Systemic Lupus Erythematosus

in Pregnancy

Dr. dr. AAN Jaya Kusuma, Sp.OG(K), MARSDivision of Maternal Fetal Medicine, Department of Obstetrics and Gynaecology,

Faculty of Medicine Udayana University/Sanglah General Hospital, Denpasar, Bali,

Indonesia

Introduction

Systemic lupus erythematosus

(SLE)

A chronic inflammatory disease with multisystem involvement in which the tissues are damaged by

autoantibodies and immune complexes

Primarily affects young female at childbearing age

Joya Sree Roy et al, 2017

CRITICAL ILL OBSTETRIC

PATIENTS

MATERNAL TO FETO-PLACENTAL

IMMUNE DYSREGULATION

Incidence and

prevalence of SLE is still very low : a

point prevalence

of 3 per 100,000

Sex specific SLEprevalence in

the UK: Females:

49.6/100,000( ie1 in 2000 adult women have

SLE) and Males: 3.6/100,000

90% of SLE cases

affects women.

Incidence during the

child bearing age being 1

in 500

SLE in Pregnancy

Epidemiology

No Nama Diagnosis

2018

1 ESG1P0000 19 minggu 2 hari T/H, SLE on treatment, HT

terkontrol, lupus nefritis

2 WFS, 26 th

G4P1111 33 minggu 1 hari T/ KJDR, letak lintang, SLE,

trombositopenia P1211 post SC + SLE + trombositopenia

susp ISK

3 SA, 24 thG3P0111 27 minggu 5 hari T/H, SLE on treatment,

trombositopenia

4 YCDG4P3001 34 minggu 5 hari T/H, ROB, LMR (bekas SC 2x),

SLE

5 WSM, 27 th

G3P2002 21 minggu 6 hari T/H, SLE, moderate efusi pleura

sinistra, lupus nefritis, hipoalbuminemia, anemia sedang, CAP

PSI class III, ISK komplikata, hypokalemia

6 GPR, 39 th G5P3013 36 minggu 2 hari T/H, SLE on treatment

7 JJ, 33 th P0101 post partum, SLE, riwayat transplantasi ginjal

8 SMM, 22 th G1P0000 Hamil Muda, SLE, Lupus Nefritis

9 GESG1P0000 31 Minggu 5 Hari T/H SLE, Lupus Nefritis on

Treatment

10 DYI, 27 thG1P0000 7 Minggu 3 hari, T/H, WLE on Treatment, OBS

Transamitis ec Susp Lupoid Hepatitis, Anemia ringan

11NS, 37 th

G3P2002 13 minggu 2 hari T/H, anemia ringan.

12 KA, 19 th G1P0000 14 minggu 1 hari T/H, SLE on treatment

No Nama Diagnosis

2019

1 AS, 30 th P3013 post SC + MOW, SLE on treatment

2 PAM, 31 th

G3P1011 37 minggu 5 hari T/H, LMR (bekas SC 1x),

SLE, trombositopenia SC + MOW lahir bayi

perempuan, 3010 g, AS 8-9

3 PMT P2002 post SC hari I + SLE on treatment

4 WS, 27 th

G8P0160 26 minggu 5 hari T/ KJDR, LMR (bekas SC 1x)

ROB, SLE on treatment, PE berat, partial HELLP

syndrome histerotomi lahir bayi laki-laki, 950 g

5 DY, 27 thG3P1011 38 minggu 4 hari T/H, PK I, SLE PK II

lahir bayi perempuan, 3000 g, AS 8-9

6 AA P1001 post SC hari ke 2, SLE

7 WDY, 28 th G3P1011 37 minggu 2 hari T/H, SLE on treatment

8 PWD Hamil muda + SLE on treatment + TB paru on treatment

9 PDL, 25 thG3P1011 17 minggu 1 hari T/H, Grave disease

(Euthyroid), SLE, ARF (Feb 2017), MR mild

SLE IN PREGNANCY, OBSTETRIC AND GYNECOLOGY DEPT/SANGLAH HOSPITAL

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

Diagnostic Criteria

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

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 risk of abortions (2-3 times), stillbirth, fetal

loss, preterm birth, and fetal growth restriction (FGR),

higher incidence of hypertensive disorders and maternal intensive care admission.

Multiple factors have been identified in association with

adverse outcomes, such as lupus activity during pregnancy, previous nephropathy, maternal

hypertension, and positivity for anti-phospholipid

antibodies

Why SLE is important in pregnancy?

Increased pregnancy related complication

due to SLE

SLE disease flares due to pregnancy.

There are two main

problems

Common pregnancy related complications

Pregnancy related hypertension

Preeclamsia-Eclampsia

HELLP syndrome

Ante-partum haemorrhage

IUGR

Neonatal Lupus

Pre-maturity, Abortion & Still birth

Gestational diabetes (increased by prednisone used for SLE

Other maternal complications of lupus

Flares

Deep vein thrombosis

Pulmonary embolism

Cerebro-vascular accident (stroke)

Pulmonary hypertension

Premature delivery

Causes : poor intrauterine growth, reduced liquor, fetal distress, rupture of membranes, pre- eclampsia, spontaneous labour.

