REVIEW

URRENT
C
OPINION

Pathogenesis of pregnancy complications in

systemic lupus erythematosus
Monika Ostensen a and Megan Clowse b

Purpose of review
In spite of the advances made in the management of pregnancies in women with systemic lupus
erythematosus (SLE), maternal complications and adverse fetal outcomes still exceed the rate of pregnancy
complications in the general population. An intriguing question relates to the observation that pregnancy
loss, intrauterine growth restriction (IUGR), preterm birth, and preeclampsia remain major complications in
SLE pregnancies, not substantially altered by improved therapy and monitoring.
Recent findings
From the review of the recent literature on the pathogenesis of pregnancy loss, IUGR, preeclampsia, and
prematurity, it appears that clinical or subclinical inflammation, presence of autoantibodies, hormonal
dysfunction, and immune alterations of lupus contribute to pregnancy complications. Impairment of early
placenta development leads to poor vascularization, resulting in placental ischemia and subsequent
endothelial damage. Depending on the extent of the pathological process, pregnancy loss, IUGR, and
preeclampsia can develop.
Summary
Early recognition of pregnancy complications is desirable in order to prevent their development or to
prompt intervention that improves the outcomes. Several biomarkers have been investigated for their ability
to predict complications at an early stage of pregnancy. However, up to date only lupus anticoagulant has
emerged as a consistent predictor for adverse pregnancy outcomes.
Keywords
intrauterine growth restriction, preeclampsia, pregnancy loss, prematurity, systemic lupus erythematosus

INTRODUCTION
In spite of substantially improved pregnancy outcomes in women with systemic lupus erythematosus (SLE) over the last 50 years, a significantly
increased rate of pregnancy loss and complications
remains. A population-based study [1] compared
maternal and pregnancy complications for all pregnancy-related admissions for childbirth of women
with and without SLE during the years 20002003.
A three-to-seven fold higher risk for maternal complications was found, as well as a two-to-three fold
increase in preeclampsia and preterm birth. Several
cohort studies [2,3] from the last 3 years have confirmed the increased risk for preeclampsia, preterm
birth, and intrauterine growth restriction (IUGR) in
SLE pregnancies exceeding the rate in the general
population two-to-six fold. A meta-analysis comprising 2751 pregnancies in patients with lupus
nephritis found adverse outcomes were significantly
related to active lupus nephritis, hypertension, and
presence of antiphospholipid antibodies (aPL) [4].
This survey analyzes the recent literature for new

insights in the pathogenesis of pregnancy loss,

IUGR, preeclampsia, and prematurity in lupus pregnancies. Studies which deal with predictors supporting risk stratification of pregnant patients were felt
to be of particular interest.

PATHOGENESIS OF PREGNANCY
COMPLICATIONS
Uterineplacental insufficiency, prompted by poor
vascularization, is a contributor to multiple pregnancy complications including pregnancy loss,
a
Department of Rheumatology, National Center of Pregnancy and Rheumatic Disease, University Hospital of Trondheim, Trondheim, Norway and
b
Division of Rheumatology, Department of Medicine, Duke University
Medical Center, Durham, North Carolina, USA

Correspondence to Professor Monika stensen, St Olavs Hospital,

Prinsesse Kristinas gt 1, N-7006 Trondheim, Norway. Tel: +47
90218687; e-mail: monika.ostensen@gmail.com
Curr Opin Rheumatol 2013, 25:591596
DOI:10.1097/BOR.0b013e328363ebf7

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Systemic lupus erythematosus and Sjogren syndrome

KEY POINTS
 An increase in miscarriage and fetal or perinatal
death leads to fewer children than expected women
with SLE.
 Placental insufficiency with poor vascularization is a
major cause of IUGR and early preeclampsia.
 Spontaneous preterm delivery relates to clinical and
subclinical inflammation and hormonal dysfunction
in SLE.
 The increased rate of induced preterm delivery reflects
the high rate of medical complications in women
with lupus.
 Except for lupus anticoagulant, few reliable biomarkers
for prediction of adverse pregnancy outcomes
have emerged.

