The implications of autoimmunity and pregnancy
Andrea T. Borchers, Stanley M. Naguwa, Carl L. Keen, M. Eric Gershwin*
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA
a b s t r a c t
There are multiple epidemiological studies that document the potential adverse affects of autoimmunity
on nearly every aspect of reproduction, even in the absence of clinically manifest autoimmune disease.
Two decades ago, it was suggested that women with autoimmune diseases avoid pregnancy due to
inordinate risks to the mother and the child. In contrast, newer epidemiological data demonstrated that
advances in the treatment of autoimmune diseases and the management of pregnant women with these
diseases have similarly improved the prognosis for mother and child. In particular, if pregnancy is
planned during periods of inactive or stable disease, the result often is giving birth to healthy full-term
babies without increased risks of pregnancy complications. Nonetheless, pregnancies in most autoim-
mune diseases are still classified as high risk because of the potential for major complications. These
complications include disease exacerbations during gestation and increased perinatal mortality and
morbidity in most autoimmune diseases, whereas fetal mortality is characteristic of the anti-phospho-
lipid syndrome (APS). In this review, we will discuss these topics, including issues of hormones, along
with potential long-term effects of the microchimerism phenomenon. With respect to pregnancy and
autoimmune diseases, epidemiological studies have attempted to address the following questions: 1) Is it
safe for the mother to become pregnant or are there acute or chronic effects of pregnancy on the course
of the disease? 2) Does the disease alter the course and/or the outcome of a pregnancy and thereby
represent an inordinate risk for the fetus and infant? And do new therapeutic and management
approaches improve the pregnancy outcomes in women with autoimmune diseases? 3) Does passage of
maternal autoantibodies represent a risk to the child? 4) Do pregnancy, parity, or other factors influ-
encing hormonal status explain the female predominance of many autoimmune diseases, and is the
pregnancy effect related to microchimerism? Answering these questions has taken on additional
importance in recent decades as women in western countries now frequently choose to delay preg-
nancies and have some or all of their pregnancies after disease onset. In this paper, we primarily focus on
APS, systemic lupus erythematosus (SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1
? 2009 Elsevier Ltd. All rights reserved.
It is increasingly recognized that autoimmunity even in the
absence of clinically manifest autoimmune disease can affect
every aspect of pregnancy, beginning with fertilization, and can
contribute to maternal complications and adverse fetal outcomes.
By examining associations between specific autoantibodies and
pregnancy-related processes, epidemiology has an important role
in identifying potentiallypathogenic autoantibodies (and rulingout
the involvement of others). Most autoimmune diseases occur much
more frequently in women than in men, with female:male ratios
ranging from w2:1 in MS and w3:1 in RA to w10:1 in systemic
lupus erythematosus SLE, 12:1 in APS, and possibly even higher
(up to 16:1) in primary biliary cirrhosis (PBC). This suggests
the possibility that sex hormones influence the development of
autoimmunity. Dramatic changes in the levels of estrogens and
progesterone, but also cortisol, norepinephrine, and dehydroepian-
drosterone, occur during pregnancy. At the same time, and partially
under the influence of these hormones, there are profound immu-
period. These immunological changes are required in order to
accommodate the semiallogeneic fetus and include immunosup-
milieu is required for successful implantation and the subsequent
vascular and tissue remodeling of the uterus, later gestation is mainly
a Th2-dominated state.
Both the hormonal and immunological changes have marked
effects on the course of autoimmune disease, and the nature of the
* Corresponding author. Tel.: þ1 530 752 2884; fax: þ1 530 752 4669.
E-mail address: firstname.lastname@example.org (M.E. Gershwin).
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Journal of Autoimmunity 34 (2010) J287eJ299
disease determines whether these effects are detrimental or
beneficial. In turn, the disease course during gestation and the
underlying immunological and possibly hormonal abnormalities of
the disease may affect the course and outcome of the pregnancy.
2. Autoimmunity and fertility, pregnancy complications,
and adverse fetal outcomes
A large variety of autoantibodies have been investigated for
their potential associationwith unexplained infertility e oftenwith
inconclusive results . For example, there is little evidence in
support for a role of autoimmunity in isolated premature ovarian
failure, one of the major causes of female infertility. Of note, fertility
does not appear to be impaired in most autoimmune diseases,
except in women treated with cytotoxic agents, particularly cyclo-
phosphamide, or high-dose corticosteroids, or suffering from renal
insufficiency. This even holds for women with SLE, a disease char-
acterized by high prevalence rates of some of the autoantibodies
that have been implicated in infertility (e.g. anti-dsDNA and anti-
nuclear antibodies in w90% and anti-phospholipid antibodies (aPL)
however, that autoimmunity plays a major role in premature
ovarian failure associated with endocrine autoimmune diseases,
such as thyroid disease or Addison's disease [1,2].
A considerable variety of non-organ-specific autoantibodies also
have been implicated in pregnancy losses, although the results for
many of them are contradictory . Notable exceptions are aPL and
anti-thyroid antibodies. As will be discussed in more detail below,
recurrent spontaneous abortions are one of the diagnostic criteria
of the APS. Even in the absence of APS, the association between aPL
and fetal loss is well documented, though it is not observed in all
investigations. Numerous studies from the US, various European
regions, some Asian countries and Brazil have investigated the
association between thyroid autoimmunity and miscarriage. The
vast majority of these studies indicates that the presence of thyroid
autoantibodies even in the absence of clinical or subclinical thyroid
dysfunction increases the risk of miscarriage, particularly of preg-
nancy losses occurring in the first trimester. There appears to be
considerable geographic variation in the prevalence of thyroid
autoantibodies. Nonetheless, there is no discernible pattern in the
geographic distribution of studies that did not find a significant
association. A meta-analysis yielded a total odds ratio of 2.73 (CI
2.2e3.40) for eight case-control studies, and of 2.30 (CI 1.80e2.95)
for 10 prospective cohort studies . Interestingly, higher autoan-
tibody titers do not confer an increased risk of miscarriage or
spontaneous abortion. Whether the observed association reflects
a causal relationship remains to be determined. It is also possible
that the presence of thyroid autoimmunity is an epiphenomenon or
marker for an underlying more general activation of the immune
system, is an indicator of subtle thyroid hormone deficiency, or
reflects the significantly higher age of women with thyroid anti-
bodies, age being an independent risk factor for miscarriage.
One of the most severe complications of pregnancy is
preeclampsia, which affects 1e5% of pregnancies worldwide in
otherwise healthy women, the frequency being much higher in
a variety of autoimmune diseases, e.g. APS, T1D, SLE, systemic
sclerosis, RA, and other connective tissue diseases. Several auto-
antibodies have been investigated for their association with
preeclampsia, but the strongest evidence exists for aPL, although
evidence in women without autoimmune diseases is inconsistent
[5,6]. In addition, much recent interest has focused on autoanti-
bodies that stimulate the angiotensin II type 1 (AT1) receptor .
