Received: 19 May 2020 Revised: 5 July 2020 Accepted: 30 July 2020

DOI: 10.1002/bdr2.1790

TERATOGEN UPDATE

Pregnancy in systemic lupus erythematosus

Aleksandra Polic | Sarah G. Običan

Department of Obstetrics and Gynecology,

Morsani College of Medicine, University
of South Florida, Tampa, Florida
Correspondence
Aleksandra Polic, Department of
Obstetrics and Gynecology, Morsani
College of Medicine, University of South
Florida, 2 Tampa General Circle,
Suite 6016, Tampa, Florida 33606.
Email: polic@usf.edu
Abstract
Objectives: Systemic lupus erythematosus (SLE) is a chronic illness that often
affects women of reproductive age. The objectives of this article are to review
the impact of SLE on pregnancy and current management strategies, including
commonly used therapies.
Methods: We conducted a review of available literature on the clinical course
of SLE, diagnosis, management and pregnancy complications.
Results: SLE has a variable clinical course characterized by flares and periods
of remission and can present unique challenges in the management of obstet-
ric patients. Pregnancy in patients with SLE is associated with multiple risks,
including fetal loss, preterm birth, fetal growth restriction, and hypertensive
disease. With advancements in disease treatment, many women have favorable
pregnancy outcomes, but appropriate preconception counseling and disease
management remain important tools in reducing complications.
Conclusion: Given the implications SLE can have on women of reproductive
age and in pregnancy, understanding the disease course and management is
important in order to optimize pregnancy outcomes.

KEYWORDS
fetal growth restriction, neonatal lupus, pre-eclampsia, preterm birth, systemic lupus
erythematosus

1 | INTRODUCTION
Systemic lupus erythematosus (SLE) is a chronic inflam-
matory autoimmune disorder that affects multiple
organs, including the musculoskeletal, cardiac, renal,
hepatic, and central nervous systems. Although there is
geographic variation in incidence and prevalence, women
are more often affected than men across all nationalities
(Rees, Doherty, Grainge, Lanyon, & Zhang, 2017) and
black women have a higher incidence and prevalence
than white women (Chakravarty, Bush, Manzi, Clarke, &
Ward, 2007; Lim & Drenkard, 2015). SLE often manifests
during the reproductive years and as such can have
important implications with regard to family planning
(Andreoli et al., 2017; Ntali et al., 2014; Østensen
et al., 2015).
2 | ETIOLOGY A ND
PATHOGENESIS
SLE is characterized by autoantibody production and
immune complex formation leading to tissue deposition
and injury (Mills, 1994; Moser, Kelly, Lessard, &
Harley, 2009). Although the etiology of SLE is unknown,
it is suspected to be multifactorial, with possible genetic
and environmental components (Lehman, Nuruzzaman, &
Taber, 2016). There is a known familial aggregation of
SLE (Alarcón-Segovia et al., 2005), and the genetic compo-
nent is further supported by the higher incidence of dis-
ease among monozygotic twins relative to other siblings
(Moser et al., 2009). Additionally, known genetic risk
factors include alleles in the major histocompatibility
complex (MHC) region, deficiencies in components of

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1116
complement, and mutations in genes encoding DNA-
degrading enzymes, cytokine production, apoptosis, and
B- and T-cell signaling (Lehman et al., 2016; Moser
et al., 2009; Rullo & Tsao, 2013). Given the increased inci-
dence in women, the contribution of hormonal factors has
been evaluated, and factors such as early menarche, com-
bined oral contraceptive use, and early menopause have
been associated with increased risk of SLE, although data
are limited (Buyon et al., 2005; Costenbader, Feskanich,
Stampfer, & Karlson, 2007). Socioeconomic factors and
certain environmental exposures, including infectious
agents and pollutants, have been implicated in the possi-
ble pathogenesis of autoimmune diseases (Borchers,
Naguwa, Shoenfeld, & Gershwin, 2010; Costenbader
et al., 2007; James et al., 1997).
3 | C L IN I C A L M A N I F E S T A T I O N S
AND DIAGNO S I S
Although the clinical course is variable, SLE is typically
characterized by periods of flares, or worsening disease,
and remission (Gabbe, 2017; Rahman & Isenberg, 2008).
