MANAGING LUPUS

IN PREGNANCY
A Practical Approach

Sidney Erwin T. Manahan, MD, FPCP, FPRA

Medical Specialist (Rheumatology)
Department of Medicine
East Avenue Medical Center
 OBJECTIVES

• Describe adverse events

observed in SLE patients who
become pregnant

• Discuss the management of

lupus pregnancies

• Discuss briefly the management

of Anti-Phospholipid Syndrome
(APS) in pregnancy
 SYSTEMIC LUPUS ERYTHEMATOSUS
1997 ACR Classification Criteria
• Malar rash
• Chronic • Discoid rash
Inflammatory • Photosensitivity
Autoimmune • Oral ulcers
Disorder • Arthritis
• Serositis
• Predominantly • Renal disorder
affecting women in • Neurologic disorder
their reproductive • Hematologic disorder
years • Immunologic disorder
• Anti-nuclear antibodies

Hochberg MC. Updating the ACR revised criteria for the classification of SLE. Arthritis Rheum 1997; 40: 1725.
 SYSTEMIC LUPUS ERYTHEMATOSUS
2012 SLICC Classification Criteria
CLINICAL IMMUNOLOGIC
• Acute cutaneous • ANA
• Chronic cutaneous • Anti-dsDNA
• Oral ulcers • Anti-Sm
• Non-scarring alopecia • Anti-Phospholipid
• Synovitis • Low complement
• Serositis • Direct Coomb’s test
• Renal
• Neurologic
• Hemolytic anemia
• Leucopenia / Lymphopenia
• Thrombocytopenia
Petri M, Orbai AM, Alarcon GS, et al. Derivation and vallidation of the SLICC Classification Criteria for SLE.
Arth & Rheum 2012; 64 (8): 2677-86.
Pregnancy/ Fetal Loss in SLE
50%

43%
40%

30%

20% 17%

10%

0%
1960-65 2000-03

Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients
with SLE over a 40-year period. J Rheumatol 2005; 32 (9): 1709-12.
 Adverse Events During Pregnancy

Maternal Premature
Mortality Birth
Frequency
Odds Ratio 20
Cesarean 39.4% Neonatal
Section Death
Lupus Odds Ratio 1.7 Frequency 2.5%
Abortion
Flares Frequency
Frequency 16%
27-70% Preterm Neonatal
Labor Lupus
Odds Ratio 2.4
Pre-
IUGR
eclampsia Odds Ratio 2.6
Odds Ratio 3.0
Stillbirth Congenital
Frequency 3.6% Heart Block
1-2% of Ro+

Clowse ME, Jamison M, Myers E, et al. A national study of the complication of lupus in pregnancy. Am J Obstet Gynecol 2008;
199 (2): 127.31-e6. Smyth A, Oliveira GH, Lahr BR, et al. A systematic review and metaanalysis of pregnancy outcomes in
patients with SLE and lupus nephritis. Am Soc Nephrol 2010; 5 (11): 2060-8.
 The Health Care Team
Expertise in
• High-risk pregnancies
• Systemic Lupus Erythematosus
• Neonatal medicine

Care should be performed in a

controlled setting

Stojan G, Baer AN. Flares of SLE during pregnancy and the puerperium: prevention,
diagnosis and management. Expert Rev Clin Immunol 2012; 8 (5): 439-53. Ramires de
Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing
Pregnancy in Patients with Lupus. Autoimmune Dis 2015; 2015: Article ID 943490.
Lateef A, Petri M. Managing lupus patient during pregnancy. Best Pract Res Clin
Rheumatol 2013; 27 (3): doi: 10.1016.
 Risk Factors for POOR
Pregnancy Outcomes
• Active disease within 6 months
prior to conception
• Active disease during pregnancy
• SLE onset during pregnancy
• Anti-phospholipid syndrome
• Hypocomplementemia
• Presence of anti-dsDNA
• Thrombocytopenia
• Chronic hypertension
• Pre-existing renal disease
• First trimester proteinuria

