You are on page 1of 13

Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

Contents lists available at ScienceDirect

Best Practice & Research Clinical

Obstetrics and Gynaecology
journal homepage:

Autoimmune connective tissue diseases

Monika Østensen, MD, PhD, Professor of Rheumatology a, *,
Irene Cetin, MD, PhD, Professor of Obstetrics and Gynecology b
Norwegian National Advisory Unit on Pregnancy and Rheumatic Diseases, St. Olavs Hospital e Trondheim
University Hospital, Norway
Unit of Obstetrics and Gynecology, Dept of Biomedical and Clinical Sciences L. Sacco and Center for Fetal
Research Giorgio Pardi, University of Milan, Via G.B. Grassi 74, 20157 Milan, Italy

Rheumatic diseases (RDs) occur preferentially in women, often

during the childbearing age. The interaction of pregnancy and the
rheumatic disease
pregnancy complications RD is varied, ranging from spontaneous improvement to aggra-
adverse pregnancy outcomes vation of disease symptoms or life-threatening flares. Risks for the
pathophysiology mother with RD and the child differ in regard to the presence of
management of pregnancy organ manifestations, organ damage, disease activity, presence of
specific autoantibodies, and therapy. Pregnancy complications
comprise hypertension, preeclampsia, premature delivery, and
side effects of therapy. Adverse pregnancy outcomes include
recurrent miscarriage, intrauterine growth restriction, and fetal
demise, and they are frequently encountered in RD with organ
manifestations and harmful autoantibodies. Because of the differ-
ence in the prevalence of RDs, knowledge on the gestational course
of disease and pregnancy outcome is limited to the fairly common
RDs such as rheumatoid arthritis, systemic lupus erythematosus,
and antiphospholipid syndrome. Pregnancies in RD are connected
with increased risks for mother and child and need interdisci-
plinary care and management.
© 2015 Elsevier Ltd. All rights reserved.

* Corresponding author. Norwegian National Advisory Unit on Pregnancy and Rheumatic Diseases, St. Olavs Hospital e
Trondheim University Hospital, Olav Kyrres gt 13, N-7006, Trondheim, Norway. Tel.: þ47 90218687.
E-mail address: (M. Østensen).
1521-6934/© 2015 Elsevier Ltd. All rights reserved.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
2 M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13


Rheumatic diseases (RDs) differ markedly in regard to maternal and fetal risks during pregnancy.
Important factors associated with risk are the type of disease, disease activity at conception and during
pregnancy, organ involvement, presence of autoantibodies, comorbidities, and therapy. As a general
rule, the extent of the immuno-inflammatory process; the involvement of vital internal organs such as
kidney, lung, and heart; and immunosuppressive therapy contribute to pregnancy complications and
adverse outcomes. The physiological adaption of the body to pregnancy can aggravate or unmask organ
dysfunction already present in the mother.
Diseases with no or few organ manifestations and predominant joint involvement are the ones
that carry few risks of pregnancy complications and child outcome [1]. Rheumatoid arthritis (RA),
juvenile idiopathic arthritis (JIA), and the spondyloarthritides (SpA) belong to the group with few
organ manifestations (Table 1) [2]. By contrast, the connective tissue diseases (CTDs), systemic
lupus erythematosus (SLE), antiphospholipid syndrome (APS), systemic sclerosis (SSc), inflamma-
tory myopathies, and vasculitis are associated with multiple autoantibodies, multiorgan involve-
ment, and more aggressive therapy (Table 1). The risk of adverse pregnancy outcomes is
significantly increased in these more severe CTDs [3]. B cell hyperactivity with abundant production
of autoantibodies is seldom found in the diseases characterized predominantly by joint inflam-
mation, but is a hallmark of SLE, SSc, and vasculitis. Autoantibodies such as antiphospholipid (aPL)
antibodies and anti-Ro and anti-La can exert negative effects on pregnancy outcome and child
health [4].
Another difference among RDs is the propensity to flare during pregnancy. Two types of flares
have to be considered: an aggravation of joint inflammation (arthritis) and a relapse or new onset
of inflammation in internal organs. Aggravation of arthritis is a frequent problem in RA, JIA, and

Table 1
Autoantibodies (only those routinely tested for are presented) and organ manifestations frequently present in different rheu-
matic diseases.

Disease Autoantibodies Frequent extra-articular

organ involvement

Rheumatoid arthritis Rheumatoid factor (RF), Present in about 30% of patients:

citrullinated protein antibodies, lung, heart, serositis, vasculature
antiphospholipid antibodies
Ankylosing spondylitis Nonea Uveitis
Psoriatic arthritis Nonea Skin psoriasis
Juvenile idiopathic arthritis RF and antinuclear antibodies in Uveitis, systemic features in
some subgroups Morbus Still
Sjogren's syndrome ANA, RF, anti-Ro, anti-La Xerophthalmia, xerostomia,
parotid gland enlargement, lung,
kidney, gastrointestinal tract,
Antiphospholipid syndrome anti-cardiolipin antibodies, Skin, vasculature, lung, heart,
b2-glycoprotein I antibodies, kidney, CNS, placenta
lupus anticoagulant
Systemic lupus erythematosus ANA, anti-dsDNA, anti-Smith, CNS, skin, lung, heart, kidney,
anti-ribonucleoprotein (RNP), vasculature, muscles,
anti-Ro, anti-La, anti-phospholipid hematopoietic system
Systemic sclerosis (diffuse and limited form) ANA, Scl 70, anti-centromer Skin, gastrointestinal tract, lung,
antibodies, RNA polymerase heart, kidney, vasculature
types II and III,
Vasculitis (granulomatosis with polyangiitis Anti-neutrophil cytoplasmic Vasculature, upper airways, skin,
(Wegener), eosinophilic granulomatosis with antibodies (ANCAs) lungs, kidney, peripheral nervous
polyangiitis (ChurgeStrauss syndrome), system, eye, CNS
microscopic polyangiitis
Autoantibodies can occur in 1e5% of the patients, but are not a characteristic of the disease.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13 3

SpA, and the second is a serious complication of SLE, APS, SSc, and vasculitis [1,5]. Inflammation in
only one, few, or in multiple joints creates pain, stiffness, and impaired function, but can be
experienced as more disabling than a silent organ manifestation [6]. The burden of systemic
inflammation depends on the extent of arthritis or of the number of organs involved. Both acute
arthritis and inflammation in internal organs during pregnancy require treatment, although
affection of internal organs often needs more aggressive therapy due to the more severe conse-
quences of organ damage.