IUGR, preterm labor, and early preeclampsia which

are increased in lupus pregnancies. Early in pregnancy, trophoblast cells from the placenta invade
into the wall of the uterus and transform the uterine
spiral arteries into wide, flaccid channels to promote
low-resistance blood flow to the placenta. If the
invasion of the placental cells is inadequate, then
the uterine spiral arteries may not enlarge properly,
leading to poor placental blood flow throughout
pregnancy. As pregnancy progresses, placental
ischemia may develop, resulting in poor oxygenation and deficient transport of nutrients to the
fetus [5,6]. Endothelial dysfunction and cell damage
ensue leading to the release of markers of endothelial damage into the maternal circulation. Endothelial factors may be tolerated in moderate doses
without developing preeclampsia (Fig. 1) [7]. At
higher levels and in women who are particularly
sensitive to them, however, preeclampsia can
develop [6].
Several studies [810] have indicated an imbalance of angiogenic and antiangiogenic factors in
pregnancies with IUGR and preeclampsia, with
formation of an antiangiogenic state in maternal
circulation and, to a lesser extent, umbilical vein
blood. In a study [9] comparing the serum concentrations of maternal and fetal angiogenic growth
factors in IUGR and normal pregnancy at the time
of delivery, soluble fms-like tyrosine kinase 1 (sFlt-1)
was increased, and placental growth factor (PlGF)
and soluble kinase domain receptor were decreased
in both maternal serum and serum from the umbilical vein. A study [10] of healthy pregnant women
found maternal plasma levels of vascular endothelial growth factor (VEGF) in early pregnancy
and PlGF levels at delivery positively, but sFlt-1/PlGF
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ratio at delivery negatively associated (P < 0.05) with

birth weight. Similarly, preeclampsia has been
associated with low levels of the angiogenic factors
VEGF and PlGF, and high levels of the antiangiogenic factor sFlt-1 and soluble Endoglin (sEng)
[6,11].

PREGNANCY LOSS
Modern multidisciplinary care has improved the
pregnancy outcomes in SLE patients but not eliminated the increased risk for miscarriage, fetal loss,
and perinatal death. A questionnaire-based study
[12 ] in women with rheumatoid arthritis and SLE
found that a majority of women with SLE had fewer
children than expected, with the rate of miscarriage
increased to 21.7%. A study [13] from Quebec, Canada, found the live-birth rate after a diagnosis of SLE
significantly lower than in the age-matched general
population. The decrease in live births correlated
with hospitalizations for SLE, but not with renal
disease or presence of antiphospholipid syndrome
(APS) [13].
A population-based cohort study [14 ] of
Australian women giving birth in New South Wales
from 2001 to 2009 identified 177 women with SLE
who had a first birth and a subsequent pregnancy.
Adverse outcomes were significantly more frequent
in SLE women than in women without SLE. The
perinatal death rate in SLE was 5.6% in the first
pregnancy, but only 0.6% in the second pregnancy.
Of the 167 women with live born first-birth infants,
second pregnancy outcomes included 11% miscarriages, 1 perinatal death, and 148 (89%) infants
discharged home. The study supports the beneficial
effect of close monitoring and therapy.
aPL including anticardiolipin antibodies (aCL),
lupus anticoagulant, and antib2GPI are present in
2555% of SLE patients, and 2025% of these
patients fulfill the criteria for APS [15]. Presence of
APS is one of the most important causes for pregnancy loss in women with SLE manifesting as recurrent miscarriage, fetal loss, or stillbirth [16]. The
study by Sciascia et al. [15] showed that the accuracy
of diagnosis of APS is increased by combining the
routine tests for aPL with new tests including
prothrombin (aPT) and the prothrombin/phosphatidylserine complex (aPS/PT). Furthermore, testing
for single, dual, or multiple positivity including
lupus anticoagulant plus anti-b2GPI plus aPS/PT
revealed that multiple positivity predicted pregnancy morbidity and thrombosis with an odds ratio
of 23.2. This is in contrast to a prospective study
[17 ] investigating serologic and clinical predictors
of adverse pregnancy outcomes in patients with aPL
with or without SLE. Among the 144 pregnant
&

