-
dromes, a component of endothelial dysfunction appears
to be of maternal origin and present before pregnancy.
Abnormal placentation in IUGR
and preeclampsia
Placentas from pregnancies complicated by IUGR and
preeclampsia have structural and cellular abnormalities
that are highly characteristic and similar, although
possibly distinguishable.1,36,45,46 The abnormal implan-
tation common to both conditions likely represents the
unsuccessful interaction between the cytotrophoblast of
the placenta and the spiral arteries of the mother,1 with
a contributor on the maternal side appearing to involve
endothelial dysfunction. The pathology of shallow im-
plantation is evident both in placental extravillous
trophoblasts and in maternal spiral arteries. Extravillous
trophoblast invasion into the spiral arteries is restricted
to the deciduas, and maternal spiral arteries fail to
become low resistance vessels.47-50
Although the aberrant placentation of IUGR/pree-
clampsia may involve many angiogenic and growth fac-
tors (eg, human placental lactogen),51,52 recent attention
has focused on placenta derived growth factor (PlGF), an
angiogenic protein predominantly expressed by tropho-
blasts and capable of forming powerful heterodiamers
with vascular endothelial growth factor (VEGF-1).53-57
PlGF is reduced and its receptor, soluble fms-like
tyrosine-kinase-1 (sFlt-1), increased in the placental tissue
and sera of some women with both IUGR and pree-
clampsia.58-65 PlGF alterations are of greater magnitude
in women with preeclampsia than in women with IUGR.
Low levels of PlGF in a subset of women with both
conditions can be demonstrated as early as the end of the
first trimester.58,60,61,64,65 This timing corresponds to
the occurrence of the second phase of placentation, that
is, the extension of trophoblasts into the myometrium,
which is thought to be defective in IUGR and pre-
eclampsia.
A key to the altered trophoblast maturation that
accompanies IUGR/preeclampsia may be hypoxia-
driven dysregulation of placental angiogenesis via the
transcription factor, hypoxia inducible factor (HIF).
Ness and Sibai
HIF is both influenced by proinflammatory cytokines
and alters the expression of cytokines, which, in turn,
modify trophoblast invasion.66-72 Hypoxia is held as a
central feature of both preeclampsia and IUGR.73-76
Low oxygen tension, reminiscent of the local environ-
ment to which trophoblasts are exposed before contact
with spiral arteries, has been demonstrated to inhibit
cytotrophoblasts from exhibiting the normally invasive
phenotype needed for deep implantation.77 Specifically,
the low levels of PlGF observed in IUGR/preeclampsia
can be explained by down-regulation by hypoxia.78
HIF-1, in response to hypoxia, induces the transcription
of a series of adaptive response genes, including gly-
colytic enzymes, inducible NO synthetase, and erythro-
poietin. It also powerfully influences production of
VEGF-family angiogenic factors, including PlGF.79-82
What evidence suggests that prepregnancy endothe-
lial dysfunction underlies hypoxia-induced shallow plac-
entation? Several animal models have been constructed
that produce preeclampsia-like syndromes via disrup-
tion of uterine, placental, or renal blood flow.83,84 These
provide extreme examples that disruption of blood flow,
and ultimately hypoxemia, can induce preeclampsia.
More directly, risk factors for IUGR/preeclampsia
include hypertension, systemic lupus erythematosus
(SLE), thrombophilias, and renal disease.19-21,23,24,85 In
all of these conditions, endothelial dysfunction is a
common feature. For example, renal microvascular
and tubular interstitial lesions (found almost universally
in individuals with essential hypertension, SLE, and
renal disease) result in activation of cyclooxygenase-2
(COX-2), the renin-angiotensin pathway, the sympa-
thetic nervous system, and oxidative stress, all of which
induce endothelial dysfunction.25 Finally, HIF-186 ap-
pears to require coregulation by hypoxia in combination
with cofactors such as proinflammatory cytokines.70
Cytokines, in turn, induce endothelial dysfunction (see
below).87-90 In fact, the interactions between hypoxia
and cytokines may constitute a feed-forward loop in
that cytokines up-regulate HIF-1 and hypoxia induces
cytokines. Low oxygen tension exposure of villous
explants results in elevated levels of the proinflamma-
tory cytokines tumor necrosis factor-alpha (TNF-a) and
interleukin-1 (IL-1).91 Infusion of angiotensin II and
resultant reduction in blood flow in isolated cotyledons
caused larger increases in TNF-a among placentas from
IUGR than from control pregnancies.92
Overall then, maternal endothelial dysfunction, al-
though not proven to cause shallow placental implan-
tation, has been indirectly linked to the placental
pathophysiology involved in IUGR/preeclampsia.