Stojan G, et al. Flares of SLE during pregnancy and the puerperium: prevention, diagnosis
and management. Expert Rev. Clin Immunol 2012; 8(5): 439-453.
Domains in Managing Lupus in Pregnancy

Pre-pregnancy Pregnancy

Choice of Therapy Anti-Phospholipid Syn

 Outcomes in Pregnant SLE Patients
New onset SLE during pregnancy (n 41) Flare of SLE during pregnancy (n 41)
Stable SLE in preganancy (n 73)

58%
54%
49% 49%
42%
37%
32%
24%
20%
14%
12%
10% 10%
6% 7%
5% 5%
2%
0% 0% 0%
Pre/eclampsia Abortion Neonatal Preterm birth Live birth Maternal Severe organ
death death damage

Yang H,Liu H, Xu D, et al. Pregnancy-related SLE: clinical features, outcome and risk factors
of disease flares – a case control study. PLoS ONE 2014; 9(8): 3104375
 Before Conception
Monitor organ involvement
1 Target disease remission; Delay pregnancy if
high disease activity OR SLEDAI>8

Check for autoantibody profile

2 Determine anti-PL, anti-Ro/ La

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing Pregnancy in Patients with
Lupus. Autoimmune Dis 2015; 2015: Article ID 943490.
 Risk factors for Flares
during Pregnancy
TYPE OF FLARE RISK FACTORS

Mucocutaneous Anti-Ro, previous involvement

Articular Anti-dsDNA

Hematologic Anti-PL, Coombs+, previous involvement

Renal Anti-dsDNA, Low C3/C4, previous involvement

CNS Previous involvement

Vascular Previous involvement

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing Pregnancy in Patients with
Lupus. Autoimmune Dis 2015; 2015: Article ID 943490.
 Before Conception
Monitor organ involvement
1 Target disease remission; Delay pregnancy if
high disease activity OR SLEDAI>8

Check for autoantibody profile

2 Determine anti-PL, anti-Ro/ La

Identify organ damage

3 Look into contraindications to pregnancy

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing Pregnancy in Patients with
Lupus. Autoimmune Dis 2015; 2015: Article ID 943490.
 CONTRAINDICATIONS
to Pregnancy
• Severe pulmonary HPN (PAP >50mmHg)
• Advanced heart failure
• Severe restrictive lung disease
• Chronic renal failure (sCrea >2.8mg/dl)

Consider DEFERRING Pregnancy When

• Current use of CTX, MMF, LEF
• Active renal or CNS disease <6 months
• Recent major thrombosis (i.e. stroke) <2 years

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing

Pregnancy in Patients with Lupus. Autoimmune Dis 2015; 2015: Article ID 943490.
Lateef A, Petri M. Managing lupus patients during pregnancy. Best Prac Res Clin Rheumatol 2013; 27 (3): doi:10/1016.
 Before Conception
Monitor organ involvement
1 Target disease remission; Delay pregnancy if
high disease activity OR SLEDAI>8

Check for autoantibody profile

2 Determine anti-PL, anti-Ro/ La

Identify organ damage

3 Look into contraindications to pregnancy

Review treatment regimen

4 Replace contraindicated meds with safer ones
Wait for 2-3 months on new regimen to ensure
disease control is maintained
Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing Pregnancy in Patients with
Lupus. Autoimmune Dis 2015; 2015: Article ID 943490.
When Do We Allow?
• No evidence of active disease >6 months
• Prednisone <10mg/d
• May take Hydroxychloroquine
• No contraindicated meds being taken >6mo
• No evidence of active disease for 2-3 months
if placed on a new regimen
 Monitor disease activity
1 Differentiate symptoms of pregnancy vs SLE

Following Conception

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al.

