Clin Rheumatol
DOI 10.1007/s10067-016-3323-9
ORIGINAL ARTICLE
Association between primary Sjögren’s syndrome and pregnancy
complications: a systematic review and meta-analysis
Sikarin Upala 1,2 & Wai Chung Yong 1 & Anawin Sanguankeo 1,2
Received: 12 May 2016 / Revised: 24 May 2016 / Accepted: 26 May 2016
# International League of Associations for Rheumatology (ILAR) 2016
Abstract Systemic autoimmune disorders may interfere with
normal reproductive function resulting in negative outcome of
pregnancy. Primary Sjögren’s syndrome (pSS) is a common
rheumatic disease that mostly affects females. There are many
reports that this condition may increase risk of pregnancy
complications and fetal loss. However, data regarding these
adverse outcomes are scarce and inconclusive. We performed
a systematic review and meta-analysis of available articles that
assess the association between pSS and adverse pregnancy
outcome. We comprehensively searched the databases of
MEDLINE and EMBASE from their dates of inception to
March 2016 and reviewed papers with validity criteria. A
random-effects model was used to evaluate pregnancy com-
plications in patients with pSS and healthy controls. From 20
full-text articles, 7 studies involving 544 patients and 1586
pregnancies were included in the meta-analysis. Fetal compli-
cations included spontaneous abortion, stillbirth, neonatal
deaths, and intrauterine growth retardation. Compared with
healthy pregnancy, patients with pSS had significantly higher
chance of neonatal deaths (pooled odds ratio (OR) = 1.77,
95 % confidence interval (CI) 1.28 to 1.46, p = 0.01).
However, there were no significant associations between
Electronic supplementary material The online version of this article
(doi:10.1007/s10067-016-3323-9) contains supplementary material,
which is available to authorized users.
* Wai Chung Yong
waichung.yong@bassett.org
1
Department of Internal Medicine, Bassett Medical Center and
Columbia University College of Physicians and Surgeons, 1 Atwell
Rd, Cooperstown, NY 13326, USA
2
Department of Preventive and Social Medicine, Faculty of Medicine
Siriraj Hospital, Mahidol University, Bangkok, Thailand
pSS and premature birth (OR = 2.10, 95 % CI 0.59–7.46,
p = 0.25), spontaneous abortion (OR = 1.46, 95 % CI 0.72–
2.93, p = 0.29), artificial abortion (OR = 1.12, 95 % CI 0.52–
2.61, p = 0.71), or stillbirth (OR = 1.05, 95 % CI 0.38–2.97,
p = 0.92). There is an increased risk of fetal loss in pregnant
patients with pSS. The presented evidence further supports
multidisciplinary care for these patients to prevent complica-
tions during pregnancy.
Keywords Pregnancy . Rheumatic disease . Sjögren’s
syndrome
Introduction
Systemic autoimmune disorders may interfere with normal
reproductive function resulting in negative outcome of preg-
nancy. The impact of autoimmune disorders on pregnancy
outcome is well established for systemic lupus erythematosus
(SLE) and antiphospholipid syndrome (APS), as both of them
have been shown to cause higher risk of fetal losses, prema-
ture deliveries, preeclampsia, and intrauterine growth retarda-
tion (IUGR) [1]. However, pregnancy outcome data is still
limited for primary Sjögren’s syndrome. Primary Sjögren’s
syndrome (pSS) is one of the most common rheumatic dis-
eases that affects females, especially at their fourth decade of
life, with a prevalence rate of 0.1–4.8 % in the total female
population. It can present either as a primary condition or
secondary to other underlying connective tissue diseases,
most commonly rheumatoid arthritis (RA) or SLE. The most
widely known and most severe complication is congenital
heart block, which is the manifestation of neonatal lupus.
Neonatal lupus is a passively transferred autoimmune disease,
resulting from transplacental passage of anti-Ro(SSA) and/or
anti-La(SSB). There are studies that showed that perfusion of