Several lines of evidence suggest a pathological role for these
autoantibodies in preeclampsia: 1) their ability to activate the AT1
receptor on a variety of cell types has been shown to result in
biological responses that are known to participate in the vascular
and placental abnormalities characteristic of preeclampsia; 2) they
induce clinical features of preeclampsia when transferred into
inwomenwith preeclampsia and are detectable before the onset of
this condition and remain detectable post-partum in some women
. Unfortunately, all available prevalence data come from German
women, although anti-AT1 antibodies also have been detected
in women from the US and the UK . There are also several
arguments against a causal role of these antibodies in the devel-
opment of preeclampsia: 1) their titers do not correlate with
confirmed markers of preeclampsia; and 2) they are not specific to
this condition. These findings suggest that they are markers for this
pregnancy complication rather than being causally involved in it.
Nonetheless, it remainspossible thattheyhaveapathological role if
combined with some other factor(s).
There are also indications that autoantibodies can affect preg-
nancy outcomes. Once again, the most convincing evidence exists
for associations between aPL or thyroid autoimmunity and preterm
delivery . In addition thyroid autoantibodies have been impli-
cated in lower birth weight and in perinatal mortality. Numerous
other associations have been suggested but the data are as yet
3. Autoimmune diseases and pregnancy
3.1. Anti-phospholipid syndrome
APS is characterized by thrombosis or pregnancy complications
in the presence of aPL. The Sapporo preliminary classification
criteria for APS published in 1999 as well as the revised Sydney
criteria from 2006 require the presence of at least one clinical
criterion, either vascular thrombosis or pregnancy morbidity, in
combination with at least one laboratory criterion . The labo-
ratory criteria are a) positivity for lupus anticoagulant (LAC),
b) medium or high titer anticardiolipin (aCL) of the IgG and/or IgM
isotype, and c) positivity for anti-b2-glycoprotein 1 (anti-b2GPI) of
the IgG and/or IgM isotype, the latter were added as part of the
Sidney revisions. APS is called primary when it occurs in the
absence of other autoimmune diseases and is still commonly
referred to as secondary if it is present in conjunction with other
autoimmune diseases, primarily SLE, but also SS, RA, SSc, systemic
vasculitis and dermatomyositis. (For simplicity, we will refer to this
subgroup as APS/SLE). The revised Sydney classification criteria
discourage the use of the term “secondary” because it is unclear
whether SLE or other connective tissue diseases provide a setting
for the development of APS or whether they each represent
independent disease entities coinciding in the same individual.
Information on the incidence, prevalence and demographics of
APS are rare, but data from a recent European multicenter study of
1000 APS patients (the Euro-Phospholipid Project) and a Spanish
and a Latin American cohort of 100 patients each indicate that APS
occurs slightly more frequently in the absence than in the presence
of other autoimmune diseases [12e14]. More specifically, between
53 and 62% of patients were found to have primary APS (pAPS),
while 38e41% had APS associated with SLE or lupus-like syndrome
(fulfilling only 2e3 ACR criteria for SLE), the remainder being
divided between other connective tissue diseases. Like most auto-
immune diseases, APS is more common in women than in men, the
overall female to male ratio being 5 or 6:1 in the European cohorts,
but 13:1 in Latin American patients. Interestingly, the female:male
ratio for pAPS was 3.5:1 in Europe, but 12:1 in Latin America
[12,15]. Mean age of onset was between 28 and 36 years for the
various European and Latin American cohorts, with a vast majority
of cases reported to occur between the ages of 15 and 50 years .
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
This indicates that women in their childbearing years are
3.1.1. Pregnancy morbidity
The specific pregnancy morbidity criteria for APS are a) one or
more unexplained deaths of a morphologically normal fetus at or
beyond the 10th week of gestation; b) one or more premature
births of a morphologically normal neonate beforethe 34th weekof
gestation because of either eclampsia or severe preeclampsia or
placental insufficiency; or c) three or more unexplained consecu-
tive spontaneous abortions before the 10th week of gestation in the
absence of anatomic, hormonal or chromosomal causes. This
highlights one of the major differences between APS and other
autoimmune diseases: whereas other autoimmune diseases may
affect the course of pregnancy, pregnancy morbidity is a manifes-
tation and a defining feature of APS. While late fetal loss is
considered to be more characteristic of APS, recurrent early fetal
loss is more common.
Before the advent of treatment, the prognosis for pregnancies in
APS patients was dismal, with only 10% or less of all pregnancies
resulting in live births [16,17], although others have reported
somewhat better outcomes. It has become common practice to
treat pregnant APS patients or SLE patients with aPL even in the
absence of clinical manifestations of APS with low-dose aspirin
alone or in combinationwith heparin, but considerable controversy
remains as to the most appropriate approach . Since the
introduction of such preventive regimens, the pregnancy outcome
among women with APS has improved dramatically. This is
partially reflected in the data from the Euro-Phospholipid cohort,
where the live birth rate was 47.7% in 590 women who had been
pregnant . As summarized in Table 1, the live birth rate in Latin
American women was very similar, even though the study period
was considerably later [14,15]. Interestingly, however, there were
significant differences in the distribution of fetal losses. Mexican,
Ecuadorian, and Colombian women with APS experienced early
pregnancy loss significantly more often than their European
counterparts, whereas their late pregnancy loss rate was lower, the
latter reaching statistical significance only in patients with pAPS
[14,15]. During a further 5 years of follow-up, the live birth rate in
the European cohort improved significantly to 76.2%, with earlyand
late pregnancy losses occurring in 17.1% and 6.7% of pregnancies,
respectively . This is consistent with numerous other studies
showing success rates of 70e80% in pregnancies of women with
APS who receive aspirin alone or in combination with heparin or
other preventive regimens.
While the pregnancy outcome has improved significantly in
recent years, the complication rates remain high. Typical compli-
cations in women with APS are preeclampsia/eclampsia, intra-
uterine growthrestriction (IUGR),prematureruptureof membrane,
Cesarean delivery and premature delivery, the latter being
primarily due to preeclampsia/eclampsia or placental insufficiency.
Overall, the reported rates of preeclampsia range between 0 and
51% and those for preterm delivery between 32 and 65% . The
Euro-Phospholipid study revealed preeclampsia in 9.5%, eclampsia
in 4.4%, premature rupture of membranes in 2.0%, and post-partum
cardiopulmonary syndrome in 0.5% of pregnancies . A
substantial numberof babiesisbornsmall forgestationalage(SGA).
As summarized in Table 1, the rates for hypertensive disorders and
premature delivery were similar in the South American cohorts.
Premature delivery was seen in 10.6% of the European pregnancies,
but this figure rose to 35% in the pregnancies that occurred during
follow-up, . In addition, IUGR occurred in 13.7% of pregnancies.