Understanding and Managing Pregnancy in Patients with Lupus
. Autoimmune Dis 2015; 2015: Article ID 943490.
 Flares During Pregnancy
New onset lupus Flare of lupus Non pregnant
during pregnancy during pregnancy SLE patients
(n 41) (n 41) (n 164)
Mucocutaneous 20 (49%) 15 (37%) 98 (60%)
Musculoskeletal 14 (34%) 3 (7%) 56 (34%)
Renal 27 (66%) 35 (85%) 102 (62%)
Cardiovascular 8 (20%) 9 (22%) 48 (29%)
Pulmonary 9 (22%) 2 (5%) 26 (16%)
Nervous system 7 (17%) 6(15%) 40 (24%)
Gastrointestinal 10 (24%) 10 (24%) 30 (19%)
Hematologic 25 (61%) 23(56%) 71 (44%)

Yang H,Liu H, Xu D, et al. Pregnancy-related SLE: clinical features, outcome and risk factors
of disease flares – a case control study. PLoS ONE 2014; 9(8): 3104375
 WHAT causes these findings?

Facial flush / Melasma Photosensitive rash

Palmar erythema Malar rash
Post partum hair loss Alopecia / lupoid hair

Arthralgias, Myalgias
Synovitis
Bland effusion of knees

Fatigue Pleuritis
Mild edema Pericarditis

Fever (T>38oC)
Lymphadenopathy

Yang H,Liu H, Xu D, et al. Pregnancy-related SLE: clinical features, outcome and risk factors
of disease flares – a case control study. PLoS ONE 2014; 9(8): 3104375
Lateef A, Petri M. Managing lupus patients during pregnancy. Best Prac Res Clin Rheumatol 2013; 27 (3): doi:10/1016.
 WHAT causes these findings?

ESR 18-46mm/hr <20 weeks ESR Increased

30-70mm/hr >20 weeks
Hgb >11 during 1st 20 weeks Hemoglobin <10.5
Hgb >10.5 beyond 20 weeks
Mild thrombocytopenia in <8% Platelet <95,000
Proteinuria <300mg/24hours Proteinuria >300mg/24hours
Rare hematuria from vaginal Hematuria or
contamination cellular casts
Anti-dsDNA Negative or stable Anti-dsDNA Rising
Normal or increasing complement Low or >25%drop in complement
Yang H,Liu H, Xu D, et al. Pregnancy-related SLE: clinical features, outcome and risk factors
of disease flares – a case control study. PLoS ONE 2014; 9(8): 3104375
Lateef A, Petri M. Managing lupus patients during pregnancy. Best Prac Res Clin Rheumatol 2013; 27 (3): doi:10/1016.
 Hypertension, Proteinuria in Pregnancy?

Features Lupus nephritis Pre-eclampsia

Hypertension Onset any time Onset after 20 weeks
Proteinuria >300mg/d >300mg/d
Urinary sediment Active Inactive
Uric acid <5.5mg/dl >5.5mg/dl
Anti-dsDNA level Rising Stable or negative
24 hr urine calcium >195mg/d <195mg/d
Complement levels >25% drop Normal
Other organs Active non-renal SLE CNS or HELLP

Stojan G, Baer AN. Flares of SLE during pregnancy and the puerperium: prevention, diagnosis and management. Expert Rev Clin
Immunol 2012; 8 (5): 439-53. Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing
Pregnancy in Patients with Lupus. Autoimmune Dis 2015; 2015: Article ID 943490. Lateef A, Petri M. Managing lupus patient during
pregnancy. Best Pract Res Clin Rheumatol 2013; 27 (3): doi: 10.1016.
 SLE Disease Activity Indices(SLEDAI)
in Pregnancy (SLEPDAI)
Feature Score Feature Score
Seizure 8 Proteinuria 4
Psychosis 8 Pyuria 4
Organic Brain syndrome 8 Rash 2
Visual disturbance 8 Alopecia 2
Cranial nerve disorder 8 Mucosal ulcers 2
Lupus Headache 8 Pleurisy 2
CVA 8 Pericarditis 2
Vasculitis 8 Low complement 2
Arthritis 4 Anti-dsDNA increasing 2
Myositis 4 Fever 1
Urinary casts 4 Thrombocytopenia 1
Hematuria 4 Leucopenia 1