Disease course during pregnancy

RDs show no uniform response to pregnancy: some ameliorate, others remain unchanged, and
several RDs aggravate [1]. The response of disease to the hormonal, immunological, and biochemical
alterations of pregnancy reflects the pathophysiology of the different RDs. RA is the RD that improves
spontaneously during pregnancy in a majority of patients [7], at least in those who have no autoan-
tibodies like rheumatoid factor (RF) or anti-citrullinated protein antibodies (ACPA) [8]. Spontaneous
improvement starts often already in the first trimester with a reduction of pain, stiffness, and joint
swelling and reaches a maximum in the third trimester [6]. RA patients without RF or ACPA will
ameliorate in 75% of cases, whereas patients positive for RF and ACPA only have a 40% chance to
improve during pregnancy [8]. Polyarticular JIA and psoriatic arthritis (PA) also show a tendency of
spontaneous gestational improvement [9,10]. By contrast, inflammatory arthritides with few joints
involved or with inflammation of the spine like ankylosing spondylitis (AS) do not show improvement
during pregnancy. Most women with AS remain active and need control of pain and stiffness in the
spine throughout pregnancy [6,11].
SLE is the prototype of a multiorgan disease with abundant autoantibody production. The flare rate
during pregnancy has differed in several caseecontrol studies from no difference in pregnant and
nonpregnant patients to an increased propensity of flare during pregnancy [5]. Definition of a flare and
type of patients included influence the flare rate observed [12e14]. In general, there is agreement that
SLE is active at some stage during pregnancy in about 50% of the patients though 60e70% of lupus
women do experience mild to moderate disease symptoms, most often in the skin, the joints, and in the
hematopoietic system. Severe organ flares in the kidney, lung, or CNS are limited to 11e25% of preg-
nancies [14]. Active SLE during pregnancy increases the rate of negative outcomes two-to fourfold [15].
SSc, inflammatory myopathies, and vasculitis are rare diseases. Published experience of their course
during pregnancy and pregnancy outcome is quite limited and consists frequently of retrospective
uncontrolled studies and case reports [16,17]. General statements on their interaction with pregnancy
are difficult to make. However, it appears that the type and extent of organ involvement as well as
disease activity are the crucial factors for pregnancy outcome [2].

Pregnancy outcome

Women with RD in general have been found to have higher risks for adverse outcomes such as
pregnancy loss, preeclampsia, preterm delivery, cesarean section (CS), and small for gestational age
(SGA) infants [18]. As expected, the pathophysiology of the underlying disease, presence of certain
autoantibodies, disease activity during pregnancy, and type of therapy influence the rate of adverse
Among the inflammatory arthritides, pregnancy outcome has been most extensively studied in RA
[19e21]. The rate of adverse outcomes reported in RA varies considerably and reflects the difference in
study design, patient populations, access to health care during pregnancy, pharmacotherapy, and
comorbidities in RA patients. A population-based study in Norway with a specific focus on the first
birth examined possible associations between chronic inflammatory arthritides (CIA) and pregnancy
outcomes with separate analyses of first and subsequent births before and after diagnosis [19]. Linkage
of data from the Norwegian Disease-Modifying Antirheumatic Drug (NOR-DMARD) Registry and the
Medical Birth Registry of Norway (MBRN) enabled a comparison of pregnancy outcomes in CIA and
non-CIA women. Excess risks were related to the first birth in women diagnosed with CIA. No increased
risk of preeclampsia was detected. Prospective studies including RA women with well-controlled

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
4 M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

disease and regular follow-up during pregnancy found that the pregnancy outcome was similar to
healthy women in patients entering pregnancy with low disease activity and limited drug therapy

Pregnancy loss

The incidence of abortions and stillbirths is significantly increased in patients with SLE, APS, and
vasculitis, reflecting the presence of harmful autoantibodies, widespread organ manifestations, and
organ damage [2]. The high rate of pregnancy losses is typical for APS within the fetal period. In SLE, the
rate of pregnancy loss has been found in the range of 11e29%, and it is 1.5e2.5 times more prevalent
than in the normal population [15,22e25]. Active lupus nephritis, proteinuria, hypertension, previous
history of fetal death, and the presence of aPL have shown to be predictive factors for fetal loss in lupus
pregnancies [25]. A study of 265 pregnancies found that active SLE in the 3 months prior to conception
corresponded with a fourfold increase in pregnancy loss [15]. The rate of stillbirth is increased in both
SLE and APS [25,26].

Premature delivery

The rate of delivery <37 weeks gestation is higher in patients with RD than in healthy women.
Preterm delivery is associated with lung immaturity, with delayed development, and impaired long-
term outcomes for children [27]. Early preterm birth (<30 weeks gestation) often leads to prolonged
hospitalization with multiple short- and long-term complications. Several studies have reported a
1.2e1.8 increased risk of preterm delivery in patients with inflammatory arthritides (mostly RA),
without relating this to birth order [19e21]. In the Norwegian population-based study, the risks of
preterm delivery and SGA children were higher for firstborn children in mothers with CIA compared
with references. [19] A recent retrospective study of 46 RA pregnancies found a high rate (28%) of
preterm deliveries; however, no analysis of indications or complications leading to preterm delivery
was given [28].
Rates of preterm birth are particularly high in SLE, APS, and SSc [25,26,29e32]. In women with SLE,
preterm deliveries are often induced for complications such as lupus nephritis, renal insufficiency,
hypertension, preeclampsia, premature rupture of the membranes, and fetal compromise [25,30]. A
key predictor for preterm delivery is lupus activity during pregnancy, even in patients with quiescent
SLE before conception or with mild to moderate activity in pregnancy [32]. A meta-analysis found that
the rate of preterm birth was 39.4% in women with lupus nephritis [25]. Other risk factors are treat-
ment with a high dose (>20e15 mg) of corticosteroids [33].
In addition, patients with SSc have a significantly increased rate of preterm birth possibly related to
placental insufficiency due to vasculopathy of the placenta [34].
Many studies have not analyzed the reason for delivery <37 weeks of gestation or separated
emergency preterm delivery from delivery for other reasons. Sometimes, preterm delivery is induced
because of anxiety in the patient or because the obstetricians fear complications should parturition
occur spontaneously. Accordingly, the rate of emergency premature delivery due to maternal com-
plications or due to fetal distress may be lower than the actual one reported. The wish for a delivery
under controlled conditions can be a strong motive for preterm delivery.

