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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