Lupus (2013) 22, 12951308

http://lup.sagepub.com

SPECIAL ARTICLE

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta
Lupus Research Unit, Womens Health Division, Kings College London, UK

Pregnancy poses an important challenge for doctors looking after women with systemic lupus
erythematosus. Knowledge about safety of medications, the effect of pregnancy on such disease, and vice versa, together with multidisciplinary team care, are basic cornerstones needed
to provide the best obstetric and medical care to these women. Pre-conceptional counselling
constitutes the ideal scenario where a patients previous obstetric history, organ damage,
disease activity, serological profile and additional medical history can be summarized.
Important issues regarding medication adjustment, planned scans and visits, and main risks
discussion should also be raised at this stage. Planned pregnancies lead to better outcomes for
both mothers and babies. Close surveillance throughout pregnancy and the puerperium, and
tailored management approach guarantee the highest rates of successful pregnancies in these
women. Lupus (2013) 22, 12951308.
Key words: Pregnancy; systemic lupus erythematosus; management; pre-pregnancy counselling; medications

Introduction
Systemic lupus erythematosus (SLE) is a multisystemic disease with a clear predilection for women
(ratio 9 : 1), particularly during reproductive age
years (ratio 15 : 1). It aects up to 1 in 1000 of
child-bearing age,1 and presents three to four times
more frequently in the population of African
background.2 Pregnancy was considered almost
prohibited in women with lupus until recent years.
A better understanding of the disease and creation of specialized multidisciplinary groups with
experience in autoimmune diseases (involving
physicians, obstetricians, paediatricians and midwives) has led to dramatic improvement in disease
management and pregnancy outcome over the last
20 years.3

Effect of pregnancy on SLE

Pregnancy is considered a high-risk time for lupus
patients, as ares during pregnancy have been
Correspondence to: Munther A Khamashta, Lupus Research Unit,
The Rayne Institute, Division of Womens Health, Kings College
London, 4th Floor Lambeth Wing, St Thomas Hospital, London
SE1 7EH, UK.
Email: munther.khamashta@kcl.ac.uk
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav

related to increased irreversible organ damage.4

However, whether or not pregnancy increases the
risk of lupus are is still an unsolved question.
Several prospective controlled observational studies have shown discordant answers to this
question.511 Some authors have suggested the
puerperium as a period of especially high risk for
lupus are.11,12 Based on these studies, lupus are
seems unpredictable, hence regular follow-up in
pregnancy and postpartum should be oered to
these women. However, the risk of are appears
to be dependent on the disease activity 612
months prior to conception. Women with quiescent
lupus over this period have lower risk of are
during pregnancy,9,13 whereas women with active
SLE during this time have a higher risk.7,14
Therefore, pregnancy should be planned when the
disease has been in remission for at least
6 months.15 Prophylactic therapies such as increasing the dose of steroids are not recommended.
Active lupus nephritis (LN) at conception confers
a higher risk of are during pregnancy,16 and even
women with LN in remission have an increased risk
of are.11,17,18 In contrast, patients with no previous
renal involvement are at the lowest risk.18 In women
with previous LN, pregnancy does not seem to
endanger long-term renal function, although generally the higher the baseline creatinine, the greater
the risk of deterioration.11,16,1921
10.1177/0961203313504637

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1296

Lupus ares during pregnancy and postpartum

are normally non-severe, characterized by articular,
dermatological and mild haematological involvement,6,7,10 and are usually well controlled with
hydroxychloroquine (HCQ) and short-term introduction or increase of oral steroids. Nonetheless,
severe ares with major organ involvement may
occur.6,15,22
A recent systematic review established the protective eects of HCQ in terms of organ damage,
disease ares, thrombosis, bone mass loss and longterm survival in the general lupus population, as
well as the potential to prevent disease activity in
pregnant women.23 Two recent prospective studies
corroborated these ndings, suggesting that women
who had taken HCQ throughout pregnancy presented lower activity scores and had lower prednisone doses at the end of pregnancy,24 whereas those
who discontinued HCQ or did not take it at all had
higher activity scores, more ares and required
higher doses of steroids.25
Distinguishing pregnancy-related signs and
symptoms from certain lupus features may sometimes be dicult, as they can mimic each other.
Assessment by experienced physicians is of great
importance in order to ensure a correct clinical
judgement. Fatigue, arthralgia, hair loss, dyspnoea,
headaches, malar and palmar erythema, oedema,
anaemia and thrombocytopenia represent some of
the most common ambiguous manifestations.
In pregnancy, erythrocyte sedimentation rate
(ESR) is usually raised due to higher production
of brinogen in the liver, hence it may not be
valid as an activity marker. Serum C3 and C4
levels also rise in pregnancy due to increased liver
production, so even in women with active lupus
may remain within normal range. Relative variation rather than absolute levels of C3 and C4
should be taken into consideration. A drop of
25% or more in serum complement levels in pregnancy may suggest lupus are.26,27
As a result of increased renal blood ow in pregnancy, glomerular ltration rate (GFR) increases
by more than 50%, leading to a reduced serum creatinine level.19 Serum creatinine and urea levels
above pregnancy normal ranges (Creatinine >
0.8 mg/dl/>70 mmol/l; Urea > 25 mg/dl/>4 mmol/l)
or levels that stay invariable and do not decrease
throughout pregnancy are signs of renal impairment. Increased tubular ow may increase urine
protein leakage, thus levels up to 300 mg/day of
proteinuria are considered normal in pregnancy.
In patients with permanent signicant protein loss
due to previous LN, proteinuria may elevate
throughout pregnancy without being indicative of
Lupus

active nephritis.18 This phenomenon may be even

more signicant in patients that withdraw
angiotensin-converting enzyme inhibitors (ACEI)
and/or angiotensin receptor blockers (ARB) shortly
before pregnancy. However, if proteinuria doubles
the baseline level it should warrant further
investigations.19
Pregnancy may have a detrimental eect on
other major organs. Patients with cardiac disease
and/or pulmonary hypertension may deteriorate
and become seriously ill due to increased circulating volume overload and other cardiovascular
changes, with associated high morbidity and mortality.2831 On the other hand, women with restrictive lung disease may worsen secondary to gravid
uterus diaphragmatic compression and higher
oxygen requirements.
Women with moderatesevere lupus are or
stroke within the previous 6 months, CKD 45
(Cr > 2.52.8 mg/dl, >220250 mmol/l; or eGFR
<35 ml/min), pulmonary hypertension, moderate
severe cardiomyopathy (ejection fraction <30
40%), or severe restrictive lung disease (forced
vital capacity <50% of predicted) are at highest
risk for medical and obstetric complications, and
should be appropriately counselled, generally
against conception or continuation of pregnancy.
In recent times, in order to improve disease activity evaluation in pregnant women with lupus, main
lupus activity indices have been adapted and validated for pregnancy with excellent results.26,32,33

Effect of SLE on mother, pregnancy and

neonate
Patients with SLE are at risk of multiple medical
and obstetric complications during pregnancy, and
should hence be considered high-risk patients. A
recent study from the USA analysed the diagnosis
at discharge of pregnant women with SLE through
13,555 deliveries.34 Lupus patients had a 20-fold
risk in maternal mortality and a higher rate of
hypertension, pre-gestational diabetes, renal
impairment, pulmonary hypertension, major infections, thrombotic events (such as stroke, deep vein
thrombosis, pulmonary embolism) and other haematological complications (such as bleeding, anaemia
and thrombocytopenia), compared with the general
population. Furthermore, the risk of pre-eclampsia,
caesarean section, preterm labour and intrauterine
growth restriction (IUGR) was two- to four-fold
higher in the former group, particularly in patients
with chronic hypertension, renal impairment and

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1297
34

women on high-dose oral steroids. In contrast,

patients with only cutaneous lupus erythematosus
seem to have pregnancy outcomes comparable with
the healthy population,35 as well as those with SLE
in remission without major organ involvement.
Some 25% percent of all lupus pregnancies end
in preterm (<37 weeks) delivery.36 Disease activity,14 hypertension37 and hypothyroidism38 have
been identied as risk factors for preterm delivery.
Placental insuciency leading to IUGR is frequent
in lupus pregnancies,39 even in those with mild disease.40 The incidence of small for gestational age
(SGA) babies is 635%.4143
Pregnancy loss occurs in up to 1 in 5 pregnancies
of lupus patients (compared with around 1 in 10 in
controls), with a high percentage of stillbirths
(up to four to six-fold compared with controls).42
Hypertension, proteinuria >500 mg/day, thrombocytopenia and secondary antiphospholipid syndrome (APS) have been recognized as risk factors
for pregnancy loss.15,43 Although women with SLE
are at high risk of adverse pregnancy outcomes, if
appropriate treatment is given, those who have a
perinatal death in their rst pregnancy can expect a
live birth for a subsequent pregnancy.44
Patients with a high grade of non-reversible
organ damage are more prone to develop complications and further damage both during and after
gestation,4 especially women with chronic renal disease.15,20 Disease activity during 6 months prior to
conception has been related to higher rate of fetal
loss.14 Women with high clinical disease activity in
pregnancy, often associated with corticosteroid use,
present worse pregnancy outcomes compared with
those with low or no activity.14,4547 Amongst the
former group, patients with hypocomplementemia
or positive anti-dsDNA antibodies have been
shown to have the highest risk for pregnancy loss
and preterm birth.37 Patients with active LN are at
particular high risk for poorer pregnancy outcome,48 therefore they should be advised to postpone pregnancy until at least 6 months (ideally
1218 months) after the last LN are.49 There is
no evidence to suggest that dierent subclasses of
LN aect this risk.48
In patients with previous LN, hypocomplementemia, proteinuria >1 g/day and GFR < 60 ml/min
have been described as independent predictors of
adverse fetal and maternal outcomes.16 Women
with creatinine >2.52.8 mg/dl (>220250 mmol/l;
approx. GFR < 3540 ml/min), on dialysis or with
renal transplant present the highest complication
rates.19,21 Amongst women who undergo renal
transplantation, pregnancy outcomes seem to be
similar in patients with previous LN compared