Cesarean section

The rate of CS is increased in all RDs [2,35]. Several population-based studies from different
geographic areas have found a 1.5e2.0 increased risk of CS in patients with RA [19e21]. The Norwegian
study has examined both acute and elective CS in CIA separately [19]. In this study, acute CS was not
observed to be more frequent in patients than references, but the rate of elective CS was doubled
among patients in both first and subsequent pregnancies. Placental dysfunction, cephalopelvic
disproportion, and combined causes constituted each one-third of the indications [19]. However, iat-
rogenic reasons or the wish of the patient for surgical delivery may play a role for choosing elective CS
in women with RD.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13 5

In the Norwegian population-based study, women with AS had the highest occurrence of elective CS
(25%) among the different diagnostic groups [19], a finding also confirmed by previous studies [36].
Inflammation or ankylosis of the sacroiliac joints is not a mechanical hindrance for the progression of
parturition nor is spinal disease. Anesthesiologists often fear that neuraxial anesthesia is difficult to
establish in patients with AS because of ankylosis in the lumbar spine. However, ankylosis of the
lumbar spine is rare in female AS patients and occurs only after three to four decades of disease
duration [37].

Neonatal and perinatal outcome

Perinatal morbidity and mortality have been found increased in RDs [2,35,38]. In the Norwegian
population-based study, the perinatal mortality rate of firstborn children of mothers diagnosed with
inflammatory arthritis was three times higher in children of patients than in references. [19] Perinatal
mortality is also increased in children born of mothers with SLE (5e20%) or APS [26,35,39]. In the APS, a
rate of up to 54% perinatal death has been observed mainly due to severe preeclampsia or the HELLP
(hemolysis, elevated liver enzymes, low platelets, and proteinuria) syndrome with resulting extreme
prematurity [40].
The Norwegian population-based study showed small, but statistically significant, lower mean birth
weight in the firstborn, but not later children of women with RD compared to references. [19] Several
studies of RA pregnancies found birth weight within the normal range, but lower than in healthy
women, and even lower in infants of RA mothers with high disease activity or on prolonged therapy
with corticosteroids [19,41,42]. In RA pregnancies with well-controlled disease activity and with no or
minimal use of prednisone, no increase in prematurity or SGA infants has been found [7,11]. The rate of
congenital malformations in children of patients with RD is not increased, except for birth defects
arising from first-trimester exposure to teratogenic drugs such as methotrexate and cyclophosphamide
(Table 2) [19].

Autoantibodies impairing pregnancy outcome

Several RDs are associated with the abundant production of autoantibodies. The APS is the classical
example of pathology and clinical manifestations connected with the presence of autoantibodies. APS
is characterized by thromboembolic events and pregnancy morbidity as major manifestations at the
presence of aPL [43]. The most prominent antibodies detected in the APS are lupus anticoagulant (LAC),
anti-cardiolipin (aCL), and anti-beta 2 glycoprotein I (ab2GP1). Several other antibodies including anti-

Table 2
Flare rates and risk of adverse pregnancy outcomes in several rheumatic diseases.

Disease Flare in pregnancy Risk of pregnancy Risk of adverse child outcome


Rheumatoid arthritis 10e25% Rare, associated with active Rare, associated with active
disease and use of corticosteroids disease and use of corticosteroids
Ankylosing spondylitis 50% Rare Not increased
Psoriatic arthritis 20% Few studies, no conclusive data Few studies, no conclusive data
Juvenile idiopathic 30e40% Few studies, no conclusive data Few studies, no conclusive data
Antiphospholipid No flare, but risks Thrombosis, Early and late miscarriage, IUGR,
syndrome for adverse outcomes preeclampsia, HELLP, stillbirth, prematurity
increased premature delivery
SLE 27e65% Hypertension, preeclampsia, Miscarriage, IUGR, still birth,
premature delivery prematurity, neonatal lupus
Systemic sclerosis No flare, symptoms Premature delivery IUGR, prematurity
largely unchanged
during pregnancy

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
6 M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

annexin V, anti-phosphatidyl serine, and anti-prothrombin have been detected, but are not used for
routine testing. Until now, no autoantibody has been found to be pathognomic for pregnancy com-
plications. However, several studies have shown that high titers of aPL, presence of LAC, and triple
positivity (aCL þ LAC þ ab2GP1) are associated with a high risk of adverse pregnancy outcomes
[44e47]. aPL are detected not only in the APS and in SLE but also in other RDs [48] as well as in
The pregnancy complications of the APS include pregnancy loss, intrauterine growth restriction
(IUGR), preeclamptic toxemia (PET), HELLP syndrome, placental abruption, stillbirth, and premature
delivery. PET has been reported to occur in about one-third of patients with APS, often with early onset
before 34 weeks of gestation [49]. The risk of HELLP is increased in APS with a frequency of 0.66e10.6%
reported, and often manifesting in the second trimester [50,51]. Both HELLP and PET occur earlier in
APS pregnancy than in the general obstetric population.
The rate of IUGR is high ranging from 15% to 43% in the APS indicating placental insufficiency [52].
However, the pathogenesis of placental insufficiency is only partly clarified. Histological studies of
placentas from patients with APS have shown varying patterns with necrosis, infarction, intravascular
fibrin deposition, syncytial knot formation, fibrosis, and sometimes inflammatory infiltrates [53].
However, these histological abnormalities are nonspecific and no specific placental lesions or patterns
of abnormalities characteristic of the APS have been detected. Furthermore, histological findings in the
placenta and pregnancy outcome are often unrelated [54].
The transplacental transfer of maternal autoantibodies to 52-kd SSA/Ro, 60-kd SSA/Ro, or SSB/La
ribonucleoproteins from the beginning of the second trimester can lead to neonatal lupus syndromes
including congenital heart block (CHB) [55]. SSA and/or SSB antibodies can occur in all RDs as well as in
healthy mothers. In susceptible children, the maternal SSA and/or SSB antibodies can damage the
conduction system of the fetal heart, with the most vulnerable period being between week 18 and
week 26 of gestation [56]. Of children born from mothers with SSA and/or SSB antibodies, 2e5%
develop CHB [57]. The fetal heart rate must therefore be monitored regularly between week 18 and 28
in pregnant women with significantly elevated levels of SSA and/or SSB antibodies [56].