The most common presenting symptoms include arthral-
gias, skin changes (including a photosensitive rash),
fatigue, malaise, and weight change; less common symp-
toms can include discoid lupus, lupus nephritis, pericardi-
tis, and seizures (Gabbe, 2017). Previously, the diagnostic
criteria for SLE required that a patient meet 4 of 11 possible
clinical and laboratory criteria. In 2019, the European
League Against Rheumatism (EULAR) and American Col-
lege of Rheumatology (ACR) revised the classification
criteria for the diagnosis of SLE (Aringer et al., 2019). The
revised criteria require an elevated antinuclear antibody
(ANA) titer for the diagnosis of SLE. If the titer is present,
several criteria, each weighed differently, can be added
to a numerical score that indicates the probability of SLE
as the underlying diagnosis. The criteria include the follow-
ing: constitutional (fever), hematologic (leukopenia, throm-
bocytopenia, autoimmune hemolysis), neuropsychiatric
(delirium, psychosis, seizure), mucocutaneous (nonscarring
alopecia, oral ulcers, subacute cutaneous or discoid lupus,
acute cutaneous lupus), serosal (pleural or pericardial effu-
sion, acute pericarditis), musculoskeletal (joint involve-
ment), renal (proteinuria >0.5 g/24 hr, renal biopsy Class
II or V lupus nephritis, renal biopsy Class III or IV lupus
nephritis), antiphospholipid antibodies (anticardiolipin
antibodies or anti-β2GP1 antibodies or lupus anticoagu-
lant), complement proteins (low C3 or low C4, low C3 and
low C4), and SLE-specific antibodies (anti-dsDNA antibody
or anti-Smith antibody; Aringer et al., 2019). Each criterion
is assigned a numerical score, and the patient is diagnosed
with SLE with a score of 10 or more (Aringer et al., 2019).
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4 | IMPACT OF PR EG NANCY
ON SLE
Overall, pregnancy does not usually affect the long-term
SLE disease progression. Disease stability in the 6 months
prior to pregnancy is indicative of not only pregnancy out-
comes but also risks of flares during pregnancy (Gladman,
Tandon, IbañEz, & Urowitz, 2010). Those patients with
severe active disease prior to conception have 60% risk of
flares compared to a 10% risk in patients with a quiescent
disease state (Webster, 2009). Certain factors increase
the risk of flares during pregnancy such as active lupus
nephritis, being primigravid (Gladman et al., 2010;
Saavedra et al., 2015), and discontinuation of antimalarial
medications (Clowse, Magder, Witter, & Petri, 2005;
Clowse, Magder, Witter, & Petri, 2006).
5 | IMPACT OF SLE ON
PREG NANC Y
Approximately 0.08% of deliveries in the United States
occur in women with a diagnosis of SLE, amounting
to slightly fewer than 4,000 each year (Chakravarty
et al., 2007). Overall, maternal mortality is 20-fold higher
in women with SLE (Clowse, Jamison, Myers, & James,
2008). Pregnancies in women with SLE are at increased
risk for complications such as fetal loss, preterm birth,
fetal growth restriction (FGR), and hypertensive disease
(Petri, 2019). In addition, the risks of cesarean section,
thrombosis, infection, and transfusion are all increased in
women with SLE (Clowse et al., 2008). Given the higher
incidence and prevalence of SLE in reproductive-aged
women, the impact of disease on the obstetric population
is important to consider.
5.1 | Fertility
Historically, when compared with women without auto-
immune diseases, women with SLE have been reported to
have similar rates of infertility (Ekblom-Kullberg et al.,
2009). Importantly, this is not the case in patients who
have undergone treatment of SLE with alkylating agents
such as cyclophosphamide (CYC), which can deplete
oocyte reserve and lead to premature ovarian failure
(Di Mario et al., 2019; Khizroeva et al., 2019). However,
recent epidemiologic studies have indicated that women
with SLE comprise a disproportionately large percentage
of patients with infertility (Hickman & Gordon, 2011).
Fertility in patients with SLE may be negatively affected
by immunosuppressant medications (including high doses
of corticosteroids and CYC), chronic renal disease, or
  AND OBIČAN
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periods of anovulation during a disease flare (Costa &
Colia, 2008; Leroy et al., 2015). In addition, autoimmune
oophoritis may contribute to premature ovarian failure,
although data are limited (Carp, Selmi, & Shoenfeld, 2012).
