Systemic Lupus Erythematosus

in Pregnancy

Dr. dr. AAN Jaya Kusuma, Sp.OG(K), MARS

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology,
Faculty of Medicine Udayana University/Sanglah General Hospital, Denpasar, Bali,
Indonesia
 Introduction

A chronic inflammatory
disease with multisystem
involvement in which the
tissues are damaged by
autoantibodies and
Systemic lupus immune complexes
erythematosus
(SLE)
Primarily affects young
female at childbearing age

Joya Sree Roy et al, 2017

 Epidemiology

Incidence
Sex specific SLE
and
prevalence in
prevalence the UK: 90% of Incidence
of SLE is still Females: SLE cases during the
very low : a 49.6/100,000( ie child bearing
point 1 in 2000 adult affects age being 1
women have
prevalence SLE) and Males: women. in 500
of 3 per 3.6/100,000
100,000
 Diagnostic Criteria
 The American College of
Rheumatology (ACR) proposed the
criteria for the diagnosis of SLE
(►Table 1). To be classified as SLE,
at least four criteria should occur in
series or simultaneously
 A consensus group of
experts on SLE, the Systemic
Lupus International
Collaborating Clinics
(SLICC), has proposed
revised criteria for the
diagnosis of SLE.
 It requires either that a
patient satisfies at least 4
out of 17 criteria including
at least one of the 11
clinical criteria and one of
the 6 immunologic criteria,
 or that the patient has
biopsy-proven nephritis
compatible with SLE and
positivity to antinuclear
antibodies (ANA) or anti-
double-stranded DNA
(dsDNA) antibodies.
Diagnostic Criteria
 Why SLE is important in pregnancy?
 Labelled as a ‘high-risk pregnancy’  SLE can create a
dangerous situation during pregnancy
 SLE associated maternal and fetal diseases and
complications
 Disease flare of SLE can occur during pregnancy.
Increased pregnancy  Increased risk of abortions (2-3 times), stillbirth, fetal
related complication loss, preterm birth, and fetal growth restriction (FGR),
due to SLE higher incidence of hypertensive disorders and
maternal intensive care admission.
SLE disease flares  Multiple factors have been identified in association with
due to pregnancy. adverse outcomes, such as lupus activity during
pregnancy, previous nephropathy, maternal
hypertension, and positivity for anti-phospholipid
antibodies
There are two main
problems
 Common pregnancy Other maternal
related complications complications of lupus
Pregnancy related
hypertension Flares

Preeclamsia-Eclampsia
Deep vein thrombosis
HELLP syndrome
Pulmonary embolism
Ante-partum haemorrhage
Cerebro-vascular accident
IUGR (stroke)

Neonatal Lupus Pulmonary hypertension

Pre-maturity, Abortion &

Still birth

Gestational diabetes (increased by

prednisone used for SLE
SLE related fetal disease and complications

Causes : poor intrauterine growth, reduced

liquor, fetal distress, rupture of membranes,
pre- eclampsia, spontaneous labour.
Premature
delivery Risk factors for premature delivery are anti-
phospholipid antibodies, active SLE at
conception, SLE flare, renal disease, high
blood pressure.

An unusual condition due to the passage of

maternal antibodies (specially Anti-Ro/SS-
Neonatal A and Anti-La/SS-B) to unborn fetus.
Lupus Main features are congenital heart block
Syndrome (CHB), transient cutaneous lupus lesions,
cytopenias, hepatic, and other systemic
manifestations
Care for Pregnant Women with SLE

Adopting a specific protocol of care for

pregnant women with lupus should
contribute to reduce the frequency of
maternal and fetal adverse outcomes,
directly or indirectly related to SLE,
improving care standards and ensuring
successful pregnancies.
Preconception Counselling and Focused Antenatal
Care
Focused ANC; but more concentration should be given to identify early
diseases flares To search for SLE related pregnancy complications
and regular monitoring of fetal conditions

Adequate counselling, planning and care before, during and

after the pregnancy must be the goal of health professionals
who look after women with SLE.

The care of pregnant women with SLE must focus on three

mainstays: a coordinated medical-obstetrical care, a well
defined management protocol and a well-structured neonatal
unit.
Preconception Counselling and Focused Antenatal
Care
Pregnancy planning is a key-
point for women with SLE.
Postponing conception until
the disease is considered
inactive for at least six
months
significantly improves the
outcomes of these
pregnancies.

Some conditions should

advise to delay pregnancy,
such as severe disease flare
within the previous six months,
recent stroke and active
lupus nephritis.

