This document discusses the obstetric management of systemic lupus erythematosus (SLE) and antiphospholipid antibody syndrome (APLS). It provides information on: 1) The increased risks of adverse pregnancy outcomes for patients with SLE/APLS including preeclampsia, intrauterine growth restriction, and preterm birth. 2) Medication management during pregnancy focusing on continuing hydroxychloroquine and tapering corticosteroids due to their safety profiles. Other immunosuppressants are generally avoided due to risks. 3) Increased monitoring is recommended during pregnancy for SLE/APLS patients including frequent visits and testing to monitor for disease flares and complications. Delivery planning focuses

1. Obstetric management
in SLE and APLS
Dr. Indunil Piyadigama

2. Connective
tissue diseases
• Group of systemic disorders which involve tissues of the body containing
collagen or elastin

3. Autoimmune connective
tissue diseases
• Abnormal immune system activity directed
against the body’s own tissues (autoimmunity),
resulting in an inflammatory response in tissues
• Both genetic and environmental factors playing
a part
• Characterized as a group by the presence of
non-organ specific autoantibodies in the
circulation
• Each have particular clinical features and typical
blood test abnormalities and antibody patterns
• Ex
• SLE, APS, Sjorgren Syndrome
• Rheumatoid arthritis
• Mixed connective tissue disease

4. Immune changes
during pregnancy
• A switch from a predominantly Th1 (cell-
mediated) to a Th2 (humoral) type immune
response
• This reverts post-partum
• Some auto-immune conditions (such as RA)
associated with a Th1 (cell-mediated)
response often improve during pregnancy
but often relapse immediately post-partum
• Those associated with a Th2 (humoral)
immune response (such as SLE) may be more
likely to flare during pregnancy.

5. Systemic Lupus Erythematosis
• Multisystemic relapsing and remitting autoimmune disease.
• The prevalence in the UK is 97/100,000
• The rate in women is six times higher than that in men
• The highest prevalence has been observed in the Black Caribbean population
• 30-40% of women with SLE have antiphospholipid antibodies (aPL)

6. Pathophysiology
antibody formation
and the creation of
immune complexes
Complement
activation

8. Case scenario
• A 31 year old woman with severe SLE presents to your
antenatal clinic to have pre-conceptual counselling

9. Preconception
• Fertility in SLE patients does not appear to be altered by
disease
• Decrease in ovarian reserve can occur in women exposed
to cyclophosphamide
• The prognosis for both mother and child is best when SLE
has been quiescent for at least six month

10. Increased risk of adverese outcomes
1. SLE at an early stage following recent diagnosis or active disease
2. Severe organ impairment
• Hypertension
• Renal involvement
• Recent stroke
• Cardiac involvement
• Pulmonary hypertension (14%)/ severe interstitial lung disease
3. Presence of aPL and anti-Ro/La antibodies
4. Women who discontinue maintenance medication, especially
hydroxychloroquine

11. Lupus nephritis
• 33% of SLE
• Renal biopsy necessary to confirm the
diagnosis
• 4 basic histological types – DPGN more
common and severe

12. • Pre-existing renal disease may worsen in pregnancy
• 20% some renal deterioration
• 10% with permanent renal deterioration
• Particularly in patients with
o heavy proteinuria
o Hypertension
o high baseline serum creatinine concentrations.
• Severe renal impairment (creatinine >250 mmol/l) <30% chance of a successful
pregnancy
• This risk of developing preeclampsia is higher if the patient has renal impairment- 30%
• Risk of SLE flare – 30%
• Advised to defer pregnancy till disease is well controlled for at least six months

13. Case Cnt:
• Her last flare up was a month ago and she is on
Hydroxychloroquine and recently finished a tapering
dose of prednisolone
• She is ANA and anti-dsDNA positive, but
antiphospholipid antibody negative
• She had a normal full blood count and renal profile at
her last outpatient appointment
• She is also concerned that she is at risk of recurrent
miscarriage and has been researching the topic on the
internet prior to her clinic appointment
• She wishes to know the teratogenic potential effects
of her medications