&

&&

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Pathogenesis of pregnancy complications Ostensen and Clowse

Myometrium

Normal placentation

Abnormal placentation

Maternal
blood
flow

Maternal
blood flow

Decidua

FIGURE 1. Spiral artery remodeling in normal and abnormal placentation [7]. Early in pregnancy, trophoblast cells from the
placenta invade into the wall of the uterus and transform the uterine spiral arteries into wide, flaccid channels to promote lowresistance blood flow to the placenta. If the cell invasion is defective, poor placental blood flow may result in placental
ischemia with poor oxygenation and deficient transport of nutrients to the fetus. Associated endothelial dysfunction and cell
damage can contribute to the development of preeclampsia.

patients studied, 19% had adverse pregnancy outcome. Analysis of the aPL profile showed that 39% of
women positive for lupus anticoagulant had adverse
outcomes compared with 3% of those without lupus
anticoagulant [17 ]. Triple positivity for aCL, lupus
anticoagulant, and antib2GPI were not better predictors for adverse pregnancy outcome than lupus
anticoagulant alone. Selection of patients and
method of laboratory testing may account for the
differences in the two studies.
In women with SLE, stillbirth or neonatal
mortality may be caused by complete atrioventricular heart block (AVB), secondary to autoantibodies
to SSA/Ro or SSB/La. A study [18] of 18 children who
had died of anti-SSA/Ro-associated cardiac manifestations of neonatal lupus revealed 17 fetal deaths,
mostly in the third trimester. In the third trimester,
fetal deaths, valvular disease, and extensive conduction system abnormalities were the predominant
lesions observed.
In a retrospective study of 175 fetuses diagnosed
with AVB, fetal death occurred in 16 and neonatal
death in 10 cases. Predictors of fetal or neonatal loss
were diagnosis of AVB around gestational week 20,
ventricular rate 5059 bpm, and hydrops fetalis.
Intrauterine mortality rate was four times higher
in fetuses diagnosed with AVB before 20 weeks of
gestation compared with those diagnosed after
23 weeks. Fetuses with a ventricular rate of 50 bpm
had five times higher intrauterine mortality than
&&

those with a ventricular rate of 55 bpm. The presence of hydrops and impaired left ventricular function increased both intrauterine mortality and
neonatal mortality by a factor of 6 and 4, respectively [19]. Fetal or neonatal outcomes were not
influenced by treatment with betamethasone or
dexamethasone in fetuses with complete heart
block, but may be improved in fetuses found in
second-degree heart block [20]. Hydroxychloroquine therapy during pregnancy may be associated
with a decreased risk of neonatal heart block
[21 ,22].
&

INTRAUTERINE GROWTH RESTRICTION

IUGR, a decrease in fetal growth rate below the
genetic potential, is significantly increased in SLE
pregnancies ranging from 11 to 29%. The pathogenesis of IUGR in SLE is not clarified, but poor placental development [5] perhaps because of persistent
clinical or subclinical inflammation, the presence of
autoantibodies, or medications may be involved.
An epigenetic modification of gene expression in
placental tissue by disease-related factors could
be contributing.
An interesting observation in the context of
therapy of SLE is the influence of excess glucocorticosteroids on vascular resistance in the placenta and
on fetal growth [23]. Glucocorticosteroids are key
mediators of vascular resistance in the systemic