Buyon JP, et al. Assessing disease activity in SLE patients during pregnancy. Lupus 1999; 8(8): 677-84.
 Follow up of the
Pregnant SLE Patient
OBSTETRICIAN
• Monthly until week 20
• Every 2 weeks until week 28
• Weekly until delivery

RHEUMATOLOGIST
• Support the obstetrician
during prenatal care
• Every 4-6 weeks
 Lab Evaluation in Pregnant SLE Patients
First Visit Quarterly Visits
• CBC with platelet count • CBC with platelet count
• PT/ PTT • Anti-ds DNA titers/ C3/ C4/
• Anti-Phospholipid Abs CH50
• Anti-Ro/ La/ Sm • Chemistry (include BUA)
• Anti-dsDNA titers/ C3/ C4/ • Urinalysis, 24 hours urine
CH50 protein or urine protein/
• Chemistry (include BUA) creatinine ratio in a single
• Urinalysis, 24 hour urine sample
protein or urine protein/
creatinine ratio in a single
sample

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding

and Managing Pregnancy in Patients with Lupus. Autoimmune Dis 2015; 2015: Article ID 943490
Lateef A, Petri M. Managing lupus patient during pregnancy. Best Pract Res Clin Rheumatol 2013; 27 (3): doi: 10.1016.
 Specific Investigations
ULTRASOUND
• Screen for fetal anomalies – between week 16-20
• Monitoring fetal growth – every 4 weeks

FOR ANTI-RO+ MOTHERS

• Fetal echocardiography every week from week 16-26 and
biweekly thereafter until delivery

FOR PRE-ECLAMPSIA
• Uterine artery doppler study – Week 20 then every 4 weeks
• Fetal umbilcal artery doppler velocimetry – Week 26 then weekly

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding

and Managing Pregnancy in Patients with Lupus. Autoimmune Dis 2015; 2015: Article ID 943490
Lateef A, Petri M. Managing lupus patient during pregnancy. Best Pract Res Clin Rheumatol 2013; 27 (3): doi: 10.1016.
 Monitor disease activity
1 Differentiate symptoms of pregnancy vs SLE

Consider low-dose Aspirin

2 To reduce risks of pre-eclampsia esp in those
with lupus nephritis

Following Conception

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al.

Understanding and Managing Pregnancy in Patients with Lupus
. Autoimmune Dis 2015; 2015: Article ID 943490.
 Up to 30% may develop pre-eclampsia
Risk factors for Pre- Consider low dose ASA (40-
eclampsia in SLE 160mg/d) before 16 weeks
AOG in high risk patients
• Pre-existing hypertension
• Preeclampsia (RR 0.6 95%
• Anti-phospholipid
CI 0.27- 0.83)
syndrome
• Severe preeclampsia (RR
• Obesity
0.3 95% CI 0.11-0.69)
• Anti-dsDNA
• Anti-RNP
• Low Complement
• Thrombocytopenia

Schramm AM, Clowse MEB. Aspirin for the prevention of pre-eclampsia in

lupus pregnancy. Autoimmune Dis 2014; 2014: ID 920467.
 Monitor disease activity
1 Differentiate symptoms of pregnancy vs SLE

Consider low-dose Aspirin

2 To reduce risks of pre-eclampsia esp in those
with lupus nephritis

Treat for APAS

3 Will discuss later

Following Conception

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al.

Understanding and Managing Pregnancy in Patients with Lupus
. Autoimmune Dis 2015; 2015: Article ID 943490.
 Risks from Medications Used
in Pregnancy
• Concerns over teratogenic risks lead
to women not taking meds during
pregnancy and lactation
• Actual estimated risk for major
malformations from meds <5%
Koren G, Bologa M, Long D, et al. Perception of teratogenic risks by pregnant women exposed to
druugs and chemical during the fist trimester. Am J Obstet Gynecol 1989; 160: 1190-4.
Koren G, Pastuszak A. Prevention of unnecessary pregnancy terminations by counselling women
on drug, chemical and radiation exposure during the first trimester. Teratology 1990; 41: 657-61.

