International Journal of Women’s Health

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Systemic lupus erythematosus: strategies to

improve pregnancy outcomes
This article was published in the following Dove Press journal:

International Journal of Women’s Health

8 July 2016
Number of times this article has been viewed
during have a relatively uncomplicated pregnancy
pregnancy. course. Factors such as appropriate
Yuriko Yamamoto Investigations to preconception counseling and medication
date show that adjustment, strict disease control prior to
Shigeru Aoki maternal and pregnancy, intensive surveillance during and
fetal risks are after pregnancy by both the obstetrician and
higher in females rheumatologist, and appropriate interventions
Perinatal Center for Maternity and Neonate, Yokohama City with SLE than in when necessary play a key role. This review
University Medical Center, Yokohama, Kanagawa Prefecture, Japan the general describes the strategies to improve pregnancy
popula-tion. outcomes in SLE patients at different time
Abstract: Systemic lupus erythematosus (SLE) is a chronic However, with points in the reproduction cycle (preconception,
autoimmune inflammatory disease with a high prevalence in females appropriate during pregnancy, and postpartum period) and
of childbearing age. Thus, reproduction in SLE patients is a major management of also details the neonatal concerns.
concern for clinicians. In the past, SLE patients were advised to defer the disease, Keywords: systemic lupus erythematosus,
pregnancy because of poor pregnancy outcomes and fear of SLE flares sufferers may pregnancy outcomes, lupus flare
smyyaoki@yahoo.co.jpX female d to defer pregnancy
s of because of poor
Correspond childbe pregnancy outcomes and
ence: Introduction aring fear of flares during
Shigeru age pregnancy. Investigations
Aoki
Perinatal Systemic lupus makes till date show that the
Center for erythematosus (SLE) is a reprod maternal and fetal risks
Maternity uction are higher for females
and chronic autoimmune
Neonate, inflammatory disease that a with SLE than for the
Yokohama
City
can affect any organ of the major general population.
University body. The prevalence rate concer However, the outcomes
Medical of SLE is 20–70 cases per n for for SLE patients in
Center, 4-
100,000 people, and it clinicia general have now
57
Urafunecho varies between ethnic ns improved, and it has also
, Minami- groups.1 In the US, females involve been shown that with
ku,
of African and Asian d in the appropriate management
Yokohama,
Kanagawa descent are two to three care of of the disease, many SLE
Prefecture times more likely to be these patients can have a
232-0024, patient relatively uncomplicated
Japan affected than those of
Tel +81 European descent.2 SLE s. In pregnancy course. This
45 261 affects females nine times the review describes the
5656 more than males and past, strategies to improve
Fax +81 occurs most frequently SLE pregnancy outcomes for
45 253 patient SLE patients at different
5784 between the age of 20
years and 39 years.2 This s were time points in the
high predisposition of advise reproduction cycle
Email
(preconception, during pregnancy, and theoretically develop ovaria ovarian reserve,3 current
postpartum period) and also details the Althoug ovarian failure due to n axis, evidence suggests that
neonatal concerns. h SLE autoimmune ovarian and they are as fertile as the
patients injury, altered dimini general population.4
Preconception can hypothalamic–pituitary– shed
nc/3 further permission from Dove Medical
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Yamamoto and Aoki DovepressX
safe option.13 However,
The exception to this is when cytotoxic immunosuppressive Table 1 Preconception risk patients on medications that
agents are used for SLE treatment prior to conception. Cyclo- assessment for SLE patients might interact with estrogen-
phosphamide is most toxic to ovarian function and can lead to containing pills such as
permanent ovarian failure depending on the patient’s age, dose, Contraindications of pregnancy6 mycophenolate,
and duration.5 It is known that initiation of treatment at older corticosteroids, cyclosporine,
age and cumulative dose are risk factors for irrevers-ible History of severe preeclampsia
and warfarin need to be
damage of ovarian function.6,7 Anti-Müllerian hormone, despite aspirin and heparin use evaluated for the risks and