human fetal heart with anti-Ro induces transient heart block
because anti-Ro may cross-react with T- and L-type calcium
channels [2, 3]. This may be the explanation of antibody-
mediated damage of the atrioventricular node. Neonatal lupus
occurs in about 1–2 % of babies born to mothers with auto-
immune diseases, mainly SLE and Sjögren’s syndrome. Many
cases occur in children of mothers who have those antibodies
but do not have symptoms of lupus or Sjögren’s syndrome at
the time of the baby’s birth, but one half of these mothers will
develop autoimmune disease in the future [4].
Otherwise, study results on pregnancy outcomes of women
with PSS are few and conflicting. Apart from the reports on
congenital heart block, data regarding other adverse pregnan-
cy outcomes are scarce and inconclusive. The purpose of this
systematic review and meta-analysis is to assess the associa-
tion between pSS and adverse pregnancy outcomes in order to
justify whether multidisciplinary care should be involved to
prevent complications during pregnancy.
Methods
This systematic review and meta-analysis was conducted and
reported according to the Meta-analysis Of Observational
Studies in Epidemiology statement [5] and was registered in
PROSPERO (registration number: CRD42016035889).
Data sources and search strategy
Two authors (SU and AS) independently searched published
studies indexed in MEDLINE and EMBASE databases from
the date of inception to March 2016. References of all selected
studies were also examined. The following main search terms
were used: Sjögren’s syndrome, Sjögren, pregnancy compli-
cations, abortion, stillbirth, labor complications, perinatal
death, and fetal growth retardation. The full search strategy
was detailed in Item S1 in the supplementary material. A
manual search of references of selected retrieved articles was
also performed.
Study selection and data extraction
Our inclusion criteria were (1) published observational studies
including cross-sectional, cohort, and case–control studies
assessing the risk or association between pSS and
pregnancy-related complications; (2) participants aged
18 years or older; (3) primary outcome was pregnancy-
related complications including abortion, total fetal loss, peri-
natal death, labor complications, still birth, or fetal growth
retardation; (4) odds ratios (ORs), relative risks (RR), or haz-
ard ratios (HR) or number participants with outcome were
provided; and (5) participants without pSS were used as a
reference group.
Clin Rheumatol
Reviews, case reports, and abstracts were excluded
because their quality of studies could not be assessed.
Two authors (SU and AS) independently reviewed titles
and abstracts of all citations that were identified. After all
abstracts were reviewed, data comparisons between the two
investigators were conducted to ensure completeness and re-
liability. The inclusion criteria were independently applied to
all identified studies. Differing decisions were resolved by
consensus between the two authors.
Full-text versions of potentially relevant papers iden-
tified in the initial screening were retrieved. If multiple
articles from the same study were found, only the arti-
cle with the most complete data was included. Data
concerning author, year of publication, study design,
study location, participant characteristics, definition of
pSS, assessment of pregnancy-related conditions, con-
founder adjustment, and quality assessment were inde-
pendently extracted by two authors. We planned to con-
tact the authors of the primary reports to request any
unpublished data. If the authors did not reply, we used
the available data for our analyses.
Assessment of quality
A subjective assessment of methodological quality for obser-
vational studies was evaluated by two authors (SU and AS)
using the Newcastle-Ottawa Scale (NOS). The NOS is a qual-
ity assessment tool for non-randomized studies. The NOS is
based on three major components: selection of the study
groups (0–4 stars), comparability of cohorts and controls (0–
2 stars), and ascertainment of outcome (0–3 stars). Discrepant
opinions between authors were resolved by consensus. A total
score of 3 or less was considered poor, 4–6 was considered
moderate, and 7–9 was deemed high quality [6]. We excluded
poor-quality study in the sensitivity analysis. Discrepant opin-
ions between authors were resolved by consensus.
Statistical analysis
We performed meta-analysis of the included studies using
Comprehensive Meta-Analysis 3.3 software from Biostat,
Inc. We calculated pooled effect estimate of mortality with
95 % confidence interval (CI) comparing between group of
SIRS or pSS and individuals without pSS. We used effect size
(OR, HR, RR) from univariate or, if available, multivariate
models with confounding factors adjusted in each study. We
reported the pooled effect estimate of a change in outcome
using a fixed effects model if I2 < 50 % and a random-effects
model if I2 ≥ 50 %. The heterogeneity of effect size estimates
across these studies was quantified using the Q statistic, its p
value, and I2 (P < 0.10 was considered significant). A value of
I2 of 0–25 % indicates insignificant heterogeneity, 26–50 %
Clin Rheumatol

low heterogeneity, 51–75 % moderate heterogeneity, and 76– Quantitative results (meta-analysis)
100 % high heterogeneity [7].
Stillbirth

Three studies [8–10] were included in the meta-analysis of

Results
Description of included studies
The initial search yielded 210 articles (Item S2); 203 articles
were excluded based on title and abstract review (not original
observational studies—86 articles), did not include partici-
pants with pSS (93 articles), or did not have pregnancy-
related complication outcomes (24 articles). A total of seven
articles underwent full-length review, and data were extracted
involving a total of 1920 participants for qualitative analysis
[1, 8–13]. The characteristics of the seven extracted studies
included in this review are outlined in Table 1.
stillbirth using a random-effects model. The pooled odds ratio
was 1.05 (95 % confidence interval [CI] 0.37–2.97). The sta-
tistical between-study heterogeneity was high with an I2 of
0 %, P = 0.73 (Fig. 1).
Artificial abortion
Three studies [8, 10, 11] were included in the meta-analysis of
artificial abortion using a random-effects model. The pooled
odds ratio was 1.16 (95 % confidence interval [CI] 0.52–
2.61). The statistical between-study heterogeneity was high
with an I2 of 79 %, P = 0.01 (Fig. 2).