With regard to the impact of SLE on family planning,
women with SLE do have fewer biologic children than
desired—a 2012 survey of women with SLE and rheuma-
toid arthritis concluded that patient concerns about
the impact of rheumatic disease on their offspring played
a significant role in women having fewer children than
initially planned (Clowse, Chakravarty, Costenbader,
Chambers, & Michaud, 2012; Khizroeva et al., 2019).
5.2 | Pregnancy loss
Another important factor contributing to smaller family
size is a higher rate of first trimester pregnancy loss
among patients with SLE (Fischer-Betz & Specker, 2017).
Although the rate of miscarriages among women with
SLE has decreased drastically, from 43% between 1960
and 1965, to approximately 17% between 2000 and 2003
(Clark, Spitzer, & Laskin, 2005), conflicting data still exist.
A 2006 study of 166 pregnancies in women with SLE
found a 16% fetal loss rate (Clowse et al., 2006), a 2008
review reported a loss rate of 19.5% (albeit with a wide
range of 4–43%; Yuen, Krizova, Ouimet, & Pope, 2009),
while a small retrospective cohort study from 2020 found
a loss rate of 43.8% (Zamani, Shayestehpour, Esfahanian, &
Akbari, 2020). A 2015 study of 202 pregnancies in women
with SLE found an 11% loss rate, with 55% occurring
within the first trimester, 40% in the second trimester, and
5% in the third trimester (Mankee, Petri, & Magder, 2015).
Importantly, this study concluded that the strongest pre-
dictor of pregnancy loss is a positive lupus anticoagulant
test in the first trimester, whereas a previous positive
result was not associated with increased risk for first tri-
mester loss (Mankee et al., 2015). In addition, low comple-
ment levels in the first trimester were also associated with
increased risk of pregnancy loss. This echoes a 2011 cohort
study of 267 pregnancies, which concluded that women at
highest risk for pregnancy loss are those with a combina-
tion of high clinical disease activity and the presence of
serologic markers (Clowse, Magder, & Petri, 2011).
5.3 | Preterm birth
Preterm birth, defined as birth prior to 37 weeks of gesta-
tion, is associated with significant neonatal complica-
tions. A known association exists between SLE and
preterm birth. When discussing the relationship between
SLE and preterm birth, it is important to consider that
1117
two-thirds of all preterm births occur spontaneously,
while the remaining third is iatrogenic and occurs due to
maternal or fetal indications (Gilman-Sachs et al., 2018).
A 2017 study of data from the Medical Birth Registry
of Norway noted an increased risk of preterm birth in
women with SLE versus controls (adjusted odds ratio
[aOR] 4.04, 95% confidence interval [CI] [2.45–6.56] in
first births and aOR 4.33, 95% CI [2.64–7.10] in subsequent
births; Wallenius, Salvesen, Daltveit, & Skomsvoll, 2014).
In 2017, a meta-analysis found a pooled relative risk of
preterm birth in SLE patients versus controls of 2.98 (95%
CI [2.32–3.83]), with the association being stronger in
patients with active disease versus those with inactive dis-
ease (Wei, Lai, Yang, & Zeng, 2017). A Taiwanese study of
2059 pregnancies complicated by SLE found a significantly
increased risk of preterm birth when compared with con-
trols (aOR 3.00, 95% CI [2.61–3.45]; Chen et al., 2020). Sev-
eral theories about why SLE is associated with preterm
birth include increased cortisol and prostaglandin produc-
tion (Voltolini et al., 2013), inflammation (Cappelletti,
Della Bella, Ferrazzi, Mavilio, & Divanovic, 2016; Gilman-
Sachs et al., 2018), and corticosteroid use (Clark, Spitzer,
Nadler, & Laskin, 2003; Wei et al., 2017).
5.4 | Fetal growth restriction
After preterm birth, FGR, defined as estimated fetal
weight below the 10th percentile, is the second most com-
mon cause of perinatal mortality (Nardozza et al., 2017).
FGR is also a known risk in pregnancies complicated by
SLE. Recently, Chen et al. found a significant increase in
the risk of FGR in women with SLE (aOR 2.24, 95% CI
[1.85–2.71]; Chen et al., 2020), which is consistent with
prior studies (Chakravarty, Nelson, & Krishnan, 2006;
Smyth et al., 2010; Wu, Ma, Bao, Di, & Zhang, 2018).