Inflammation and complicated pregnancies
Pregnancy is thought to be a proinflammatory state;
excessive inflammatory up-regulation is a characteristic
Ness and Sibai
of both preeclampsia and IUGR.93,94 C-reactive protein
and cytokine elevations have been reported in the first
and second trimesters among women bound to develop
both conditions, compared with controls in some,95-98
but not all99 studies, suggesting that proinflammatory
influences occur early.
In preeclampsia, granulocyte and monocyte subsets
are elevated. Circulating leukocytes exhibit an activated
phenotype with decreased expression of CD62L and
increased generation of reactive oxygen species.100
The products and regulators of activated inflammatory
cells, proinflammatory cytokines, and activated clotting
and complement pathways, circulate at elevated
levels.97,98,101-104 The placenta and decidua may be
involved in this inflammatory up-regulation; proinflam-
matory T lymphocyte (Th-1) cytokine TNF-a, IL-1, and
IL-2 production and expression can be localized to the
placenta or deciduas,105-110 whereas decreased placental
anti-inflammatory T lymphocyte (Th-2) cytokine pro-
duction (eg, IL-10 and 15) has been reported in some but
not all studies. Because one well-conducted study did not
find elevated cytokine expression in preeclamptic pla-
centas,101 it has been proposed that sources other than
the placenta may contribute to the elevated concentra-
tions of proinflammatory cytokines in preeclampsia.
Inflammation appears to trigger the signs of pree-
clampsia, as administration of endotoxin to pregnant
rats induces a preeclampsia-like syndrome characterized
by hypertension, proteinuria, and intravascular coagu-
lation.111 Moreover, various infections, which predict-
ably stimulate the maternal immune response, have been
linked to preeclampsia, including urinary tract infec-
tions, malaria, Chlamydia pneumoniae, and cytomegalo-
virus (CMV).15,112-119 Finally, suppression of immune
function was associated with markedly reduced rates of
preeclampsia among pregnant women with human im-
munodeficiency virus (HIV-1) infection who received no
antiretroviral therapy in one study.120
In IUGR, circulating neutrophils are also acti-
vated.121 However, inappropriate delays in spontaneous
neutrophil apopotosis, a marker of neutrophil activation
in inflammation, was not observed in the plasma of
women with IUGR, while it was observed among
women with early onset preeclampsia,122 suggesting
that the inflammatory state in IUGR may not be as
developed as that in preeclampsia. Particularly when
accompanied by reduced placental blood flow, growth-
retarded pregnancies demonstrated elevated serum and
placental levels of proinflammatory cytokines, including
IL-6, TNF-a, IL-1, and IL-8.92,94,104,123 Placental
mRNA for the Th-2 cytokine IL-10 was significantly
reduced among IUGR pregnancies.124 In IUGR pla-
centas, pathologic examination can show the chronic
inflammatory infiltrates of chorioamnionitis, identical to
that found in preterm deliveries and also in preeclamp-
sia.125 Also as in preeclampsia, infection has been linked
43
to IUGR. Specifically, malaria is associated with deliv-
ery of low-birth-weight infants and in malaria-infected
placentas, overexpression of TNF-a and IL-8 were
associated with IUGR.126,127 On the other hand,
IUGR has not been linked to evidence of past infection
with C. pneumoniae or CMV, as has preeclampsia.119
Proinflammatory, and particularly cytokine, altera-
tions in IUGR/preeclampsia convincingly demonstrate
that inflammation is a shared component of their path-
ophysiologies, although inflammation appears to be
more strongly dysregulated in preeclampsia than in
IUGR. Inflammatory up-regulation occurs relatively
early in pregnancy, may be of placental origin, and seems
to be positively influenced by restriction of placental
blood flow and/or hypoxia.