Table 1 Differences between pre-eclampsia and lupus

nephritis
Pre-eclampsia

Lupus nephritis

Headache
Visual problems
(e.g. flashing lights)
Epigastric or RUQ tenderness
Nausea or vomiting
Clonus (>2 beats)
Increased liver function tests
Rising serum uric acid level
Haemolysis

Onset <20 weeksgestation

Active urinary sediment
Low or falling complement levels
High or increasing anti-dsDNA
Evidence of lupus flare involving
other organs

RUQ: right upper quadrant.

with those with any other nephropathy.50

History of any chronic nephropathy, including
LN, is associated with hypertensive disorders in
pregnancy.48,51
Overall, women with SLE have a three- to fourfold increased risk to develop pre-eclampsia,46,52,53
compared with the general population54.
Dierentiating pre-eclampsia from LN may not
be straightforward, as both may include hypertension, raising proteinuria, oedema, renal function
impairment and thrombocytopenia, and sometimes
both may overlap. The risk of developing preeclampsia is increased in women with chronic
hypertension, chronic kidney disease, diabetes mellitus, hypertensive disease during a previous pregnancy, SLE, APS, age >40, body mass index (BMI)
>35 kg/m2, family history of pre-eclampsia, sickle
cell disease, multiple pregnancy and in primipara or
in those with a pregnancy interval >10 years.19,5557
Table 1 shows useful ndings to dierentiate preeclampsia/toxaemia from LN.51,56,58 If renal biopsy
is indicated, special caution and surveillance is warranted due to the higher bleeding risk after biopsy
in pregnancy.59
Antiphospholipid antibodies
Antiphospholipid antibodies (aPL) are found more
frequently in patients with SLE (3040%) than in
the background population (15%),60,61 and represent the major risk factor for poor obstetric outcome.48 Several studies have identied aPL carrier
women at increased risk of developing preeclampsia, IUGR, prematurity and fetal loss
during pregnancy.48,6270 Positivity for both anticardiolipin antibodies (aCL) and lupus anticoagulant (LA); triple aPL positivity (aCL, LA and
anti-b2-glycoprotein-I); or history of thrombotic
APS multiply that risk.67,71 Moreover, women
with thrombotic APS have worse obstetric outcomes than those with obstetric APS or aPL
Lupus

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1298

carriers.71,72 Two recent studies conrmed the

latter, but interestingly also showed that LA is the
primary predictor of adverse pregnancy outcome
after 12 weeks gestation in aPL-associated pregnancies.73,74 As the existence of aPL also raises
the risk for maternal thrombosis, rechecking aPL
in patients with a previous diagnosis of SLE is
advisable.75
Neonatal lupus
Anti-Ro and/or anti-La antibodies are present in
approximately 30% of lupus patients, frequently
related to photosensitivity, subacute lupus erythematosus and Sjogrens syndrome.7679 Women with
other autoimmune diseases such as undierentiated
connective tissue disease, rheumatoid arthritis, or
healthy asymptomatic carriers may present these
antibodies.80 The prevalence of these antibodies in
the general population may be up to 13%.81 AntiRo/La cross the placenta by active transport
between the 16th and 30th weeks of gestation,
and may cause several clinical syndromes in the
fetus and neonate.82 Known as neonatal lupus syndromes (NNLS), involvement of skin, heart and
liver, and/or cytopenias may be present.83
Cutaneous neonatal lupus (CNL) is the most
common manifestation, and can aect around 5%
of children born to anti-Ro/La-positive mothers.82
It generally presents within the rst 2 weeks of life
as erythematous geographical lesions in lightexposed areas (i.e. face, scalp, trunk, and limbs)
and resemble those seen in subacute cutaneous
lupus. The rash may worsen with ultraviolet light
exposure, and usually disappears within 36
months, when maternal antibodies are cleared
from babys circulation. Residual scarring beyond
the rst or second year of age is unusual.82
Congenital heart block (CHB) is the most severe
NNLS and happens in around 2% of babies born
to anti-Ro/La-positive mothers.84 This risk
increases up to 18% if the mother has already
had a child aected by CHB, and up to 50% if
she has had two aected children.84 In women
with a previous baby aected by CNL, the risk of
CHB in a subsequent neonate raises six- to tenfold.85 Interestingly, in >80% of children with
CHB the mother will have anti-Ro and/or anti-La
antibodies.82,8688 CHB normally develops between
16 and 24 weeks of gestation, and can be detected
by fetal low heart rate (<60 beats per minute).82
Anti-Ro/La antibodies target fetal atrioventricular
node and myocardium, provoking immunemediated inammation and subsequent brosis in
aected tissues, which result in variable grades of
Lupus

heart block and, more rarely, cardiomyopathy.82,89

The risk of perinatal death amongst aected children is approximately 1020%, and most of surviving children need a permanent pacemaker.88,90,91
Incomplete forms such as rst or second-degree
heart block may be found, which can progress to
complete forms during childhood.82
Current demographic data suggest that additional factors other than maternal antibodies may
be involved in the pathogenesis of CHB, although
these remain unknown.82 Albeit no specic antibody prole for NNLS has so far been detected,
higher maternal antibody levels, dierent IgG subclasses and fetus genetics have been suggested as
possible relevant risk factors,82,92,93 whereas other
groups have not found such results.94 Regardless of
the background disorder, there is no correlation
between mothers severity of disease and ospring
damage grade. Less frequent cardiac manifestations
have been also described as part of NNLS,
such as cardiomyopathy95 and endocardial
broelastosis.96,97
Early diagnosis is crucial for correct management in CHB. Ultrasound is the accepted technique
for fetal CHB diagnoses.98 Current recommendations include serial fetal echocardiograms between
18 and 28 weeks of gestation for pregnant women
with anti-Ro and/or anti-La antibodies.82,99
Dierent treatment regimens for CHB have been
attempted.100 Fluorinated steroids (betametasone
and dexametasone), due to their ability to cross
the placenta, are generally reserved for cases with
myocarditis, hydrops or incomplete heart block, as
a potential for reversibility has been suggested.82,101
The use of these drugs should be carefully indicated, and never prescribed without CHB signs or
as prophylactic treatment, as the high doses that
are usually administered (dexametasone 48 mg/
day until the end of the pregnancy) have important
side eects for both the mother (i.e. diabetes, hypertension, osteoporosis, infections) and the fetus (i.e.
oligohydramnios, IUGR, adrenal suppression,
learning disabilities).82
In a murine model, treatment with intravenous
immunoglobulins (IVIG) was proved to inhibit
anti-Ro/La antibodies placental transfer and their
consequent fetal heart damage.102 Nevertheless,
two multi-centre prospective studies failed to
reduce the risk of CHB in women, with a previously
aected baby, treated with IVIG during pregnancy.103,104 In a dierent study, plasmapheresis
also failed to prevent the incidence of CHB.105 A
recent multi-centre case-control study suggested
that, in mothers with anti-Ro/La, exposure to

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1299

HCQ during pregnancy may decrease the risk of

fetal development of CHB.106
Fertility
Fertility in women with SLE seems to be similar to
women in the general population,107 although
patients with chronic renal failure (GFR < 50 ml/
min), amenorrhoea due to previous high cumulative dose of cyclophosphamide, and/or active disease may present reduced fertility.108110 Patients
who take nonsteroidal anti-inammatory drugs
(NSAID) should be encouraged to stop them
when trying to conceive because of the risk of luteinized unruptured follicle syndrome.111,112 This condition is a well-described anovulatory state
characterized by clinical signs of ovulation in the
absence of follicular rupture and ovum release,
which is caused by the inhibition of the cyclooxygenase-2 (COX-2) needed during follicular
development.
In women who are keen to undergo in vitro fertilization and embryo transfer techniques, regardless of the infertility cause, ovarian stimulation for
oocytes collection process involves the use of highdose oestrogens with a subsequent increased risk of
disease are and thromboembolic events113,114 (the
latter especially related to ovarian hyperstimulation
syndrome (OHS), aPL and/or other prothrombotic
risk factors). Therefore, identication of high-risk
patients, pre-cycle counselling, adequate thromboprophylaxis and close surveillance are essential for
correct management in these situations.115,116
Ovarian stimulation with clomiphene, singleembryo transfer, avoidance of OHS, and the use
of natural estradiol and/or progestagens through
a non-oral route have been suggested as safe
approaches in SLE and APS patients.115
Offspring
Amongst children born to women with lupus, there
is an increased risk of poorer neuropsychological
development, mainly associated with preterm
birth and low birth weight complications.117
Increased incidence of learning disabilities such as
dyslexia, dysgraphia and dyscalculia, and higher
risk of autism have also been described in SLE ospring.118,119 No dierences in intelligence (IQ
scores) have been seen compared with normal
population.120 However, in addition to wellestablished factors such as male sex and being
born preterm, both maternal SLE and CHB may
inuence neurodevelopment.121 A prospective
multi-centre registry recently showed that the presence of neurodevelopmental abnormalities seems to

be more frequent in children born to mothers with

APS.122 These studies may justify long-term followup in SLE/APS ospring.
The use of immunosuppressive drugs during
pregnancy does not generally hamper the correct
development of the newborns immune system
and its response to scheduled vaccinations.123126
However, a recent observational study showed
that azathioprine (AZA) exposure during SLE
pregnancy was independently associated with
increased special education services utilization in
ospring, after controlling for confounders.127