• Background rate for congenital

anomalies ranges from 1-5%
Loebstein R, Addis A, et al. Pregnancy outcomes following gestational exposure to fluoroquinolones: a
multicenter prospective controlled study. Antimicrob Agents Chemother 1998; 42: 1336-9
Bird TM, Hobbs CA, et al. National rates of birth defects among hospitalized newborns. Birth Def Res
Clin Mol Teratol 2006: 76: 762-9
 Gaps in Medication Use
During Pregnancy
• Only half of all pregnancies are
planned and, as a result, many women
are already taking medications when they
become pregnant

• In 2006, US Data shows that in >6

Million pregnancies
>90% were taking at least 1 medication
50% were taking 3-4 medications

Finer LB, Zolna MR. Unintended pregnancies in the US 2006. Contraception 2011; 84: 478-85
 ACR Reproductive
Health Summit
The GREATEST RISKS to the outcome
of the mother and the fetus comes from
• Uncontrolled disease activity
• Disease flares during pregnancy
• Disease flares during the post partum
period

Kavanaugh A, Cush JJ, Ahmed MS, et al. Proceedings from the ACR Reproductive Health Summit: The management of fertility,
pregnancy and lactation in women with autoimmune and systemic inflammatory diseases. Arthritis Care Res 2015; 67 (3): 313-25.
 What medications to give?
US FDA Pregnancy Categories: http://chemm.nlm.nih.gov/pregnancycategories.htm

US FDA CLASSIFICATION
Studies in pregnant women failed to
A demonstrate a risk to the fetus
No studies in pregnant women but animal
studies failed to show risk OR No studies in
B pregnant women but animal studies show a
risk
No studies in pregnant women but animal
studies show an adverse event but benefits
C outweigh risks in humans OR No studies in
humans and animals

Evidence of fetal risk in humans but benefits

D outweigh risks
Evidence of fetal risk in humans or animals
X and risks outweighs benefits
 Towards Better
Understanding of
Medication Use in
Pregnancy

FDA
Amendments
Act of 2007
 Medications in Pregnancy
LOW RISK NO DATA HIGH RISK
Steroids
Hydroxychloroquine
Azathioprine Rituximab Methorexate
Ciclosporin Belimumab Leflunomide
Tacrolimus Tofacitinib Mycophenolate MMF
Aspirin Tocilizumab Cyclophosphamide
Heparin or LMWH Ustekinumab Warfarin
IVIG
TNF-inhibitors*
* Generally safe in 1st and 2nd trimester; drug specific recommendations: Mabs – discontinue before 30
weeks and avoid live vaccine in infant until 6 months , ETN – discontinue 4 weeks before dellivery,
certolizumab can be continued.

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing Pregnancy in Patients with
Lupus. Autoimmune Dis 2015; 2015: Article ID 943490. Kavanaugh A, Cush JJ, Ahmed MS, et al. Proceedings from the ACR
Reproductive Health Summit: The management of fertility, pregnancy and lactation in women with autoimmune and systemic
inflammatory diseases. Arthritis Care Res 2015; 67 (3): 313-25.
 Medications When Breast Feeding
LOW RISK NO DATA HIGH RISK

Azathioprine
Ciclosporin
Steroids Methorexate
Tacrolimus
Hydroxychloroquine Leflunomide
Rituximab
Aspirin Mycophenolate MMF
Belimumab
Heparin or LMWH Cyclophosphamide
Tofacitinib
IVIG Warfarin
Tocilizumab
TNF-inhibitors

Ramires de Jesus G, Mendoza-Pinto C, Ramires de Jesus N, et al. Understanding and Managing Pregnancy in Patients with
Lupus. Autoimmune Dis 2015; 2015: Article ID 943490. Kavanaugh A, Cush JJ, Ahmed MS, et al. Proceedings from the ACR
Reproductive Health Summit: The management of fertility, pregnancy and lactation in women with autoimmune and systemic
inflammatory diseases. Arthritis Care Res 2015; 67 (3): 313-25.
 Anti-Phospholipid Syndrome (APS)

