Lupus (2006) 15, 156160

www.lupus-journal.com

REVIEW

Pregnancy, lupus and antiphospholipid

syndrome (Hughes syndrome)
A Tincani1*, D Bompane2, E Danieli1 and A Doria3
1Rheumatology

and Clinical Immunology, Brescia Hospital and University, Italy; 2Rheumatology Department,
University of Rome, La Sapienza, Italy; and 3Division of Rheumatology, Department of Clinical and
Experimental Medicine, University of Padova, Italy

Autoimmune diseases (AD) occur frequently in women during their childbearing years and may
influence pregnancy outcome and neonatal health. Patients with systemic lupus erythematosus (SLE)
can experience a disease flare-up during pregnancy with potential negative effects on the product of
conceptus, especially if the disease is active. Recurrent pregnancy loss is now considered as a
treatable clinical condition associated with the presence of circulating antiphospholipid antibodies
(aPL). The neonatal lupus syndromes (NLS), caused by the transplacental passage of maternal IgG
anti-Ro/SS-A and anti-La/SS-B antibodies to the fetus, carry significant morbidity and mortality in
case of cardiac manifestations. Immunosuppressive agents are often administered during pregnancy in
order to control maternal disease and to ensure a better pregnancy outcome. Nowadays, owing to our
increasing knowledge of the disease pathophysiological mechanisms and the development of
combined medical-obstetric clinics, pregnancy outcome in patients with AD has notably improved.
Lupus (2006) 15, 156160.
Key words: antiphospholipid syndrome; immunosuppressive drugs; neonatal lupus syndrome;
pregnancy; systemic lupus erythematosus

Introduction
Pregnancy represents an extremely dynamic state,
which markedly alters the normal womans physiology
through a series of hormonal, immunological and
coagulation modifications.1
Autoimmune diseases (AD) have a higher prevalence in women, especially during their childbearing
age. For many years, the general advice to these women
was to avoid pregnancy as there was an important risk
of maternal and fetal morbidity and mortality.2
More recently, owing to the better prognosis of these
diseases, to the continuation of an appropriate treatment and to the development of a multi-disciplinary
team committed to managing the gestation of this
kind of patients, pregnancy outcome has considerably
improved.
AD can affect maternal disorder, pregnancy and
neonatal outcome.
Patients with systemic lupus erythematosus (SLE)
may experience a disease flare-up during pregnancy
with potential considerable effects on the product of
*Correspondence: Angela Tincani, Reumatologia e Immunologia Clinica,
Ospedale Civile, Piazza Spedali Civili 1, 25125 Brescia, Italy. E-mail:
tincani@bresciaseumatologia.it
2006 Edward Arnold (Publishers) Ltd

conceptus.3 Thus, SLE patients should contemplate a

pregnancy in a period of complete and sustained
remission.4
Antiphospholipid syndrome (APS), if properly
managed, respresents one of the few treatable causes
of pregnancy loss.5 Nonetheless, it represents one of
the most frequent causes of early and late pregnancy
morbitdity.
The transplacental passage of maternal IgG antiRo/SS-A and anti-La/SS-B antibodies to the fetus may
be responsible for the so-called neonatal lupus syndrome (NLS). The most peculiar and life-threatening
manifestation of this passively acquired autoimmune
disease is complete congenital heart block (CHB).6
Immunosuppressive drugs administration during
pregnancy is, sometimes, necessary in order to prevent
a disease flare and to ameliorate the pregnancy outcome. In deciding to continue or stop the drug, the
degree of the disease activity and the organ involved
should be considered.