Medications during pregnancy and breastfeeding

Most of the data regarding the safety of medications in pregnancy and lactation are extracted from
retrospective case series and isolated case reports.
The pregnancy categories of the United States
Food and Drug Administration (FDA) are frequently of little help for the clinicians who are dealing with women with chronic diseases during
pregnancy and lactation. However, a recent
experts consensus dened the safety in pregnancy
and lactation of many of the drugs used in autoimmune and rheumatic diseases.128
NSAIDs
NSAIDs are generally safe drugs in pregnancy if
they are used for short limited courses, but may
be associated with renal and cardiac failure, hypertension, and uid overload in the mother, and oligohydramnios and renal impairment in the fetus if
they are used for long periods of time. Their use
should be withheld towards the end of pregnancy
(>3032 weeks) due to increased risk of premature
closure of babys ductus arteriosus, and increased
risk of maternal bleeding and asthma in the
child.128,129 At present there are no reliable data
on selective COX-2 inhibitors and they should
therefore be avoided.
Antimalarials
Antimalarials are one of the fundamental treatments in SLE because of their protective properties
on activity, damage, long-term survival and thrombosis.23 HCQ is the preferred drug due to its low
side-eect rates. Its safety prole for both the
mother and the baby has been widely addressed,
with no reported fetal neuro-sensorial toxicity or
malformations.130 In contrast, chloroquine has
been associated with increased risk of retinopathy
Lupus

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1300

in the mother23,131 and fetal ototoxicity.132 Taking

into account these characteristics and those mentioned earlier, HCQ should be continued throughout and after pregnancy in lupus patients.
Mepacrine, in contrast, should be avoided because
of the lack of safety data.

with AZA in women with quiescent LN for pregnancy planning rarely leads to renal ares.142
Intravenous immunoglobulins can be safely used
in pregnancy and lactation, and are useful when
there is a desire to withhold strong immunosuppressants, especially in situations where infection
and are cannot be easily dierentiated.128

Corticosteroids
Fluorinated
corticosteroids
(betamethasone,
dexamethasone) are not inactivated by placental
hydroxylases and easily cross the placenta.
Non-uorinated corticosteroids (e.g. prednisone,
prednisolone, methylprednisolone, hydrocortisone)
are largely metabolized by placental 11bHydroxysteroid dehydrogenase, and thus minimal
amounts reach the fetal circulation (<10% of total
dose).133 Nevertheless, the use of these drugs is
related to several complications such as hypertension, pre-eclampsia, diabetes, infections and premature rupture of membranes,46,47 hence minimum
maintenance doses (prednisone <7.5 mg/day), combined with steroid-sparing agents are recommended, rather than higher (prednisone >7.5 mg/
day) sustained doses.134,135 Stress doses of hydrocortisone at delivery are recommended in patients
on long-term therapy. Non-uorinated corticosteroids are mildly excreted into breast milk (525%)
and, therefore, allowed in breastfeeding. When high
doses are used (prednisone > 40 mg/day) timing
breastfeeding before and after the dose may be
considered.128
Immunosuppressants
The majority of immunosuppressive drugs are contraindicated during pregnancy and breastfeeding,
with the exception of AZA, cyclosporin (CS) and
tacrolimus (FK-506).128,136 With regards to the
latter drugs, their use should be justied and the
aim should be to keep them at the lowest eective
dose. CS use during pregnancy, although safe, has
been related to higher incidence of hypertension,
pre-eclampsia
and
gestational
diabetes.137
Tacrolimus is considered safe during pregnancy
and breastfeeding, but cautious drug-level monitoring is warranted in order to adjust drug levels
during these periods.138141 In patients taking
mycophenolate mofetil (MMF), methotrexate or
cyclophosphamide (CPA), these drugs should be
switched to safer ones (e.g. AZA, tacrolimus) and
conception should be delayed at least 3 months, in
order to monitor new ares and side eects.128 A
recent observational study showed that, amongst
patients with previous nephritis, replacing MMF
Lupus

Lupus flares during pregnancy

Mild ares during pregnancy can be treated with
NSAID, HQC and low dose of oral steroids. For
severe disease, the use of methylprednisolone pulses
followed by rapid reduction of oral steroids to low
maintenance doses, combined with safe immunosuppressants and/or IVIG may be necessary.143
More severe cases may require prioritizing the
patients welfare over fetus viability, and therefore
using stronger agents such as MMF or cyclophosphamide beyond the organogenesis period.
Biological drugs
Rituximab and belimumab are the most used biological drugs in lupus. The experience in pregnancy
with the latter is scarce, hence the current recommendation is to withdraw it at least 4 months prior
to conception.144 In the case of rituximab, two
recent retrospective series identied 240 exposed
pregnancies to the drug with dierent autoimmune
and haematological diseases, including data from
clinical trials and isolated reports of maternal
exposure. Pregnancy outcomes were available for
162 exposures. Over 61% (n 99) resulted in live
births of which 26% delivered preterm, while the
rst trimester miscarriage rate was 20%. Eleven
neonates had haematological abnormalities, but
none presented infectious complications. Two
cases of congenital malformations were described
(clubfoot in a twin, and cardiac malformations in
a singleton). Given the maternal indications for its
use and the heterogeneity of the reports, until more
robust data are available women should be counselled against pregnancy for 612 months after
rituximab exposure due to the risk of neonatal
B-cell depletion.145,146 Neonates who were exposed
to this biological during the second or third trimester should receive close white blood cell and infection surveillance.
Drugs for pulmonary hypertension
Endothelin receptor antagonists such as bosentan,
sitaxsentan and ambrisentan are considered category X by the FDA. Their eect in human pregnancies is still unknown, but they are teratogenic in

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1301

rodents and conception should be delayed for at

least 3 months after stopping these agents.
Phosphodiesterase type 5 inhibitors such as sildenal and tadalal are considered category B by
the FDA. Their use in human pregnancy has not
resulted in fetal side eects.147
Prostaglandin derivatives such as prostacyclin
(epoprostenol) and iloprost are considered category
B by the FDA and have been safely used in pregnancy and breastfeeding.148
Anti-hypertensives
The drugs of choice for managing hypertension in
pregnancy are labetalol, methyldopa and nifedipine, and less frequently hydralazine and doxazosin.56 ACEI, ARB and diuretics are related to fetal
renal impairment and oligohydramnios, and ACEI
and ARB have an increased risk of miscarriage,149
and higher risk of malformations if they are used
during the second and third trimester.150 Therefore,
these drugs are generally contraindicated during
pregnancy. However, despite previous controversy,
exposure to ACEI-ARB in the rst trimester may
be safe and not related to malformations in the
fetus.149,151 Post-natally, methyldopa should be
avoided because of higher risk of depression, and
also ARB because of lack of data.56

warfarin during second and third trimesters with

close INR controls can be safely performed in special situations such as previous thromboembolic
events on therapeutic dose of LMWH, some
women with mechanical heart valves or in countries/settings where both the health system and the
women cannot aord the expense of LMWH.152
Vitamin K antagonists are safe in lactation.128
Fondaparinux crosses the placenta (fetal levels
about 10% of maternal ones) suggesting that,
although less innocuous than heparin, it could be
safely used with precaution.128,153
Currently, little is known about the safety of the
new anticoagulants (e.g. rivaroxaban, dabigatran)
during pregnancy and lactation, and therefore their
use is not recommended.128
Bisphosphonates
Although they are considered as class C by the
FDA, the safety of bisphosphonates (BPs) in
human pregnancies is unknown. A recent review
of the literature154 identied 78 cases of mothers
exposed to BPs before conception or during pregnancy; 69 resulted in live births (88.5%), and none
of the infants had serious adverse events secondary
to BPs. Due to insucient robust data, pregnancy
should be postponed for at least 6 months after
withdrawal of bisphosphonates.128

Antiplatelets and anticoagulants

Treatment with low-dose aspirin (LDA; 75100 mg/
day) and dipyridamole is safe.128 If indicated,
aspirin should be continued throughout pregnancy
and there is no evidence to discontinue it before
labour or spinal/epidural anaesthesia in order to
decrease haemorrhagic complications. Clopidogrel
and ticlopidine, although considered class B by the
FDA, are usually not recommended because of the
lack of safety data, and generally avoided near term
due to increased bleeding risk peripartum.128
Heparins (both unfractionated and low molecular
weight heparin (LMWH)) do not cross the placenta
and are safe during pregnancy and breastfeeding. In
contrast, warfarin and coumadin are teratogenic
during organogenesis (610 weeks of gestation)
and they should be avoided during this period.
Their use is related to increased risk of fetal bleeding.128 Current recommendations include switching
patients to high prophylactic dose of LMWH (e.g.
enoxaparin 0.60.7 mg/kg BD) as soon as pregnancy
is conrmed in those with previous venous thrombosis, or to full anticoagulant dose LMWH (e.g.
enoxaparin 1 mg/kg BD) in those with previous
arterial events. This regime is generally continued
throughout pregnancy, although switching back to

Statins
The available data regarding the teratogenic risk of
statins are contradictory, thus they are considered
contraindicated in pregnancy. However, data from
recent studies are encouraging.155,156 Their pleiotropic eects of vascular protection have been suggestive of potential benet in the management of
pre-eclampsia. Dierent statins have shown positive eects on serum markers involved in preeclampsia in murine models.157,158 Pravastatin has
favourable safety and pharmacokinetic proles.
Moreover, animal studies and human pregnancy
exposure data do not support teratogenicity
claims for pravastatin. Thus, a multi-centre phaseI pilot trial was started last year in the USA to
collect maternalfetal safety data and to evaluate
pravastatin pharmacokinetics when used as a
prophylactic daily treatment in high-risk pregnant
women (NCT01717586, Pravastatin for prevention
of pre-eclampsia).159 The ongoing StAmP trial
(Statins to Ameliorate early onset Pre-eclampsia)
in the UK will hopefully provide some insight
into the ability of pravastatin to restore the angiogenic balance during pregnancy and possible eect
on pregnancy outcomes.
Lupus