An analysis of nationwide obstetric hospitalization data in the USA
similarly showed that women with APS had a significantly
increased frequency of hypertensive disorders (13.0%), IUGR (5.1%),
premature rupture of membranes (1.8%) and cesarean delivery
(44.6%) compared to the general obstetric population . Women
with APS were significantly older, but even after adjusting for age,
their risk of these pregnancy complications remained significantly
elevated. There are indications that the complication rates, partic-
ularly for preterm delivery, giving birth to an SGA baby and
preeclampsia, are higher in women who have thrombotic mani-
festations of APS .
3.1.2. Possible effects of pregnancy morbidity on the disease course
From the limited available data, it is difficult to determine
whether recurrent pregnancy loss represents a risk factor for
subsequent thrombosis in APS patients. One of the few prospective
studies examining this issue used a definition of ?2 miscarriages as
recurrent pregnancy loss and compared patients with aPL with or
without clinical manifestations of APS . In this investigation,
miscarriages were not significantly associated with the subsequent
occurrence of thrombosis, whereas a history of vascular disease
constituted a risk factor for subsequent miscarriages. This is
consistent with other observations, including the finding from the
Euro-Phospholipid cohort, where only 2.5% of women with
exclusively obstetric APS manifestations at study begin developed
a thrombotic event during 5 years of follow-up [19,24]. These
findings are in marked contrast to the results of a retrospective
analysis of data from three tertiary referral centers in the USA on
65 patients whose only clinical manifestation for the diagnosis of
APS was recurrent pregnancy loss . This subgroup of APS
patients was found to be at high risk of subsequent thrombosis,
particularly when not continuously treated with low-dose aspirin
for the prevention of thrombotic events. Specifically, the non-
aspirin-treated group of 34 patients had 20 events, including
7 venous thromboses, 5 strokes, and 5 transient ischemic attacks,
during a mean follow-up of w8 years, resulting in an event rate of
7.4/100 patient-years, whereas the aspirin-treated group had an
event rate of 1.3/100 patient-years. Mean duration from initial
pregnancy loss to clinical event was 4.2 years. Of note, pregnancy
and the post-partum period may also represent a time of particular
susceptibility to catastrophic APS (for more details, the reader is
referred to [26,27]).
3.1.3. Antibodies in APS
The diagnosis of APS is first and foremost clinical. At the same
time, it is crucially dependenton serological markers because of the
Pregnancy morbidity in women with APS.
CountryStudy periodNo. of patients/
Europe (13 countries)
Europe (13 countries)
Mexico & Ecuador
Mexico, Ecuador, and Colombia e pAPS
Euro-Phospholipid e pAPS
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
high prevalence of thrombosis and pregnancy complications in the
generally population. The classical aPL, LA and aCL, remain the
major serological markers of APS. These antibodies were originally
thought to bind directly to negatively charged membrane phos-
pholipids. It has since become recognized that aPL constitute
a heterogeneous group of antibodies that recognize negatively
charged phospholipids, phospholipid-binding plasma proteins or
complexes of the two. It is now widely accepted that the major
target antigen of aCL and many LA is b2-glycoprotein I (b2GPI).
Other plasma proteins that are targets of the humoral response in
In addition, a long list of other autoantibodies have been identified
in APS patients . It should be pointed out that, despite efforts
to standardize assays for LA, aCL and anti-b2GPI, inter-assay and
inter-laboratory agreement remains rather poor due to calibration
and other methodological issues, but mainly because the cut-off
values for positivity vary widely.
The inclusion of anti-b2GPI antibodies among the laboratory
criteria for the classification of APS did not find unanimous
support, and their utility in comparison to LA or aCL remains
controversial. However, b2GPI is a potent natural anticoagulant
and this activity appears to be abrogated by anti-b2GPI antibodies.
Therefore, enhanced uteroplacental thrombosis could be one
mechanism by which these antibodies affect pregnancy outcome.
In addition, b2GPI is expressed by the trophoblast starting at 7
weeks of gestation, and anti-b2GPI antibodies have been shown to
be capable of binding to trophoblast cells in vitro. Furthermore,
these antibodies have been implicated in abnormal trophoblast
proliferation and placentation, and inflammatory mechanisms may
play a role in these processes [29,30]. Together, these findings
suggest a pathogenic role for these autoantibodies in the obstetric
manifestations of APS. This has prompted numerous investigations
of the possible association between anti-b2GPI antibodies and
pregnancy morbidity, with highly varying results. In a group of
Viennese women who were persistently positive for LA, anti-b2GPI
antibodies were significantly associated with pregnancy loss .
This is consistent with earlier findings from Argentine women
whose APS was diagnosed because of recurrent fetal loss and who
were compared with parous womenwho were also positive for aCL
and/or LA, but had no history of reproductive problems .
A significantly higher frequency of IgM anti-b2GPI distinguished
the women with a history of recurrent fetal from those without
reproductive failure. In addition, the subgroup with late pregnancy
loss showed higher levels of IgM aCL as well as IgM and IgG anti-
b2GPI. The same group of researchers found IgM anti-b2GPI to be
significantly associated with fetal loss in a group of aPL-positive
patients with various clinical manifestations of this syndrome .
In contrast, others reported that the IgG isotype of anti-b2GPI was
associated with fetal loss in patients with either pAPS or APS/SLE,
whereas IgM was not . In a study from the UK, women who
were persistently positive for aPL and had experienced recurrent
fetal loss had a similar frequency of anti-b2GPI as women with
recurrent fetal loss who were persistently negative for aPL or
healthy controls . Similarly conflicting results have been
obtained in investigations of SLE patients with or without APS or
aPL. In Colombian and Spanish SLE patients, IgG anti-b2GPI, but not
IgM, correlated with a history of fetal loss , and a very strong
association between IgG anti-b2GPI (IgM was not investigated) has
also been reported from Thailand . In contrast, others did not
detect any significant association in a large US cohort , and
smaller cohorts from India or Japan [38,39].
The results of a recent meta-analysis do not support a role for
anti-b2GPI (IgM or IgG) in recurrent pregnancy loss in women
without autoimmune diseases  and this is consistent with more
recent studies from Italy, the Czech Republic, Israel and Tunisia
[41e44]. However, there are data suggesting that anti-b2GPI of the
IgA isotype is significantly associated with ?3 pregnancy losses at
less than 10 weeks of gestation or unexplained fetal death at >10
weeks of gestation . Both the frequency and the levels of IgA
anti-b2GPI were found to be higher in these women compared to
normal parous women. In another study, however, IgA anti-b2GPI
was not associated with recurrent pregnancy loss . In Tunisian
women, positivity for anti-b2GPI did not correlate with recurrent
pregnancy loss overall, but the IgM isotype showed a significant
association with early pregnancy loss, while IgG was associated
with late pregnancy loss [46,47]. In addition, the results of a large
prospective trial in women with 510 healthy pregnant women
indicated that anti-b2GPI antibodies were significantly associated
with preeclampsia/eclampsia even in the absence of LA or aCL .