Although there are numerous etiologies of FGR, including
intrauterine infections, chromosomal anomalies, and
multiple gestations, FGR due to placental insufficiency in
women with SLE is common (Gluhovschi, Gluhovschi,
Petrica, Velciov, & Gluhovschi, 2015). Immune responses
have been implicated in the development of placental
insufficiency, with complement activation and T-cell sig-
naling playing possible roles (Girardi, Yarilin, Thurman,
Holers, & Salmon, 2006; Gluhovschi et al., 2015).
5.5 | Hypertensive disease
Hypertensive disease itself increases maternal and fetal
complications, including preterm birth and low birth
weight, further complicating the management of patients
with SLE. Pre-eclampsia, characterized by blood pressure
1118
elevations and proteinuria, typically complicates approxi-
mately 2–8% of pregnancies (Fischer-Betz & Specker,
2017; Steegers, von Dadelszen, Duvekot, & Pijnenborg,
2010). However, studies have reported rates of pre-
eclampsia in women with SLE ranging from 12% (Borella
et al., 2014) to 22.5% (Clowse et al., 2008), and 26%
(Arkema et al., 2016). While the cause of pre-eclampsia
remains unknown, proposed mechanisms include
uteroplacental ischemia (Dekker & Sibai, 1998) and
imbalances in angiogenic factors (Levine et al., 2006).
Women with SLE have an increased risk of developing
hypertensive disease in pregnancy, including gestational
hypertension, pre-eclampsia with and without severe fea-
tures, and hemolysis, elevated liver enzymes, and low
platelet (HELLP) syndrome (Chen et al., 2020).
6 | NEONA TAL LU PU S
Neonatal lupus occurs in 1–2% of all pregnancies affected
by SLE and is caused by the passage of maternal IgG anti-
bodies (anti-Ro/SSA and anti-La/SSB) through the pla-
centa. One third of all SLE patients have anti-SSA and/or
anti-SSB antibodies and the potential to cause neonatal
lupus. Neonatal lupus lasts 14–16 weeks and can be mar-
ked by a photosensitive rash and hepatic manifestations
such as elevated liver enzymes or fulminant liver disease.
Additionally, the neonate can be affected by hematologic
aberrations such as anemia, thrombocytopenia, and
cardiac manifestations such as dilated cardiomyopathy,
endocardial fibroelastosis, and congenital heart block
(CHB; specifically associated with the presence of anti-
SSA antibody; Limaye, Buyon, Cuneo, & Mehta-Lee,-
2020; Lee, 2004). CHB, occurring mostly between 18 and
24 weeks, affects 2% of pregnancies with positive anti-
bodies and no history of previously affected pregnancies.
The risk increases substantially to 10–15% in those who
have a prior family history of another neonate affected
with cutaneous lupus and up to 15–20% in those with a
prior neonate affected with CHB. CHB is a long-term,
essentially irreversible complication with increased fetal
and neonatal mortality and the need for a pacemaker in
up 70% of affected neonates (Webster, 2009).
7 | MANAGEMENT IN
PREGNANCY
Active SLE during pregnancy is associated with increased
risk of the maternal and fetal complications mentioned
previously. For women not choosing pregnancy, contra-
ception plays an important role, and patients should be
counseled on appropriate methods. For women who are
pregnant or planning a pregnancy, obtaining a thorough
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medical and obstetric history is important in manage-
ment. In 2017, EULAR released a list of parameters with
recommendations for pregnancy counseling and risk
stratification, which includes criteria such as SLE activ-
ity, previous adverse pregnancy outcomes, serological
activity (including complement and anti-dsDNA titers),
lupus nephritis, history of thrombosis, antiphospholipid
profile, anti-Ro/SSA and anti-La/SSB antibodies, and
hypertension (Andreoli et al., 2017). Patients should be
counseled on the risks and complications that are associ-
ated with pregnancy in SLE.