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1302

Pregnancy management plan

Pre-pregnancy counselling, risk assessment, multidisciplinary approach, tailored antenatal and postnatal management plan, together with experienced
and reliable neonatal unit, and early recognition of
signs related to SLE complications (either medical
and/or obstetric), are essential cornerstones for
both maternal and fetal successful outcomes.
The pre-conceptional visit should include a
detailed summary of previous obstetric history
and chronic organ damage, recent serologic prole
(aPL, anti-Ro/La, anti-dsDNA, complement),
current disease activity and last are date, medical
history and risk factors of interest (e.g. diabetes,
hypertension, cardiac and cardiovascular problems,
nephropathy, thyroid function, detrimental habits,
and their complications), and baseline blood pressure, urine analysis and renal function.58
Presence of aPL/APS and/or anti-Ro/La, poor
previous obstetric history, presence of independent
factors for pre-eclampsia, severe irreversible
damage, other medical co-morbidities, and active
disease are associated with obstetric and medical
complications. Main risks for the mother and the
baby should be discussed accordingly. Women with
active lupus should postpone conception until
stable disease remission is achieved, particularly
those with internal organ involvement and
damage. Pregnancy should be contraindicated in
patients with severe lupus are or stroke over the
last 6 months, pulmonary hypertension, moderatesevere heart failure (ejection fraction of left ventricle <40%), severe restrictive lung disease
(FVC < 1 l), severe chronic renal impairment
(approx. GFR < 35 ml/min), uncontrolled hypertension, and previous severe pre-eclampsia despite
therapy with aspirin plus heparin.58
Women considered at high risk should be managed in a joint experienced medicalobstetrical setting throughout pregnancy, continuing with
adequate post-partum joint care. Women with
mild disease and/or considered to be at low risk
could be managed by their obstetricians with complementary medical visits as needed. Harmful or
unsafe medications should be stopped or changed
to safer ones at this stage, and discussion of
planned scans and visits should be undertaken.
The frequency of antenatal visits will depend on
the past history and the progress of the ongoing
pregnancy. As a guide, from 16 weeks to 26
weeks of gestation women should be reviewed
every 4 weeks, fortnightly from 2632 weeks of gestation, and weekly from 32 weeks onwards.
Lupus

Every visit should include urine analysis and maternal assessment, with special attention to hypertension and other features of pre-eclampsia. Women
with previous renal and/or hypertensive diseases
should have more frequent regular blood pressure
checks. Conrmation of proteinuria by protein
creatinine ratio is mandatory in case of positive
urine dipstick. Regular blood tests including full
blood count, liver function tests, renal prole,
anti-dsDNA and complement every 48 weeks are
recommended.58
Anomaly scan and uterine artery Doppler is recommended around 20 weeks of gestation and the
latter should be repeated around the 24th week if
abnormal. Abnormal waveforms are good predictors of pre-eclampsia, whereas normal results
are related to good obstetric outcomes.160162
Ultrasound scans (including biophysical prole
and amniotic uid volume assessment) around
2830 and 3234 weeks of gestation are recommended. Regular umbilical artery Doppler should
be performed with the previous scans, as their
abnormal values (particularly absent or reverse diastolic ow) are predictor of mortality and risk of
fetal compromise.163 Additional scans may be indicated depending on previous obstetric history and
the progress of the pregnancy.
In women with anti-Ro/La, regular fetal echocardiography between 16 and 28 weeks of gestation
is oered to identify CHB.82,99
All women on steroids and those with risk factors for diabetes should have a glucose tolerance
test around 2428 weeks gestation in order to
exclude gestational diabetes and avoid further
obstetric risk.164
All women should ideally take folic acid (0.4 mg/
day) 12 weeks before and after conception in order
to prevent fetal neural tube defects, and should be
encouraged to stop smoking and to reduce/cease
their alcohol intake. Concomitant prophylactic
calcium and Vitamin D supplements should be
prescribed to women on corticosteroids, heparin
and/or at high risk for osteoporosis.58
Haemoglobinopathy prole assessment may be
indicated in certain circumstances.

Pre-eclampsia and thromboprophylaxis

Patients with SLE and/or aPL present higher risk to
develop pre-eclampsia compared with the general
population. Low-dose aspirin started before 16
weeks of gestation signicantly reduces the risk of
perinatal death, pre-eclampsia and its complications

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1303
165168

in women at higher risk of pre-eclampsia,

and its maximum eect is probably achieved when
it is taken in the afternoon or at bedtime.169
Dipyridamole probably has similar eects.56
Taking into account its low side eects and recent
data suggesting its benet in all women,170 antiplatelet therapy for the prevention of pre-eclampsia is
recommended in patients with lupus.56,171 In addition, all women with aPL should take LDA to
decrease their risk of miscarriage and late obstetric
complications.172,173
A recent meta-analysis of 13 randomized trials
comparing the intake of at least 1 g of calcium daily
versus placebo during pregnancy showed a >50%
reduction in the risk of pre-eclampsia and a 25%
reduction in the risk of preterm delivery;174 therefore calcium supplementation is of great importance in these patients.
Treatment of women with obstetric APS is still a
subject of controversy and should be individualized, as most of the evidence is based on observational studies.175,176 Current recommendations
include LDA, alone or with prophylactic LMWH,
for women with recurrent early miscarriages (<10
weeks of gestation), and LDA plus prophylactic
LMWH for women with previous fetal death
(>10 weeks of gestation) and/or preterm delivery
(<34 weeks of gestation).58,173,175,177
All women should be assessed regarding risk factors for venous thromboembolism prior to conception and periodically throughout pregnancy, and
should receive thromboprophylaxis accordingly.152
Risk factors for venous thrombosis in pregnancy
and puerperium and their management have been
described elsewhere.152,175,178
Women receiving high prophylactic or therapeutic doses of LMWH should discontinue them
or decrease them to prophylactic doses (e.g. enoxaparin 0.60.7 mg/kg OD) 24 h prior to the planned
delivery. Those on prophylactic doses of LMWH
should not continue LMWH once labour is established. Re-establishment of LMWH should be postponed until the placenta is delivered. Epidural
anaesthesia can be safely used 12 or 24 h after the
last dose of LMWH on prophylactic or high
prophylactic/therapeutic
doses,
respectively.
LMWH can be restarted 24 h after the epidural
catheter has been removed.179,180

Postpartum
Because of the high risk of are and thrombosis,
close surveillance should be ensured within the rst

23 months after delivery. A medical visit should be

arranged within the rst 46 weeks postpartum,
which should consist of a thorough history
review, physical examination, urine analysis,
blood pressure check and blood tests including
full blood count, liver function tests, renal prole,
anti-dsDNA and complement.
All women with aPL should receive at least
prophylactic LMWH for 7 days after delivery, in
the absence of other risk factors.152,181183 Some
experts recommend extending this treatment for
48 weeks postpartum.175 Those who received
prophylactic doses of LMWH during pregnancy
for maternal purposes or those with high venous
thromboembolic risk should prolong this treatment
to 6 weeks postpartum.152 Women with previous
thrombosis may require long-term anticoagulation.
LMWH can be switched to warfarin or coumadin
when the risk of haemorrhage is low (usually 57
days postpartum).152 After delivery therapeutic
LMWH can be safely used as a single dose daily
(e.g. enoxaparin 1.5 mg/kg OD).
Contraception
Counselling on contraception is of great importance in SLE, as planned pregnancy is associated
with fewer complications and higher pregnancy
successful rates. However, it still remains an unresolved matter.184,185 Among contraceptives, barrier
methods, hormonal contraceptives and intrauterine
devices (IUD) are the eligible methods and should
be selected based on individual characteristics.186
Barrier methods, including condom and diaphragm, represent an eective form of contraception (8397% success) and are the only methods
protective
against
sexually
transmitted
187
infections.
Hormonal methods include oral contraceptives
(OC) (combined or progestogen only) and subcutaneous devices (i.e. implants, injectables, skin
patches and vaginal rings). Despite the classic
advice against the use of oestrogen-containing OC
in women with lupus,188 current evidence supports
the safety of combined OC in well-dened SLE
patients with stable and/or low-active disease.189,190
However, because of the increased risk of thrombosis, combined OC are contraindicated in patients
with aPL, and/or other risk factors such as
moderatesevere active disease, history of thrombosis, hypertension, smoking and obesity.191,192
Progestogen-only preparations are safe and do
not aect disease activity or thrombosis risk,193
but may decline bone density when used for >2
years.194,195 The latter eect seems to be reversible
Lupus

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1304

after discontinuation. Interactions between hormonal contraceptives and other chronic or new medications may provoke contraceptive failure and/or
alterations in metabolism of those drugs. Hence,
rigorous and regular check of medications interactions becomes mandatory when using hormonal
contraceptives.
IUD (either as copper IUD non-hormonal
devices or progestogen IUD hormonal devices)
are safe, eective (98% success) and reduce menstrual bleeding, but have 5% chance of expulsion
and confer a higher pelvic infection risk (1%),196
thus are generally preferred in patients with single
sexual partner.

Funding
This research received no specic grant from any
funding agency in the public, commercial, or notfor-prot sectors.

Conflict of interest
None declared.