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Systemic lupus erythematosus and Sjogren syndrome

circulation. In a study [23] of placental resistance

arteries, chronic treatment with glucocorticosteroids was found to potentiate vasoconstriction,
thereby increasing the vascular resistance in the
placenta.
IUGR is associated with an increased risk for
perinatal morbidity and mortality, as well as
short-term and long-term neurological complications in the children [24]. Changes in cerebral
brain blood perfusion in IUGR fetuses have been
detected by Doppler ultrasound techniques [25].
IUGR plays a key role also in the development of
diseases later in life, such as type II diabetes, cardiovascular diseases, hypertension, and obesity [26].
IUGR is frequently triggered by poor placentation
and endothelial dysfunction. A shift from angiogenic
to antiangiogenic factors has been identified in such
pregnancies. In addition, an increase in circulating
mitochondrial DNA content in the mother was
associated with IUGR [5]. Extended studies are
necessary to test the validity of serum markers for
improved and more specific monitoring of pregnancies at risk for IUGR. Early diagnosis would be useful
in the detection of the optimal timing for delivery.
Indeed, changing from an unfavorable intrauterine
environment and implementing nutritional procedures may allow IUGR infants to decrease their risk
of developing the metabolic syndrome [5].

PRETERM BIRTH
The rate of preterm birth, defined as a delivery more
than 3 weeks prior to the due date (<37 weeks
gestation), is higher in women with lupus than in
healthy women. Although the rates vary in different
studies, a meta-analysis found the rate of preterm
birth was 39.4% in women with lupus [4]. The key
predictor of preterm birth is lupus activity during
pregnancy, with the rate increasing to two-thirds in
women with moderate-to-severe lupus activity
during this period [27]. Even women with quiescent
lupus prior to and during lupus, however, have a
higher rate of preterm delivery compared with
healthy women. Preterm delivery, even a few weeks
prior to term, is associated with delayed development and lung immaturity of the newborn as well as
poorer long-term outcomes for children [28]. Early
preterm birth (<30 weeks gestation) often leads to
prolonged hospitalization with multiple short-term
and long-term complications.
In discerning the cause of preterm birth, it is
important to distinguish between spontaneous preterm birth and induced preterm birth. In the general
population, about one-third of preterm deliveries
are medically induced, but in lupus pregnancies this
rate is likely higher because of the high rates of
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preeclampsia, placental insufficiency manifesting

as slow fetal growth, or lupus flares [29].
Lupus may trigger spontaneous preterm labor
through several possible routes. Activation of the
maternal or fetal hypothalamus pituitary axis by
stress leads to a rise in placental corticotropin-releasing hormone, and prompts labor through cortisol
and prostaglandin production [30 ]. The stress to
trigger preterm birth can be emotional, physiological, or from vascular insufficiency in the placenta.
Estrogens are produced in very high levels during
pregnancy by the placenta and poor placental development may be detected by lower than expected
estradiol levels. Having an unexpectedly low estradiol level at mid-pregnancy may be associated with
preterm birth in women with lupus [29].
Inflammation from local and systemic infections, and perhaps systemic rheumatologic disease,
can induce labor through cytokine, prostaglandin,
and complement activation [31]. Whereas it is difficult to measure inflammation with a sedimentation rate or C-reactive protein, both of which
can be artificially elevated during pregnancy, ferritin may be an acute-phase reactant that reflects
inflammation in pregnancy; an elevated ferritin
mid-pregnancy is associated with early delivery
[29,32]. Elevated antidsDNA and hypocomplementemia, particularly when coupled with active lupus,
are also associated with preterm birth [33]. Women
with lupus may have an increased rate of preterm
premature rupture of membranes and preterm labor
[34]. Finally, oral prednisone may be associated with
preterm birth, independently of the inflammation
that it is treating. It has been associated with preterm birth in APS, asthma, and lupus [35,36].
Many preterm deliveries are induced by medical
complications in women with lupus. Significant
lupus activity, prior and especially current lupus
nephritis, renal insufficiency, the lupus anticoagulant, hypertension, and corticosteroid use all increase
the risk for induced preterm delivery [17 ,27,37].
Progesterone supplementation has been shown
to decrease the risk of preterm birth in women with a
prior preterm birth. Progesterone both suppresses
uterine contractility and maintains immune modulation needed to protect against preterm delivery
[38]. It is not known whether women with lupus
could benefit from progesterone therapy during
pregnancy, but this is an intervention that deserves
future study.
&