7.1 | Preconception counseling and
preparing for pregnancy
The current recommendation for patients with SLE is to
achieve a well-controlled disease state with and, ideally, a
prolonged remission for at least 6 months prior to attempting
pregnancy (Andreoli et al., 2017; Fischer-Betz & Specker,
2017). The preconception visit is the optimal time for
patient counseling and assessment of disease status, as
well as a thorough review of medical, surgical, and psychiat-
ric history. All medications should be reviewed with the
patient. Important to consider are the relative contraindica-
tions for pregnancy, including severe connective tissue dis-
ease flare or stroke over the past 6 months, pulmonary
hypertension, moderate to severe heart failure (left ventricu-
lar ejection fraction <40%), severe restrictive lung disease
(forced vital capacity <1 L), chronic kidney disease stage 4–5
(estimated glomerular filtration rate < 30 ml/min), uncon-
trolled hypertension, and previous severe early-onset
(<28 weeks) pre-eclampsia despite management with aspi-
rin and heparin (Ateka-Barrutia & Nelson-Piercy, 2013). Of
note, patients with SLE planning pregnancy should be urged
to establish or continue care with a rheumatologic team for
optimal disease management (Petri, 2019). Prenatal vitamins
and/or folic acid supplementation with are recommended
for all patients planning conception. Regarding medications
used to treat SLE, certain medications may be continued dur-
ing pregnancy, while others are contraindicated and should
be discontinued due to risk of adverse events (please see
section on “medical management in pregnancy”). A recent
study demonstrated that discontinuation of medical thera-
pies upon diagnosis of pregnancy is common in women with
SLE, illustrating a need for improved patient education
regarding risks and benefits of medications (Zusman, Sayre,
Aviña-Zubieta, & De Vera, 2019).
7.2 | Early pregnancy
Accurate pregnancy dating with last menstrual period
and ultrasonography is important in patients with SLE,
  AND OBIČAN
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especially given the increased risk for FGR. EULAR
recommendations encourage routine ultrasonographic
assessment between 11 and 14 weeks of gestation. As in
standard prenatal care, baseline blood pressure assess-
ment should be performed and prenatal labs obtained. A
baseline assessment of serum creatinine and urine pro-
tein excretion is recommended in patients with lupus
nephritis and can be considered in patients without
known renal involvement (Gabbe, 2017). Women on
chronic glucocorticoid steroids should undergo early
screening for gestational diabetes.
Daily low-dose aspirin, initiated prior to 16 weeks of
gestation, has been associated with a reduction of risk of
pre-eclampsia with severe features (Roberge et al., 2012).
Given the increased risk of developing pre-eclampsia in
women with SLE, the United States Preventive Services
Task Force (USPSTF), the American College of Obstetri-
cians and Gynecologists (ACOG), and ACR recommend
the initiation of daily low-dose aspirin prior to 16 weeks
of gestation in women with SLE (LeFevre, 2014; ACOG
Committee Opinion (No. 743), 2018). In addition,
ACR recommends the initiation of hydroxychloroquine
(HCQ) in patients who are not taking the medication
(Sammaritano et al., 2020).
The management of women with antiphospholipid
antibody syndrome (APS) is of particular importance dur-
ing this time period. APS is an autoantibody-mediated
thrombophilia characterized by recurrent thrombosis and
pregnancy complications, including recurrent pregnancy
loss (Ruiz-Irastorza & Khamashta, 2011). To improve
maternal and fetal outcomes, women with APS and a his-
tory of thrombosis should be started on low-dose aspirin
and prophylactic anticoagulation with heparin through-
out pregnancy (and up to 6 weeks postpartum; Bates,
Greer, Pabinger, Sofaer, & Hirsh, 2008; Branch, 2003).
Women with APS without a history of thrombosis but
with a history of recurrent pregnancy loss can be man-
aged in the same fashion, seeing as these interventions
can reduce pregnancy loss by 50% (Empson, 2002).
7.3 | Second and third trimesters
Second trimester evaluation of fetal anatomy by ultrasound
is recommended, according to guidelines, around 20 weeks
of gestation. Given the increased risk of CHB in patients
with positive maternal anti-Ro/SSA antibodies, fetal echo-
cardiography (Andreoli et al., 2017) and determination of
fetal PR interval every 1–2 weeks between 16 and 28 weeks
of gestation can be considered. However, CHB may not be
detected even with these methods. Women whose pregnan-
cies are complicated by FGR should undergo assessments
of fetal growth every 3–4 weeks in addition to umbilical
artery Doppler velocimetry; antepartum fetal surveillance
1119
is indicated in this patient population given the increased
risk of stillbirth (ACOG Practice Bulletin (No. 204), 2019).