14. Foetal risks
• More likely to have unsuccessful pregnancy – 20%
• Miscarriage
• Losses in T2 and T3 – 40%
• Intrauterine growth restriction (IUGR)
• Intrauterine death
• Fetal deaths are associated with aPLs. Presence of aPLs has been the single
most sensitive predictor of fetal death. Positive predictive value – 50%
• If prior death this increases to 85%
• eNAs can lead to neonatal lupus and heart block

15. Hydroxychloroquine
• Continue use of hydroxychloroquine (HCQ) during pregnancy
• Fewer disease flares and better outcomes in patients continuing HCQ during pregnancy
• Reduce the prednisolone dosage
• No increase in adverse events or congenital malformations
• Decrease in occurrence of congenital heart block in at-risk foetuses of mothers with anti-
Ro and anti-LA antibodies

16. Cyclosporin - Cat C
Azathioprin – Cat D
Tocrolymus – Cat C
• Azathioprine is compatible with pregnancy
• AZA is metabolized to 6-MP in vivo
• Foetus lacks enzyme to convert to active form
• Neonatal immunosuppression rare if dose <2 mg/kg and normal maternal white cell count
• A calcineurin inhibitor
• No increase in congenital malformations
• No increase in congenital malformations

17. Biologic medications - Category B
• Use during pregnancy are limited
• Given that IgG does not cross the placenta in significant
amounts can be used throughout pregnancy
Rituximab – B-cell depleting antibody
Belimumab - BAFF inhibitor
Etanercept - soluble fusion protein
Infliximab - chimeric monoclonal antibody
Adalimumab - humanized monoclonal
antibody

18. Mycophenolate mofetil
Cyclophosphamide
Methotrexate
• Alkylating agent
• associated with congenital malformations
• Stop 3 months prior
• should be avoided during the first 10 weeks of gestation
• However, in life-threatening clinical situations, this medication has been used in late pregnancy
• Congenital anomalies have been reported. This medication should be avoided during pregnancy
• Azathioprine, tacrolimus or glucocorticoids can be substituted for mycophenolate
• Ideally, this transition in medication should take place six months prior to conception
• Folate antagonist. Teratogenic. Discontinue at least 3 months prior to conception
Leflunomide
• While not a definitive teratogen, this medication should be avoided during pregnancy.
• Patients taking this medication who would like to conceive should do a cholestyramine washout
until blood levels are undetectable
Contraindicated
medications

19. NSAIDs – up to 30 weeks
• NSAID use is not associated with congenital anomalies
• There is conflicting evidence as to whether exposure to NSAIDs during the first trimester
increases the risk of spontaneous abortion
• Use of NSAIDs after 30 weeks of gestation may cause premature closure of the ductus
arteriosus - indomethacin and ibuprofen
• Transient oligohydramnios has been reported with daily use of Diclofenac
• Neonatal haemorrhage and effects on the foetal kidney

20. Booking visit
• Blood pressure
• Baseline assessment of
• liver function
• Quantification of renal function- eGFR, S Cr
• Urine analysis, Quantification of proteinuria -uPCR
• Uric acid
• full blood count
• Disease activity markers
• anti-double stranded DNA antibodies
• C3 and C4
• Lupus anticoagulant and anticardiolipin antibodies
• Anti Ro and Anti La antibodies

21. Avoiding maternal complications
• All women with SLE should be commenced on aspirin from 12 weeks
to reduce the risk of pre-eclampsia.
• Thromboprophylaxis with aspirin and/or low molecular weight
heparin
• If the woman is aPL positive or
• has gross proteinuria

22. Monitoring
• Frequent antenatal visits
• Visits every 1-2 weeks in T1 and T2
• Weekly in T3
• Monthly full blood count
• Considered every trimester
• Renal and liver function, uric acid and full blood count
• eGFR, urinalysis, uPCR
• Anti-double stranded DNA antibodies, C3 and C4
• Lupus anticoagulant and anticardiolipin antibodies

23. Flares 25 - 60%

24. Lupus flare
Rising dsDNA titre
Fall in C3 and C4
Pre-eclampsia
Raised uric acid
Thrombocytopenia
Abnormal liver function tests
Low levels of PLGF

