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The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta
Lupus 2013 22: 1295
DOI: 10.1177/0961203313504637

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 Lupus (2013) 22, 1295–1308
http://lup.sagepub.com

SPECIAL ARTICLE

The challenge of pregnancy for patients with SLE

O Ateka-Barrutia and MA Khamashta
Lupus Research Unit, Women’s Health Division, King’s 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 dis-
ease, 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 patient’s 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, 1295–1308.

Key words: Pregnancy; systemic lupus erythematosus; management; pre-pregnancy counsel-

ling; medications

Introduction related to increased irreversible organ damage.4

However, whether or not pregnancy increases the
Systemic lupus erythematosus (SLE) is a multisyste- risk of lupus flare is still an unsolved question.
mic disease with a clear predilection for women Several prospective controlled observational stu-
(ratio 9 : 1), particularly during reproductive age dies have shown discordant answers to this
years (ratio 15 : 1). It affects up to 1 in 1000 of question.5–11 Some authors have suggested the
child-bearing age,1 and presents three to four times puerperium as a period of especially high risk for
more frequently in the population of African lupus flare.11,12 Based on these studies, lupus flare
background.2 Pregnancy was considered almost seems unpredictable, hence regular follow-up in
prohibited in women with lupus until recent years. pregnancy and postpartum should be offered to
A better understanding of the disease and cre- these women. However, the risk of flare appears
ation of specialized multidisciplinary groups with to be dependent on the disease activity 6–12
experience in autoimmune diseases (involving months prior to conception. Women with quiescent
physicians, obstetricians, paediatricians and mid- lupus over this period have lower risk of flare
wives) has led to dramatic improvement in disease during pregnancy,9,13 whereas women with active
management and pregnancy outcome over the last SLE during this time have a higher risk.7,14
20 years.3 Therefore, pregnancy should be planned when the
disease has been in remission for at least
6 months.15 Prophylactic therapies such as increas-
Effect of pregnancy on SLE ing the dose of steroids are not recommended.
Active lupus nephritis (LN) at conception confers
a higher risk of flare during pregnancy,16 and even
Pregnancy is considered a high-risk time for lupus women with LN in remission have an increased risk
patients, as flares during pregnancy have been of flare.11,17,18 In contrast, patients with no previous
renal involvement are at the lowest risk.18 In women
Correspondence to: Munther A Khamashta, Lupus Research Unit, with previous LN, pregnancy does not seem to
The Rayne Institute, Division of Women’s Health, King’s College endanger long-term renal function, although gener-
London, 4th Floor Lambeth Wing, St Thomas’ Hospital, London
SE1 7EH, UK.
ally the higher the baseline creatinine, the greater
Email: munther.khamashta@kcl.ac.uk the risk of deterioration.11,16,19–21
! The Author(s), 2013. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203313504637

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 The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1296
Lupus flares during pregnancy and postpartum
are normally non-severe, characterized by articular,
dermatological and mild haematological involve-
ment,6,7,10 and are usually well controlled with
hydroxychloroquine (HCQ) and short-term intro-
duction or increase of oral steroids. Nonetheless,
severe flares with major organ involvement may
occur.6,15,22
A recent systematic review established the pro-
tective effects of HCQ in terms of organ damage,
disease flares, thrombosis, bone mass loss and long-
term 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 findings, suggesting that women
who had taken HCQ throughout pregnancy pre-
sented lower activity scores and had lower prednis-
one doses at the end of pregnancy,24 whereas those
who discontinued HCQ or did not take it at all had
higher activity scores, more flares and required
higher doses of steroids.25
Distinguishing pregnancy-related signs and
symptoms from certain lupus features may some-
times be difficult, 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 fibrinogen 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 vari-
ation rather than absolute levels of C3 and C4
should be taken into consideration. A drop of
25% or more in serum complement levels in preg-
nancy may suggest lupus flare.26,27
As a result of increased renal blood flow in preg-
nancy, glomerular filtration rate (GFR) increases
by more than 50%, leading to a reduced serum cre-
atinine 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 impair-
ment. Increased tubular flow may increase urine
protein leakage, thus levels up to 300 mg/day of
proteinuria are considered normal in pregnancy.
In patients with permanent significant protein loss
due to previous LN, proteinuria may elevate
throughout pregnancy without being indicative of
Lupus
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active nephritis.18 This phenomenon may be even
more significant 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 effect on
other major organs. Patients with cardiac disease
and/or pulmonary hypertension may deteriorate
and become seriously ill due to increased circulat-
ing volume overload and other cardiovascular
changes, with associated high morbidity and mor-
tality.28–31 On the other hand, women with restrict-
ive lung disease may worsen secondary to gravid
uterus diaphragmatic compression and higher
oxygen requirements.
Women with moderate–severe lupus flare or
stroke within the previous 6 months, CKD 4–5
(Cr > 2.5–2.8 mg/dl, >220–250 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 activ-
ity evaluation in pregnant women with lupus, main
lupus activity indices have been adapted and vali-
dated 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 infec-
tions, thrombotic events (such as stroke, deep vein
thrombosis, pulmonary embolism) and other haem-
atological 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