Limited data exist regarding the recommendation for ante-
natal fetal surveillance in women with SLE and APS with-
out evidence of FGR, but surveillance is recommended
by ACOG.
7.4 | Delivery
SLE itself is not an indication for preterm or early-term
delivery. However, given the high risk for pregnancy com-
plications, many patients with SLE may have indications
for delivery prior to 39 weeks due to FGR or hypertensive
disease. Route of delivery should be determined by stan-
dard obstetric indications. Patients with SLE on glucocor-
ticoid therapy for symptom management present a
management challenge in the peripartum period. Chronic
glucocorticoid therapy can suppress the hypothalamic–
pituitary axis and may be associated with adrenal insuffi-
ciency in times of increased stress (such as surgery or
vaginal delivery). Although data on the subject are very
limited, increased doses of glucocorticoids at the time of
surgery or obstetric procedures have historically been rec-
ommended for patients with suspected suppression of the
HPA axis, including patients taking more than the equiva-
lent of 20 mg/day of prednisone for more than 3 weeks
(MacKenzie & Goodman, 2016).
7.5 | Postpartum
Continued care in the postpartum period is important in
women with SLE given the increased risk of lupus flares.
Women with APS are particularly vulnerable to thrombo-
sis during this time period and should be monitored
closely (Ruiz-Irastorza & Khamashta, 2011).
8 | MEDICAL MANAGEMENT
IN PREGNANCY
Several medications used in the management of SLE
have important implications in pregnancy. See below for
the overview of commonly used therapies.
8.1 | Hydroxychloroquine
ACR recommends HCQ as primary medical management
of pregnant women affected by SLE (American College of
Rheumatology Ad Hoc Committee on Systemic Lupus
Erythematosus Guidelines, 1999). Importantly, HCQ
should be continued in women with SLE if pregnancy is
1120
diagnosed, as cessation has been associated with increased
risk of lupus flares (The Canadian Hydroxychloroquine
Study Group, 1991). Classically used as an antimalarial
agent, HCQ has anti-inflammatory, immunomodulatory,
and antithrombotic mechanisms of action through several
molecular pathways, including inhibition of Toll-like
receptors, reduction of pro-inflammatory cytokines, and
prevention of endothelial dysfunction (Fox, 1993; Gómez-
Guzmán et al., 2014). HCQ crosses the placenta, and con-
centrations in the fetal blood closely resemble those in the
maternal blood (Costedoat-Chalumeau et al., 2002). While
chloroquine, which shares some similarities with HCQ,
has been associated with fetal ototoxicity and retinal toxic-
ity in isolated case studies (Phillips-Howard & Wood, 1996;
Ullberg, Lindquist, & SjöStrand, 1970), these complications
have not been demonstrated in more recent studies and
have not been associated with HCQ use (Levy et al., 2001;
Parke & West, 1996; Tunks, Clowse, Miller, Brancazio, &
Barker, 2013). A large prospective cohort study of pregnant
women with SLE with and without a history of HCQ expo-
sure noted significantly decreased disease severity in
women taking HCQ (Clowse et al., 2006). Importantly, this
study also noted the absence of fetal toxicity. Other studies
have found no increased risk of fetal death, premature
birth, or fetal toxicity in pregnant women with SLE taking
HCQ (Costedoat-Chalumeau et al., 2003). A systematic
review of studies between 1980 and 2007 found no associa-
tion between HCQ use in pregnancy and increased risk of
congenital defects, fetal death, preterm birth, or pregnancy
loss (Sperber, Hom, Chao, Shapiro, & Ash, 2009). HCQ is
considered compatible with breastfeeding. Cardiology eval-
uation and monitoring can be considered in patients taking
HCQ. Recent data have shown a possible benefit of HCQ
in pregnant patients with SLE in lowering the risk of pre-
eclampsia (Seo et al., 2019).