Pathophysiology of adverse pregnancy outcome in RD

Pregnancy complications associated with RD originate with the involvement of the mater-
nalefetal interface and the development of adequate placental function (Fig. 1). Mainly, these pa-
thologies are represented by repeated miscarriage, preeclampsia, IUGR, and fetal demise.
Preeclampsia and IUGR also contribute to increase the rate of premature deliveries, and therefore
they are associated with high neonatal and maternal morbidity, long-term pediatric disability, and
consequences in adulthood.
Proper development of the placenta is a requisite of normal pregnancy. Many studies have
addressed how the trophoblast interacts with the decidualized endometrial cells with a sequence of
events from a hypoxic environment to the development of an adequate maternalefetal vasculari-
zation to provide an appropriate exchange of nutrients and oxygen to the fetus. When these pro-
cesses fail or are inadequate, complications may range from early abortion to fetal demise, or they
may lead to inadequate nutrient and oxygen transfer to the fetus with fetal growth restriction.
Moreover, the presence of an adverse environment may lead to the placental release of unbalanced
angiogenic and pro-inflammatory factors that damage the maternal endothelium and lead to pre-
eclampsia [58]. In the last years, a wealth of studies have described the placental phenotype asso-
ciated with preeclampsia and IUGR, and recently much attention has focused on the presence of
oxidatevely stressed microparticles released by the placenta, associated with decreased circulating
levels of vascular endothelial growth factor (VEGF) and placental growth factor (PlGF), proangiogenic
factors produced by the placenta, already 4e5 weeks prior to the development of the disease [59].
Moreover, in some cases of preeclampsia, lipid-filled foam cells accumulate in the walls of the spiral
arteries of the uteroplacental circulation. These lesions resemble the early stages of atherosclerosis
and are thought to regress after delivery. The mechanisms that contribute to acute atherosis are
largely unknown, but are related to defective vascular remodeling of the spiral arteries in the first
half of pregnancy [59].

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13 7

Involvement of feto-maternal FETUS

interface (APS)

EMISE Neonatal
IUGR mortality
implanta on

concep on delivery

Maternal inflammatory
(chronic inflamma on of
rheuma c disease) MOTHER

Fig. 1. Graphical representation of mechanisms involved in the development of adverse pregnancy outcomes in RD and their effects
on the fetal and maternal side. The related pregnancy complications then lead to prematurity, increased neonatal morbidity and
mortality, and long-term outcomes.

APS is the RD with the highest impact on pregnancy. The pathogenic role of aPL has been
demonstrated in experimental animals, with massive infusion causing fetal death [60]. However, the
initial hypothesis that placental thrombosis would be responsible for the related fetal losses has not
been supported by data reported in affected placentas. Many studies have indeed shown that aPL have
direct effects on human placental trophoblast cells, by reducing trophoblast invasiveness, differenti-
ation, syncytia formation, and HCG production [61,62]. Phospholipid-binding proteins such as b2GP1
are necessary for binding aPL to cardiolipin and b2GP1 has been demonstrated on trophoblast cell
membranes, explaining the tropism of aPL for placenta [63]. Thus, aPL bind to b2GP1 adhered to
phospholipids, causing defective placentation.
Moreover, a direct effect of aPL on endometrial angiogenesis has been reported in in vitro studies
[64]. Timely endometrial angiogenesis is needed for successful placentation, and involves VEGF and its
receptors. Therefore, aPL can affect both trophoblast invasion and endometrial angiogenesis, processes
needed to establish the proper maternalefetal interface, potentially leading to early abortion, or to
later on complications implying fetal death or growth restriction and preeclampsia. Indeed, it is well
known now that the mechanisms preceding preeclampsia originate in the early stages of implantation;
therefore, potential therapies should be initiated as early as possible. In this context, recent studies
address the potential role of molecules competing with binding of b2GP1 to the cell targets, in order to
inhibit its recognition by specific autoantibodies [65].
While the pathophysiology of adverse pregnancy outcomes in APS is being unraveled, hypothesis
can only be made for the other RDs. In particular, the development of an excessive pro-inflammatory
maternal status has a key role in the physiopathological pathways of obstetrical complications [58]. In
preeclampsia, a dysfunctional uteroplacental circulation leads to ischemia reperfusion injury [66] and
the release of pro-inflammatory trophoblast-derived factors, causing an excessive maternal inflam-
matory response and endothelial dysfunction. In particular, preeclampsia is thought to be caused by
excessive release of anti-angiogenic sFLT-1 (the soluble VEGF receptor) from the oxidatively stressed
placenta [67]. Therefore, while normal pregnancy is associated with a stronger type 2 anti-
inflammatory cytokine profile, preeclampsia is characterized by a type 1 immune bias.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
8 M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

Interleukin (IL)-33, the most recently discovered member of the IL-1 superfamily, has been recently
addressed in the pathogenesis of chronic autoimmune diseases, such as SSc, RA, and SLE [68]. IL-33 is
involved in T-cell-mediated immune responses through the activation of the ST2 receptor, which is
widely expressed particularly by helper T2 cells and mast cells, as well as macrophages and natural
killer (NK) cells, to induce type 2 cytokines. A soluble variant of ST2 (sST2L) acts as a decoy receptor and
regulates the activity of IL-33. Macrophage-derived IL-33 is a critical factor for orienting extravillous
trophoblast invasion and therefore the development of an adequate placenta. Moreover, IL-33 en-
hances proliferation and invasiveness of decidual stromal cells [69]. Recently, maternal circulating
levels of sST2L have been found to be significantly increased in preeclampsia [70,71]. sST2L seems to be
a second anti-angiogenic factor (besides sFLT-1) produced by the placenta in excess amounts in pre-
eclampsia. Moreover, a dysregulation of IL-33/ST2 activation in decidualized stromal cells is associated
with recurrent pregnancy loss [72].
These pathways might be involved in the pathogenesis of pregnancy pathologies in RDs, although
data are still lacking in this regard (see Fig. 1).