In some situations, pregnancy

may be contraindication
Preconception Counselling & Planning for
Pregnancy
 The incidence of flare during pregnancy with conception
while in remission is less than 10%
 Best time for conception is after 6-12 months of remission with
hydroxychloroquine but no cytotoxic drugs
 At the preconception visit, obtaining a complete set of
autoantibody profile is recommended, including
antiphospholipid (aPL) antibodies (anticardiolipin and lupus
anticoagulant), complement serum levels, anti-SSA and
anti-SSB antibodies.
 Evaluating the pregnancy risk and assessing the SLE activity
and the organ function is important to maintain disease
control only in safe medications
 Prenatal /Antenatal Follow-up
 Requires close collaboration between the MFM- obstetrician and the clinicians
(rheumatologist, nephrologist or hematologist), and management in a high-risk referral
center/Tertiary Hospital
 An evaluation by the clinician should occur every 4–6 weeks, whereas the obstetric visit
should be every 4 weeks until 20 weeks of gestation; then, every 2 weeks until 28 weeks, and
then, weekly until the expected delivery date.
 At every prenatal visit, blood pressure, weight gain, uterine size, fetal heart rate and
urinalysis (through a quick outpatient analysis with the dipstick testing) should be assessed,
as well as inquiring about symptoms related to lupus flares.
 Signs and symptoms of lupus flares often mimic the ones of normal pregnancy.
 Those flares are less frequent in the third trimester, although they may occur at any time
during pregnancy or in the immediate postpartum period.
 SLE Flare
 unpredictable bouts of the disease after a
Flare :
period of remission.
 A number of validated indices are available for quantifying
disease activity or flare of SLE. “Systemic Lupus Erythematosus
Disease Activity Index” (SLEDAI) and the “British Isles Lupus
Activity Group” (BILAG), have been the predominant ones
used for defining flare
 The “Safety of Estrogen in Lupus: National Assessment”
• A higher risk of flare
(SELENA) new definitions  ‘‘mild/ moderate’’ flare from
during pregnancy is ‘‘severe’’ flare.
noticed when lupus  The fatal complications of SLE flare are renal involvement and
nephritis occurs at CNS manifestations
conception, even in
women in remission  Lupus increases maternal morbidity, risk of premature delivery
• A recent meta-analysis & fetal loss. Most important thing is therapeutic issues and the
reported rates ranging drugs is teratogenic
from 1.5 to 83% for a
lupus nephrites flare
during pregnancy
 Evaluation at first visit
Initial evaluation should be based on thorough history taking and
physical examination along with careful BP measurement
Investigations during first visit:
• Routine urine analysis • Serum C3 &C4 level (low C3 indicates active SLE or
• Hb%, ESR, total WBC count, differential impending flare in over 80% of patients.)
count and platelet count • Fasting blood glucose if at high risk
• Serum creatinine & Clearance • Serum lipids if patient is nephrotic or on steroids
• 24hr urinary total protein • Ultrasound examination(Should be selective rather than
• Anti-ds-DNA (raised level indicates active routine)
SLE or impending flare.) • Others: Hepatitis B & C serology, Anti HIV screening,
• Anti-Ro(SS-A) and Anti-La(SS-B), Anti- Syphilis serology
Phospholipid Antibodies (Anti cardoilipin
Ab & Lupus anticoagulant)

• Because of the risk of fetal congenital heart block, for women with anti-SSA/SSB antibodies, a fetal
echocardiography should be performed at 18–20 weeks and 26–28 weeks to exclude fetal congenital
heart block.
• An urgent referral to a tertiary care center should be prompted in case of any fetal heart rate
abnormality, mostly a slow heart rate
 Follow up at subsequent visits
 History and clinical examinations should be focused on identification
of disease flares and pregnancy related complication

Laboratory assessment includes:

• Blood counts including platelet, Hb%, ESR
• Routine urine analysis
• Serum creatinine, Urinary protein:creatinine ratio
• FBG/Modified OGTT 24 to 28 weeks
• anti-dsDNA and C3 {At the end of each trimester}
• Biophysical profile (BPP) scoring from 28 weeks
• Women detected to have either anti-Ro or anti-La antibodies should be offered serial fetal
echocardiograms between 16-24 weeks of gestation
 General Principles of Treatment of Lupus
Pregnancy
 Treatment principle of SLE is an integrated management protocol to maintain
good health, prevent complications and early detection & rapid treatment of flares
 Counselling of patient and family members is important
 Patient should known the danger signs