secreted from growing ovarian follicles, is considered to be a Heart failure benefits of its use. For
reliable marker of ovarian reserve, and there are attempts to use patients with a higher risk of
this indicator to aid treatment for patients who wish to Restrictive lung disease (FVC ,1 thrombosis, progestin-only
conceive.4 Fertility preservation options should be dis-cussed L) contraception may be an
with patients prior to treatment. If the patient has a history of option. However, information
pregnancy, obstetric outcomes should be carefully reviewed, Renal insufficiency (Cr .2.8 on the risk of
including history of fetal growth restriction (FGR), pregnancy- mg/dL) thromboembolism in SLE
induced hypertension and preeclampsia, miscar-riage, preterm patients on progestin-only
birth, and intrauterine fetal death. Severe pulmonary hypertension contraception is still not
(sPAP .50 mmHg) Suspend sufficient, and guidelines on
pregnancy until stable for 6 months
its use are still controversial.14
Based on expert opinion, lupus patients with established organ
Because of its low effective-
damage may be advised to avoid pregnancy, including patients Active lupus nephritis
ness, barrier methods such as
with severe pulmonary hypertension (estimated sys-tolic
condoms and diaphragms
pulmonary artery pressure .50 mmHg), advanced renal Recent SLE flare may be necessary as a
insufficiency (creatinine level .2.8 mg/dL), severe restrictive
second-line method when
lung disease (forced vital capacity ,1 L), heart failure, a his-tory High-risk patients
other options are
of severe preeclampsia or a severe lupus flare within the past 6
contraindicated. Emergency
months, active lupus nephritis, or stroke.8 Active lupus nephritis or SLE contraception is indicated
flare within 6 months regardless of disease activity
In order to improve pregnancy outcomes in SLE patients, or aPL status, and patients
pregnancy should be well planned. Disease activity at the time APS should be well informed of
of conception is an indicator of maternal outcomes, and high the option.15
activity leads to poor outcomes. Based on a multi-center Anti-SS-A or SS-B antibodies
analysis of 56 pregnancies of patients diagnosed with SLE Low-risk patients
before pregnancy, many agree that prognosis for both mother Medication
and child is best when SLE activity is in remission for at least 6 No history of severe organ damage
Quiescent disease at conception
months before conception.9,10 Compared with patients with Abbreviations: SLE, systemic lupus Discontinuation of
clinically active SLE before conception, those in remission for erythematosus; FVC, forced vital medication before
at least 6 months before conception had a higher live birth rate capacity; Cr, creatinine; sPAP, conception by the patient
(64% versus 88%), full-term delivery (64% versus 56%), and systolic pulmonary artery pressure;
APS, antiphospholipid syndrome. for fear of fetotoxicity is a
lower rate of exacerbation of SLE during pregnancy or
frequently encountered
postpartum (32% versus 28%).11 In a retrospective analysis of
problem in practice. Patients
183 pregnancies in Korean females with SLE, based on a
should be well informed
receiver operating characteristic curve for prediction of adverse antibodies, age, reproductive
pregnancy outcomes, Ko et al stated that a stable period of at history, and other factors such that discontinuation of
least 4 months is essential in reducing pregnancy loss, as patient’s preference and medication may activate
premature birth, pregnancy-induced hypertension, and FGR. 12 cultural values. Intrauterine SLE and lead to pregnancy
An overview of the risk assessment in the SLE patients is device is a safe option, and no complications.
summarized in Table 1. increased risk is reported for
infection with combined use When planning pregnancy,
of immunosuppressive medication of the patient
Contraception medication.12 For stable must be reviewed and
patients with low disease adjusted to minimize its
Contraception options for SLE patients depends on current activity and negative aPLs, effect on the fetus while
disease activity, presence of antiphospholipid (aPL) estrogen–progestin maintaining the current stable
contraception seems to be a condition of the mother.
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266 Women’s Health