Quality assessment of included studies Premature birth

The quality of included studies was evaluated by NOS (Table 1).
Total score ranged from 5 to 7. Skopouli, Julkunen, and Priori
et al. had the lowest quality (total score = 5). Takaya et al. had the
highest quality (total score = 7). None of the studies was exclud-
ed from meta-analysis because of having poor quality.
Five studies [1, 8–10, 13] were included in the meta-analysis
of premature birth using a random-effects model. The pooled
odds ratio was 2.10 (95 % confidence interval [CI] 0.59–
7.46). The statistical between-study heterogeneity was high
with an I2 of 59 %, P = 0.05 (Fig. 3).

Table 1 Characteristics of included studies

Study (year) Study design Source of population N Age Outcome assessment Quality assessment
(Newcastle-Ottawa
Scale)

Siamopoulou- Retrospective General population 154/419 48 ± 9 Premature delivery, SA, stillbirth, Selection: 3
Mavridou et study fetal loss, comparability: 1
al. [9] outcome: 2
Takaya et al. Retrospective General population 40/1147 42.6 ± 9.2 SA, premature delivery, artificial Selection: 3
[8] study abortion, stillbirth comparability: 2
outcome: 2
Skopouli et al. Retrospective Outpatient rheumatology 98/385 50.67 ± 10.99 SA, stillbirth, premature delivery, Selection: 3
[10] study division of Ioannina induced abortion, total fetal loss comparability: 1
Medical School outcome: 1
Julkunen et al. Retrospective NR 105/249 NR Fetal loss, SA, premature delivery, Selection: 2
[12] study IUGR, stillbirth comparability: 1
outcome: 2
Hussein et al. Case–control Malmo University Hospital NR/96 33.6 Miscarriage, premature delivery, Selection: 3
[13] LBW, SGA, fetal death, CHB comparability: 2
outcome: 1
Priori et al. Case–control Multicenter (four referral 245/484 59 Miscarriage, fetal death, neonatal Selection: 3
[11] centers) cohort death, induced abortion, preterm comparability: 1
delivery, CHB outcome: 1
Carolis [1] Electronic Tertiary referral center NR/170 34.8 SA, stillbirth, preterm delivery, fetal Selection: 3
case loss, IUGR, LBW, induced comparability: 1
records abortion outcome: 2