Planning a pregnancy

In order to secure pregnancies with good maternal and child outcomes, awareness for reproduction
and family planning issues is required in physicians caring for patients with RD. Family planning should
be actively addressed in all female patients of fertile age regardless of whether they are single or live
with a partner. A wish for pregnancy has an impact on the choice of drug treatment. The major goal
when selecting therapy for a patient wishing for children is to achieve remission or at least low disease
activity, because most studies have shown that active disease at conception is a predictor for adverse
outcomes [15,73].
Risk assessment in regard to possible maternal or fetal risks during a future pregnancy is essential
for counseling an individual patient and adjusting therapy [2]. Major maternal risks are active disease
at conception, a flare during pregnancy, conception in a stage of active organ involvement or at severe
organ damage, the presence of aPL and antibodies against SSA and SSB. A clinical workup and labo-
ratory tests will allow a stratification into a high-, moderate-, or low-risk profile according to the
presence of risk factors. As discussed in the previous paragraphs, RDs differ in regard to maternal and
child risks. Therapy adjustment as well as type and frequency of monitoring will relate to the risk
profile in the individual patient (Fig. 2). Patients with active organ disease or damage in vital organs
such as the kidney, lungs, or heart should be discouraged from pregnancy. Symptomatic pulmonary
hypertension, extensive restrictive lung disease, cardiomyopathy, and severely reduced renal function
as well as a history of previous HELLP syndrome are associated with increased morbidity and mortality.
Patients with recent arterial thrombosis or current active renal disease should postpone pregnancy.
Of note, a significantly increased thrombotic risk can arise in women with RD treated for infertility,
mainly because of the protocols for induction of ovulation and the increased maternal age [73].
Therefore, appropriate counseling and particular attention should be paid to these patients, to avoid
the associated risks of ovarian hyperstimulation.

Management of pregnancy

Women who plan a pregnancy often stop taking medications out of fear of harming the fetus,
especially in the first trimester. Withdrawal of effective therapy in RD may lead to aggravation of
disease activity with adverse effects on both the mother and fetus [74]. Adjustment of medication must
therefore be discussed in good time with patients desiring children, so an ill-timed cessation of therapy
can be avoided. It is essential to discuss therapy necessary before conception or during pregnancy with
all specialists involved in family planning or follow-up during pregnancy of an individual patient.
Contradictory advice given by different specialists can be disastrous. The patient gets confused and
does not know in whom of the caregivers she should trust. Comprehensive information on effects and
side effects of immunosuppressive drugs and their safety during pregnancy should help the patient to
understand that effective disease control during pregnancy is important for a normal pregnancy course
and for child health. She should also be reassured about the possibilities to control a flare of RD during

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13 9

Patient with rheumatic

disease planning a

Disease in remission or at low, Disease at early Severe impairment of organ

stable activity and on stable stage or presence of function, severe organ
medication active organ disease damage

Adjust therapy to Discourage

drugs compatible with pregnancy
pregnancy Postpone pregnancy. Achieve
improvement or remission by
immunosuppressive drugs or biologicals
or combination therapy

Substantial improvement or
remission of rheumatic disease

Pregnancy may be planned

Fig. 2. Algorithm for decision making in patients with rheumatic disease planning a pregnancy.

pregnancy even when short-term high-dose corticosteroids or drugs not approved for pregnancy
should be necessary (Table 3) [75].
As soon as pregnancy is recognized, a complete clinical and laboratory assessment should be made
in order to monitor disease activity. High-risk pregnancies are best monitored by an interdisciplinary
specialist team including the obstetrician, the rheumatologist/internist, and, in special cases, the
pediatrician. Controls during pregnancy should be scheduled according to the patient's disease activity,
type of therapy, and the presence of risk factors. However, frequent clinical evaluation for monitoring of
arterial blood pressure and proteinuria should be performed after 20 weeks. Regular assessment of
fetal growth, starting with ultrasound for correct dating in the first trimester, can predict whether the
fetus is at risk. Doppler flow techniques evaluating the uteroplacental and umbilical circulation help
predict complications such as preeclampsia and IUGR. The negative predictive value of uterine Doppler
studies is very high, so a normal examination is reassuring. In particular, women with a previous
history of preeclampsia, placental insufficiency, hypertension, renal disease (even if in remission and
with normal renal function), and aPL, as well as those with multiple pregnancies, are candidates for
Doppler studies starting at week 20. Serial fetal echocardiography between weeks 18 and 28 is rec-
ommended for detecting early incomplete heart block and myocarditis in a fetus with anti-Ro/SSA and/
or anti-La/SSB-positive mother, as both conditions have the potential for improvement after treatment
with betamethasone. The mode of delivery should also be addressed to dispel unnecessary anxieties

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
10 M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

Table 3
Use of antirheumatic drugs during pregnancy.

Drugs to be discontinued Drugs to be discontinued Drugs to be discontinued at Drugs that can be used
before a planned pregnancya during the first trimesterb the end of the second trimesterc throughout pregnancy

Methotrexate Golimumab Non-selective anti-inflammatory Hydroxychloroquine,

drugsd chloroquine
Leflunomide Ustekinumab Infliximab Sulfasalazine
Mycophenolate mofetil Belimumab Adalimumab Azathioprine
Cyclophosphamide Etanercept Cyclosporine
Rituximab Tacrolimus
Abatacept Prednisone, prednisolone
Tocilizumab Low dose aspirin
Intravenous immunoglobulin
drugs that are either known as teratogenic or where the effect on the embryo/fetus is not known.
drugs where available data do not indicate harm when administered in the first trimester, but where no data for fetal safety
exist for use throughout the second and third trimester.
drugs where adverse effects on the fetus/newborn child are possible particularly when administered near term.
pregnancy data for selective COX-2 inhibitors are insufficient, they are best avoided during pregnancy.

before birth. The mode of delivery should be dictated by individual circumstances, but spontaneous
delivery is often possible, even in women with prosthetic hip joints. Postpartum visits should be
scheduled already in the third trimester in order to detect a postpartum flare of RD. The risk of a relapse
is approximately doubled in the first 6 months after delivery, but there is no need to boost the dose of
immunosuppression unless a flare occurs.