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Dovepress Pregnancy in systemic lupus erythematosus X
from preeclampsia. Recently, adverse outcomes is reported
Nonsteroidal anti-inflammatory drug is commonly prescribed attention is less on whether to substantially increase for
to SLE patients and is generally safe during pregnancy, except flare is likely or not and is females with a history of
in the third trimester, which may cause premature closure of more on which specific nephritis, positive aPL, and
ductus arteriosus. Low-dose aspirin, which is often used for the population of patients needs active disease at
prevention of preeclampsia, is also considered safe. special attention for conception.46,47 Lupus
Antihypertensive medications such as nifedipine, methyldopa, exacerbation of SLE. Some nephritis and
and hydralazine are widely used during preg-nancy.16 On the argue that in patients with antiphospholipid syndrome
other hand, angiotensin-converting enzyme inhibitors and stable condition at the time of (APS) are discussed
angiotensin II receptor blockers are contrain-dicated throughout conception, disease activity is separately in the following
pregnancy because of their association with congenital generally not worsened, and sections.
anomalies and pregnancy complications.17 Hydroxychloroquine even if so, the flare is usually
use is encouraged throughout preg-nancy because of its safety mild and seldom requires a Pregnant females with SLE
profile and possible preventive effect against neonatal change in the treatment.9,11,31 should be closely monitored
congenital heart block (described in the “Neonatal concerns” A history of lupus nephritis by both an experienced
section). The effects of glucocor-ticoids include a possible and active disease at the time
obstetrician and a
increase in the incidence of oral cleft in the fetus, FGR, and of conception are indicators
rheumatologist. Neonatal
premature rupture of membranes, although reports are of poor maternal
outcomes.32,33 care should be readily
conflicting.18 available considering the
high rate of premature birth.
Among the immunosuppressive agents, cyclophosph-amide, On the other hand, the effects
Although no consensus has
methotrexate, and mycophenolate are contraindicated during of the disease on preg-nancy been reached on
pregnancy because of their association with congenital outcomes are clear. The
management strategies,
anomalies.19–21 Azathioprine is considered relatively safer than incidence of complications, recommendations have been
other immunosuppressive drugs, and many reports encourage including preeclampsia,
prematurity, FGR, and fetal made to achieve early
transition for patients who wish to conceive.22 However,
loss, is higher in SLE patients detection of change in SLE
recently, concerns have been raised for late developmental
delays in children who were exposed to aza-thioprine in utero. 23 than that in the general
activity, fetal compromise,
Calcineurin inhibitors such as tacrolimus and cyclosporine also popula-tion. Preeclampsia is and maternal
seem to be acceptable options.24,25 The biological agents such as reported to occur in 7.5%– complications.48,49 The key
anti-TNF agents and rituximab administered by pregnant 22%34–38 of pregnant SLE points in management of
females with rheumatoid arthritis and inflammatory bowel patients, which is higher than pregnant SLE patients are
disease do not seem to place the mother and fetus at risk at the ~3% in the general described in Table 2.
time of conception and during the first trimester.26 However, population.39 It is not clear
their use in the third trimester must be cautioned, as these why these adverse outcomes
agents readily cross the placenta and fatal infection has been are increased in SLE patients;
Lupus nephritis
reported after live vaccination in an exposed infant.27 lupus nephritis and aPL
antibodies have been Patients with a previous
identified as risk factors. The history of lupus nephritis or
During pregnancy direct effect on placental active lupus nephritis during
trophoblast and complement pregnancy require careful
Whether SLE activity is influenced by pregnancy has been a activation, as well as monitoring during pregnancy,
controversial subject for decades. It is generally considered that procoagulant effect of aPL, as they are associated with
SLE flares are likely during pregnancy. However, some argue seems to play a role in the higher rates of maternal and
that SLE activity is worsened,28,29 while others report that no pathogenesis.40,41 Premature fetal complications. In a
change in disease activity is observed.30 The mixed results are delivery, either indicated or cohort study of 166
understandable, as the studies were mostly retro-spective in spontaneous, is observed in pregnancies, first-trimester
design and patient history such as disease activity at the time of 12.1%–54% of patients.9,11,34– proteinuria, indicative of
conception, previous history of disease, and medication profile 38,42–44 The incidence rate of lupus nephritis, resulted in a
were diverse. In addition, different defini-tions were given for fetal loss was reported as 2.6-fold increase in
disease flare and, as described below, 3%–36%, which varies pregnancy loss.46 Renal
among studies.33,35,38,44,45 The involvement, defined as
incidence rate of these proteinuria in the absence of
lupus flare during pregnancy is often difficult to distinguish
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Yamamoto and Aoki DovepressX