References
1 Bernatsky S, Joseph L, Pineau CA, Tamblyn R, Feldman DE,
Clarke AE. A population-based assessment of systemic lupus erythematosus incidence and prevalenceresults and implications of
using
administrative
data
for
epidemiological
studies.
Rheumatology (Oxford) 2007; 46: 18141818.
2 Domsic RT, Ramsey-Goldman R, Manzi S. Epidemiology and classification of systemic lupus erythematosus. In: Hochberg MC,
Silman AJ, Smolen JS, et al (eds), Rheumatology, 4th ed.
Philadelphia, PA: Mosby Elsevier, 2008. pp. 12111216.
3 Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates
in patients with systemic lupus erythematosus over a 40-year period.
J Rheumatol 2005; 32: 17091712.
4 Andrade RM, McGwin Jr G, Alarcon GS, et al. Predictors of postpartum damage accrual in systemic lupus erythematosus: Data from
LUMINA, a multiethnic US cohort (XXXVIII). Rheumatology
2006; 45: 13801384.
5 Lockshin MD, Reinitz E, Druzin ML, Murrman M, Estes D. Lupus
pregnancy: Case-control prospective study demonstrating absence
of lupus exacerbation during or after pregnancy. Am J Med 1984;
77: 893898.
6 Mintz G, Nitz J, Gutierrez G, et al. Prospective study of pregnancy
in systemic lupus erythematosus: Results of a multi-disciplinary
approach. J Rheumatol 1986; 13: 732739.
7 Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy: The Hopkins lupus pregnancy center experience. Arthritis
Rheum 1991; 34: 15381545.
8 Wong KL, Chan FY, Lee XP. Outcome of pregnancy in patients
with systemic lupus erythematosus. A prospective study. Arch Intern
Med 1991; 151: 269273.
9 Urowitz MB, Gladman DD, Farewell VT, Stewart J,
McDonald J. Lupus and pregnancy studies. Arthritis Rheum
1993; 36: 13921397.
Lupus

10 Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus

flare during pregnancy and the puerperium. Br J Rheumatol 1996;
35: 133138.
11 Tandon A, Ibanez D, Gladman DD, Urowitz MB. The effect of
pregnancy on lupus nephritis. Arthritis Rheum 2004; 50:
39413946.
12 Khamashta MA, Ruiz-Irastorza G, Hughes GRV. Systemic lupus
erythematosus flares during pregnancy. Rheum Dis Clin North Am
1997; 23: 1530.
13 Le Thi Huong D, Wechsler B, Vauthier-Brouzes D, et al. Outcome
of planned pregnancies in systemic lupus erythematosus: A prospective study on 62 pregnancies. Br J Rheumatol 1997; 36:
772777.
14 Clowse ME, Witter FR, Magder LC, Petri M. The impact of
increased lupus activity on obstetrical outcomes. Arthritis Rheum
2005; 52: 514522.
15 Moroni G, Ponticelli C. Pregnancy after lupus nephritis. Lupus
2005; 14: 8994.
16 Imbasciati E, Tincani A, Gregorini G, et al. Pregnancy in women
with pre-existing lupus nephritis: Predictors of fetal and maternal
outcome. Nephrol Dial Transplant 2009; 24: 519525.
17 Soubassi L, Haidopoulos D, Sindos M, et al. Pregnancy outcome
in women with pre-existing lupus nephritis. J Obs Gynaecol 2004;
24: 630634.
18 Day CJ, Lipkin GW, Savage CO. Lupus nephritis and pregnancy
in the 21st century. Nephrol Dial Transplant 2009; 24: 344347.
19 Germain S, Nelson-Piercy C. Lupus nephritis and renal disease in
pregnancy. Lupus 2006; 15: 148155.
20 Williams D, Davidson J. Chronic disease in pregnancy. BMJ 2008;
336: 211215.
21 Imbasciati E, Gregorini G, Cabiddu G, et al. Pregnancy in CKD
stages 3 to 5: Fetal and maternal outcomes. Am J Kidney Dis 2007;
49: 753762.
22 Petri M. The Hopkins lupus pregnancy center: Ten key issues in
management. Rheum Dis N Am 2007; 33: 227235.
23 Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta
MA. Clinical efficacy and side effects of antimalarials in systemic
lupus erythematosus: A systematic review. Ann Rheum Dis 2010;
69: 2028.
24 Levy RA, Vilela VS, Cataldo MJ, et al. Hydroxychloroquine
(HCQ) in lupus pregnancy: Double-blind and placebo-controlled
study. Lupus 2001; 10: 401404.
25 Clowse M, Magder L, Witter F, Petri M. Hydroxychloroquine in
lupus pregnancy. Arthritis Rheum 2006; 54: 36403647.
26 Buyon JP, Kalunian KC, Ramsey-Goldman R, et al. Assessing
disease activity in SLE patients during pregnancy. Lupus 1999; 8:
677684.
27 Baines MG, Millar KG, Mills P. Studies of complement levels in
normal human pregnancy. Obstet Gynecol 1974; 43: 806810.
28 Weiss BM, Zemp L, Seifert B, Hess OM. Outcome of pulmonary
vascular disease in pregnancy: A systematic overview from 1978
through 1996. J Am Coll Cardiol 1998; 31: 16501657.
29 Ruiz-Irastorza G, Khamashta MA, Hughes GRV. Heart disease,
pregnancy and systemic autoimmune diseases. In: Oakley C,
Warnes CA, (eds) Heart disease in pregnancy. 2nd ed. Blackwell
Publishing, 2007, pp.136-150.
30 Bonnin M, Mercier FJ, Sitbon O, et al. Severe pulmonary hypertension during pregnancy. Mode of delivery and anesthetic management of 15 consecutive cases. Anesthesiology 2005; 102:
11331137.
31 Ma L, Liu W, Huang Y. Perioperative management for parturients
with pulmonary hypertension: Experience with 30 consecutive
cases. Front Med 2012; 6: 307310.
32 Doria A, Cutolo M, Ghirardello A, et al. Steroid hormones and
disease activity during pregnancy in systemic lupus erythematosus.
Arthritis Rheum 2002; 47: 202209.
33 Ruiz-Irastorza G, Khamashta MA, Gordon C, et al. Measuring
systemic lupus erythematosus activity during pregnancy:
Validation of the Lupus Activity Index in Pregnancy scale.
Arthritis Rheum 2004; 51: 7882.
34 Clowse MEB, Jamison M, Myesr E, James AH. A national study
of the complications of lupus in pregnancy. Am J Obstet Gynecol
2008; 199: 127.e1e6.

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1305
35 Hamed HO, Ahmed SR, Alzolibani A, et al. Does cutaneous lupus
erythematosus have more favorable pregnancy outcomes than systemic disease? A two-center study. Acta Obstet Gynecol Scand
2013; 92: 934942.
36 Yan Yuen S, Krizova A, Ouimet JM, Pope JE. Pregnancy outcome
in systemic lupus erythematosus (SLE) is improving: Results from
a case control study and literature review. Open Rheumatol J 2008;
2: 8998.
37 Clowse ME, Magder LS, Petri M. The clinical utility of measuring
complement and anti-dsDNA antibodies during pregnancy in
patients with systemic lupus erythematosus. J Rheumatol 2011;
38: 10121016.
38 Stagnaro-Green A, Akhter E, Yim C, Davies TF, Magder L, Petri
M. Thyroid disease in pregnant women with systemic lupus erythematosus: Increased preterm delivery. Lupus 2011; 20: 690699.
39 Magid MS, Kaplan C, Sammaritano LR, Peterson M, Druzin ML,
Lockshin MD. Placental pathology in systemic lupus erythematosus: A prospective study. Am J Obstet Gynecol 1998; 179: 226234.
40 Hayslett JP. The effect of systemic lupus erythematosus on pregnancy and pregnancy outcome. Am J Reprod Immunol 1992; 28:
199204.
41 Yasmeen S, Wilkins EE, Field NT, Sheikh RA, Gilbert WM.
Pregnancy outcomes in women with systemic lupus erythematosus.
J Matern Fetal Med 2001; 10: 9196.
42 Clark CA, Spitzer KA, Nadler JN, Laskin CA. Preterm deliveries
in women with systemic lupus erythematosus. J Rheumatol 2003;
30: 21272132.
43 Clowse ME, Magder LS, Witter F, Petri M. Early risk factors for
pregnancy loss in lupus. Obstet Gynecol 2006; 107: 293299.
44 Shand AW, Algert CS, March L, Roberts CL. Second pregnancy
outcomes for women with systemic lupus erythematosus. Ann
Rheum Dis 2013; 72: 547551.
45 Vinet E, Clarke AE, Gordon C, et al. Decreased live births in
women with systemic lupus erythematosus. Arthritis Care Res
(Hoboken) 2011; 63: 10681072.
46 Chakravarty EF, Colon I, Langen ES, et al. Factors that predict
prematurity and preeclampsia in pregnancies that are complicated
by systemic lupus erythematosus. Am J Obstet Gynecol 2005; 192:
18971904.
47 Andrade R, Sanchez ML, Alarcon GS, et al. Adverse pregnancy
outcomes in women with systemic lupus erythematosus from a
multiethnic US cohort: LUMINA (LVI). Clin Exp Rheumatol
2008; 26: 268274.
48 Smyth A, Oliveira GH, Lahr BD, Bailey KR, Norby SM, Garovic
VD. A systematic review and meta-analysis of pregnancy outcomes
in patients with systemic lupus erythematosus and lupus nephritis.
Clin J Am Soc Nephrol 2010; 5: 20602068.
49 Rahman FZ, Rahman J, Al-Suleiman SA, Rahman MS. Pregnancy
outcome in lupus nephropathy. Arch Gynecol Obstet 2005; 271:
222226.
50 McGrory CH, McCloskey LJ, DeHoratius RJ, Dunn SR, Moritz
MJ, Armenti VT. Pregnancy outcomes in female renal recipients: A
comparison of systemic lupus erythematosus with other diagnoses.
Am J Transplant 2003; 3: 3542.
51 Mackillop LH, Germain SJ, Nelson-Piercy C. Systemic lupus erythematosus. Br Med J 2007; 335: 933936.
52 Moroni G, Ponticelli C. The risk of pregnancy in patients with
lupus nephritis. J Nephrol 2003; 16: 161167.
53 Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations
in the United States for women with systemic lupus erythematosus
and rheumatoid arthritis. Arthritis Rheum 2006; 54: 899907.
54 Meis PJ, Goldenberg RL, Mercer BM, et al. for the Maternal-Fetal
Medicine Units Network of the National Institute of Child Health
and Human Development. The preterm prediction study: risk factors for indicated preterm births. Am J Obstet Gynecol 1998; 178:
562567.
55 Milne F, Redman C, Walker J, et al. The pre-eclampsia community
guideline (PRECOG): How to screen for and detect onset of preeclampsia in the community. Br Med J 2005; 330: 576580.
56 National Institute for Health and Clinical Excellence.
Hypertension in pregnancy: The management of hypertensive disorders during pregnancy (clinical guideline 107), www.nice.org.uk/
CG107 (2010, accessed August 2013).