The response of RD to the hormonal, immunological, and biochemical alterations of pregnancy

reflects the pathophysiology of the different RD. A more detailed understanding of the pathology of RD
will help to assess maternal and fetal risks, analyze clinical symptoms and biomarkers that can predict
pregnancy outcomes, and design appropriate interventions for monitoring and supporting pregnancy.
In order to reach that goal, prospective studies of pregnancies in all RDs, particularly in rare RDs, such
as SSc, poly- and dermatomyositis, and vasculitis, are necessary. More knowledge is needed on the
effect of medications during pregnancy. Collaboration between different specialists will enhance the
quality of care that can be offered to patients with RD desiring children or being pregnant.

Practice points

" RDs differ in their response to pregnancy.

" RD with predominant joint involvement, few organ manifestations, and few autoantibodies
rarely impair pregnancy outcomes.
" aPL or APS increase risk of miscarriage, preeclampsia, IUGR, fetal death, and prematurity.
" SSA/Ro, SSB/La antibodies predispose to neonatal lupus syndromes and CHB.
" Active disease at conception, renal disease, aPL, and high-dose corticosteroids predict
complications in RD pregnancies.
" Assessment of maternal and fetal risks is a prerequisite for preconceptional counseling.
" Adjustment of medication instead of global drug withdrawal in the first trimester is
" Interdisciplinary care and management is a prerequisite for successful pregnancy outcomes.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13 11

Research agenda

" Prospective clinical and laboratory studies of rare RD during pregnancy.

" Effect of chronic inflammation on placenta development and function.
" Search for interventions improving pregnancy outcomes.
" Search for biomarkers as predictors for pregnancy outcome.

Conflict of interest

The authors declare no conflict of interest.


[1] Østensen M, Villiger PM, Fo €rger F. Interaction of pregnancy and autoimmune rheumatic disease. Autoimmun Rev 2012;
[2] Østensen M, Dolhain R, Ruiz-Irastorza G. Obstetrics and pregnancy. In: Watts RA, Conaghan PG, Denton C, et al., editors.
Oxford Textbook of Rheumatology 4e; 2013.
[3] Ostensen M, Brucato A, Carp H, et al. Pregnancy and reproduction in autoimmune rheumatic diseases. Rheumatology
(Oxford) 2011;50:657e64.
[4] Carp H, Selmi C, Shoenfeld Y. The autoimmune bases for infertility and pregnancy loss. J Autoimmun 2012;38:266e74.
[5] Stojan G, Baer AN. Flares of systemic lupus erythematosus during pregnancy and the puerperium: prevention, diagnosis
and management. Expert Rev Clin Immunol 2012;8:439e53.
[6] Fo€rger F, Ostensen M, Schumacher A, et al. Impact of pregnancy on health related quality of life evaluated prospectively in
pregnant women with rheumatic diseases by the SF-36 health survey. Ann Rheum Dis 2005;64:1494e9.
[7] de Man YA, Dolhain RJ, van de Geijn FE, et al. Disease activity of rheumatoid arthritis during pregnancy: results from a
nationwide prospective study. Arthritis Rheum 2008;59:1241e8.
[8] de Man YA, Bakker-Jonges LE, Goorbergh CM, et al. Women with rheumatoid arthritis negative for anti-cyclic citrullinated
peptide and rheumatoid factor are more likely to improve during pregnancy, whereas in autoantibody-positive women
autoantibody levels are not influenced by pregnancy. Ann Rheum Dis 2010;69:420e3.
[9] Østensen M, Almberg K, Svean Koksvik H. Sex, reproduction, and gynecological disease in young adults with a history of
juvenile chronic arthritis. J Rheumatol 2000;27:1783e7.
[10] Østensen M. Pregnancy in psoriatic arthritis. Scand J Rheumatol 1988;17:67e70.
[11] Østensen M, Fuhrer L, Mathieu R, et al. A prospective study of pregnant patients with rheumatoid arthritis and ankylosing
spondylitis using validated clinical instruments. Ann Rheum Dis 2004;63:1212e7.
[12] Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy. The Hopkins Lupus Pregnancy Center experience.
Arthritis Rheum 1991;34:1538e45.
[13] Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare during pregnancy and the puerperium. Br J Rheumatol
[14] Doria A, Cutolo M, Ghirardello A, et al. Steroid hormones and disease activity during pregnancy in systemic lupus ery-
thematosus. Arthritis Rheum 2002;47:202e9.
[15] Clowse M, Magder LS, Witter F, et al. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum 2005;
[16] Chakravarty EF, Khanna D, Chung L. Pregnancy outcomes in systemic sclerosis, primary pulmonary hypertension, and
sickle cell disease. Obstet Gynecol 2008;111:927e34.
[17] Clowse M, Richeson RL, Pieper C, et al. Pregnancy outcomes among patients with vasculitis. Arthritis Care Res 2013;65:
[18] Skomsvoll JF, Ostensen M, Irgens LM, et al. Pregnancy complications and delivery practice in women with connective
tissue disease and inflammatory rheumatic disease in Norway. Acta Obstet Gynecol Scand 2000;79:490e5.
**[19] Wallenius M, Skomsvoll JF, Irgens LM, et al. Pregnancy and delivery in women with chronic inflammatory arthritides
with a specific focus on first birth. Arthritis Rheum 2011;63:1534e42. **Population-based study that has shown an
increased rate of adverse pregnancy outcome after a first birth but not before disease onset or after subsequent birth in
patients with chronic inflammatory arthritis.
[20] Norgaard M, Larsson H, Pedersen L, et al. Rheumatoid arthritis and birth outcomes: a Danish and Swedish nationwide
prevalence study. J Intern Med 2010;268:329e37.
[21] Barnabe C, Faris PD, Quan H. Canadian pregnancy outcomes in rheumatoid arthritis and systemic lupus erythematosus.
Int J Rheumatol 2011;2011:345727.
[22] Clowse ME, Magder LS, Witter F, et al. Early risk factors for pregnancy loss in lupus. Obstet Gynecol 2006;107(2 Pt 1):
[23] Molokhia M, Maconochie N, Patrick AL, et al. Cross-sectional analysis of adverse outcomes in 1,029 pregnancies of Afro-
Caribbean women in Trinidad with and without systemic lupus erythematosus. Arthritis Res Ther 2007;9:R124.
[24] Cortes-Hernandez J, Ordi-Ros J, Paredes F, et al. Clinical predictors of fetal and maternal outcome in systemic lupus er-
ythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford) 2002;41:643e50.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
12 M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13