25. Treatment
• IV immunoglobulin - first line treatment for SLE flares if there is diagnostic doubt as to
whether the condition is a flare or sepsis
• Control of flare include prednisolone and hydroxychloroquine
• For severe flares, immunosuppressants such as azathioprine, cyclosporine and tacrolimus
may need to be considered

26. Glucocorticoides
• Use the lowest possible dose of prednisolone
• Ideally less than 10 mg/day
• ? cleft lip, with and without cleft palate - studies have failed to
consistently demonstrate an increased risk of this malformation
• ? premature rupture of membranes, and IUGR
• 88% of prednisolone is inactivated as it crosses the placenta
• Dexamethasone
• IV hydracortisone

27. Foetal
monitoring
• Detailed anomaly scan at 18-22 weeks
gestation
• Regular four weekly growth scans from 20
weeks are recommended
• Fetal surveillance with KCC, CTG, Amniotic
fluid volume one to 2 times per week
from 30 weeks
• Deliver at term. Avoid postdates

28. Postpartum
• VTE risk assessment
• Oral contraceptives do not increase the risk of flare among
women with SLE whose disease is stable
• Oestrogen containing contraceptives increase the risk of
VTE and should be avoided in those with APS

29. Antiphospholipid
syndrome
• Systemic autoimmune disorder characterized by
venous or arterial thrombosis and/or pregnancy
loss in the presence of persistent
antiphospholipid antibodies (aPL)
• Primary 53%, Secondary 47%
• Body recognizes phospholipids (part of a cell's
membrane) as foreign and produces antibodies
against them.
• Antiphospholipid antibodies are a family of
approximately 20 antibodies
• The main types of aPL of concern during
pregnancy are
• lupus anticoagulant (LA)
• anticardiolipin antibodies (aCL – IgG and
IgM) > 40IU
• anti-beta-2-glycoprotein I antibodies > 40IU

30. Copyrights apply
Updated Sapporo
(Sydney) criteria
At least one clinical and one laboratory criteria
Clinical criteria
1. Vascular thrombosis
Clinical arterial or venous thrombosis confirmed objectively
2. Pregnancy morbidity
a. Unexplained death of a morphologically normal fetus beyond 10
weeks
b. Premature birth of a morphological normal neonate before 34
weeks due to severe preeclampsia or placental insufficiency
c. Recurrent miscarriages before 10 weeks. Maternal anatomical,
hormonal causes and maternal paternal chromosomal causes
excluded
Laboratory criteria (2 occasions 12 weeks apart)
1. Lupus anticoagulant in plasma
2. Anticardiolipin antibody in medium or high titers
3. Anti-beta-2-glycoprotein-I (titer > 99th centile)

31. New biomarkers
• C4 complement - gaining credence as additional predictors of outcome of
patients with aPL antibodies
Generally accepted features of placental insufficiency
• Abnormal or non-reassuring foetal surveillance tests (eg,
lack of fetal heart rate accelerations, low score on a
biophysical profile)
• Absent or reversed EDF
• Oligohydramnios
• Birth weight <10th for the gestational age (FGR/SGA)
APS is not associated with placental abruption
Placental abruption is not a defining morbidity for APS

32. Pathophysiology of pregnancy morbidity
• Incompletely understood.
• Uteroplacental thrombosis and vascular insufficiency may be one mechanism
• aPL appears to have a direct effect on human placental trophoblast function
• decreasing trophoblast viability,
• syncytialization,
• capacity for invasion as measured by an in vitro assay
• APS-associated pregnancy complications may reflect a general autoimmune
mechanism and aPL may affect the production of hormones and signalling
molecules by cells in the trophoblast
• aPL (anti-beta-2-glycoprotein I) activates Toll-like receptor 4 on trophoblast,
resulting in inflammation at the maternal-foetal interface and altered trophoblast
function