57 Management of sickle cell disease in pregnancy. Green Top

Guideline 61. Royal College of Obstetricians and Gynaecologists,
London,
www.rcog.org.uk/womens-health/clinical-guidance/
sickle-cell-disease-pregnancy-management-green-top-61
(2011,
accessed August 2013).
58 Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy:
Integrating clues from the bench and bedside. Eur J Clin Invest
2011; 41: 672678.
59 Chen HH, Lin HC, Yeh JC, Chen CP. Renal biopsy in pregnancies
complicated by undetermined renal disease. Acta Obstet Gynecol
Scand 2001; 80: 888893.
60 Cervera R, Khamashta MA, Font J, et al. Antiphospholipid syndrome: Clinical and immunologic manifestations and pattern of
disease expression in a cohort of 1.000 patients. Arthritis Rheum
2002; 46: 10191027.
61 Cervera R, Boffa MC, Khamashta MA, Hughes GR. The EuroPhospholipid project: Epidemiology of the antiphospholipid syndrome in Europe. Lupus 2009; 18: 889893.
62 Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS.
Antiphospholipid antibodies in pregnancy: Prevalence and clinical
associations. Br J Obstet Gynaecol 1993; 100: 909913.
63 Lynch A, Marlar R, Murphy J, et al. Antiphospholipid antibodies
in predicting adverse pregnancy outcome. A prospective study. Ann
Inten Med 1994; 120: 470475.
64 Yasuda M, Tkakuwa K, Tokunaga A, Tanaka K. Prospective
studies of the association between anticardiolipin antibody and
outcome of pregnancy. Obstet Gynecol 1995; 86: 555559.
65 Katano K, Aoki A, Sasa H, Ogawara M, Matsumura E, Yagami
Y. Beta 2-Glycoprotein I-dependent anticardiolipin antibodies as a
predictor of adverse pregnancy outcomes in healthy pregnant
women. Hum Reprod 1996; 11: 509512.
66 Faden D, Tincani A, Tanzi P, et al. Anti-beta 2 glycoprotein I
antibodies in a general obstetric population: Preliminary results
on the prevalence and correlation with pregnancy outcome. Eur
J Obstet Gynecol Reprod Biol 1997; 73: 3742.
67 Yamada H, Atsumi T, Kobashi G, et al. Antiphospholipid antibodies increase the risk of pregnancy-induced hypertension and
adverse pregnancy outcomes. J Reprod Immunol 2009; 79: 188195.
68 Nodler J, Moolamalla SR, Ledger EM, Nuwayhid BS, Mulla ZD.
Elevated antiphospholipid antibody titers and adverse pregnancy
outcomes: Analysis of a population-based hospital dataset. BMC
Pregnancy Childbirth 2009; 9: 11.
69 Yamada H, Atsumi T, Amengual O, et al. Glycoprotein-I antibody
increases the risk of pregnancy-induced hypertension: A casecontrolled study. J Reprod Immunol 2010; 84: 9599.
70 do Prado D, Piovesan M, Staub L, Horta L. Association of anticardiolipin antibodies with preeclampsia. Obstet Ginecol 2010; 116:
14331443.
71 Ruffatti A, Calligaro A, Hoxha A, et al. Laboratory and clinical
features of pregnant women with antiphospholipid syndrome and
neonatal outcome. Arthritis Care Res 2010; 62: 302307.
72 Bramham K, Hunt BJ, Germain S, et al. Pregnancy outcome in
different clinical phenotypes of antiphospholipid syndrome. Lupus
2010; 9: 5864.
73 Lockshin MD, Kim M, Laskin CM, et al. Prediction of adverse
pregnancy outcome by the presence of lupus anticoagulant, but not
anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum 2012; 64: 23112318.
74 Clark CA, Davidovits J, Spitzer KA, Laskin CA. The lupus anticoagulant: Results from 2257 patients attending a high-risk pregnancy clinic. Blood 2013; 122: 341347.
75 Khamashta MA. Systemic lupus erythematosus and pregnancy.
Best Pract Res Clin Rheumatol 2006; 20: 685694.
76 Arbuckle MR, McClain MT, Rubertone MV, et al. Development
of autoantibodies before the clinical onset of systemic lupus erythematosus. N Engl J Med 2003; 349: 15261533.
77 To CH, Petri M. Is antibody clustering predictive of clinical subsets
and damage in systemic lupus erythematosus? Arthritis Rheum
2005; 52: 40034010.
78 Faria AC, Barcellos KS, Andrade LE. Longitudinal fluctuation of
antibodies to extractable nuclear antigens in systemic lupus erythematosus. J Rheumatol 2005; 32: 12671272.
Lupus

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1306
79 Alsaleh J, Jassim V, Elsayed M, Saleh N, Harb D. Clinical and
immunological manifestations in 151 SLE patients living in
Dubai. Lupus 2008; 17: 6266.
80 Gordon PA. Congenital heart block: Clinical features and therapeutic approaches. Lupus 2007; 16: 642646.
81 Hayashi N, Koshiba M, Nishimura K, et al. Prevalence of
disease-specific antinuclear antibodies in general population:
Estimates from annual physical examinations of residents of a
small town over a 5-year period. Mod Rheumatol 2008; 18:
153160.
82 Izmirly PM, Rivera TL, Buyon JP. Neonatal lupus syndromes.
Rheum Dis Clin N Am 2007; 33: 267285.
83 Silverman E, Jaeggi E. Non-cardiac manifestations of neonatal
lupus erythematosus. Scand J Immunol 2010; 72: 223225.
84 Brucato A, Frassi M, Franceschini F, et al. Risk of congenital
complete heart block in newborns of mothers with anti-Ro/SSA
antibodies detected by counterimmunoelectrophoresis: A prospective study of 100 women. Arthritis Rheum 2001; 44:
18321835.
85 Izmirly PM, Llanos C, Lee LA, Askanase A, Kim MY, Buyon JP.
Cutaneous manifestations of neonatal lupus and risk of subsequent congenital heart block. Arthritis Rheum 2010; 62:
11531157.
86 Brucato A, Grava C, Bortolati M, et al. Congenital heart block
not associated with anti-Ro/La antibodies: Comparison with antiRo/La-positive cases. J Rheumatol 2009; 36: 17441748.
87 Meilof JF, Frohn-Mulder IM, Stewart PA, et al. Maternal
autoantibodies and congenital heart block: No evidence for the
existence of a unique heart block-associated anti-Ro/SS-A autoantibody profile. Lupus 1993; 2: 239246.
88 Eliasson H, Sonesson SE, Sharland G, et al. Isolated atrioventricular block in the fetus: A retrospective, multinational, multicenter study of 175 patients. Circulation 2011; 124: 19191926.
89 Llanos C, Friedman D, Saxena A, et al. Anatomical and pathological findings in hearts from fetuses and infants with cardiac
manifestations of neonatal lupus. Rheumatology 2012; 51:
10861092.
90 Buyon JP, Hiebert R, Copel J, et al. Autoimmune-associated congenital heart block: Demographics, mortality, morbidity and
recurrence rates obtained from a national neonatal lupus registry.
J Am Coll Cardiol 1998; 31: 16581666.
91 Eronen M, Siren MK, Ekblad H, Tikanoja T, Julkunen H,
Paavilainen T. Short- and long-term outcome of children with
congenital complete heart block diagnosed in utero or as a newborn. Pediatrics 2000; 106: 8691.
92 Salomonsson S, Strandberg L. Autoantibodies associated with
congenital heart block. Scand J Immunol 2010; 72: 185188.
93 Jaeggi E, Laskin C, Hamilton R, Kingdom J, Silverman E. The
importance of the level of maternal anti-Ro/SSA antibodies as a
prognostic marker of the development of cardiac neonatal lupus
erythematosus: A prospective study of 186 antibody-exposed
fetuses and infants. J Am Coll Cardiol 2010; 55: 27782784.
94 Tunks RD, Clowse ME, Miller SG, Brancazio LR, Barker PC.
Maternal autoantibody levels in congenital heart block and
potential prophylaxis with antiinflammatory agents. Am J
Obstet Gynecol 2013; 208: 64.e1e7.
95 Moak JP, Barron KS, Hougen TJ, et al. Congenital heart block:
development of late-onset cardiomyopathy, a previously underappreciated sequela. J Am Coll Cardiol 2001; 37: 238242.
96 Guettrot-Imbert G, Cohen L, Fermont L, et al. A new presentation of neonatal lupus: 5 cases of isolated mild endocardial fibroelastosis associated with maternal anti-SSA/Ro and anti-SSB/La
antibodies. J Rheumatol 2011; 38: 378386.
97 Nield LE, Silverman ED, Taylor GP, et al. Maternal anti-Ro and
anti-La
antibody-associated
endocardial
fibroelastosis.
Circulation 2002; 105: 843848.
98 Sonesson SE. Diagnosing foetal atrioventricular heart blocks.
Scand J Immunol 2010; 72: 205212.
99 Brucato A. Prevention of congenital heart block in children of
SSA-positive mothers. Rheumatology (Oxford) 2008; 47: i35i37.
100 Hutter D, Silverman ED, Jaeggi ET. The benefits of transplacental treatment of isolated congenital complete heart block
Lupus

101

102

103

104

105

106

107

108

109

110

111

112

113

114

115

116

117
118

119

associated with maternal anti-Ro/SSA antibodies: A review.