**[25] Smyth A, Oliveira GHM, Lahr BD, et al. A systematic review and meta-analysis of pregnancy outcomes in patients with
systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010;5:2060e8. **Meta-analysis of pregnancy
outcomes in women with lupus nephritis showing presence of aPL increase the risk of maternal hypertension and premature
*[26] Cervera R, Serrano R, Pons-Estel GJ, et al. Morbidity and mortality in the antiphospholipid syndrome during a 10-year
period: a multicentre prospective study of 1000 patients. Ann Rheum Dis 2014.
2013-204838. *European multicenter study of 1000 patients with APS revealing the pregnancy morbidity of APS.
[27] Dong Y, Yu JL. An overview of morbidity, mortality and long-term outcome of late preterm birth. World J Pediatr 2011;7:
[28] Langen ES, Chakravarty E, Liaquat M, et al. High rate of preterm birth in pregnancies complicated by rheumatoid arthritis.
Am J Perinatol 2014;31:9e14.
[29] Clark CA, Spitzer KA, Nadler JN, et al. Preterm deliveries in women with systemic lupus erythematosus. J Rheumatol
[30] Imbasciati E, Tincani A, Gregorini G, et al. Pregnancy in women with pre-existing lupus nephritis: predictors of fetal and
maternal outcome. Nephrol Dial Transplan 2009;24:519e25.
[31] Stagnaro-Green A, Akhter E, Yim C, et al. Thyroid disease in pregnant women with systemic lupus erythematosus:
increased preterm delivery. Lupus 2011;20:690e9.
*[32] Clowse M, Wallace D, Weisman M, et al. Predictors of preterm birth in patients with mild systemic lupus erythematosus.
Ann Rheum Dis 2013;72:1536e9. *This study shows that even subclinical disease activity is associated with an increased risk
of preterm birth in SLE and correlates with elevated ferritin and lowered oestradiol levels at midgestation.
[33] Empson M, Lassere M, Craig J, et al. Prevention of recurrent miscarriage for women with antiphospholipid antibody or
lupus anticoagulant. Cochrane Database Syst Rev 2005;2:CD002859.
*[34] Taraborelli M, Ramoni V, Brucato A, et al. Successful pregnancies but a higher risk of preterm births in patients with
systemic sclerosis: an Italian multicenter study. Arthritis Rheum 2012;64:1970e7. *This study investigated 109 pregnancies
in patients with SSc and found a higher than-normal risk of preterm delivery, intrauterine growth restriction, and babies with
very-low birth weight.
[35] Clowse ME, Jamison M, Myers E, et al. A National Study of the Complications of Lupus in Pregnancy. Am J Obstet Gynecol
[36] Ostensen M, Ostensen H. Ankylosing spondylitisethe female aspect. J Rheumatol 1998;25:120e4.
[37] Gran JT, Ostensen M. Spondyloarthritides in females. Baillieres Clin Rheumatol 1998;12:695e715.
[38] Skomsvoll JF, Østensen M, Irgens LM, et al. Perinatal outcome in pregnancies of women with connective tissue disease
and inflammatory rheumatic disease in Norway. Scand J Rheumatol 1999;28:352e6.
[39] Yasmeen S, Wilkins EE, Field NT, et al. Pregnancy outcomes in women with systemic lupus erythematosus. J Matern Fetal
Med 2001;10:91e6.
[40] Hanouna G, Morel N, Le Thi Huong D, et al. Catastrophic antiphospholipid syndrome and pregnancy: an experience of 13
cases. Rheumatology (Oxford) 2013;52:1635e41.
[41] Motta M, Rodriguez-Perez C, Tincani A, et al. Neonates born from mothers with autoimmune disorders. Early Hum Dev
2009;85(10 Suppl.):S67e70.
[42] de Man YA, Hazes JM, van der HH, et al. Association of higher rheumatoid arthritis disease activity during pregnancy with
lower birth weight: results of a national prospective study. Arthritis Rheum 2009;60:3196e206.
[43] Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for
definite antiphospholipid syndrome (APS). J Thromb Haemostasis 2006;4:295e306.
[44] Nodler J, Moolamalla SR, Ledger EM, et al. Elevated antiphospholipid antibody titers and adverse pregnancy outcomes:
analysis of a population-based hospital dataset. BMC Pregnancy Childbirth 2009;9:11e31.
[45] Yamada H, Atsumi T, Kobashi G, et al. Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension
and adverse pregnancy outcomes. J Reprod Immunol 2009;79:188e95.
[46] Ruffatti A, Calligaro A, Hoxha A, et al. Laboratory and clinical features of pregnant women with antiphospholipid syn-
drome and neonatal outcome. Arthritis Care Res 2010;62:302e7.
*[47] Lockshin M, Kim M, Laskin CA, et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but
not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012;64(7):2311e8. *Contrary
to previous studies, lupus anticoagulant alone and not a combination of aPL was found to be the primary predictor of adverse
pregnancy outcomes in patients with phospholipid antibodies.
[48] Fort JG, Cowchock S, Abruzzo JL, et al. Anticardiolipin antibodies in patients with rheumatic diseases. Arthritis Rheum
[49] Heilmann L, Schorsch M, Hahn T, et al. Antiphospholipid syndrome and pre-eclampsia. Semin Thromb Hemost 2011;37:
[50] Appenzeller S, Souza FH, Wagner Silva de Souza A, et al. HELLP syndrome and its relationship with antiphospholipid
syndrome and antiphospholipid antibodies. Semin Arthritis Rheum 2011;41:517e23.
[51] Le Thi Thuong D, Tieulie " N, Costedoat N, et al. The HELLP syndrome in the antiphospholipid syndrome: retrospective
study of 16 cases in 15 women. Ann Rheum Dis 2005;64:273e8.
[52] Abou-Nassar K, Carrier M, Ramsay T, et al. The association between antiphospholipid antibodies and placenta mediated
complications: a systematic review and meta-analysis. Thromb Res 2011;128:77e85.
[53] Stone S, Pijnenborg R, Vercruysse L, et al. The placental bed in pregnancies complicated by primary antiphospholipid
syndrome. Placenta 2006;27:457e67.
[54] Østensen M, Andreoli L, Tincani A, BMJ group. Pregnancy in rheumatic diseases and the antiphospholipid syndrome. In:
Bijlsma JWJ, editor. EULAR Textbook on rheumatic diseases; 2012. p. 522e54570.
[55] Izmirly PM, Rivera TL, Buyon JP. Neonatal lupus syndromes. Rheum Dis Clin N Am 2007;33:267e85.
[56] Friedman DM, Rupel A, Buyon JP. Epidemiology, etiology, detection, and treatment of autoantibody-associated congenital
heart block in neonatal lupus. Curr Rheumatol Rep 2007;9:101e8.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),
M. Østensen, I. Cetin / Best Practice & Research Clinical Obstetrics and Gynaecology xxx (2015) 1e13 13