Fig. 1 Forest plot assessing risk of stillbirths in individuals with primary
Sjögren’s syndrome. Square data markers represent ORs; horizontal
lines, the 95 % CIs with marker size reflecting the statistical weight of
Total fetus loss
Four studies [9–12] were included in the meta-analysis of total
fetus loss using a random-effects model. The pooled odds
ratio was 1.77 (95 % confidence interval [CI] 1.28–2.46).
The statistical between-study heterogeneity was high with an
I2 of 0 %, P = 0.46 (Fig. 4).
Sensitivity analysis and publication bias
Sensitivity analysis, meta-regression, and publication bias
were not performed because there were too few included stud-
ies in the analysis.
Discussion
Our systematic review and meta-analysis found that pSS is
associated with about a 1.7-fold increased odds of neonatal
deaths. However, our current understanding is that pregnancy
outcomes among patients with pSS are generally similar to
those of healthy women. This is because pSS often starts
post-menopause, and therefore, pregnancies are not frequent
[14]. A recent retrospective cohort study [15] reported that
positive anti-Ro/SSA in addition to antiphospholipid syn-
drome (APS) was associated with fetal loss (OR = 6.41
Fig. 2 Forest plot assessing risk of artificial abortion in individuals with
primary Sjögren’s syndrome. Square data markers represent ORs;
horizontal lines, the 95 % CIs with marker size reflecting the statistical
Clin Rheumatol
the study using random-effects meta-analysis. A diamond data marker
represents the overall OR and 95 % CI for the outcome of interest
(95 % CI = 1.57–26.14), P = 0.018); otherwise, it did not affect
pregnancy outcomes. Those who have anti-Ro antibodies are
at risk for giving birth to babies with neonatal lupus [11].
Multiple studies have confirmed that fertility is not affected
by pSS [8, 10, 13]. Besides that, limited studies were conduc-
ted to find the correlation between pSS and pregnancy
outcomes.
A recent population-based cohort study in December 2015
[16] included patients with rare autoimmune diseases
(polyarteritis nodosa, polymyositis, dermatomyositis, system-
ic sclerosis, Sjögren’s syndrome, Behcet’s disease) from 2001
to 2011 but excluded SLE and rheumatoid arthritis (RA).
They have concluded that pregnant women with rare autoim-
mune diseases had significantly higher incidence per pregnan-
cy of pregnancy hypertension, antepartum hemorrhage, and
severe maternal morbidity (respiratory failure, cerebrovascu-
lar hemorrhage, shock, and cardiac arrest). They also had
higher likelihood of perinatal deaths (stillbirth and neonatal
death), labor induction, and cesarean delivery even though
the majority of them delivered healthy infants. However, it is
noteworthy that patients in the pSS subgroup of this study [16]
were shown to have a non-statistically significant increased
risk of aforementioned morbidity. The only significant find-
ings were increased risk of labor induction, cesarean delivery,
and severe maternal morbidity. No concordance of outcome
was noted comparing our study to this study, but they also
weight of the study using random-effects meta-analysis. A diamond data
marker represents the overall OR and 95 % CI for the outcome of interest
Clin Rheumatol
Fig. 3 Forest plot assessing risk of premature birth in individuals with
primary Sjögren’s syndrome. Square data markers represent ORs;
horizontal lines, the 95 % CIs with marker size reflecting the statistical
suggested close cooperation between women and their health
care providers to involve a multidisciplinary team throughout
the perinatal period for vigilant surveillance.
By further analysis of our study, we found that patients with
pSS have statistically higher incidence of spontaneous abor-
tion but not stillbirth in a study by Siampoulou et al. [9],
resulting in increased risk of their total fetal loss. On the other
hand, Skoupouli et al. [10] did not find an increased rate of
spontaneous abortion or stillbirth, but the rate of induced abor-
tion was significantly increased in the pSS patient group,
which is most likely the contributing factor of increased risk
of their total fetal loss. Although Julkunen et al. [12] showed
an increased rate of fetal loss, they precluded us from knowing
the incidence of spontaneous abortion and stillbirth as they did
not report them separately. Interestingly, after they [12] ex-
cluded one patient with four fetal losses, the RR of fetal loss
remained high but was no longer statistically significant.
Hussein et al. discovered a higher rate of small for gestation
age (SGA) in a pSS group that was diagnosed before pregnan-
cy. They proposed that SLE and pSS are partly overlapping
diseases. Carolis et al. [1] suggested that the mechanism of
low birth weight (LBW) could be an underlying placental
insufficiency, related to immunological disturbance [13]. To
our knowledge, the presence of anticardiolipin and
Fig. 4 Forest plot assessing risk of total fetal loss in individuals with
primary Sjögren’s syndrome. Square data markers represent ORs;
horizontal lines, the 95 % CIs with marker size reflecting the statistical
weight of the study using random-effects meta-analysis. A diamond data
marker represents the overall OR and 95 % CI for the outcome of interest
antiphospholipids can lead to placental vasculitis, vascular
thrombosis, placental insufficiency, and/or infarction.
Although these studies did not confirm the increased fetal loss
risk, the Bimmunological disturbance^ could be an explana-
tion to the increased risk of fetal loss in our study finding.
Further exploration is needed to clarify the association of im-
munological disturbance of placental and fetal viability. The
immunological disturbance can be complicated because mul-
tiple studies did not reveal the relationship between the out-
come of pregnancy and either anti-Ro, anti-La, rheumatoid
factor, antiphospholipid (aPL), anticardiolipin (aCL), ANA,
or dsDNA. However, there have been several studies trying
to address the association between aPL, aCL, anti-Ro, anti-La,
and pregnancy loss or other thrombotic events.
First of all, Schwartz et al. [17] examined the correlation
between placental growth and hCG secretion in vitro in SLE
women. They reported that the reduction in placental growth
and hCG secretion is induced by aPL antibodies but not anti-
Ro and/or anti-La, suggesting that anti-Ro and/or anti-La may
not play a role in the placental growth and only cause congen-
ital heart block. In addition, the indirect link between pSS and
antiphospholipid syndrome (APS) or thrombotic disorders has
been reported in multiple studies. Chung et al. [18] reported a
3.21-fold greater risk of pulmonary embolism in a
weight of the study using random-effects meta-analysis. A diamond data
marker represents the overall OR and 95 % CI for the outcome of interest