Scand J Immunol 2010; 72: 235241.
Friedman DM, Kim MY, Copel JA, Llanos C, Davis C, Buyon
JP. Prospective evaluation of fetuses with autoimmune-associated
congenital heart block followed in the PR interval and dexamethasone evaluation (PRIDE) study. Am J Cardiol 2009; 103:
11021106.
Tran HB, Cavill D, Buyon JP, Gordon TP. Intravenous immunoglobulin and placental transport of anti-Ro/La antibodies:
Comment on the letter by Kaaja and Julkunen. Arthritis Rheum
2004; 50: 337338.
Friedman DM, Llanos C, Izmirly PM, et al. Evaluation of fetuses
in a study of intravenous immunoglobulin as preventive therapy
for congenital heart block: Results of a multicenter, prospective,
open-label clinical trial. Arthritis Rheum 2010; 62: 11381146.
Pisoni CN, Brucato A, Ruffatti A, et al. Failure of intravenous
immunoglobulin to prevent congenital heart block: Findings of a
multicenter, prospective, observational study. Arthritis Rheum
2010; 62: 11471152.
Makino S, Yonemoto H, Itoh S, Takeda S. Effect of steroid
administration and plasmapheresis to prevent fetal congenital
heart block in patients with systemic lupus erythematosus and/
or Sjogrens syndrome. Acta Obstet Gynecol Scand 2007; 86:
11451146.
Izmirly PM, Costedoat-Chalumeau N, Pisoni CN, et al. Maternal
use of hydroxychloroquine is associated with a reduced risk of
recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012; 126: 7682.
Hardy CJ, Palmer BP, Morton SJ, Muir KR, Powell RJ.
Pregnancy outcome and family size in systemic lupus erythematosus: A case-control study. Rheumatology 1999; 38: 559563.
Hickman RA, Gordon C. Causes and management of infertility in
systemic lupus erythematosus. Rheumatology (Oxford) 2011; 50:
15511558.
Packham DK, Lam SS, Nicholls K, Fairley KF, Kincaid-Smith
PS. Lupus nephritis and pregnancy. Quart J Med 1992; 83:
315324.
Silva CA, Bonfa E, Ostensen M. Maintenance of fertility in
patients with rheumatic diseases needing antiinflammatory and
immunosuppressive drugs. Arthritis Care Res 2010; 62:
16821690.
Stone S, Khamashta MA, Nelson-Piercy C. Nonsteroidal antiinflammatory drugs and reversible female infertility: Is there a
link? Drug Saf 2002; 25: 545551.
Micu MC, Micu R, Ostensen M. Luteneized unruptured follicle
syndrome increased by inactive disease and selective cyclooxygenase 2 inhibitors in women with inflammatory arthropathies.
Arthritis Care Res 2011; 63: 13341338.
Guballa N, Sammaritano L, Schwartzman S, Buyon J, Lockshin
MD. Ovulation induction and in vitro fertilization in systemic
lupus erythematosus and antiphospholipid syndrome. Arthritis
Rheum 2000; 43: 550556.
Le Thi Huong D, Wechsler B, Vauthier-Brouzes D, et al.
Importance of planning ovulation induction therapy in systemic
lupus erythematosus and antiphospholipid syndrome: A single
center retrospective study of 21 cases and 114 cycles. Semin
Arthritis Rheum 2002; 32: 174188.
Bellver J, Pellicer A. Ovarian stimulation for ovulation induction
and in vitro fertilization in patients with systemic lupus erythematosus and antiphospholipid sindrome. Fertil Steril 2009; 92:
18031810.
Udoff LC, Branch DW. Management of patients with antiphospholipid antibodies undergoing in vitro fertilization.
J Autoimmun 2000; 15: 209211.
Fang S. Management of preterm infants with intrauterine growth
restriction. Early Hum Dev 2005; 81: 889900.
Bomba M, Galli J, Nacinovich R, et al. Neuropsychiatric aid in
children born to patients with rheumatic diseases. Clin Exp
Rheumatol 2010; 28: 767773.
Urowitz MB, Gladman DD, MacKinnon A, et al. Neurocognitive
abnormalities in offspring of mothers with systemic lupus erythematosus. Lupus 2008; 17: 555560.

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1307
120 Neri F, Chimini L, Bonomi F, et al. Neuropsychological development of children born to patients with systemic lupus erythematosus. Lupus 2004; 13: 805811.
121 Skog A, Tingstrom J, Salomonsson S, Sonesson SE, WahrenHerlenius M. Neurodevelopment in children with and without
congenital heart block born to anti-Ro/SSA-positive mothers.
Acta Paediatr 2013; 102: 4046.
122 Mekinian A, Lachassinne E, Nicaise-Roland P, et al. European
registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis 2013; 72: 217222.
123 Motta M, Tincani A, Meroni PL, Cimaz R. Follow-up of children
exposed antenatally to immunosuppressive drugs. Rheumatology
(Oxford) 2008; 47(Suppl. 3): iii32iii34.
124 Cimaz R, Meregalli E, Biggioggero M, et al. Response to tetanus
vaccination in infants exposed in utero to immunosuppressants
for maternal autoimmune disorders. Lupus 2007; 16: 129132.
125 Cimaz R, Meregalli E, Biggioggero M, et al. Alterations in the
immune system of children from mothers treated with immunosuppressive agents during pregnancy. Toxicol Lett 2004; 149:
155162.
126 Motta M, Ciardelli L, Marconi M, et al. Immune system development in infants born to mothers with autoimmune disease,
exposed in utero to immunosuppressive agents. Am J Perinatol
2007; 24: 441447.
127 Marder W, Ganser MA, Romero V, et al. In utero azathioprine
exposure and increased utilization of special educational services
in children born to mothers with systemic lupus erythematosus.
Arthritis Care Res (Hoboken) 2013; 65: 759766.
128 stensen M, Khamashta MA, Lockshin M, et al. Anti-inflammatory and immunosuppressive drugs and reproduction. Arthritis
Res Ther 2006; 8: 209227.
129 Nezvalova-Henriksen K, Spigset O, Nordeng H. Effects of ibuprofen, diclofenac, naproxen, and piroxicam on the course of
pregnancy and pregnancy outcome: A prospective cohort study.
BJOG 2013; 120: 948959.
130 Sperber K, Hom C, Chao CP, Shapiro D, Ash J. Systematic
review of hydroxychloroquine use in pregnant patients with autoimmune diseases. Pediatr Rheumatol Online J 2009; 7: 9.
131 Jover JA, Leon L, Pato E, et al. Long-term use of antimalarial
drugs in rheumatic diseases. Clin Exp Rheumatol 2012; 30:
380387.
132 Hart CW, Naunton RF. The ototoxicity of chloroquine phosphate. Arch Otolaryngol 1964; 80: 407412.
133 Benediktsson R, Calder AA, Edwards CRW, Seckl JR. Placental
11b-hydroxysteroid dehydrogenase: A key regulatorof fetal glucocorticoid exposure. Clin Endocrinol 1997; 46: 161166.
134 Ruiz-Irastorza G, Khamashta MA. Managing lupus patients
during pregnancy. Best Pract Res Clin Rheumatol 2009; 23:
575582.
135 Ruiz-Irastorza, Danza A, Khamashta M. Glucocorticoid use and
abuse. Rheumatology 2012; 51: 11451153.
136 Casanova MJ, Chaparro M, Domenech E, et al. Safety of thiopurines and anti-TNF-a drugs during pregnancy in patients with
inflammatory bowel disease. Am J Gastroenterol 2013; 108:
433440.
137 Paziana K, Del Monaco M, Cardonick E, et al. Ciclosporin use
during pregnancy. Drug Saf 2013; 36: 279294.
138 Zheng S, Easterling TR, Umans JG, et al. Pharmacokinetics of
tacrolimus during pregnancy. Ther Drug Monit 2012; 34: 660670.
139 Gouraud A, Bernard N, Millaret A, et al. Follow-up of tacrolimus breastfed babies. Transplantation 2012; 94: e38e40.
140 Hebert MF, Zheng S, Hays K, et al. Interpreting tacrolimus concentrations during pregnancy and postpartum. Transplantation
2013; 95: 908915.
141 Bramham K, Chusney G, Lee J, Lightstone L, Nelson-Piercy C.
Breastfeeding and tacrolimus: Serial monitoring in breast-fed and
bottle-fed infants. Clin J Am Soc Nephrol 2013; 8: 563567.
142 Fischer-Betz R, Specker C, Brinks R, Aringer M, Schneider M.
Low risk of renal flares and negative outcomes in women with
lupus nephritis conceiving after switching from mycophenolate
mofetil to azathioprine. Rheumatology (Oxford) 2013; 52:
10701076.