Of note, the Sidney criteria now recognize that multiple posi-
tivity for aPL confers a risk factor for more severe manifestations of
APS . In a group of 53 Italian women with APS and positive for
aCL and anti-b2GPI, additional positivity for LA (triple positivity)
was significantly associated with late pregnancy loss . Triple
positivity also correlated with the presence of thromboembolic
events, and the combination of such an event and triple positivity
was found to be an independent predictor of another unsuccessful
pregnancy during a mean duration of follow-up of 6.3 years. Similar
findings were reported in another study from the same center,
which included 79 APS patients with 97 pregnancies . Patients
with triple positivity were found to have a significantly higher rate
of pregnancy loss compared to women with double positivity (aCL
and anti-b2GPI without LA). Although it was also higher compared
to single positive patients, the difference did not reach statistical
It is currently impossible to determine to what extent ethnic
differences contribute to these discrepancies. Too many other
factors make direct comparison between these studies impossible.
These include differences in patient selection, the definition of
recurrent pregnancy loss, assay methods for detecting anti-b2GPI
and the cut-off values used for determining positivity. Of note,
a group of European researchers recently provided rather
convincing evidence that the most relevant anti-b2GPI antibodies
are those recognizing domain I of this protein . Using sera from
200 women from nine tertiary rheumatology centers in Europe, it
was shown that this subset of anti-b2GPI antibodies correlated
significantly with two of the three obstetric criteria of APS, namely
fetal death beyond the 10th week of gestation and a history of
premature birth(s) before the 34th week of gestation due to
preeclampsia or placental insufficiency. When using an assay that
detects antibodies against the complete b2GPI protein, these
researchers did not observe a significant association with any
obstetric APS criteria. Whether this domain dependence provides
an explanation for some of the observed discrepancies remains to
Data for antibodies to other phospholipid-binding proteins that
are not included among the laboratory criteria for the classification
of ASP are equally inconsistent. While some studies identify anti-
prothrombin antibodies as a strong risk factor for early pregnancy
loss in APS patients [39,43], others do not detect a significant
association in APS or SLE patients [31,32,51] or women with
recurrent miscarriages in Italian women . Anti-annexin V
antibodies have been found to be significantly associated with
recurrent miscarriage in studies from such geographically diverse
areas as Italy, Tunisia, and Japan [39,41,44,46,52], but this is not
a consistent finding either [34,53]. Finally, the results from a large
Czech study indicate that antibodies against various negatively
charged phospholipids, in particular phosphatidylinositol and
phosphatidylserine, were significantly more frequent in women
with ?3 miscarriages or repeated in vitro fertilization failure .
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
3.1.4. Prevalence, isotype distribution, and clinical associations
of aPL in different populations
The prevalence of LAC and aCL in the general population shows
considerable geographic variation, ranging between of 0.3% and
w4% for LAC in subjects from the USA, Canada, various European
and some Arab countries. Interestingly, a much higher prevalence
(7%) was recently reported from healthy parous Tunisian women
. The corresponding figures for aCL are 1e4% for IgG, 0.5e5%
IgM, and 2e5% for IgG/IgM combined. In patients with APS or SLE,
there are at least equally pronounced geographical or ethnic
differences in the prevalence and isotype distribution of aPL, and
these are accompanied by differences in their clinical associations.
The frequency of aCL positivity in SLE patients of European descent
generally ranges between 25% and 40%, but appears to be signifi-
cantly lower in Asian cohorts , while markedly higher rates
(>70%) have been reported in patients from several Arab countries
[55,56], though not in others [57,58]. Whereas earlier data from
India indicated a similarly low prevalence of aCL as observed in
other Asian cohorts, a more recent analysis reported detection of
aCL in of 51% in Indian SLE patients . Although all were positive
for IgG either alone or in combination with other isotypes, only the
presence of seizures was associated with aCL (or anti-b2GPI)
positivity, whereas venous thrombosis was rare in this population,
and neither thrombosis nor recurrent pregnancy loss showed an
association with either of these antibodies . A significantly
lower prevalence of any aPL (LAC or aCL) has also been reported for
Chinese SLE patients compared to non-Chinese patients from the
USA (African American of European ancestry), and this correlated
with a markedly lower frequency of venous thrombosis .
Positivity for aCL and/or LA is a criterion for the diagnosis of APS,
and isolated anti-b2GPI positivity is relatively rare. Consequently,
the prevalence of the classical aPL is high among APS patients.
Among the 1000 participants of the Euro-Phospholipid Project,
more patients had aCL (87.9%) than LA (53.6%) . Two studies
from Latin America used the same protocol for the assessment of
clinical and laboratory characteristics as the Euro-Phospholipid
Project, allowing direct comparison of the results. These showed
that mestizo APS patients from Mexico and Ecuador had a very
similarfrequencyof aCLpositivityoverall (88.1%), buta significantly
lower proportion of patients was positive for the IgG isotype of
aCL alone (22% versus 43.6%) . In addition, significantly fewer
mestizo patients had LA (38.5% versus 53.6%). Interestingly,
a comparison between patients with pAPS from Mexico, Ecuador,
and Colombia with pAPS patients from the Euro-Phospholipid
Project did not reveal any significant differences in the frequency
and isotype distribution of aPL, except that aCL of the IgM isotype
was less prevalent among Europeans compared to Latin Americans
. This was not observed in a direct comparison of Colombian
patient groups differed in the frequency and isotype distribution
of anti-b2GPI antibodies, with IgG being the major isotype in
Colombians and IgM predominating in Spaniards. Notably, both IgG
aCL and IgG anti-b2GPI were associated with thrombosis and
fetal loss in Colombian as well as Spanish SLE patients; however
they were additionally associated with livedo reticularis among
Spaniards, but with thrombocytopenia in Colombians. There are
numerous indications that IgA is the most frequent isotype of aCL
and anti-b2GPI antibodies in African American as well as South
African APS and SLE patients [37,51,60,61]. Although generally aCL
and/oranti-b2GPI of the IgG isotype are most strongly implicated in
the clinical manifestations of APS, in two of these studies IgA aCL
was found to be associated with thrombosis, but not with recurrent
pregnancy loss in African American patients , and with any
clinical APS manifestation in South African patients . Unfortu-
nately, aCL, LA, or anti-b2GPI of the IgA isotype are not routinely
measured, and other data on their association with clinical mani-
festations are limited and controversial.
It is obvious that ethnic differences in the prevalence and iso-
type distribution could account for some of the disparities seen in
the rates of pregnancy complications reported in cohorts from
different geographical areas and for some of the discrepant results
obtained in investigations of the clinical association of various aPL.