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 activ-
ity,14 hypertension37 and hypothyroidism38 have
been identified as risk factors for preterm delivery.
Placental insufficiency leading to IUGR is frequent
in lupus pregnancies,39 even in those with mild dis-
ease.40 The incidence of small for gestational age
(SGA) babies is 6–35%.41–43
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, thrombo-
cytopenia and secondary antiphospholipid syn-
drome (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 first 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 compli-
cations and further damage both during and after
gestation,4 especially women with chronic renal dis-
ease.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.14,45–47 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 out-
come,48 therefore they should be advised to post-
pone pregnancy until at least 6 months (ideally
12–18 months) after the last LN flare.49 There is
no evidence to suggest that different subclasses of
LN affect this risk.48
In patients with previous LN, hypocomplemen-
temia, 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 >2.5–2.8 mg/dl (>220–250 mmol/l;
approx. GFR < 35–40 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
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The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1297
Table 1 Differences between pre-eclampsia and lupus
nephritis
Pre-eclampsia Lupus nephritis
Headache Onset <20 weeks’gestation
Visual problems Active urinary sediment
(e.g. flashing lights) Low or falling complement levels
Epigastric or RUQ tenderness High or increasing anti-dsDNA
Nausea or vomiting Evidence of lupus flare involving
Clonus (>2 beats) other organs
Increased liver function tests
Rising serum uric acid level
Haemolysis
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 four-
fold increased risk to develop pre-eclampsia,46,52,53
compared with the general population54.
Differentiating pre-eclampsia from LN may not
be straightforward, as both may include hyperten-
sion, raising proteinuria, oedema, renal function
impairment and thrombocytopenia, and sometimes
both may overlap. The risk of developing pre-
eclampsia is increased in women with chronic
hypertension, chronic kidney disease, diabetes mel-
litus, hypertensive disease during a previous preg-
nancy, 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.19,55–57
Table 1 shows useful findings to differentiate pre-
eclampsia/toxaemia from LN.51,56,58 If renal biopsy
is indicated, special caution and surveillance is war-
ranted due to the higher bleeding risk after biopsy
in pregnancy.59
Antiphospholipid antibodies
Antiphospholipid antibodies (aPL) are found more
frequently in patients with SLE (30–40%) than in
the background population (1–5%),60,61 and repre-
sent the major risk factor for poor obstetric out-
come.48 Several studies have identified aPL carrier
women at increased risk of developing pre-
eclampsia, IUGR, prematurity and fetal loss
during pregnancy.48,62–70 Positivity for both antic-
ardiolipin antibodies (aCL) and lupus anticoagu-
lant (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 out-
comes than those with obstetric APS or aPL
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 The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1298
carriers.71,72 Two recent studies confirmed the
latter, but interestingly also showed that LA is the
primary predictor of adverse pregnancy outcome
after 12 weeks’ gestation in aPL-associated preg-
nancies.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 erythe-
matosus and Sjögren’s syndrome.76–79 Women with
other autoimmune diseases such as undifferentiated
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 1–3%.81 Anti-
Ro/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 syn-
dromes (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 affect around 5%
of children born to anti-Ro/La-positive mothers.82
It generally presents within the first 2 weeks of life
as erythematous geographical lesions in light-
exposed 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 3–6
months, when maternal antibodies are cleared
from baby’s circulation. Residual scarring beyond
the first 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 affected by CHB, and up to 50% if
she has had two affected children.84 In women
with a previous baby affected by CNL, the risk of
CHB in a subsequent neonate raises six- to ten-
fold.85 Interestingly, in >80% of children with
CHB the mother will have anti-Ro and/or anti-La
antibodies.82,86–88 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 immune-
mediated inflammation and subsequent fibrosis in
affected tissues, which result in variable grades of
Lupus
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heart block and, more rarely, cardiomyopathy.82,89
The risk of perinatal death amongst affected chil-
dren is approximately 10–20%, and most of surviv-
ing children need a permanent pacemaker.88,90,91
Incomplete forms such as first or second-degree
heart block may be found, which can progress to
complete forms during childhood.82
Current demographic data suggest that add-
itional factors other than maternal antibodies may
be involved in the pathogenesis of CHB, although
these remain unknown.82 Albeit no specific anti-
body profile for NNLS has so far been detected,
higher maternal antibody levels, different IgG sub-
classes 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 mother’s severity of disease and offspring
damage grade. Less frequent cardiac manifestations
have been also described as part of NNLS,
such as cardiomyopathy95 and endocardial
fibroelastosis.96,97
Early diagnosis is crucial for correct manage-
ment in CHB. Ultrasound is the accepted technique
for fetal CHB diagnoses.98 Current recommenda-
tions include serial fetal echocardiograms between
18 and 28 weeks of gestation for pregnant women
with anti-Ro and/or anti-La antibodies.82,99
Different 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 indi-
cated, and never prescribed without CHB signs or
as prophylactic treatment, as the high doses that
are usually administered (dexametasone 4–8 mg/
day until the end of the pregnancy) have important
side effects for both the mother (i.e. diabetes, hyper-
tension, 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
affected baby, treated with IVIG during preg-
nancy.103,104 In a different 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