Divergence between preeclampsia and IUGR:
Antenatal metabolic syndrome
Thus far, preeclampsia and IUGR seem to be more
similar than dissimilar in their predispositions and
intrapartum pathophysiologies. At the same time, pre-
eclampsia is associated with a greater degree of endo-
thelial dysfunction and inflammation. Next, we will
review the literature that suggests that maternal adipos-
ity, insulin resistance, hyperlipidemia, and coagulation
factors play a larger role in preeclampsia than in IUGR.
We posit that the interaction of these metabolic factors
and inflammation feeds oxidative stress and disrupts
maternal endothelial function until the process crosses a
clinical threshold in the form of maternal organ hypo-
perfusion, a clinical characteristic of preeclampsia but
not of IUGR.
The normal physiologic response to pregnancy, in-
cluding a transient excursion into insulin resistance,
hyperlipidemia, and increased coagulation,128-130 is ac-
centuated in preeclampsia. Insulin resistance,131-133 hy-
perglycemia, and hyperlipidemia (including marked
elevations in free fatty acids and triglycerides) are all
evident. A shift toward the small dense low-density
lipoprotein (LDL) particles known to contribute to
oxidative stress35,134-137 is characteristic of the lipid
pattern of preeclampsia. Since adipose tissue is known
to mediate all of these metabolic changes, not surpris-
ingly, one of the strongest predictors of preeclampsia is
being overweight. Women with preeclampsia, compared
with normotensive pregnant women, are up to 5-fold
more likely to be overweight.138-143 In a large prospective,
population-based cohort of pregnant women, the 3000
women in the study with morbid obesity experienced
preeclampsia about 5 times more often than did the
normal weight women.144 Excessive waist circumference,
a marker of the biologically active abdominal fat that
induces insulin resistance but also elevates the risk for
metabolic syndrome independent of insulin resistance,145
was associated in 1 study with an almost 3-fold elevation
44
for developing preeclampsia.146 A biomarker for visceral
fat and insulin resistance, plasminogen activator inhibi-
tor (PAI), is elevated early in preeclampsia147,148 and is a
strong predictor for the development of the syndrome.147
Similarly, aberrancies in platelet function, coagulation,
and thrombotic factors, known to be influenced by
adiposity, are strongly associated with the development
of preeclamspia.149-151 Finally, obesity in pregnancy is
associated with impaired endothelial function, higher
blood pressure, and inflammatory up-regulation.152
Many elements of metabolic syndrome are evident
early in pregnancy among women, as a group, with
preeclampsia. For example, women bound to develop
preeclampsia, experience abnormally large declines in
high-density lipoprotein (HDL) and increases in mean
concentrations of the major free fatty acids (oleic, linoleic,
palmitic) by 20 weeks of gestation;135,136 elevations in
triglycerides are seen as early as 10 weeks of gestation.137
After preeclamptic pregnancies, metabolic syndrome
markers tend to remain elevated, as does cardiovascular
risk.8,42-44 Women with previous preeclampsia or ec-
lampsia seen 6 months’ to O20 years’ postpartum had
higher triglycerides, total cholesterol, LDL, apolipopro-
tein B, blood pressures, measures of insulin resistance,
and uric acid, as well as greater endothelial dysfunc-
tion.38,153-157 Women studied after preeclampsia also
had higher levels of 8-isoprostane, a marker of oxidative
stress, and plasma von Willebrand factor, a marker of
endothelial dysfunction. How these metabolic aberra-
tions translate into the syndrome of preeclampsia,
particularly through the mechanism of oxidative
stress,158 has been the topic of several excellent re-
views.159-161 Key to this pathophysiology may be lipid
dysregulation. The combination of insulin resistance
and hyperlipidemia, but not hyperglycemia alone, seems
to be a potent accelerator of atherosclerosis.162-164
Women with IUGR do not appear to have a preg-
nancy-specific predisposition to metabolic syndrome,
although this has not been well studied. None of the
lipoproteins, including cholesterol, triglycerides, HDL,