Unfortunately, the patient selection criteria and the assay tech-
niques used are too variable to allow determination of the extent to
which ethnic differences may play a role.
220.127.116.11. Systemic lupus erythematosus. SLE is a systemic autoim-
mune disease that affects primarily women in their childbearing
years, the female:male ratio being w10:1. The presence of SLE was
long thought to be a contraindication to pregnancy since early
studies indicated that the disease represented a high risk of
detrimental outcomes to both the mother and the fetus. With the
advent of more effective therapeutic regimens, the outlook has
improved considerably in recent decades. Only women with SLE
who have pulmonary hypertension and renal failure are still
strongly advised not to become pregnant because of the high risk
of mortality to both the mother and child. Actually the effect of
pregnancy on disease activity has long been and remains a matter
of debate. The proportion of women experiencing flares during
pregnancy varies enormously between studies, ranging from 2% in
Indian and 4% in a Portuguese SLE patients to 85% in a Brazilian
cohort that included almost 40% of patients with probable or
possible SLE (see also Table 2). Relatively few studies compared the
flare frequency during pregnancy and post-partum to that of the
pre- or post-pregnancy period or to that in a control group of non-
pregnant SLE patients. The results are quite variable, with
prospectively gathered data from a US cohort (the Hopkins lupus
cohort) indicating that flare frequency increases during pregnancy
regardless of whether patients serve as their own controls or are
compared to a control group of non-pregnant patients with SLE
. Similar results have been reported from a Spanish cohort .
In contrast, disease exacerbations occurred with similar frequency
in pregnant (13.5%) and non-pregnant Greek SLE (22%) patients
. A major cause of these discrepancies is likely to be the lack of
a standardized definition of flare.
There is considerable variability in the types and frequencies of
pregnancy complications that have been reported in SLE in the
literature. In addition, direct comparisons with healthy controls are
rarely included. Notable exceptions are two analyses of nationwide
obstetric hospitalization data in the US. These studies demonstrate
that women with SLE were significantly older than controls but,
even after adjusting for age, were at increased risk of hypertensive
disorders including preeclampsia, cesarean delivery, preterm
delivery and IUGR compared to the general obstetric population
[21,65]. Other fetal outcomes could not be assessed in these studies.
In addition, SLE was associated with a markedly elevated risk of
infection, thrombosis and thrombocytopenia and, most notably, an
almost 18-fold higher risk of maternal mortality. These results
agree with other investigations, which in addition indicate that
pregnant SLE patients have a significantly increased frequency of
fetal loss, including spontaneous abortions, miscarriages, and
stillbirths (see alsoTable 3). Their infants more often have low birth
weight (LBW), and neonatal mortality is increased. Furthermore,
SLE patients frequently (25e65%) harbor anti-SSA/SSB antibodies,
which are tightly associated with the risk of neonatal lupus
syndrome, one of several examples of the detrimental effects that
can result from transplacental passage of maternal autoantibodies
(discussed in more detail below). Of particular note, some of the
pregnancy complications and adverse fetal outcomes are already
seen in women who only later are diagnosed with SLE .
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
A variety of risk factors for these pregnancy complications and
adverse pregnancy outcomes have been identified. Disease
activity, particularly at the time of conception and during early
pregnancy, is consistently associated with preterm delivery and
possibly IUGR. Active nephritis shows a strong association with
fetal loss, whereas a majority of investigations indicate that a past
history of lupus nephritis does not constitute a significant risk
factor for adverse pregnancy outcomes. Hypertension at concep-
tion or during pregnancy increases the risk of preterm delivery and
possibly IUGR and fetal loss. Although the association of aPL and
particularly APS with fetal loss is well established, such an asso-
ciation is seen in some, but not all, studies of pregnant SLE
patients. This may be partly due to differences in the approaches
used in treating pregnant women with aPL and APS. As discussed
above, APS is also related to preeclampsia, placental insufficiency,
prematurity and giving birth to LBW or SGA babies. There are
indications that the combination of APS and SLE results in a higher
frequency of these complications than APS alone, suggesting that
other disease-related factors contribute. Other associations that
are not as consistently examined or observed include hypo-
complementemia with spontaneous abortions and stillbirths,
proteinuria at conception with prematurity, and corticosteroids
with IUGR. The latter may be an indicator of active disease during
pregnancy requiring treatment with corticosteroids rather than an
independent risk factor.
In addition, anti-SSA/SSB antibodies were found to be signifi-
cantly associated with fetal loss in SLE patients from certain ethnic
groups [67,68], whereas others saw an association only in non-SLE
patients , did not detect anyeffect , or actually showed anti-
SSA/SSB antibodies to be protective . These discrepancies could
simply reflect random variations in the absence of a true associa-
tion. Another possibility is suggested by the finding that only
recognition of specific epitopes by anti-SSA antibodies appears to
cause congenital complete heart block. One could speculate that
such specificities are also involved in fetal loss. If these specificities
were more frequent in certain ethnic groups, this might explain
why the associations between anti-SSA/SSB antibodies and fetal
loss show such ethnic variation. Interestingly, the prevalence of
groups, with 24e40% of European and Latin American SLE patients
showing anti-SSA positivity, while rates up to 64% have been
reported from certain Arab populations [56e58]. Unfortunately,
data on pregnancy complications and outcomes are not yet avail-
able from these regions. Yet, such studies may provide important
insights into the effects of these antibodies on the course and
outcome of SLE pregnancies.
Fetal and neonatal outcomes in SLE patients (percentage of patients affected).
Country Study periodLive birthsNeonatal
Preterm deliveryIUGR LBW (<2500 g) Reference
Brazil (62% ACR)
14 20.0 
n.a. ¼ not available.
Flare frequency and pregnancy complications in SLE patients (percentage of patients affected).
Country Study period No. of patients/
Flare up to 1 year afterPreeclampsiaHypertensive
Brazil (juvenile SLE)
Brazil 62% ACR
2 puerperium, 8 later
4.1 puerperium 11 20.863.6
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
18.104.22.168. Multiple sclerosis (MS). The incidence of MS varies by
a factor of almost 20-fold between various regions of the world
(e.g. 0.61/100,000 in Japan to 10.73 in Greece in some of the most
recent studies), but appears to have increased worldwide in recent
decades. There are indications, however, that the originally iden-
tified gradient of higher incidence with increasing latitude is
diminishing. MS affects women approximately twice as frequently
as men. The peak onset is during the 3rd and 4th decades of life,
i.e., during the childbearing years. The disease is classified into
relapsing-remitting, secondary progressive and primary progres-
sive forms. More than 90% of the patients included in epidemio-
logical studies on the interactions between MS and pregnancy
have the relapsing-remitting course, while pregnancy in women
with the primary progressive course is very rare. MS is one of
the autoimmune diseases that improves during pregnancy, and
a decrease in the relapse rate during pregnancy compared to the
year preceding it has been seen very consistently in studies from
various regions of the world, including Germany, Finland, Spain,
other European countries, Iran, Brazil and Argentina (summarized
in Table 4). The most significant decrease is always observed in the
third trimester. Relapses during pregnancy generally are mild and
do not require therapy. Unfortunately, the existent data provide
little information on the course of MS during individual pregnan-
cies, which seems to be quite variable . There is also general
agreement among all recent studies that the relapse rate increases
significantly post-partum, mainly in the first 3 months after
delivery, frequently exceeding the pre-pregnancy rate. In addition,
post-partum relapses are severe in a substantial portion of patients.