retrospective cohort study; however, they did not report the
association between pSS and aCL, lupus anticoagulant (LA),
or anti-beta2-glycoprotein (anti-β2GP1).
Nevertheless, aPLs are the most frequently detected atypi-
cal autoantibodies in pSS [19, 20]. The prevalence of aPL
reported to be nearly 25–35 %. However, its association with
APS-related manifestations is infrequent. Ramos-Casals et al.
reported that merely 10 % had thrombotic events and 6 % had
fetal losses among 134 patients that were included in their
study. Twelve percent of their study patients had an associated
APS according to the 1999 classification criteria. The expla-
nation of high aPL prevalence in pSS patients is due to non-
covalent bond on the ELISA test related to polyclonal B cell
proliferation and hypergammaglobulinemia but not correlated
with APS or clinical manifestations of pSS [20]. Previously,
two studies [21, 22] demonstrated that the anti-phospholipid
antibodies in pSS are predominantly IgA isotypes, which are
not associated with thromboembolic events in pSS. Two other
studies [20, 23] reported that the thromboembolic events were
not correlated with aCL antibodies, but both studies had dif-
ferent conclusions regarding the thrombogenicity of
anti-β2GP1, yet the general understanding is that LA is a
marker for stroke and deep vein thrombosis, particularly in
young pSS patients [20, 24, 25]. Our study mainly addressed
the risk of fetal loss, premature birth, spontaneous abortion,
artificial abortion, and stillbirth. Based on current literature
and studies, our meta-analysis concluded that patients with
pSS have increased risk of fetal loss but no significant associ-
ation between pSS and the other aforementioned pregnancy
outcomes. Nevertheless, although we reported higher associ-
ation of total fetal loss in pSS, the majority of studies reported
increased fetal loss risk dated back to the 1990s. The studies
that were published in the 2000s mainly reported no difference
in patients with pSS. Carolis et al. argued that the previous
studies that evaluated the fetal outcome in patients with pSS
used older classification criteria and different data resources:
questionnaire and interview and delivery registry. The in-
creased interval between pregnancy and questioning,
overreporting data, and the absence of miscarriage registries
are the principal bias of these data resources. Carolis et al. also
mentioned that their findings of increased rate of spontaneous
abortion could be explained by the older age of patients versus
controls and secondly by the fact that younger patients with
pSS often suffer more severe and systemic disease, thus caus-
ing them to delay their first pregnancy until the disease sever-
ity has reduced. Similarly, the reason for increased fetal loss
risk reporting in studies from the 1990s could be due to the
fact that pregnant patients with pSS and physicians had less
understanding of pSS, and thus less multidisciplinary pre-,
peri-, or post-partum care, which led to subsequent fetal loss.
Now, with more understanding of this disease, patients with
pSS would want to delay their plan of pregnancy and hence
reduce fetal loss.
Clin Rheumatol
Further study is warranted to investigate the outcome dif-
ference before versus after pSS being diagnosed. The studies
that reported increased risk of total fetal loss did not report
such data. On the contrary, other studies reported no difference
of pregnancy outcome regardless of the timing of diagnosis.
However, due to small sample sizes in these studies, further
study is needed. The other limitation of our study includes
negative pregnancy outcomes such as IUGR, SGA, and
LBW, which were not addressed in our study due to too few
studies. Nonetheless, we concur with the study by Chen et al.
[16] to involve multidisciplinary health care providers to pre-
vent adverse pregnancy outcomes.
In conclusion, fetal loss in patients with pSS may be in-
creased. The presented evidence supports multidisciplinary
care for these patients to prevent complications during preg-
nancy. The coexistence of pSS and APS should be considered
an infrequent (but not exceptional) event [19] because even
though studies that were included in our meta-analysis did not
find a correlation between aPL and pregnancy loss, there are
risks of pregnancy loss if patients are LA and/or anti-β2GP1
positive. Furthermore, it is also crucial to notify patients about
risk of congenital heart block or neonatal lupus if patients are
positive for anti-Ro and anti-La. Further understanding of the
underlying pathophysiological changes of the mother, placen-
ta, and/or fetus in patients with pSS could help to reduce the
likelihood of fetal loss or other negative pregnancy outcomes.
Compliance with ethical standards
Fund support None.
Conflict of interest The authors declare that they have no conflicts of
interest.
Ethical approval This article does not contain any studies with human
participants or animals performed by any of the authors.
Informed consent No informed consent.
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