Table 2 Key points in managing the pregnant SLE patients

Observant Timing Monitoring details

First visit
Maternal
Obstetrician
First visit
Repeat every month until
monitoring History taking, physical
postpartum
examination, complement,
Fetal monitoring
anti ds-DNA antibody, SS-A
Obstetrician
and SS-B antibodies,
Starting at 16 weeks
cardiolipin antibodies, lupus
anticoagulant
History taking, physical
Repeated monthly until 20 weeks examination, complement
Starting at 24 weeks

CBC, chemistry (including

uric acid, liver enzymes,
Every 2 weeks until 24 weeks
Repeated every week until delivery creatinine) Protein–creatinine
ratio
Neonatologist
Every week until delivery When signs of fetal compromise Echocardiogram
detected
Rheumatologist BPP, fetal growth, umbilical
First visit Cardiologist artery Doppler velocimetry
When signs of CHB or heart failure
detected Consultation for appropriate
timing/mode of delivery
Repeat every month until postpartum History taking, physical examination, urine Consultation for therapy and
analysis (if dipstick is positive for protein, appropriate timing/mode of
measure protein–creatinine ratio) delivery
Both
Abbreviations: SLE, systemic lupus erythematosus; CBC, complete blood count; BPP, biophysical profile; CHB, congenital heart block; dsDNA, double stranded DNA.
that in during also known to be slightly ,4.9 mg/dL90
nonpregnancy. pregnancy is elevated during pregnancy.51 Complement
No change
The choice of challenging, The C3 and C4 levels must be
preeclampsia or dysmorphic Table 3 Key Decrease from
medication and as many evaluated in caution, because points to baseline
hematuria and cellular casts in
dose depends on physiologica differentiate
urine, was reported as a
the severity and l changes in preeclampsia
prognostic factor of FGR
the degree of normal from lupus
and/or preeclampsia in a even a sign of slight decrease during
organ pregnancy nephritis
retrospective study of 65 pregnancy
involvement. and obstetric in the normal range might (could be
pregnancies.38 As discussed
However, complication indicate lupus flare.50
earlier, in order to improve
special s may mimic
pregnancy out-come in this In particular, renal flare and Preeclampsia
consideration is SLE
patient population, females Lupus within the
necessary for symptoms. preeclampsia are difficult to nephritis
with active lupus nephritis normal range)
the possible For instance, differentiate, which share Anti-dsDNA
should be advised to postpone clinical features including
harm it may do mild No change
pregnancy until the disease is in
to the fetus. The thrombocyto hypertension, proteinuria, and Increased
remission for at least 6 months. thrombocytopenia. More-over, Other signs
risks and penia,
Lupus nephritis in pregnancy the two conditions may Absent
benefits of anemia, Onset
should be dealt with caution, Present
initiat-ing arthralgia, coexist, further complicating After 20 weeks of SLE activity
because it can possibly lead to Possible onset
treatment should edema, mild management of the
irreversible renal injury.33 In before
be evaluated dyspnea, and condition.48,52–54 When
addition, it is often difficult to
carefully. When effusion of preeclampsia is suspected as
differentiate renal flare and Urinary
indicated, the knees, which the culprit of the medical
preeclampsia, which can cause condition and termi-nation of 20 weeks ,195 mg/24
treatment should are all
dilemma in the choice of pregnancy is indicated, one Hypertension hours
not be withheld frequent .195 mg/24
treatment. Details on treatment should always keep in mind
Present
due to observations May be present hours91
are described as follows. the possibility of coexisting
pregnancy, as it during or absent calcium
may lead to pregnancy, lupus nephritis. When lupus Urinary
Treatment of SLE serious can be nephritis is involved in the Negative
Positive
morbidity and confused pathogenesis, the patient’s
flare during mortality.32 with early condition might worsen.52
sediment
pregnancy signs of Some key points to differenti-
Abbreviations:
dsDNA, double
Diagnosis of flare.48,50 ate preeclampsia and renal stranded DNA;
Complement flare are listed in Table 3. It is Uric acid SLE, systemic
The treatment of SLE flare SLE lupus
levels are .4.9 mg/dL
during pregnancy is the same as exacerbation erythematosus.
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Dovepress Pregnancy in systemic lupus erythematosus X
postpartum to reduce the
essential that obstetricians discuss each case individually pregnancy and also risks of thrombosis in APS
with a rheumatologist. anticoagulation with heparin patients.69–71
there is a study termination of believed to be pacemaker
that shows aspirin pregnancy, espe- caused by implantation is
Antiphospholipid alone is equally cially in patients transplacental required for ~70%
syndrome effective in with active transfer of the of patients by the