The overall data indicate that the course of MS during pregnancy is
very homogeneous throughout the world, even if data from non-
Caucasian women are still rare.
The effects of MS on the course and outcome of pregnancy have
only rarely been examined. In a population-based study from the
USA (Seattle, WA) that used obstetric hospitalization data for
1987e1996, 198 women with MS were no more likely than 1584
healthy womentohavecomplicationsduring pregnancyordelivery
or to give birth to preterm or LBW infants . In previous preg-
nancies, womenwith and without MS reported similar rates of fetal
loss (spontaneous abortions and miscarriages). This is in keeping
with several smaller studies indicating that MS does not signifi-
cantly affect the course and outcome of pregnancies, although
In contrast, in population-based studies from Norway, womenwith
MS were at increased risk of cesarean delivery (though planned
and not due to emergencies) and giving birth to SGA babies or with
lower mean birth weight . An increased risk of SGA babies and
cesarean delivery was also detected in a population-based study
from Taiwan . In addition, Taiwanese MS patients were more
likely to have preterm delivery.
There is general agreement that pregnancy does not appear to
have negative effects on the long-term prognosis of MS. Indeed,
a recent study from Iran indicates that disease progression slowed
in the 5 years after childbirth, despite an increased flare rate
immediately post-partum . In addition, the results of several
investigations (from Sweden, Belgium, the Netherlands, and
Denmark) suggests that pregnancy after disease onset is associated
with less disability and a lower risk of changing from a relapsing-
remitting to a chronic progressive course. It is possible that these
findings are a reflection of the bias that could result if women who
are less disabled by MS are both more likely to become pregnant
and to have a better prognosis.
22.214.171.124. Rheumatoid arthritis (RA). The incidence of RA in women
rises with increasing age, reaches a peak around 40e50 years of age
and remains stable thereafter. As a result, while RA affects w1% of
thepopulation, it is muchless commoninwomen betweenthe ages
of 16 and 45, with a study from the UK estimating the prevalence in
this age group to be 1 or 2 per 1000. Overall, women are affected
2e3 times more frequently than men, but in women in their
reproductive years the female:male ratio exceeds 4:1. Thereis some
geographic variation in the incidence of RA, with North America
and northern Europe having higher rates compared to southern
Europe and developing countries.
According to a considerable number of both retrospective and
prospective studies, dating mostly from the 1950s and 1960s,
a majority (>70%) of women with RA reported considerable
improvement or even remission of their disease activity during
pregnancy, particularly during the third trimester. An almost equal
proportion of women indicated that their disease flared post-
partum. More recent large prospective studies from the UK and the
Netherlands, using both subjective and objective measures of
disease activity, confirmed the amelioration of RA during preg-
nancy and the increased disease activity post-partum [77,78]. They
also indicated, however, that neither the improvement nor the
relapse rate after childbirth was as substantial as suggested by
earlier investigations. Specifically, remission during the third
trimester was only seen in 16% of patients in one study (which
which used a different definition of remission, the percentage of
womenin remissionincreasedfromw11%beforeconception to27%
in the third trimester . In addition, post-partum flares of mostly
moderate severity occurred in only 39% of patients in this study. Of
note, the pregnancy-associated decrement in disease activity was
greatest in patients with high disease activity during the first
trimester. This strongly suggests that, with the recent advances in
therapy, more RA patients have little or no disease activity before
pregnancy, leaving less room for improvement during gestation.
Contemporary reviews frequently leave the impression that the
course and outcome of pregnancies in women with RA is not
substantially different from that of the general population. This is,
however, not quite correct, even though surprisingly limited data
are available on the subject, and almost exclusively from the US and
some European countries. There are three recent large population-
based studies investigating the effects of RA on certain pregnancy
complications and outcomes, two from the US [21,79] and one from
Taiwan . All three found women with RA to be at significantly
Relapse rates (RR) before, during and after pregnancy in MS patients.
CountryStudy periodN ¼
Pre-pregnancy RR Pregnancy RRs (1st/2nd/3rd trimester)Post-partum RRReference
n.a. ¼ not available.
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
increased risk of cesarean delivery. Taiwanese women also faced
a significantly higher risk of preeclampsia than the control group
, and a similar tendency was apparent in both of the US studies.
Taiwanesewomenwith RAwereat increased risk of delivering LBW
and SGA infants, whereas the rate of prematurity was only non-
significantly increased (p ¼ 0.077) among patients compared to
US cohorts were significantly more likely to be born preterm .
The increased frequency of LBW was no longer significant after
adjusting for gestational age, suggesting that prematurity accoun-
ted for most cases of LBW. Women with RA tended to have more
in the other. These results largely recapitulate the findings of older
and smaller studies that included, but rarely focused specifically on,
women with RA. It has also been suggested that women with RA
confirmed in several other studies. Unfortunately, there is very
limited information on the rates of miscarriage, stillbirth or
congenital abnormalities in patients with RA.
126.96.36.199. Type 1 diabetes (T1D). Worldwide incidence rates of T1D
vary widely, ranging from 0.1/100,000 in China to 37/100,000 in
Finland and Sardinia. Very high rates have also been reported
from the US and Canada, several Scandinavian countries, as well
as some Arab populations. Non-Scandinavian European countries
generally have a high incidence, whereas the rates in Asian
countries are generally low and those in sub-Saharan Africa low to
T1D differs from many other autoimmune diseases in that its
onset generally precedes (rather than coinciding with or occurring
after) the childbearing years. Its sex distribution is about equal, at
least in Europe, North America, and some North African countries,
whereas a clear female predominance has been reported from
various Chinese regions (with female:male ratios as high as 4:1). In
addition, the diminished function of the organ targeted by the
autoimmune reaction, rather than the immunological features or
the activity of the disease, has a negative impact on the course and
outcome of pregnancies.