33. Risk of thrombosis in nonpregnant woman
• Thrombosis is the hallmark of APS
• Venous thrombosis 70% – deep veins of the lower extremities
• Arterial thrombosis - Cerebral vasculature (stroke and transient
ischemic attack)
• Catastrophic APS - Multiple simultaneous vascular occlusions through
out the body
• History of arterial or venous thrombosis are at high risk of recurrent
thrombosis and are generally treated with warfarin for lifelong

34. Thrombosis and pregnancy and peuperium
• Normally associated with an increased risk for thrombosis
• Risk of thromboembolic disease during pregnancy or postpartum
• 0.025 to 0.10% in the general obstetric population
• 5 to 12% among women with known APS
• Treated patients, it is unknown but is likely less than 1%

35. Factors associated with a higher risk of adverse
obstetric outcome
• Lupus anticoagulant – appears to be the major predictor of poor
pregnancy outcome in women with APS
• In a prospective cohort study
• 144 singleton pregnancies among patients
• with systemic lupus erythematous or primary APS
• with moderate to high titer aPL
Antibody status Adverse outcomes (%)
LA 39
aCL IgG 8
aCL IgM 0
anti-beta-2-glycoprotein I IgG 0
anti-beta-2-glycoprotein IgM 13

36. Triple positivity
• Multicentre retrospective cohort study of 750 singleton pregnancies
with primary APS treated with low-dose aspirin and prophylactic low
molecular weight heparin from the first trimester
30%
70%
Triple +
Live birth
Adverse outcomes
80%
20%
Single Ab
Live birth
Adverse outcome

37. Higher risk of adverse obstetric outcome -ctd
• Women with thrombosis-associated APS have higher rates of
pregnancy complications than those with only obstetric-associated AP

38. Placental problems
• PIH/ preeclampsia – 50%
• IUGR – 30%
• Preterm birth – 50%

39. Copyrights apply
Management of Pregnant/ postpartum with aPL
Thrombosis
Therapeutic LMWH +
Aspirin
Pregnancy morbidity
Type of pregnancy
morbidity
Early pregnancy
Prophylactic LMWH + Aspirin
Same postpartum
Preeclampsia or placental insufficiency
Antepartum – Aspirin
Postpartum
• VD – Apirin for 6 weeks
• CS – Prophylactic LMWH + Aspirin 6 weeks
Antepartum – Aspirin
Postpartum –
• VD – Apirin for 6 weeks
• CS – Prophylactic LMWH + Aspirin 6 weeks
Yes
No
Yes
No
American College of Rheumatology (ACR) Reproductive Health Guidelines and by the European League Against
Rheumatism (EULAR)

40. Management of APLS

41. Early pregnancy morbidity
Low-dose ASA (50 to 100 mg per day) - beginning when conception is attempted
prophylactic-dose LMWH - upon confirmation of intrauterine pregnancy
Aspirin alone Combination of heparin
and Aspirin
Reduction of pregnancy
loss (RR)
0.46, 95% CI 0.29-0.71
first-trimester pregnancy
loss (OR)
0.39, 95% CI 24-0.65
Increased live births (RR) 1.3, 95% CI 1.04-1.63
Live birth rates (%) 42-80 71-84
• The rate of fetal loss may exceed 90% in untreated patients

42. Poor pregnancy outcome despite
antithrombotic therapy
• Conventional treatment fails to prevent obstetric morbidity in 20%
• There is no second line therapy with proven efficacy
• hydroxychloroquine appears to depress aPL levels
• This effect might be beneficial in women with APS-related recurrent
pregnancy loss
• However, it takes approximately three months for hydroxychloroquine
to have an effect, thus it should be started prior to pregnancy

43. Pregnancy morbidity due to preeclampsia or
placental insufficiency
• One of the risk criteria for preeclampsia
• Aspirin beginning at the end of the first trimester and continuing through
delivery
• Some data suggest that the optimum dose to reduce the risk of
preeclampsia may be 100 to 150 mg
• Aspirin may also reduce the risk of arterial thrombosis
• Although some clinicians prescribe LMWH as well, available evidence does
not support this approach
• In selective cases of Aspirin failure or when placental examination shows
extensive decidual inflammation and vasculopathy – Combination of
Aspirin and LMWH