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 cumula-
tive dose of cyclophosphamide, and/or active dis-
ease may present reduced fertility.108–110 Patients
who take nonsteroidal anti-inflammatory drugs
(NSAID) should be encouraged to stop them
when trying to conceive because of the risk of lutei-
nized unruptured follicle syndrome.111,112 This con-
dition 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 cyclo-
oxygenase-2 (COX-2) needed during follicular
development.
In women who are keen to undergo in vitro fer-
tilization and embryo transfer techniques, regard-
less of the infertility cause, ovarian stimulation for
oocytes collection process involves the use of high-
dose oestrogens with a subsequent increased risk of
disease flare and thromboembolic events113,114 (the
latter especially related to ovarian hyperstimulation
syndrome (OHS), aPL and/or other prothrombotic
risk factors). Therefore, identification of high-risk
patients, pre-cycle counselling, adequate thrombo-
prophylaxis and close surveillance are essential for
correct management in these situations.115,116
Ovarian stimulation with clomiphene, single-
embryo 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 off-
spring.118,119 No differences in intelligence (IQ
scores) have been seen compared with normal
population.120 However, in addition to well-
established factors such as male sex and being
born preterm, both maternal SLE and CHB may
influence neurodevelopment.121 A prospective
multi-centre registry recently showed that the pres-
ence of neurodevelopmental abnormalities seems to
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The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1299
be more frequent in children born to mothers with
APS.122 These studies may justify long-term follow-
up in SLE/APS offspring.
The use of immunosuppressive drugs during
pregnancy does not generally hamper the correct
development of the newborn’s immune system
and its response to scheduled vaccinations.123–126
However, a recent observational study showed
that azathioprine (AZA) exposure during SLE
pregnancy was independently associated with
increased special education services utilization in
offspring, after controlling for confounders.127
Medications during pregnancy and breastfeeding
Most of the data regarding the safety of medica-
tions 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 fre-
quently of little help for the clinicians who are deal-
ing with women with chronic diseases during
pregnancy and lactation. However, a recent
experts’ consensus defined the safety in pregnancy
and lactation of many of the drugs used in auto-
immune 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, hyper-
tension, and fluid overload in the mother, and oli-
gohydramnios 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
(>30–32 weeks) due to increased risk of premature
closure of baby’s 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 treat-
ments in SLE because of their protective properties
on activity, damage, long-term survival and throm-
bosis.23 HCQ is the preferred drug due to its low
side-effect rates. Its safety profile 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
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 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 men-
tioned earlier, HCQ should be continued through-
out and after pregnancy in lupus patients.
Mepacrine, in contrast, should be avoided because
of the lack of safety data.
Corticosteroids
Fluorinated corticosteroids (betamethasone,
dexamethasone) are not inactivated by placental
hydroxylases and easily cross the placenta.
Non-fluorinated corticosteroids (e.g. prednisone,
prednisolone, methylprednisolone, hydrocortisone)
are largely metabolized by placental 11b-
Hydroxysteroid 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 hyperten-
sion, pre-eclampsia, diabetes, infections and prema-
ture rupture of membranes,46,47 hence minimum
maintenance doses (prednisone <7.5 mg/day), com-
bined with steroid-sparing agents are recom-
mended, rather than higher (prednisone >7.5 mg/
day) sustained doses.134,135 Stress doses of hydro-
cortisone at delivery are recommended in patients
on long-term therapy. Non-fluorinated corticoster-
oids are mildly excreted into breast milk (5–25%)
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 con-
traindicated 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 justified and the
aim should be to keep them at the lowest effective
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 monitor-
ing is warranted in order to adjust drug levels
during these periods.138–141 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 flares and side effects.128 A
recent observational study showed that, amongst
patients with previous nephritis, replacing MMF
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with AZA in women with quiescent LN for preg-
nancy planning rarely leads to renal flares.142
Intravenous immunoglobulins can be safely used
in pregnancy and lactation, and are useful when
there is a desire to withhold strong immunosup-
pressants, especially in situations where infection
and flare cannot be easily differentiated.128
Lupus flares during pregnancy
Mild flares 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 immuno-
suppressants and/or IVIG may be necessary.143
More severe cases may require prioritizing the
patient’s welfare over fetus viability, and therefore
using stronger agents such as MMF or cyclophos-
phamide beyond the organogenesis period.
Biological drugs
Rituximab and belimumab are the most used bio-
logical drugs in lupus. The experience in pregnancy
with the latter is scarce, hence the current recom-
mendation is to withdraw it at least 4 months prior
to conception.144 In the case of rituximab, two
recent retrospective series identified 240 exposed
pregnancies to the drug with different 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 ¼ 99) resulted in live
births of which 26% delivered preterm, while the
first 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 coun-
selled against pregnancy for 6–12 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 trimes-
ter should receive close white blood cell and infec-
tion surveillance.
Drugs for pulmonary hypertension
Endothelin receptor antagonists such as bosentan,
sitaxsentan and ambrisentan are considered cat-
egory X by the FDA. Their effect in human preg-
nancies is still unknown, but they are teratogenic in