Epidemiological studies have established that, compared to the
general obstetric population, women with T1D face a significantly
increased risk of maternal complications during pregnancy and
delivery, including gestational hypertension, preeclampsia, and
particular pregnancy loss, perinatal mortality, congenital anomalies,
premature delivery, macrosomia (birth weight > 4000 g), respiratory
distress syndrome, and neonatal hypoglycemia, is markedly elevated
women with T1D and their neonates. Epidemiological studies also
have provided evidence that tighter glycemic control substantially
reduces the malformation and perinatal mortality rates. Indeed, in
selected populations with intensive management and care at
specialized tertiary centers, the pregnancy outcomes of women with
T1D were reported to approach those of the non-diabetic population.
Large population-based and nationwide cohort studies indicate that
pregnancy outcomes have improved substantially in recent decades
. Nonetheless, they also highlight that meeting the currently
targeted values for “good” metabolic control does not yield results as
set out by the St. Vincent's declaration of 20 years ago, namely to
achieve pregnancy outcomes similar to those seen in the healthy
control population [82e84]. The risk of congenital malformations
remains at least 2-fold and up to 6-fold higher, while the risk of
perinatal mortality continues to be between 3.5 and 8.5-fold higher
than in the general population , even in carefully planned and
monitored pregnancies in women who mostly achieved good to
excellent glycemic control .
As a result, some investigators argue that even tighter glycemic
control should be aimed for, especially after recent studies showed
that fasting and postprandial glucose values in pregnancies of
healthy women were significantly lower than the targets currently
set for glycemic control in pregnant diabetic patients. Note,
however, that many of the newer formulations of insulin that are
designed to provide enhanced metabolic control frequently are not
associated with significantly improved pregnancy outcomes. In
addition, tighter metabolic control increases the risk of hypogly-
cemia, which has not been shown to adversely affect pregnancy
outcomes, but does represent a significant risk to the mother.
Others suggest that factors other than glycemic control may play
a role in the increased risk of adverse pregnancy outcomes in T1D.
There are considerable differences in the malformation and peri-
natal mortality rates in different ethnic groups and geographic
locations (see also Table 5). Note that a direct comparison between
studies is severely hampered by the use of different definitions for
perinatal mortality (with some authors including neonatal death
up to 28 days after birth, whereas others refer to the immediate
neonatal period 7 days after birth only). In addition, the rates of
detection and termination of pregnancies with congenital anoma-
lies differ considerably between cohorts. Since such anomalies
account for a large portion of neonatal deaths, the termination rate
will considerably influence the perinatal mortality rate. Despite
these limitations, a comparison of international results highlights
Rates (in %) of perinatal mortality (PM), congenital malformations (CM), and other adverse fetal outcomes in T1D.
CountrySubgroups n [total/type 1
(% type 1)]
Study periodPMStill-birth Neonatal
Fetal lossCM Macrosomia
2 (all minor)
M 20/LGA 33
M 8.0 (>4500 g)/
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
that diabetic women in some countries with less than optimal
health care have very low rates of congenital malformation and
macrosomia. Therefore, more extensive comparisons between
ethnic groups with high and low malformation and perinatal
mortality rates may help identify factors beyond glycemic control
that influence pregnancy outcomes.
Maternal autoantibodies could be among these factors, yet
surprisingly few investigations have addressed this issue. There are
data suggesting that maternal insulin could be transferred across
the placenta via maternal anti-insulin antibodies, thereby resulting
Conversely, it could be hypothesized that maternal antibodies
against glutamic acid decarboxylase or tyrosine phosphatase could
reduce fetal insulin secretion and result in reduced birth weight.
However, recent studies found no association between the pres-
ence of any of these autoantibodies in the mother or in cord blood
with the infant's birth weight [87,88]. Nonetheless, the possibility
remains that maternal autoantibodies are associated with poor
pregnancy outcomes other than birth weight.
4. Neonatal disease caused by transplacental passage
of maternal autoantibodies
In addition to causing pregnancy complications and adverse
pregnancy outcomes, transplacental passage of maternal autoan-
tibodies of the IgG isotype can result in a variety of neonatal
diseases (summarized in Table 6) . Among the best known of
these is the neonatal lupus syndrome (NLS), which can manifest as
cutaneous lesions resembling those of SLE (16e50%), life-threat-
ening congenital complete heartblock(CCHB,1e2%), hematological
(w26%) and hepatobiliary manifestations (9e24%). It is almost
invariably associated (in 95% of cases) with maternal antibodies
against Ro/SSA alone or in conjunction with anti-La/SSB. Anti-U1-
RNP (ribonucleoprotein) antibodies are associated exclusively with
the cutaneous manifestations of NLS. All of these antibodies are
found primarily inwomenwith SLE or Sjögren's syndrome (SS), but
can also occur in women with other connective tissue diseases and
in completely asymptomatic women. Interestingly, there are some
suggestions that infants of mothers with SLE are more rarely
affected by CCHB than those of mothers with SS or with undiffer-
entiated connective tissue disease [90,91]. In contrast, there are
indications that the presence of hypothyroidism increases the risk
of CCHB, but not NLS overall, in infants of anti-SSA-positive
mothers regardless of whether they have an underlying autoim-
mune disease or are asymptomatic .
Data on the incidence of NLS are rare. The prevalence of anti-
SSA/SSB varies considerably in different ethnic groups, not only in
SLE and SS patients, but also in the general population (with
a prevalence of 2.6% reported from Japan and 0.4% in Brazil).
Overall, w1e2% of women are thought to have anti-SSA/SSB anti-
bodies, and estimates of their risk of having a child affected by NLS
range between 2% and 52% in prospective studies [90,91]. Only
1e2% will give birth to a child with CCHB. The large variation stems
from differences in the thoroughness with which the various (and
frequently asymptomatic) manifestations of NLS are determined
and the length of follow-up since some of the NLS symptoms,
including the cutaneous lesions, are not always obvious at birth.
The risk that a second child is affected rangesbetween 15% and 20%.
The fact that not all children of women with anti-SSA/SSB anti-
bodies develop NSL indicates that other factors, probably including
fetal ones, play a role.
Of particular note, a recent report on the long-term follow-up of
49 children with NSL indicated that definite autoimmune diseases
were already present in 6 of 49 affected children (5 of them female)
at a mean age of 14.8 years, but in none of the 45 unaffected siblings
or the 53 unrelated controls . Similarly, it has been reported
that children and adolescents diagnosed with autoimmune thyroid
disease had been exposed to maternal thyroid peroxidase anti-
bodies in utero significantly more frequently than randomly
selected control children . This strongly suggests that, in
addition to inheritance of susceptibility genes from an affected
mother, transplacental exposure to maternal autoantibodies
predisposes to the development of autoimmune diseases.