Systemic lupus erythematosus

Women with SLE usually have normal fertility rates,
however disease activity, end-stage renal disease, and
10.1191/0961203306lu2279rr

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157

drugs used to treat SLE (ie, cyclophosphamide) can

contribute to the development of menstrual disorders
or ovarian failure.7
The impact of pregnancy and puerperium on the
course of SLE is still matter of debate. Several studies
which included carefully matched controls failed to
show an increased rate of lupus flares during pregnancy,810 while others in which the recurrence rate
during pregnancy were compared to that of the same
subject in the follow-up demonstrated a higher rate of
flares.11,12 However, according to our experience, the
majority of flares are mild, including haematologic,
articular and dermatologic manifestations, and require
none or only minor therapeutic adjustment. The most
relevant predictor of a SLE flare during pregnancy and
its degree seem to be the number and the severity of
flares before conception.13
Lupus pregnancies are characterised by an increased
prevalence of intrauterine deaths, fetal growth retardation, pre-eclampsia and preterm deliveries.12
In our centre we evaluated prospectively 132 pregnancies in 90 SLE patients reporting a rate of 61% of
at term deliveries, 22% of preterm deliveries and 17%
of pregnancy losses. Obstetric complications such as
pre-eclampsia and premature rupture of membranes
(PROM) occurred in 12% and 20% of pregnancies,
respectively. The most important predictors for pregnancy loss seemed to be hypertension, the number of
flares before pregnancy and the steroid intake. The
presence of antiphospholipid antibodies (aPL) was
mainly associated with the risk of pre-eclampsia and
preterm delivery, while SLE activity score (ECLAM)
in the six months before pregnancy was connected
with PROM. Gestational hypertension was also associated with fetal growth retardation as it may induce
placental insufficiency.14 This condition is related to
restriction of nutrient and oxygen to the fetus and may
lead, when particularly severe, to fetal death.15 It has
been recently suggested that adults who suffered from
severe intrauterine growth restriction (IUGR) have a
significantly increased incidence of hypertension,
insulin resistance and type 2 diabetes, and are more
prone to develop lifelong growth alterations.16
The offspring of lupus mothers have a normal intelligence level when compared with children born at the
same gestational age, however an increased rate of
learning disabilities was shown. Interestingly, dyslexia
was reported in up to 45% of male children if
compared to female, this is probably due to a more
energetic maternal immune response to the male
fetus which lead to an impairment in the brain
development.1719
Regarding the genetic background relevance in the
pathogenesis of SLE with consequent influence on the
long-term prognosis of SLE patient offspring, 195

children (aged between four months and 26 years)

were examined. Two cases were diagnosed with SLE,
and a significantly higher percentage of patietns (especially female subjects) was found to be positive for
antinuclear antibodies if compared with a control
group of 57 children born to mothers without SLE
(27% versus 7%).20

Antiphospholipid syndrome
(Hughes syndrome)
APS is a prothrombotic disorder characterised by
arterial and/or venous thrombosis, recurrent spontaneous pregnancy loss in the presence of circulating
aPL.21 This autoantibodies are found in up to 5% of
apparently healthy controls and up to 37% of patients
with SLE and, less frequently, in the course of other
autoimmune diseases.22 The main pregnancy-related
clinical features of APS are pregnancy loss, IUGR,
placental insufficiency, pre-eclampsia and preterm
delivery.
In animal models the infusion of aPL during pregnancy causes pacental insufficiency with subsequent
miscarriage.23 The pathogenic mechanism which lead
to the placental thrombosis may be determined
by endothelial cell activation, inhibition of protein
C/S system and fibrinolysis24 as well as annexin V
displacement.25 However, especially early pregnancy
loss may result from a failure of placentation owing
to the direct effects of aPL on anionic phospholipids
and the co-factor 2-glycoprotein I on trophoblasts.26
On the other hand second- and third-trimester losses
are more likely to result from thrombotic damage to
the uteroplacental vasculature.27
Nowadays, with an appropriate treatment, a close
obstetric monitoring and a careful delivery timing,
APS patients can reach a successful pregnancy rate of
70%.5
In order to investigate APS pregnancy outcome, we
performed a control study evaluating 69 pregnancies in
58 primary APS patients which resulted in 71 live
births compared with 71 babies from healthy mothers.
The two groups were matched for gestational age,
birth weight, way of delivery and obstetrical complications. Although no significant difference was found in
the occurrence of neonatal complications between the
two groups, the main problem seemed to be prematury
which occurred in up to 18.8% of the pregnancies,
followed by pre-eclampsia (11.6%), PROM (4.3%)
and IUGR (6%).28
Between 1987 and 2002, 13 cases of aPL-related
neonatal thromboses have been published, 10 events
involved arterial vasculature, mainly the brain, while
venous thrombosis were present only in two cases.29
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We described a case of aPL-associated fetal stroke