143 Ruiz-Irastorza G, Khamashta MA. Lupus and pregnancy: Ten

questions and some answers. Lupus 2008; 17: 416420.
144 Benlysta O` (Belimumab). Package insert. USA: Human Genome
Sciences and GlaxoSmithKline, March 2011.
145 Vinet E, Pineau C, Gordon C, Clarke A, Bernatsky SR. Biologic
therapy and pregnancy outcomes in women with rheumatic diseases. Arthritis Rheum 2009; 61: 587592.
146 Chakravarty EF, Murray ER, Kelman A, Farmer P. Pregnancy
outcomes after maternal exposure to rituximab. Blood 2011; 117:
14991506.
147 von Dadelszen P, Dwinnell S, Magee LA, et al. Sildenafil citrate
therapy for severe early-onset intrauterine growth restriction.
BJOG 2011; 118: 624628.
148 Bendayan D, Hod M, Oron G, et al. Pregnancy outcome in
patients with pulmonary arterial hypertension receiving prostacyclin therapy. Obstet Gynecol 2005; 106: 12061210.
149 Moretti ME, Caprara D, Drehuta I, et al. The fetal safety of
angiotensin converting enzyme inhibitors and angiotensin II
receptor blockers. Obstet Gynecol Int 2012; 2012: 658310.
150 Boix E, Zapater P, Pico A, Moreno O. Teratogenicity with angiotensin II receptor antagonists in pregnancy. J Endocrinol Invest
2005; 28: 10291031.
151 Li DK, Yang C, Andrade S, Tavares V, Ferber JR. Maternal
exposure to angiotensin converting enzyme inhibitors in the first
trimester and risk of malformations in offspring: A retrospective
cohort study. BMJ 2011; 343: d5931.
152 RCOG. Reducing the risk of thrombosis and embolism during
pregnancy and the puerperium. Green-top Guidelines No. 37, 2009:
1-35,
http://www.rcog.org.uk/womens-health/clinical-guidance/
reducing-risk-of-thrombosis-greentop37 (accessed August 2013).
153 Dempfle CEH. Minor transplacental passage of fondoparinux
in vivo. N Engl J Med 2004; 350: 19141915.
154 Stathopoulos EP, Liakou CG, Katsalira A, et al. The use of
bisphosphonates in women prior to or during pregnancy and lactation. Hormones (Athens) 2011; 10: 280291.
155 Kusters DM, Lahsinoui HH, van de Post JA, et al. Statin use
during pregnancy: A systematic review and meta-analysis.
Expert Rev Cardiovasc Ther 2012; 10: 363378.
156 Winterfeld U, Allignol A, Panchaud A, et al. Pregnancy outcome
following maternal exposure to statins: A multicentre prospective
study. BJOG 2013; 120: 463471.
157 Kumasawa K, Ikawa M, Kidoya H, et al. Pravastatin
induces placental growth factor (PGF) and ameliorates preeclampsia in a mouse model. Proc Natl Acad Sci U S A 2011;
108: 14511455.
158 Ahmed A, Singh J, Khan Y, Seshan SV, Girardi G. A new mouse
model to explore therapies for pre-eclampsia. PLoS One 2011; 5:
e13663.
159 Costantine MM, Cleary K. Pravastatin for the prevention of preeclampsia in high-risk pregnant women. Obstet Gynecol 2013; 121:
349353.
160 Le Thi Huong D, Wechsler B, Vauthier-Brouzes D, et al. The
second trimester Doppler ultrasound examination is the best predictor of late pregnancy outcome in systemic lupus erythematosus
and/or the antiphospholipid syndrome. Rheumatology (Oxford)
2006; 45: 332338.
161 Castellino G, Capucci R, Govoni M, Mollica G, Trotta F.
Uterine artery Doppler in predicting pregnancy outcome in
women with connective tissue disorders. Rheumatology
(Oxford) 2006; 45: 11741175.
162 Cnossen JS, Morris RK, ter Riet G, et al. Use of uterine artery
Doppler ultrasonography to predict pre-eclampsia and intrauterine growth restriction: A systematic review and bivariable metaanalysis. CMAJ 2008; 178: 701711.
163 Morris RK, Malin G, Robson SC, Kleijnen J, Zamora J, Khan
KS. Fetal umbilical artery Doppler to predict compromise of
fetal/neonatal wellbeing in a high-risk population: Systematic
review and bivariate meta-analysis. Ultrasound Obstet Gynecol
2011; 37: 135142.
164 RCOG. Diagnosis and treatment of gestational diabetes.
Scientific impact paper No. 23, http://www.rcog.org.uk/files/
rcog-corp/uploaded-files/SIP_No_23.pdf (2011, accessed August
2013).
Lupus

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta

1308
165 Duley L, Henderson-Smart DJ, Meher S, et al. Antiplatelet agents
for preventing pre-eclampsia and its complications. Cochrane
Database Syst Rev 2007; 2: CD004659.
166 Askie LM, Duley L, Henderson-Smart DJ, et al. Antiplatelet
agents for prevention of pre-eclampsia: A meta-analysis of individual patient data. Lancet 2007; 369: 17911798.
167 Roberge S, Giguere Y, Villa P, et al. Early administration of lowdose aspirin for the prevention of severe and mild preeclampsia: A
systematic review and meta-analysis. Am J Perinatol 2012; 29:
551556.
168 Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E.
Prevention of perinatal death and adverse perinatal outcome
using low-dose aspirin: A meta-analysis. Ultrasound Obstet
Gynaecol 2013; 41: 491499.
169 Ayala DE, Ucieda R, Hermida RC. Chronotherapy with lowdose aspirin for prevention of complications in pregnancy.
Chronobiol Int 2013; 30: 260279.
170 Chan AT, Manson JE, Feskanich D, Stampfer MJ, Colditz GA,
Fuchs CS. Long term aspirin use and mortality in women. Arch
Int Med 2007; 167: 562572.
171 Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent
miscarriage for women with antiphospholipid antibody or Lupus
anticoagulant. Cochrane Database Syst Rev 2005; 18: CD002859.
172 Soh MC, Pasupathy D, Gray G, Nelson-Piercy C. Persistent antiphospholipid antibodies do not contribute to adverse pregnancy
outcomes. Rheumatology (Oxford) 2013; 52: 16421647.
173 Branch DW. Report of the Obstetric APS Task Force: 13th
International Congress on Antiphospholipid Antibodies, 13th
April 2010. Lupus 2011; 20: 158164.
174 Hofmeyr GJ, Lawrie TA, Atallah AN, Duley L. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 2010;
8: CD001059.
175 Bates SM, Greer IA, Middeldorp S, et al. VTE, thrombophilia,
antithrombotic therapy, and pregnancy: Antithrombotic Therapy
and Prevention of Thrombosis, 9th ed: American College of Chest
Physicians Evidence-Based Clinical Practice Guidelines. Chest
2012; 141: e691Se736S.
176 Ruiz-Irastorza G, Crowther MA, Branch DW, Khamashta MA.
Antiphospholipid syndrome. Lancet 2010; 376: 14981509.
177 Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: A systematic review and meta-analysis. Obstet Gynecol 2010; 115:
12561262.
178 Sultan AA, Tata LJ, West J, et al. Risk factors for first venous
thromboembolism around pregnancy: A population-based cohort
study from the United Kingdom. Blood 2013; 121: 39533961.
179 Horlocker T, Wedel D, Rowlingson J, Enneking F American
College of Chest Physicians. Regional anesthesia in the patient
receiving antithrombotic or thrombolytic therapy: American
Society of Regional Anesthesia and Pain Medicine EvidenceBased Guidelines (Third Edition). Reg Anesth Pain Med 2010;
35: 64101.
180 Douketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative
management of antithrombotic therapy: Antithrombotic Therapy

Lupus

181

182

183
184
185
186

187
188
189
190
191
192

193
194
195

196

and Prevention of Thrombosis, 9th ed: American College of Chest

Physicians Evidence-Based Clinical Practice Guidelines. Chest
2012; 141: e326Se350S.
Giron-Gonzalez JA, Garc a del R o E, Rodr guez C, Rodr guezMartorell J, Serrano A. Antiphospholipid syndrome and asymptomatic carriers of antiphospholipid antibody: Prospective
analysis of 404 individuals. J Rheumatol 2004; 31: 15601567.
Ruffatti A, Del Ross T, Ciprian M, et al. Risk factors for a first
thrombotic event in antiphospholipid antibody carriers: A prospective multicentre follow-up study. Ann Rheum Dis 2011; 70:
10831086.
Branch W. Obstetric task force. Report of the Obestetric Task
Force: 13th International Congress on Antiphospholipid
Antibodies, 13th April 2010. Lupus 2010; 20: 158164.
Yazdany J, Trupin L, Kaiser R, et al. Contraceptive counseling
and use among women with systemic lupus erythematosus: A gap
in health care quality? Arthritis Care Res 2011; 63: 358365.
Ostensen M. Connective tissue diseases: Contraception counselling in SLE an often forgotten duty? Nat Rev Rheumatol 2011; 7:
315316.
Culwell KR, Curtis KM, Del Carmen Cravioto M. Safety of
contraceptive method use among women with systemic lupus
erythematosus. A systematic review. Obstet Gynecol 2009; 114:
341353.
Kestelman P, Trussell J. Efficacy of the simultaneous use of condoms and spermicides. Fam Plann Perspect 1991; 23: 226227,
232.
Cutolo M, Capellino S, Straub RH. Oestrogens in rheumatic diseases: Friend or foe? Rheumatology (Oxford) 2008; 47: iii2iii5.
Sanchez-Guerrero J, Uribe AG, Jimenez-Santana L, et al. A trial
of contraceptive methods in women with systemic lupus erythematosus. N Engl J Med 2005; 353: 25392549.
Petri M, Kim MY, Kalunian KC, et al. Combined oral contraceptives in women with systemic lupus erythematosus. N Engl J
Med 2005; 353: 25502558.
Askanase AD, Buyon JP. Reproductive health in SLE. Best Pract
Res Clin Rheumatol 2002; 16: 265280.
RCOG. Venous thromboembolism and hormonal contraception.
Green-top Guidelines No. 40, 2010: 1-13, http://www.rcog.org.
uk/files/rcog-corp/GTG40VenousThromboEmbolism0910.pdf
(accessed August 2013).
Chabbert-Buffet N, Amoura Z, Scarabin PY, et al. Pregnane progestin contraception in systemic lupus erythematosus: A longitudinal study of 187 patients. Contraception 2011; 83: 229237.
Kaunitz AM, Arias R, McClung M. Bone density recovery after
depot medroxyprogesterone acetate injectable contraception use.
Contraception 2008; 77: 6776.
Gai L, Zhang J, Zhang H, Gai P, Zhou L, Liu Y. The effect of
depot medroxyprogesterone acetate DMPA on bone mineral
density BMD and evaluating changes in BMD after discontinuation of DMPA in Chinese women of reproductive age.
Contraception 2011; 83: 218222.
Clowse MEB. Managing contraception and pregnancy in the
rheumatologic diseases. Best Pract Res Clin Rheumatol 2010; 24:
373385.

Reproduced with permission of the copyright owner. Further reproduction prohibited without
permission.