Risk factors for premature delivery are anti-phospholipid antibodies, active SLE at conception, SLE flare, renal disease, high blood pressure.

Neonatal Lupus

Syndrome

An unusual condition due to the passage of maternal antibodies (specially Anti-Ro/SS-A and Anti-La/SS-B) to unborn fetus.

Main features are congenital heart block(CHB), transient cutaneous lupus lesions, cytopenias, hepatic, and other systemic manifestations

SLE related fetal disease and complications

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.

Care for Pregnant Women with SLE

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

Best time for conception is

after 6-12 months of remission

with hydroxychloroquine but no

cytotoxic drugs

Preconception Counselling and Focused Antenatal Care

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.

In some situations, pregnancy

may be contraindication

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.

Antenatal Follow-up

Flare : unpredictable bouts of the disease after a 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” (SELENA) new definitions ‘‘mild/ moderate’’ flare from ‘‘severe’’ flare.

The fatal complications of SLE flare are renal involvement and CNS manifestations, A recent meta-analysis reported rates ranging from 1.5 to 83% for a lupus nephrites flare during pregnancy

Lupus increases maternal morbidity, risk of premature delivery & fetal loss. Most important thing is therapeutic issues and the drugs is teratogenic

SLE Flare

Initial evaluation should be based on thorough history taking and

physical examination along with careful BP measurement

• Routine urine analysis

• Hb%, ESR, total WBC count, differential

count and platelet count

• Serum creatinine & Clearance

• 24hr urinary total protein

• Anti-ds-DNA (raised level indicates active

SLE or impending flare.)

• Anti-Ro(SS-A) and Anti-La(SS-B), Anti-

Phospholipid Antibodies (Anti cardoilipin

Ab & Lupus anticoagulant)

Investigations during first visit:

• Serum C3 &C4 level (low C3 indicates active SLE or

impending flare in over 80% of patients.) • Fasting blood glucose if at high risk

• Serum lipids if patient is nephrotic or on steroids

• Ultrasound examination(Should be selective rather than

routine)

• Others: Hepatitis B & C serology, Anti HIV screening,

Syphilis serology

• 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

FANC: Evaluation at first visit

• 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

Laboratory assessment includes:

Follow up at subsequent visits

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

NSAID,ANTIMALARIAL(Hydroxychloroquine ),STEROIDS, CytoToxic

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

General Principles of Treatment of Lupus Pregnancy

Prednisone at a dosage of 5–10 mg per day is

usually considered safe.

Lupus flares that fit into

mild activity can be

treated with low-dose prednisone (less than 20

mg/d).

Higher doses of

corticosteroids,

including pulse dose

steroids, are options to

treat moderate to severe lupus activity.

• Hydroxychloroquine is not a teratogenic drug.

• Its use is recommended to prevent disease activity and reduce the risk of cardiac-neonatal lupus in patients who are carriers of anti-SSA/-antibody.

• In addition, it improves the prognosis of SLE nephritis and prevents death.

Recommended SLE Treatment during Pregnancy

Cyclophosphamide should not

be prescribed during the first

trimester, because of its

association to chromosomal

impairment.

During the second or third

trimester, it should be reserved

only to severe flares unamenable

with methylprednisolone pulses or

other drugs.

The use of cyclophosphamide

during the second and third

trimesters does not seem to

increase the risk for congenital

abnormalities. Nevertheless,

miscarriages and preterm birth

may be more frequent.

Regarding cyclosporine 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

exposed to them.

• Leflunomide is associated to teratogenic and fetotoxic effects in animals, and its metabolite is detectable in plasma up to 2 years after discontinuation.

• Thus, in pregnant women, it is formally contraindicated; and pregnancy must be excluded before starting it.

NOT-Recommended SLE Treatment during Pregnancy

• Methotrexate is another teratogenic drug, classified by the FDA as X (contraindicated in pregnancy).

• If used in the first trimester, it is associated to FGR and some major malformations, such as absence or hypoplasia of the frontal bones, craniosynostosis, large fontanelle and ocular hypertelorism

During the first trimester, rituximabhas very low transplacentaltransfer, with some studies reporting safe pregnancies and deliveries in those cases of exposure.

However, during the second or third trimester, it can cross the placenta and induce severe neonatal lymphopenia.

Drugs Toxicity in pregnancy

Prednisolone Increased risk of Cleft lip, cleft palate, premature

rupture of membrane, hypertension, preeclampsia, DM

Azathioprine

Found to be safe in therapeutic dose in different studies some clinicians believe it causes bone

marrow suppression both in mother and fetus and

has been found to be teratogenic in mice and rabbits

Cyclosporine

Found to be safe in therapeutic dose in different studies The most important problem faced in the

newborn whose mother is treated by cyclosporine is the severe IUGR

Cyclophosphamide

Crosses the placenta and can cause fetal toxicity. Abnormalities (missing fingers and/or toes,

cardiac defects, hernias) have occurred in infants

born to women treated with the drug during the

pregnancy. Other complications: haemorrhagiccystitis, bone marrow suppression, infection

MTX Potentially teratogenicneural tube defect

Recommended SLE Treatment during 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.