General advice:
 Avoiding sun exposure prevent flares, low salt diet containing adequate amount of vitamins and minerals
 Treatment when there is no sign of flares or complications: Drugs those can be used safely during pregnancy
 Hydroxychloroquine
 Low dose Aspirin(75mg/d ) if Antiphospholipid antibodies present, in high risk patient or presence of
nephritis for prevention of pre-eclampsia
 There are many controversies of using steroid in this group of patient to prevent flares as flare prophylaxis.
Use of steroid increases the risk of fetal cleft palate, IUGR, PROM, DM, pre-eclamsia
 Recommended SLE Treatment during Pregnancy

 Prednisone at a dosage • Hydroxychloroquine is Cyclophosphamide should not

of 5–10 mg per day is
usually considered safe. • Its use is
 Lupus flares that fit into
mild activity can be
treated with low-dose
prednisone (less than 20
mg/d).
 Higher doses of • In addition, it
corticosteroids,
including pulse dose
steroids, are options to
treat moderate to
severe lupus activity.
not a teratogenic drug. be prescribed during the first
trimester, because of its
recommended to association to chromosomal
prevent disease impairment.
activity and reduce
the risk of cardiac- During the second or third
neonatal lupus in trimester, it should be reserved
patients who are only to severe flares unamenable
carriers of anti-SSA/- with methylprednisolone pulses or
antibody. other drugs.
The use of cyclophosphamide
improves the during the second and third
prognosis of SLE trimesters does not seem to
nephritis and increase the risk for congenital
prevents death.
abnormalities. Nevertheless,
miscarriages and preterm birth
may be more frequent.
 Recommended SLE Treatment during Pregnancy

 Regarding cyclosporine • Leflunomide is • Methotrexate is another

and tacrolimus, the FDA
classifies as category C;
however, some meta-
analysis studies did not
find significant
differences related to
birth defects when
pregnant women were • Thus, in pregnant
exposed to them.
associated to teratogenic drug, classified by
teratogenic and the FDA as X (contraindicated
fetotoxic effects in in pregnancy).
animals, and its
metabolite is • If used in the first trimester, it is
associated to FGR and some
detectable in
plasma up to 2 major malformations, such as
years after absence or hypoplasia of the
discontinuation. frontal bones, craniosynostosis,
large fontanelle and ocular
hypertelorism
women, it is
formally
contraindicated;
and pregnancy
must be excluded
before starting it.
 Recommended SLE Treatment during Pregnancy
Drugs Toxicity in pregnancy
 During the first Increased risk of Cleft lip, cleft palate, premature
trimester, rituximab
has very low Prednisolone rupture of membrane, hypertension,
transplacental preeclampsia, DM
transfer, with some Found to be safe in therapeutic dose in different
studies reporting studies some clinicians believe it causes bone
safe pregnancies Azathioprine marrow suppression both in mother and fetus and
and deliveries in has been found to be teratogenic in mice and
those cases of
exposure. rabbits
Found to be safe in therapeutic dose in different
 However, during studies The most important problem faced in the
the second or third Cyclosporine
trimester, it can newborn whose mother is treated by cyclosporine
cross the placenta is the severe IUGR
and induce severe Crosses the placenta and can cause fetal toxicity.
neonatal Abnormalities (missing fingers and/or toes,
lymphopenia. Cyclophosphamid cardiac defects, hernias) have occurred in infants
e born to women treated with the drug during the
pregnancy. Other complications: haemorrhagic
cystitis, bone marrow suppression, infection
MTX Potentially teratogenicneural tube defect
Issue of medical termination of pregnancy
 Pregnant mothers on SLE treatment of MTX or Cyclophosphamide 
offered diagnostic tests with a view to early detection of teratogenicity;
 CVS, Amniocentesis, Cordocentesis, 3-D ultrasound, Fetal MRI depends on
suitable for age of gestational period
 If the result shows untreatable fetal condition or associated with significant
handicap  may be suggested for termination of pregnancy
 Alternatively, time, place and mode of delivery may be planned in order
to ensure the optimal prognosis of neonate.
 Time and Mode of Delivery
 Women who have required glucocorticoids to Neonatal care Puerperium
control SLE during pregnancy need an
• After delivery heart • Mother should be
increased dose, called a stress dose, during
rate of the baby watched for infection
delivery
should be counted and disease
 The increased dose helps the body respond and search for any exacerbation; both
normally to the physical stresses of childbirth cutaneous lesion require aggressive
• Treatment of treatment, when
 Delivery should be done in such hospital where
established detected
(NICU) is available
congenital heart • In Anti- phospholipid
 Indications for Caesarian section include block (CHB) is antibody Syndrome,
maternal reasons (avascular necrosis of the difficult;  it is better warfarin is restarted
hips with inadequate hip abduction) or foetal to prevent during after bleeding stops
reasons (foetal distress, abnormal nonstress test, pregnancy
cephalo-pelvic disproportion and transverse • Most of the time
presentation etc) cutaneous lesion can
be treated with
topical steroids
 Breast-feeding and Contraception
Issues of Breast-feeding:
 If the dose of prednisolone is greater than 30 mg/day, feeding should be avoided for 4
hours after ingestion of the morning dose of steroid. By this time the blood levels are quite
low and very limited amounts are secreted into the milk.
 Breastfeeding is contraindicated if mother is on cyclophosphamide, azathioprine,
hydroxychloroquine for SLE