rodents and conception should be delayed for at
least 3 months after stopping these agents.
Phosphodiesterase type 5 inhibitors such as sil-
denafil and tadalafil are considered category B by
the FDA. Their use in human pregnancy has not
resulted in fetal side effects.147
Prostaglandin derivatives such as prostacyclin
(epoprostenol) and iloprost are considered category
B by the FDA and have been safely used in preg-
nancy and breastfeeding.148
Anti-hypertensives
The drugs of choice for managing hypertension in
pregnancy are labetalol, methyldopa and nifedi-
pine, and less frequently hydralazine and doxazo-
sin.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 first 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
Antiplatelets and anticoagulants
Treatment with low-dose aspirin (LDA; 75–100 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 (6–10 weeks of gestation)
and they should be avoided during this period.
Their use is related to increased risk of fetal bleed-
ing.128 Current recommendations include switching
patients to high prophylactic dose of LMWH (e.g.
enoxaparin 0.6–0.7 mg/kg BD) as soon as pregnancy
is confirmed in those with previous venous throm-
bosis, 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
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The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1301
warfarin during second and third trimesters with
close INR controls can be safely performed in spe-
cial situations such as previous thromboembolic
events on therapeutic dose of LMWH, some
women with mechanical heart valves or in coun-
tries/settings where both the health system and the
women cannot afford 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 identified 78 cases of mothers
exposed to BPs before conception or during preg-
nancy; 69 resulted in live births (88.5%), and none
of the infants had serious adverse events secondary
to BPs. Due to insufficient robust data, pregnancy
should be postponed for at least 6 months after
withdrawal of bisphosphonates.128
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 pleio-
tropic effects of vascular protection have been sug-
gestive of potential benefit in the management of
pre-eclampsia. Different statins have shown posi-
tive effects on serum markers involved in pre-
eclampsia in murine models.157,158 Pravastatin has
favourable safety and pharmacokinetic profiles.
Moreover, animal studies and human pregnancy
exposure data do not support teratogenicity
claims for pravastatin. Thus, a multi-centre phase-
I pilot trial was started last year in the USA to
collect maternal–fetal 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 angio-
genic balance during pregnancy and possible effect
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, multi-
disciplinary approach, tailored antenatal and post-
natal 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 profile
(aPL, anti-Ro/La, anti-dsDNA, complement),
current disease activity and last flare 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 pres-
sure, 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 flare or stroke over the
last 6 months, pulmonary hypertension, moderate-
severe heart failure (ejection fraction of left ven-
tricle <40%), severe restrictive lung disease
(FVC < 1 l), severe chronic renal impairment
(approx. GFR < 35 ml/min), uncontrolled hyper-
tension, and previous severe pre-eclampsia despite
therapy with aspirin plus heparin.58
Women considered at high risk should be man-
aged in a joint experienced medical–obstetrical set-
ting 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 com-
plementary 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 26–32 weeks of ges-
tation, and weekly from 32 weeks onwards.
Lupus
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Every visit should include urine analysis and mater-
nal assessment, with special attention to hyperten-
sion and other features of pre-eclampsia. Women
with previous renal and/or hypertensive diseases
should have more frequent regular blood pressure
checks. Confirmation 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 profile,
anti-dsDNA and complement every 4–8 weeks are
recommended.58
Anomaly scan and uterine artery Doppler is rec-
ommended around 20 weeks of gestation and the
latter should be repeated around the 24th week if
abnormal. Abnormal waveforms are good pre-
dictors of pre-eclampsia, whereas normal results
are related to good obstetric outcomes.160–162
Ultrasound scans (including biophysical profile
and amniotic fluid volume assessment) around
28–30 and 32–34 weeks of gestation are recom-
mended. Regular umbilical artery Doppler should
be performed with the previous scans, as their
abnormal values (particularly absent or reverse dia-
stolic flow) are predictor of mortality and risk of
fetal compromise.163 Additional scans may be indi-
cated depending on previous obstetric history and
the progress of the pregnancy.
In women with anti-Ro/La, regular fetal echo-
cardiography between 16 and 28 weeks of gestation
is offered to identify CHB.82,99
All women on steroids and those with risk fac-
tors for diabetes should have a glucose tolerance
test around 24–28 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 profile 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 significantly reduces the risk of
perinatal death, pre-eclampsia and its complications