Issue of medical termination of pregnancy

Women who have required glucocorticoids to

control SLE during pregnancy need an

increased dose, called a stress dose, during

delivery

The increased dose helps the body respond

normally to the physical stresses of childbirth

Delivery should be done in such hospital where

(NICU) is available

Indications for Caesarian section include

maternal reasons (avascular necrosis of the

hips with inadequate hip abduction) or foetal

reasons (foetal distress, abnormal nonstress test,

cephalo-pelvic disproportion and transverse

presentation etc)

Time and Mode of Delivery

Neonatal care Puerperium

• After delivery heart

rate of the baby

should be counted

and search for any

cutaneous lesion

• Treatment of

established

congenital heart

block (CHB) is difficult; it is better

to prevent during

pregnancy

• Most of the time

cutaneous lesion can

be treated with

topical steroids

• Mother should be

watched for infection

and disease

exacerbation; both

require aggressive

treatment, when

detected

• In Anti- phospholipid

antibody Syndrome,

warfarin is restarted

after bleeding stops

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

Breast-feeding and Contraception

DECISION TREE –

Managing

pregnancy in

women at risk for

offspring with

neonatal lupus

The prothrombotic

state in APS is in large

part due to the three

characteristic

antibodies

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

APS

Lupus anticoagulant

AnticardiolipinAnti-β2-glycoprotein 1

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)

Antiphospholipid syndrome (APS) Co-Incidence to SLE

Antiphospholipid syndrome (APS)

The risk of

thrombosis is

increased

with:

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

Lupus anticoagulant or antibodies against β2-glycoprotein 1 occurring alone (higher risk of thrombosis than with anticardiolipin alone);

High antibody titres (particularly IgG)

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).

Revised classification criteria for antiphospholipidsyndrome

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.

it may be considered in patients with high risk antiphospholipid antibodies (ie, triple or multiple positivity, lupus anticoagulant, persistent medium to high titre antibodies) and if other thrombotic risk factors (eg, hypertension, smoking, diabetes, hyperlipidaemia, recent surgery) are present.

APS is managed in

conjunction with a

haematologist.

If associated with an

autoimmune disease (such

as SLE), it may also be

managed by a

rheumatologist.

The management of APS

includes primary prophylaxis

for first thrombotic event and

obstetric event, secondary

prophylaxis for venous and

arterial thrombotic events,

management of recurrent

thromboses, and

management of obstetric 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.

Primary prophylaxis

The use of aspirin to prevent a first thrombotic event in the presence of antiphospholipid antibodies remains controversial.

For patients with APS associated with SLE, hydroxychloroquine has been shown to be of benefit as primary prophylaxis leading to a reduction in thromboembolic events and is thus recommended.

Treatment

Prevention of venous thrombosis

In patients with APS who developed

unprovoked venous thrombosis,

anticoagulation with unfractionated

heparin or low molecular weight

heparin followed by a vitamin K

antagonist (warfarin) aiming for an

international normalized ratio (INR) of

2–3 is recommended.

Anticoagulation should continue long

term as the risk of recurrent thrombosis is

high if it is stopped.

Patients undergoing long distance air

travel may consider adopting other

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.

Prevention of arterial thrombosis

• There is no consensus due to lack of high quality evidence for the optimal management of APS with arterial thrombosis.

• Owing to the higher rates of recurrent arterial thrombosis in APS, experts recommend anticoagulation with warfarin, aiming for an INR > 3.0, or combination aspirin and warfarin with an INR target of 2–3.

• Data from a prospective cohort study, the Antiphospholipid Antibody and Stroke Study, suggested that warfarin or aspirin monotherapy were equally effective in preventing ischaemic stroke in patients with a prior history of stroke and a single positive antiphospholipid antibody test result.

Treatment

The current recommended treatment is low dose aspirin and prophylactic dose low molecular weight heparin..

Keeling D, Mackie I, Moore GW, et al. Guidelines on the investigation and management of antiphospholipid

syndrome. Br J Haematol 2012; 157: 47–58.

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.

Obstetric APS

Conclusion

Before Pregnancy

During Pregnancy

After Pregnancy

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.

Assess Clinical and Serologic

lupus activity

Asses Lupus Co-

Morbid:PoHT,Renal,ec

Asses drug use for Lupus

Asses previous pregnancy

outcomes

Pregnancy planing at least 6 mo

remission

Discontinue drug(MTX,Cyclop

Initiate HCQ and Azathriopine

APS

Folic acid

Monitor Lupus activity

Monitor pregnancy

complication

Monitor Fetal

Complication

Treat lupus flare(low dose

pred,HCQ,azathripine)

APS Management

Preeclampsia protocol

Steroid for Heart block

Monitor Lups activity

Monitor maternal complication

Monitor fetl congenital heart block

Treat lupus flare(steroid,aza,HCQ

APS and Hypertension

management

Heart block

Breast feed management

contraceptive