diagnosed two months after delivey which developed
West syndrome and left hemiparesis.30 The rarity of
these events in children born to aPL positive mothers
may be explained by the lack of fetal concomitant risk
factors31 and by the protective effect of placenta in
reducing the amount of antibodies towards the fetal
blood circulation.32
As far as childhood neuropsychological development is concerned, we have recently reported an
increased rate of learning disabilities in offspring of
mothers with SLE and concomitant aPL.33 This observation is supported by both animal models, in which a
prolonged exposure to aPL can lead to hyperactivity
and anxiety,34 and in vitro data that showed a direct
binding of aPL to the brain endothelial cells.35 An
early diagnosis of these developmental disorders
is extremely important in order to provide the appropriate support to these children especially in the
school age.

Neonatal lupus syndrome

NLS is a polymorphous syndrome resulted from the
transplacental passage of maternal IgG autoantibodies
reactive with the intracellular soluble ribonucleoproteins Ro/SS-A (52 kD or 60 kD) and/or 48 kD La/SS-B.
These autoantibodies are, more frequently, linked to
the development of CHB and transient photosensitive
skin rash. The rash typically appears during the first
weeks after birth with a predilection for the scalp, face
and periorbital region and clears up with the concomitant disappearance of maternal autoantibodies from the
neonatal circulation. Hepatobiliary disorders, such as
liver failure in utero or at birth, transient conjugated
hyperbilirubinaemia and transaminase elevation,36
along with cytopenias are also described.37 Despite
these well known manifestations, there are contrasting
data about the role of anti-Ro/SS-A antibodies on other
pregnancy complications. In fact, while several studies
advocated a higher rate of adverse pregnancy effects,38
others failed to show these evidences.39
We have conducted a prospective cohort study
evaluating the pregnancy outcome of 100 anti-Ro/SSA women compared with a control group of 107 antiRo/SS-A negative patients. Apart from two cases of
CHB in the anti-Ro/SS-A group, no other adverse
effects on pregnancy were reported.40
CHB is a very rare disorder in the general population with an incidence of about one in 22 000 live
births.41 Although anti-Ro/SS-A and anti-La/SS-B
antibodies are identified in more than 85% of mothers
with CHB children, only about 2% of the first
pregnancy is complicated by CHB.42 This evidence
Lupus

suggests that the presence of these autoantibodies are

necessary but not sufficient, and probably a fetal factor
and/or the in utero environment may play a role in the
determinism of CHB.43
The risk of recurrence of CHB rises up dramatically
to 19% if the previous child had CHB or neonatal
rash.44
CHB does not occur randomly during fetal
development, but rather is mainly detected between
18 and 24 weeks of gestation when the binding of antiRo/SS-A and anti-La/SS-B antibodies to the heart
conduction tissue causes an inflammatory/fibrotic
reaction.45 Interestingly, in a recent prospective
study by Sonesson et al., was demonstrated that antiRo/SS-A 52 kD-positive pregnant women frequently
carry fetuses with Doppler echocardiographic signs of
first-degree atrioventricular block. In most of the
fetuses these blocks reverted spontaneously, whilst
progression to a more severe degree of block occurred
in some.46
Since CHB high rate of mobidity (over 60% of
affected children require lifelong pacemakers) and
mortality (approximately 20%),47 in pregnant patients
at risk, a careful monitoring by serial fetal echocardiograms should be performed starting from 16 weeks of
gestation in order to recognize early signs of the disease and to start the treatment as promptly as possible.6
The presence of anti-Ro/SS-A and anti-thryroid
antibodies was shown in children of mothers with
developmental disorders especially dyslexia.48,49
According to a more recent paper, anti-Ro/SS-A and
anti-La/SS-B antibodies during pregnancy significantly
predicted learning disabilities in the offspring.17
Concerning the long-term prognosis of NLE
children, it has been speculated that some of these
children may develop other AD during their childhood.50