LDL, very-low-density lipoprotein (VLDL), or interme-
diate-density lipoprotein (IDL), appear to be elevated
antepartum in pregnancies complicated by IUGR.165
Indeed, these lipids are lower in women with pregnan-
cies complicated by IUGR. Unlike preeclampsia, which
is markedly more common in women with obesity, the
incidence of IUGR is predictably more common in
women of lower height, weight, and body mass index
(BMI).17,166,167 Furthermore, diabetes mellitus, charac-
terized by hyperglycemia and a major risk factor for
preeclampsia, is not associated with reduced fetal size.168
Indeed, diabetes mellitus is associated with macrosomia,
as is gestational diabetes.169,170 Older women who
report having had a low-birth-weight baby are more
likely to demonstrate elevated blood pressure and higher
insulin resistance scores.14 Possibly the blood pressure
Ness and Sibai
elevations, which existed before pregnancy, eventually
trigger insulin resistance that develops late in life. There
is little evidence for preconception insulin resistance
among women with IUGR.
Interactions between metabolic parameters and in-
flammation suggest a pattern of positive reinforcement.
IL-6, IL-8, and TNF-a are all overexpressed in insulin
resistant, compared with insulin sensitive, individuals.171
The converse, that IL-6 induces insulin resistance, has
also been shown in adipocyte cell lines.171 In pregnancy,
TNF-a predicts insulin resistance (with insulin resistance
defined using the sensitive glucose clamp method),
whereas cortisol and leptin are less predictive.172 All of
this suggests a mutual up-regulation between cytokines
and insulin resistance, an interaction that provides a well-
described feed-forward mechanism for dysregulation of
insulin action, lipid metabolism, inflammation, coagula-
tion, and endothelial dysfunction, perhaps through the
central mechanism of oxidative stress.128
This model, implicating metabolic syndrome as a key
link between abnormal placentation and the maternal
syndrome of preeclampsia, may help explain a long-
standing paradox: that tobacco is strongly related to
IUGR but inversely related to preeclampsia. Tobacco
smoking explains the largest component of risk for
IUGR and is related in a dose-response fashion to degree
of fetal growth impairment.173 In contrast, women who
smoke tobacco have consistently been observed to be at
reduced risk for preeclampsia.174 Metabolic products of
cigarette smoke cause marked endothelial dysfunction
and cytokine elevation.175 The relatively rare group of
smokers who have concomitant metabolic syndrome may
be at elevated risk for developing fulminate preeclamp-
sia.174 At the same time, tobacco smokers in general tend
not to be overweight, and so are probably relatively
protected from metabolic syndrome and thus from the
development of preeclampsia.
Synopsis and recommendations for
additional research
From this summary of relevant research, a parsimonious
hypothesis emerges, the outline of which is in agreement
with the previous theory that maternal-fetal interaction
is involved in preeclampsia. Here we propose that both
IUGR and preeclampsia share a complex placental
pathophysiology but differentially interact with the
metabolic syndrome. Devotees of the preeclampsia and
IUGR literature will note the lack of discussion of a
number of other well-studied players, such as homocys-
teine, uric acid, ferritin, angiogensin/angiotensinogen,
neurokinin B, growth factors, and others. These are
important downstream effects or interacting factors and
beyond the scope of the simplified model presented here.
Although some of the biology discussed is relatively
well understood, much is not. Areas which warrant
Ness and Sibai
further research include studies examining the tissue of
production, regulators of and effects of the elevated
cytokine levels observed in IUGR and preeclampsia;
clarification of the divergent effects of cigarette smoking
on preeclampsia versus IUGR; and the cardiovascular
disease risk profile some years after women have had a
growth-restricted baby, to name a few. Clearly, much
additional research is needed to either elaborate on or
further modify the proposed theory.
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