[57] Brucato A, Frassi M, Franceschini F, et al. Congenital heart block risk to newborns of mothers with anti-Ro/SSA antibodies
detected by counterimmunoelectrophoresis. A prospective study of 100 women. Arthritis Rheum 2001;44:1832e5.
[58] Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science 2005;308:1592e4.
[59] Redman CW, Sargent IL, Staff AC. IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of
preeclampsia? Placenta 2014;35(Suppl.):S20e5.
[60] Branch DW, Dudley DJ, Mitchell MD, et al. Immunoglobin G fraction from patients with antiphospholipid antibodies
cause fetal death in Balb7C mice: a model for autoimmune fetal loss. Am J Obstet Gynecol 1990;163:210e6.
[61] Di Simone N, Ferrazzani S, Castellani R, et al. Heparin and low-dose aspirin restore placental human chorionic gonad-
otropin secretion abolished by antiphospholipid antibody-containing sera. Hum Reprod 1997;12:2061e5.
[62] Di Simone N, Caliandro D, Castellani R, et al. Low-molecular weight heparin restores in-vitro trophoblast invasiveness
and differentiation in presence of immunoglobulin G fractions obtained from patients with antiphospholipid syndrome.
Hum Reprod 1999;14:489e95.
[63] La Rosa L, Meroni PL, Tincani A, et al. Beta 2 glycoprotein I and placental anticoagulant protein I in placentae from pa-
tients with antiphospholipid syndrome. J Rheumatol 1994;21:1684e93.
[64] Di Simone N, Di Nicuolo F, D’Ippolito S, et al. Antiphospholipid antibodies affect human endometrial angiogenesis. Biol
Reproduction 2010;83:212e9.
**[65] Di Simone N, D’Ippolito S, Marana R, et al. Antiphospholipid antibodies affect human endometrial angiogenesis: pro-
tective effect of a synthetic peptide (TIFI) mimicking the phospholipid binding site of b2glicoprotein 1. Am J Reprod
Immunol 2013;70:299e308. **Evidence for the protective effects of TIFI, a synthetic peptide able to compete with anti-
phospholipid (aPL) antibodies in the binding to endothelium, with the potential to restore aPL-inhibited endometrial
[66] Hung TH, Skepper JN, Burton GJ. In vitro ischaemia-reperfusion injury in term human placenta as a model for oxidative
stress in pathological pregnancies. Am J Pathol 2001;159:1031e43.
**[67] Young BC, Levine RJ, Karumanchi SA. Pathogenesis of preeclampsia. Annu Rev Pathol 2010;5:173e92. **A thorough re-
view on the role of upregulated placental antiangiogenic factors in the disruption of the maternal endothelium as contibutors
to preeclampsia.
[68] Liew FY, Pitman NI, McInnes IB. Disease associated functions of IL-33: the new kid in the IL-1 family. Nat Rev Immunol
**[69] Hu WT, Li MQ, Liu W, et al. IL-33 enhances proliferation and invasiveness of decidual stromal cells by up-regulation of
CCL2/CCR2 via NF-kB and ERK1/2 signaling. Mol Hum Reprod 2014 Jan 10 [Epub ahead of print]. **This study provides
evidence for the molecular mechanism of IL-33 in promoting proliferation and invasiveness of decidual stromal cells.
[70] Granne I, Southcombe JH, Snider JV, et al. ST2 and IL-33 in pregnancy and preeclampsia. Plos One 2011;6:1e9.
[71] Stampalija T, Chaiworapongsa T, Romero R, et al. Maternal plasma concentrations of sST2 and angiogenic(anti-angiogenic
factors in preeclampsia. J Matern Fetal Neonatal Med 2013;26:1359e70.
[72] Salker MS, Nautiyal J, Steel JH, et al. Disordered IL-33/ST2 activation in decidualizing stromal cells prolongs uterine
receptivity in women with recurrent pregnancy loss. PLoS One 2012;7:e52252.
[73] Hansen AT, Kesmodel US, Juul S, et al. Increased venous thrombosis incidence in pregnancies after in vitro fertilization.
Hum Reprod 2014 Mar;29(3):611e7.
[74] Fo€rger F, Vallbracht I, Helmke K, et al. Pregnancy mediated improvement of rheumatoid arthritis. Swiss Med Wkly 2012;
*[75] Ostensen M, Fo €rger F. Management of RA medications in pregnant patients. Nat Rev Rheumatol 2009;5:382e90.
Comprehensive survey on immunosuppressive drugs and biological agents used for treatment of RA and SLE.

Please cite this article in press as: Østensen M, Cetin I, Autoimmune connective tissue diseases, Best
Practice & Research Clinical Obstetrics and Gynaecology (2015),