Immunosuppressive therapy
during pregnancy
In the current clinical practise the use of medications
during pregnancy is often necessary in order to protect
the health of the mother and to improve pregnancy
outcome.
To date, precise guidelines on the use of immuosuppressive drugs are not available and controlled studies
exist only for few drugs. The only information on the
drug safety during pregnancy and lactation is derived
from experimental animal studies, case reports and
small series.51
Cyclosporine A and azathioprine are the drugs
mostly studied during pregnancy especially on transplant recipient women. Their administration during
gestation may potentially cause pregnancy and neonatal

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159

complications such as PROM, preterm delivery, low

birth weight and IUGR, although it might be diffcult to
discriminate between the effect of the drug itself and
that of the underlying maternal disease.52,53 In a recent
study, nine children from mothers with connective
tissue diseases, exposed to cyclosporine A (n 2),
azathioprine (n 1) and dexamethasone (n 3)
during gestation were compared with a non-treated
group. No significant difference in immunoglobulin
levels and lymphocyte subpopulations were detected,
and furthermore these children developed a satisfactory immune response to hepatitis B vaccinations.54
Another work was carried out to measure the response
to Clostidrium tetani toxoid vaccination of 26 infants
whose mothers with autoimmune disease received
immunossuppressants during pregnancy. A considerable proportion of children was not, or only partially
protected after a normal cycle of vaccination antiClostridium tetani toxoid.55
The use of methotrexate, cyclophosphamide and
mycophenolate mofetil is contraindicated in pregnancy
due to their teratogenic effects, so they should be
discontinued at least three to six months before
conception.51
Corticosteroids (ie, prednisolone and prednisone)
are inactivated by the placental 11-hydroxygenase and
therefore only less than 10% of the maternal blood
level can reach the fetus. In contrast, fluorinated corticosteroids (ie, dexamethasone and bethametasone)
escape from this process, and indeed are the drugs of
choice used to avoid the progression from the inflammatory to the fibrotic irreversible state of complete
CHB.56 Some data reported an impaired cerebral
development57 and an increased risk of leukomalacia
at two years of age following prolonged fetal exposure
to dexamethasone rather than bethametasone.58
In this regard, we recently evaluated 11 children
exposed to very high dosages of dexamethasone in
utero because of CHB, all of them were found
to have a completely normal neuropsychological
development.59 Another interesting study was realized
to assess thymic lymphocyte production, T cell subset
number and function in eight children with CHB aged
from two to 12 years who received prolonged dexamethasone treatment during their intrauterine life. The
analysis of the immune system did not disclose any
clinically relevant abnormality.60
Currently, there is a collaborative European study
of prophylactic intravenous immunoglobulins use in
pregnancy of anti-Ro/SS-A positive mothers who had
previous infants with CHB with the aim of trying to
eradicate this life-threatening condition.61
Antimalarials are largely employed in AD because
of their beneficial effects on cutaneous and articular
manifestations. Since their long elimination half-life

and their tendency to accumulate in certain tissues,

including the retina and the inner ear, their discontinuation in pregnancy does not prevent a fetal exposure,
and may even result in an exacerbation of the disease.
Costedoat-Chalumeau and colleagues recently
reported their experience concerning hydroxychloroquine (HCQ) treatment in 133 SLE patient pregnancies
compared with a control group. According to previous
evidences,62,63 this study did not show any significant
difference in pregnancy and neonatal outcome
between the two groups.64 Intriguingly, the ophthalmologic examination with funduscopy and flash electroretinography performed in a small group of babies
exposed to HCQ in utero, and some of them also
during breast-feeding, were found completely
normal.65 In another very recent observational study,
infants born from mothers treated with HCQ during
pregnancy and breastfeeding were followed up.
Preterm delivery was the main complication detected
(20.5%), probably reflecting the maternal disease
activity. No significant congenital malformations or
neonatal infections were observed. All babies had
normal visual function and neurodevelopmental
outcome.66

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