Advice of contraception:
 Barrier methods are the safest method for contraception’
 Low dose estogen or progesterone only pills are relatively safe
 High dose estrogen containing pill should be avoided
 OCP should be avoided in antiphospholipid syndrome, other thromboembolic diseases, highly
active disease, migraine, Raynaud’s phenomenon.
 IUD controversial because it causes infections like endometritis, PID etc
DECISION TREE –
Managing
pregnancy in
women at risk for
offspring with
neonatal lupus
 Antiphospholipid syndrome (APS) Co-Incidence to
SLE
 Frequently associated with systemic lupus erythematosus (SLE) and other autoimmune
diseases, but occurs in the absence of other autoimmune disease in many cases (primary
APS).
 In autoimmune disease, particularly SLE, the prevalence is as high as 30% (Unlu, 2016)

Lupus
 The prothrombotic anticoagulant
state in APS is in large
part due to the three
characteristic
antibodies APS
Anti-β2-
Anticardiolipin
glycoprotein 1

Giannakopoulos B, Krilis SA. The pathogenesis of the antiphospholipid syndrome. N Engl J Med 2013; 368: 1033–1044.
Proposed pathogenesis and key clinical
effects of antiphospholipid syndrome

B cells produces
antiphospholipid Antibodies bind to β-glycoprotein
1 leading to activation of vascular
antibodies agains β- endothelium and other
glycoprotein 1 ( in inflammatory cells
susceptible px)

1. Vascular
thrombosis
2. Other organ 1. Reduced
complications
Proposed second hit Subsequent protein C and
(eg., smoking,
(eg, renal
pregnancy,
prothrombotic tissue factor
dysfunction) state via multiple inhibitor
3. Pregnancy malignancy) leading activity
complications to clinical syndrome mechanisms 2. Increased
vascular tone
 Antiphospholipid syndrome (APS)
Lupus anticoagulant or antibodies against β2-glycoprotein 1
 The risk of occurring alone (higher risk of thrombosis than with
anticardiolipin alone);
thrombosis is
increased
High antibody titres (particularly IgG)
with:

Positivity for multiple antibodies (associated with the highest

risk of thrombosis)

Additional risk factors for thrombosis at the time of diagnosis

(eg, hypertension, smoking and diabetes mellitus for arterial
thrombosis, and hyperlipidaemia for venous thrombosis).

Kelchtermans H, Pelkmans L, de Laat B, Devreese KM. IgG/IgM antiphospholipid antibodies present in the classification criteria for the
antiphospholipid syndrome: a critical review of their association with thrombosis. J Thromb Haemost 2016; 14: 1530–1548.
Zuo Y, Fan J, Sarode R, et al. Identifying additional risk factors for thrombosis and pregnancy morbidities among antiphospholipid
antibodies carriers. Clin Appl Thromb Hemost 2018; 24: 980–985
Revised classification criteria for antiphospholipid
syndrome
Antiphospholipid syndrome is present if at least one of the clinical criteria and one of the laboratory
criteria that follow are met. Clinical criteria:
 Vascular thrombosis:
 One or more clinical episodes of arterial, venous or small vessel thrombosis, in any tissue or
organ. Thrombosis must be confirmed by objective validated criteria. For histopathological
confirmation, thrombosis should be present without significant evidence of inflammation in the
vessel wall.
 Pregnancy morbidity:
 One or more unexplained deaths of a morphologically normal fetus at or beyond the 10th
week of gestation, with normal fetal morphology documented by ultrasound or by direct
examination of the fetus.
 One or more premature births of a morphologically normal neonate before the 34th week of
gestation because of (i) eclampsia or severe pre‐eclampsia defined according to standard
definitions, or (ii) recognized features of placental insufficiency.
 Three or more unexplained consecutive spontaneous abortions before the 10th week of
gestation, with maternal anatomical or hormonal abnormalities and paternal and maternal
chromosomal causes excluded.
Revised classification criteria for
antiphospholipid syndrome
 Laboratory criteria
 Lupus anticoagulant present in plasma, on two or more occasions at least 12
weeks apart.
 Anticardiolipin antibody of IgG and/or IgM isotype in serum or plasma, present
in medium or high titre (ie, > 40 GPL or MPL or > 99th percentile), on two or more
occasions, at least 12 weeks apart.
 Anti-β2-glycoprotein 1 antibody of IgG and/or IgM isotype in serum or plasma
(in titre > 99th percentile), present on two or more occasions, at least 12 weeks
apart.

Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification criteria for
definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.
 Treatment
 APS is managed in
Primary prophylaxis
conjunction with a
haematologist.
 If associated with an The use of aspirin to prevent a first thrombotic event
autoimmune disease (such in the presence of antiphospholipid antibodies
as SLE), it may also be remains controversial.
managed by a  it may be considered in patients with high risk
rheumatologist. antiphospholipid antibodies (ie, triple or multiple positivity,
 The management of APS lupus anticoagulant, persistent medium to high titre
includes primary prophylaxis antibodies) and if other thrombotic risk factors (eg,
for first thrombotic event and hypertension, smoking, diabetes, hyperlipidaemia, recent
obstetric event, secondary surgery) are present.
prophylaxis for venous and
 For patients with APS associated with SLE,
arterial thrombotic events,
hydroxychloroquine has been shown to be of benefit as
management of recurrent
primary prophylaxis leading to a reduction in
thromboses, and
management of obstetric thromboembolic events and is thus recommended.
complications.

Miyakis S, Lockshin MD, Atsumi T, et al. International consensus statement on an update of the classification
criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost 2006; 4: 295–306.
 Treatment
Prevention of venous thrombosis Prevention of arterial thrombosis

 In patients with APS who developed • There is no consensus due to lack of high quality
evidence for the optimal management of APS with
unprovoked venous thrombosis, arterial thrombosis.
anticoagulation with unfractionated
heparin or low molecular weight • Owing to the higher rates of recurrent arterial
heparin followed by a vitamin K thrombosis in APS, experts recommend
anticoagulation with warfarin, aiming for an INR >
antagonist (warfarin) aiming for an
3.0, or combination aspirin and warfarin with an
international normalized ratio (INR) of INR target of 2–3.
2–3 is recommended.
• Data from a prospective cohort study, the
 Anticoagulation should continue long Antiphospholipid Antibody and Stroke Study, suggested
term as the risk of recurrent thrombosis is that warfarin or aspirin monotherapy were equally
high if it is stopped. effective in preventing ischaemic stroke in
 Patients undergoing long distance air patients with a prior history of stroke and a single
travel may consider adopting other positive antiphospholipid antibody test result.
general measures for venous
thromboembolism prevention (eg
compression stockings).
Keeling D, Mackie I, Moore GW, et al. Guidelines on the investigation and management of antiphospholipid
syndrome. Br J Haematol 2012; 157: 47–58.
 Obstetric APS
 The current recommended treatment is low dose aspirin and prophylactic
dose low molecular weight heparin.
 For patients with obstetric and thrombotic complications, treatment should
include low dose aspirin and therapeutic dose low molecular weight
heparin.

 Up to 20% of pregnancies are unsuccessful despite treatment.

 Risk factors for an unsuccessful pregnancy include triple antiphospholipid antibody
positivity, associated autoimmune disease and thrombotic manifestations.
 Treatments for refractory obstetric APS include hydroxychloroquine, low dose
prednisolone until 14 weeks’ gestation, immunoglobulin, plasma exchange
and immunoadsorption.

Keeling D, Mackie I, Moore GW, et al. Guidelines on the investigation and management of antiphospholipid
syndrome. Br J Haematol 2012; 157: 47–58.
 Conclusion

 SLE is a multisystemic disease.

 Therefore, interdisciplinary approach is needed to treat the
disease.
 Doctor, patient and her family should work together for planning
of pregnancy and during pregnancy to overcome the
complications.