165–168
in women at higher risk of pre-eclampsia,
and its maximum effect is probably achieved when
it is taken in the afternoon or at bedtime.169
Dipyridamole probably has similar effects.56
Taking into account its low side effects and recent
data suggesting its benefit in all women,170 antipla-
telet therapy for the prevention of pre-eclampsia is
recommended in patients with lupus.56,171 In add-
ition, 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 there-
fore calcium supplementation is of great import-
ance in these patients.
Treatment of women with obstetric APS is still a
subject of controversy and should be individua-
lized, as most of the evidence is based on observa-
tional 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 fac-
tors for venous thromboembolism prior to concep-
tion 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 thera-
peutic doses of LMWH should discontinue them
or decrease them to prophylactic doses (e.g. enox-
aparin 0.6–0.7 mg/kg OD) 24 h prior to the planned
delivery. Those on prophylactic doses of LMWH
should not continue LMWH once labour is estab-
lished. Re-establishment of LMWH should be post-
poned 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 2–4 h after the epidural
catheter has been removed.179,180
Postpartum
Because of the high risk of flare and thrombosis,
close surveillance should be ensured within the first
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The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1303
2–3 months after delivery. A medical visit should be
arranged within the first 4–6 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 profile,
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.152,181–183 Some
experts recommend extending this treatment for
4–8 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 5–7
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 import-
ance in SLE, as planned pregnancy is associated
with fewer complications and higher pregnancy
successful rates. However, it still remains an unre-
solved 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 dia-
phragm, represent an effective form of contracep-
tion (83–97% success) and are the only methods
protective against sexually transmitted
infections. 187
Hormonal methods include oral contraceptives
(OC) (combined or progestogen only) and subcuta-
neous 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-defined SLE
patients with stable and/or low-active disease.189,190
However, because of the increased risk of throm-
bosis, combined OC are contraindicated in patients
with aPL, and/or other risk factors such as
moderate–severe active disease, history of throm-
bosis, hypertension, smoking and obesity.191,192
Progestogen-only preparations are safe and do
not affect disease activity or thrombosis risk,193
but may decline bone density when used for >2
years.194,195 The latter effect seems to be reversible
Lupus
 The challenge of pregnancy for patients with SLE
O Ateka-Barrutia and MA Khamashta
1304
after discontinuation. Interactions between hormo-
nal contraceptives and other chronic or new medi-
cations may provoke contraceptive failure and/or
alterations in metabolism of those drugs. Hence,
rigorous and regular check of medications inter-
actions becomes mandatory when using hormonal
contraceptives.
IUD (either as copper IUD – non-hormonal
devices – or progestogen IUD – hormonal devices)
are safe, effective (98% success) and reduce men-
strual 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 specific grant from any
funding agency in the public, commercial, or not-
for-profit sectors.
Conflict of interest
None declared.
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