pregnancy loss.64 disease at autoantibodies age of 10 years.77,78
These trials are of conception and anti-Ro/SSA and
APS is an autoimmune disorder
small scale, vary in during anti-RA/SSB to the In order to
characterized by the occur-rence of
therapeutic pregnancy.72 Of newborn. The improve outcomes
venous and arterial thromboses, which
protocols, and, incidence rate of in fetus/neonates
may or may not coexist with other note, for those
most importantly, cardiac NL was diag-nosed with
autoimmune diseases such as SLE. In a who have
exclude SLE reported as 1%– heart block, close
study of 1,000 patients with a diagnosis of terminated
patients. Some 2% in mothers who monitoring is
APS, 36.2% were found to have SLE.55 Its pregnancy due to are antibody
retrospective necessary during
diagnosis consists of the presence of both SLE flare or with positive and can
studies on the pregnancy and
specific autoantibodies and clinical coexisting
effectiveness of increase to as high after delivery, as a
manifestations.56 One of the major clinical preeclampsia,
pharmacological as 18% in mothers first- or second-
manifestations of APS is adverse obstetric intensive
treatment for APS who had degree heart block
outcomes such as 1) three or more
patients include monitoring for previously given can potentially
consecutive spontaneous abortions before
SLE patients, but severe maternal birth to an affected progress to a third-
10 weeks of gestation, 2) one or more
unexplained fetal loss beyond 10 weeks of
their therapeutic postpregnancy child.74,75 The degree heart block,
regimens and exacerbations is major clinical necessitating
gestation, or 3) one or more premature
diagnosis of APS needed.52,73 The manifestations of pacemaker
births of a morphologically normal
are not treatment for NL are rash and implantation. Heart
neonate before 34 weeks of gestation due
consistent.64–67 One postpartum heart block. block is often
to eclampsia or preeclampsia.56 When
systematic review females with Cutaneous diagnosed between
APS is diagnosed together with SLE or
based on two small active SLE is involvement is 18 weeks and 24
other autoimmune diseases, the risk of
trials concluded similar to that for typically observed weeks of gesta-tion
adverse pregnancy outcomes is higher.57
that a combination as multiple by using
The treatment for APS includes pre- nonpregnant
of heparin and erythematous echocardiography,
vention of adverse pregnancy outcomes females. Many
aspirin reduced macules or plaques and a diagnosis of
by aspirin or aspirin in combination with medications for around the head
pregnancy loss by onset is rare after
heparin started empirically to prevent aggressive
54% in patients and neck at birth to 30 weeks of
thrombosis.58 However, studies from therapy are not 20 weeks of age.
with a history of at pregnancy.74,79
animal models suggest that inflammation compatible with The mean age of
least one Thus, intensive
also plays a key role in the pathogenesis breastfeeding.18 detection of the
pregnancy loss and fetal
of APS,59,60 and the anti-inflammatory Breastfeeding
positive aPL.68 rash was 6 weeks.76 echocardiography
aspect of heparin might also be
Well-designed females must be It is usually self- during this period
responsible for the effect on outcomes.49,51
trials are necessary informed of the limiting, is essential for
Management of APS during pregnancy
depends on whether the patient has a
to find the risks and benefits disappearing as the early diagnosis. In
appropriate of continuing circulating addition, prenatal
history of thrombosis. For those with a
treatment for lupus lactation during antibodies are fluorinated steroids
his-tory of thrombotic event, most experts
patients with APS. treatment. removed, but some can reverse a
recommend heparin use until 6 weeks
Currently, expert might have second-degree
postpartum. Although the effectiveness is
opinion favors the residual heart block,79–81
not proven, it is common to use aspirin in Neonatal telangiectasia and
use of aspirin although its
combination with heparin. The optimal
treatment for those without a history of
during concerns hyperpigmentation efficacy is still
in the affected controversial.77
thrombosis is not well studied.61
area.76 Cardiac
Randomized controlled trials have shown Postpartu Neonates born to manifestation of Intravenous
that the combination of aspirin and hepa- mothers with SLE NL is more seri- immunoglobulin
rin is superior to aspirin alone in m period need to be and
ous, with a plasmapheresis
preventing pregnancy loss and that monitored for reported mortality have also been
pregnancies that ended in live births had SLE flares can neonatal lupus as high as 16%– considered as
favorable outcomes62,63 on the other hand occur after (NL). NL is 17.5% and candidate
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