44. Foetal monitoring and timing of delivery in APS
• Weekly or twice per week tests of foetal well-being
• nonstress tests and/or biophysical profile scoring
• beginning at 32 weeks of gestation because of the
increased risk of antepartum foetal death
• Delivery (induction or caesarean) at 39 weeks of gestation to
control the timing of discontinuation of antithrombotic drugs

45. Pregnancy with aPL without APS
• Prevalence of aCL in women with uncomplicated pregnancies ranges from 0 to 11%
• Little or no increase in risk in this group/ uncertain
• Treatment decision made on an individual basis. Therapeutic options in pregnancy
• no therapy
• low-dose aspirin alone
• low-dose ASA and prophylactic-dose heparin
• Majority of the Advisory Board of the 10th International Congress on aPL, which favoured prescribing low-dose ASA
alone during pregnancy for these patients
• The rationale for using
• Antiplatelet effects
• Enhances leukocyte-derived interleukin-3 production, which stimulates normal trophoblast growth and
hormone expression

46. IVF and APS
• IVF is potentially dangerous in women with APS since ovulation induction regimens
trigger an oestrogen-induced hypercoagulable state.
• women with a history of thrombosis-associated APS should be switched from their
usual oral anticoagulant to therapeutic dose unfractionated heparin, which should be
maintained after oocyte retrieval.
• If the patient conceives, she should be switched to LMWH
• If she does not conceive, she should be maintained on unfractionated heparin
through repeated IVF cycles or switched back to her usual anticoagulant if further
cycles are not planned

47. Neonatal APS
• aPL in the neonate almost always results from
placental transfer of maternal antibody and
thus may not have the same significance as
endogenously produced antibody
• Passively acquired aPL completely disappears
by 6 to 12 months of age
• Neonatal APS is rare
• Diagnosis is the same as the adult criteria

48. Extractable Nuclear
Antibodies - anti-Ro and
anti-La)

49. • Anti-Ro and/or anti-La antibodies may be found in patients with SLE,
SS, RA and healthy asymptomatic carriers
• The prevalence of antibodies in the general population - 1–3%
• antibodies cross the placenta by active transport between the 16th
and 30th weeks of gestation
• Neonatal lupus syndrome (NNLS), involving skin, heart, liver and/or
cytopenia.

50. • Occurs in around 5% of babies
• Usually presents as a rash at approximately 2 weeks
of age
• Erythematous geographical lesions in light-exposed
areas (generally face and scalp)
• Disappears within 3–6 months without residual
scarring, when maternal antibodies are cleared
from the baby's circulation
• Mother should be reassured

51. Congenital
heart block
• The most serious foetal
manifestation
• Affects approximately 2% of
mothers with eNA autoantibodies
• This risk increases to
• 15-20% if one child has
previously been affected
• 50% if two children have been
affected
• CHB normally develops during 16
and 24 weeks of gestation and
presents with a foetal bradycardia

52. Congenital
heart block
• Overall mortality of complete heart block is
around 20%
• There is no treatment yet to reverse complete
heart block
• But infants do well if they survive the neonatal
period
• Two-thirds require pacemakers
• Incomplete heart block - Various treatments have
been used, including steroids, if detected
antenatally, but results are variable
• less frequent cardiac manifestations have also
been described as part of NNLS, such as
cardiomyopathy and endocardial fibroelastosis

53. Foetal
monitoring in
eNAs
• Foetal heart rate should be documented at each
visit
• Foetal echocardiography offered at 18-20 weeks
to identify any evidence of cardiac conduction
abnormalities.
• Repeat Echo again in the third trimester
• If foetal echocardiography is normal up to 28
weeks’ gestation it is highly unlikely the foetus
will have any cardiac manifestations
• Some centres prefer serial weekly foetal
echocardiograms between 16 and 26 weeks of
gestation, and fortnightly between 26 and 32
weeks

54. Other manifestations of neonatal lupus syndrome
• Autoimmune hemolytic anemia
• Leukopenia
• Thrombocytopenia
• Hepatosplenomegaly
• Other autoimmune diseases later in life

55. Thank you