&&

PREECLAMPSIA
Preeclampsia is a syndrome unique to pregnancy
that manifests with hypertension and proteinuria,
and resolves following delivery. It is most often
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Pathogenesis of pregnancy complications Ostensen and Clowse

classified as mild and occurs at term. Severe preeclampsia is marked by very high blood pressure
and proteinuria, as well as other manifestations,
including thrombocytopenia, hemolysis, renal insufficiency, and liver involvement. Preeclampsia can be
classified as early (<34 weeks gestation) and late
(>34 weeks gestation). Pathologic studies suggest
that early preeclampsia is associated with poor placentation, whereas later preeclampsia is more related
to maternal factors [6]. In the general population,
preeclampsia is seen in 35% of pregnancies with first
pregnancy, prior preeclampsia, maternal obesity, hypertension, twin pregnancies, African descent, and
older maternal age as clinical risk factors [6,39 ]. In
addition, diseases that promote endothelial dysfunction, including diabetes, renal disease, and lupus, all
increase the risk of preeclampsia. The frequency of
preeclampsia varies widely in lupus cohorts and can
be difficult to discern without detailed obstetrical
records. In addition, preeclampsia and lupus nephritis present very similarly, so distinguishing between
these two processes can be unreliable. Whereas a
meta-analysis of lupus pregnancy found a preeclampsia rate of 7.8%, other studies [4,40] suggest that it
can be twice as high, particularly in women with
nephritis.
Angiogenesis is key to proper placental development and markers of dysfunctional angiogenesis
have been associated with preeclampsia. Just as in
IUGR, placental endothelial dysfunction that can be
identified through maternal serum levels of VEGF,
PlGF, and sFlt-1 can be predictive of preeclampsia.
When a pregnant woman has lower than expected
levels of the proangiogenic factors VEGF and PlGF,
and high levels of the antiangiogenic factor sFlt-1
and soluble Endoglin (sEng), she is likely to develop
early preeclampsia [6,11]. These factors are likely
reflecting poor placental perfusion and impaired
angiogenesis in the rapidly growing placenta.
The role of uterine artery Doppler in predicting
preeclampsia is evolving. Increased vascular resistance in the uterine artery suggests poor uterine
perfusion and may be predictive of preeclampsia.
Placentas from pregnancies with high uterine artery
resistance on Doppler show deficient spiral artery
remodeling [41]. Pregnancies with increased placental resistance are at increased risk for early preeclampsia and IUGR, but it is not as predictive for
late preeclampsia.
Aspirin has been demonstrated through large
trials and meta-analyses to decrease the risk of preeclampsia and preterm birth in women at high risk
for these complications. Although studies of aspirin
in pregnancies in women with lupus have not been
conducted, we can likely extrapolate that there is a
benefit for this population, as well. Aspirin may
&

improve early placentation by modifying the ratio

of prostacyclin and thromboxane to promote
improved placental blood flow. This allows
improved placental invasion into the uterine wall
early in pregnancy. When started before 16 weeks
gestation, aspirin can lower the risk by 90% of
preterm preeclampsia, which is thought to be primarily caused by poor placentation. On the other
hand, aspirin may not have a significant impact
on preeclampsia at term, which is more related to
maternal factors than placental development [42].

CONCLUSION
The disease process of SLE with chronic inflammation, production of autoantibodies, and hormonal disturbances can exert adverse effects on
pregnancy outcome depending on the extent of
alterations present [43]. Prevention and early identification of placental dysfunction are the aims of
ongoing research; however, reliable predictors of
placental disorders early in pregnancy are still lacking. Therapeutic interventions for the prevention of
pregnancy complications are limited and need to
be studied.
Acknowledgements
None.
Conflicts of interest
Disclosure: M.. has received speaker fees from Mepha;
MSD; Pfizer; Roche; and UCB, Inc. M.C. is a consultant
for UCB, Inc.

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47:202209.

Volume 25  Number 5  September 2013

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