8.2 | Glucocorticoids
SLE flares in pregnancy are often managed with non-
fluorinated glucocorticoids, such as prednisone and methyl-
prednisolone. In contrast to fluorinated glucocorticoids
such as betamethasone and dexamethasone, nonfluorinated
glucocorticoids are associated with very low teratogenic
risk as they undergo extensive placental metabolism
and only minimal amounts enter the fetal circulation
(Sammaritano, 2017). With regard to fetal risk, some stud-
ies have found associations between in utero exposure to
glucocorticoids and clef lip and palate (Carmichael
et al., 2007), while others have not (Bay Bjørn et al., 2014).
Chronic glucocorticoid use in pregnancy may be associated
with FGR, hypertensive disease, diabetes, and preterm
prelabor rupture of membranes (Lunghi et al., 2010). Glu-
cocorticoids are compatible with breastfeeding.
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8.3 | Azathioprine
Azathioprine (AZA) is an immunosuppressive medica-
tion used in the management of SLE. 6-mercaptopurine,
the active metabolite of AZA, inhibits purine synthesis
and cell proliferation. However, it does not cross the pla-
centa, and thus does not alter trophoblastic cell division
(Hutson et al., 2011). Large studies have not found an
association between AZA use in pregnancy and congeni-
tal anomalies (Coelho et al., 2011; Goldstein et al., 2007;
Radomski et al., 1995). Some studies have reported a
potential association between AZA use in pregnancy and
FGR, although data are limited (Cleary & Källén, 2009).
AZA should be continued in pregnancy and is compatible
with breastfeeding (Sammaritano, 2017).
8.4 | Cyclosporine A
Cyclosporine A suppresses the immune response by
inhibiting the production and release of interleukin-2.
Cyclosporine use in pregnancy has not been associated
with an increased risk of congenital anomalies, and the
medication can be continued in the management of SLE
(Bar Oz, Hackman, Einarson, & Koren, 2001). Minimal
excretion in breast milk occurs (Moretti et al., 2003), but
data on breastfeeding are limited.
8.5 | Cyclophosphamide
CYC is an alkylating agent that has been associated
with teratogenicity when used in the first trimester
(Kirshon, Wasserstrum, Willis, Herman, & McCabe,
1988; Mirkes, 1985). Use in the second and third trimes-
ters, however, does not appear to result in structural
anomalies (Ring et al., 2005) and can be considered
in women with severe disease. CYC is excreted in
breast milk and is contraindicated in breastfeeding
(Sammaritano, 2017).
8.6 | Nonsteroidal anti-inflammatory
drugs
Nonsteroidal anti-inflammatory drug (NSAID) use in
pregnancy is not associated with congenital anomalies
(Källén, 1998; Kozer et al., 2002; Nezvalová-Henriksen,
Spigset, & Nordeng, 2013; Slone et al., 1976). Data
are limited as to whether first trimester NSAID use
increases the risk of pregnancy loss (Chan & Yuen, 2001).
Use in the third trimester is discouraged due to an
increased risk for premature closure of the ductus arteri-
osus (Koren, Florescu, Costei, Boskovic, & Moretti, 2006)
  AND OBIČAN
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and oligohydramnios (Norton, 1997). NSAIDs are mini-
mally excreted in breast milk and can be used while
breastfeeding.
8.7 | Mycophenolate mofetil
Mycophenolate mofetil is a teratogenic immunosuppres-
sive medication that is contraindicated in pregnancy and
breastfeeding; its use should be discontinued at least
6 weeks prior to conception (Østensen et al., 2006; Perez-
Aytes et al., 2017).
9 | C ON C L U S I ON S
SLE frequently affects women of reproductive age and
can have a significant impact on pregnancy management.
The condition is associated with increased risk of preg-
nancy loss, FGR, preterm labor, and hypertensive disease.
Management in pregnancy is centered on close monitor-
ing of disease status, continuation of appropriate thera-
pies, and fetal surveillance.
DATA AVAILABILITY STATEMENT
Data sharing is not applicable to this article as no new
data were created or analyzed in this study.
ORCID
c https://orcid.org/0000-0002-9852-8553
Aleksandra Poli
R EF E RE N C E S
ACOG Committee Opinion (No. 743). (2018). Low-dose aspirin use
during pregnancy. Obstetrics & Gynecology, 132(1), e44–e52.
https://doi.org/10.1097/AOG.0000000000002708
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How to cite this article: Polic A, Običan SG.
Pregnancy in systemic lupus erythematosus. Birth
Defects Research. 2020;112:1115–1125. https://doi.
org/10.1002/bdr2.1790