5. Parity, pregnancy, and the risk of developing
Parity or total number of pregnancies was not associated with
the development of SLE in women from the USA or Sweden
[95e97]. In contrast, a recent study from Denmark found that
women with at least one live-born child were at decreased risk of
developing SLE than nulliparous women and the risk was further
decreased in women with 2 or more children . Recurrent
pregnancy losses, however, increased the risk of SLE. The results of
studies examining the association between oral contraceptive use,
hormone replacement therapy or other indicators of hormonal
status (age at menarche and at menopause) and the development
of SLE are equally contradictory. Several case-control studies from
the USA and Finland, failed to detect significant associations
[95,99,100]. In contrast, a slight increase in risk was seen in the
Neonatal diseases caused by maternal autoantibodies .
Neonatal diseaseMaternal disease Causative antibody Proportion of antibody-positive
% Affected neonates of
Neonatal lupus syndrome SLE, SS, RA, other connective tissue
diseases, or asymptomatic
Immune thrombocytopenic purpura
Anti-SSA/SSB1e2% Up to 52%
Neonatal autoimmune neutropenia
Neonatal Graves' disease
Autoimmune hemolytic anemia
Autoimmune hemolytic anemia
Primary or secondary APS or
aTSH thyroid-stimulating hormone receptor.
bOf infants overall.
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
Nurses' Health Study cohorts (USA) , and UK case-control
studies indicated an increased risk of SLE development with past
and particularly current use of combined oral contraceptives and in
some cases with postmenopausal hormone replacement therapy
Consistent with the favorable effects of pregnancy on disease
activity in MS, a prospective Swedish incidence cohort study
showed that the onset of MS symptoms was significantly less likely
to occur during gestation compared to the periods before and after
pregnancy . In addition, a significantly higher proportion of
womenwith MS were nulliparous at disease onset thanwould have
been expected from population data. This could suggest a protec-
tive role for pregnancy in the development of MS; however, it could
also reflect that some health impairments already exist in women
who later develop MS, since only healthy women are likely to
become pregnant. Data from three large cohort studies and one
case-control study (3 from the UK and 1 from the US) indicate that
parity and oral contraceptive use do not significantly affect the risk
of MS . One of them provides some indication, however, that
the risk of MS onset is temporarily increased during the first 6
months after childbirth; in addition, the current use of oral
contraceptives may delay the onset of MS.
Although addressed in a large number of studies, it remains
unclear whether there is an association between parity and risk of
RA, with a number of older studies finding that nulliparity consti-
tutes a risk factor for RA, whereas the prospective Nurses' Health
study did not detect any association , nor did a large Finnish
cohort study . The Nurses' Health study found a strong trend
towards decreasing RA risk with increasing duration of breast-
feeding . Therefore the protective effect of parity detected in
some studies may have been confounded by breastfeeding. Simi-
larly, a majority of studies show no significant association between
oral contraceptive use and risk of RA onset, although some found
a significant protective effect. In at least one study, the association
was stronger in women who used the earlier OC preparations,
suggesting that higher doses of estrogens and progestins provided
stronger protection .
Pregnancy involves highly complex and dynamic interactions
between hormonal and immunological factors. It seems possible,
therefore, that it could have differential effects on the development
of an autoimmune disease depending on its timing relative to the
initiation or progression events that are likely to precede manifest
disease. This might explain some of the discrepancies in these
results. Because of their inconsistency, the currently available data
do not provide convincing evidence that parity provides an
explanation for the female predominance in SLE, MS, RA and other
Chimerism is defined as the persistence in an individual of DNA
or cells from a genetically distinct individual. The term micro-
chimerism refers tothe presence of low levels of such donor cells. It
had long been known that bidirectional trafficking of cells occurs
during pregnancy, with maternal cells entering the fetal circulation
and fetal cells passing into the maternal circulation. It was not until
1996/7, however, that chimeric cells were discovered to persist in
the circulation of the host (fetal cells in the mother and maternal
cells in the offspring) for several decades. This suggested the
possibility that fetal microchimerism could account for the female
predominance of certain autoimmune diseases. Specifically, it was
hypothesized that fetal microchimerism could trigger a graft-
of systemic sclerosis (SSc), an autoimmune diseases that has
marked similarities with graft-versus-host disease (GVHD). When
testing thishypothesis,Nelsonet al. foundsignificantlyhigher
levels of fetal DNA, but a similar frequency of positivity, in women
with SSc compared to healthy controls, both groups of women
having given birth to at least one son. This and subsequent studies
also suggested that HLA class II compatibility between mother and
child contributed to the persistence of fetal microchimerism. This
represents a further similarity to GVHD, where HLA relationship
between donor and host is known to play an important role.
Although similar results were obtained in several subsequent
investigations, more recent data raise some doubts concerning the
association between fetal microchimerism and SSc. In addition,
several analyses found that nulliparous women were at increased
risk of developing SSc compared to women who had ever been
pregnant and that the risk decreased with increasing numbers of
Like SSc, PBC and SS, have clinical and immunological features
resembling GVHD and are characterized by a high female predom-
inance. Explorations of the possible role of fetal microchimerism in
peripheral blood and salivary glands of patients with SS have
yielded highly variable results. However, the limited data available
indicate that the risk of developing the disease is increased in
parous compared to nulliparous women. The great majority of
studies of microchimerism in PBC have failed to demonstrate an
association between PBC and fetal microchimerism in peripheral
blood and liver tissue. Data on the association between parity and
the development of PBC are conflicting, with one study reporting
a significant positive association , whereas another pop-
ulation-based study did not find a significant relationship .
Similarly inconclusive results have been obtained in other auto-
into immune competent cells. This along with the results of
a limited number of studies suggested that chimeric cells could
actively participate in alloimmune reactions. Since then, it has been
recognized that both fetal and maternal chimeric cells show
considerable plasticity and are capable of differentiation into
a variety of tissue-specific somatic cell types. While this raises the
possibility that they also could become targets of inflammatory
reactions, there is growing evidence suggesting that both fetal and
maternal chimeric cells participate in tissue repair processes.
Of note, there are some indications that in some women fetal
cells from only one specific child persist, even though they have
delivered several children. This suggests that specific maternal and/
or fetal factors are required for the persistence of chimeric cells. It
also seems possible that only specific chimeric cell types are path-
ological, whereas others participate in repair processes. As long as
do not allow conclusions as to the role of microchimerism in the
development of autoimmune diseases. They also do not support
the hypothesis that fetal microchimerism accounts for the female
predominance of these diseases.
7. Concluding remarks
Women with autoimmune diseases were long advised not to
become pregnant or to have therapeutic abortions if they did e
because of earlier case reports and series indicating poor outcomes
for both the mother and the baby. Thanks to epidemiological
studies it has become obvious that advances in treatment and
careful and multidisciplinary management in the periconception
period and throughout pregnancy, the outlook in essentially all
autoimmune diseases has improved considerably. Particularly
patients with stable disease at the time of conception frequently
have uneventful pregnancies without disease exacerbation and
Borchers, A.T., et al. / Journal of Autoimmunity 34 (2010) J287eJ299
give birth to healthy full-term infants without an increased risk of
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