NON CRITERIA FEATURES

Vascular
• Thrombocytopenia
Thrombosis • Hemolytic Anemia
• Livedo reticularis
• Cardiac valve vegetations
Pregnancy • Renal thrombotic
Morbidity microangiopathy
• Cognitive dysfunction
• Catastrophic APS (CAPS)
Anti-Phospholipid (aPL)
Antibodies
Lockshin MD. Anticoagulation in Management of Anti-Phospholipid Antibody Syndrome in Pregnancy. Clin Lab Med 2013;
33(2): 267-476. Asheron RA, et al. Catastrophic Antiphospholipid Syndrome: International Consensus Statement on
classification and treatment guidelines. Lupus 2003; 12 (7): 530-4.
2006 Sydney (modified Sapporo) Criteria

• Arterial thrombosis (e.g. stroke)

Vascular • Venous thrombosis (e.g. DVT, PTE)
Thrombosis • Small vessel occlusion

• >3 consecutive spontaneous abortions (REM)

<10 weeks
Pregnancy • >1 fetal death beyond 10 weeks
Morbidity • >1 premature birth <34 weeks due to severe
pre-eclampsia, eclampsia or placental
insufficiency

Anti-Phospholipid (aPL) • Positive Lupus anticoagulant (LAC)

Antibodies • Anti-Cardiolipin (aCL) IgM / IgG (> 40 GPU/ MPU)
Documented 12 weeks apart • Anti-2 Glycoprotein I (a2GPI) IgM/ IgG (>40 units)

Lockshin MD. Anticoagulation in Management of Anti-Phospholipid Antibody Syndrome in Pregnancy. Clin Lab Med 2013;
33(2): 267-476. Asheron RA, et al. Catastrophic Antiphospholipid Syndrome: International Consensus Statement on
classification and treatment guidelines. Lupus 2003; 12 (7): 530-4.
 Nuances of aPL Testing
Pregnancy Vascular
Anti-Phospholipid
Morbidity Thrombosis

Lupus anticoagulant (LAC)  

Anti-Cardiolipin (aCL)  
Anti-2 Glycoprotein I (a2GPI)  

OR Thrombosis OR Pregnancy Morbidity

59.6 LAC + aCL + 2GPI 34.3 LAC + aCL + 2GPI
42.3 LAC + a2GPI 5 aCL + a2GPI
11.4 LAC

Giannalopoulos B, et al. How we diagnose the antiphospholipid syndrome. Blood 2009; 113: 985-994
Lockshin MD. Anticoagulation in Management of Anti-Phospholipid Antibody Syndrome in Pregnancy. Clin Lab Med 2013;
33(2): 267-476. Asheron RA, et al. Catastrophic Antiphospholipid Syndrome: International Consensus Statement on
classification and treatment guidelines. Lupus 2003; 12 (7): 530-4.
 TREATMENT
THROMBOSIS
ARTERIAL EVENT
VENOUS EVENT Warfarin to target INR 3-4 OR
Warfarin to target INR 2-3 Target INR 1.5-2.5 and ASA 325
? Long term treatment mg/day
Indefinitely
PREGNANCY MORBIDITY
WITHOUT PRIOR THROMBOSIS
WITH PRIOR THROMBOSIS
Heparin 5000 u SC BID +
Heparin 10000 u SC BID
ASA 75-81mg/d
+ ASA 75-81-100mg/d
Conception to 6-12 weeks
Conception to Indefinitely
postpartum
NO PRIOR EVENTS
?? ASA 81mg/d for SLE Patients (both pregnant / non-pregnant)
Lim W. Antiphospholipid Syndrome. Hematology 2013; 675-80.
Lockshin MD. Anticoagulation in Management of APS in Pregnancy. Clin Lab Med 2013; 33(2): 367-376.
Lim W, Crowther MA, Eikelboom JW. Management of APAS: A Systematic Review. JAMA 2006; 295: 1050-57.
 SUMMARY
• Pregnant SLE patients are high risk
for having multiple adverse events

• Care of the pregnant SLE patient

should be a collaborative effort

• Care starts before conception until

the post partum period with specific
concerns needing to be addressed

• APAS may complicate lupus

pregnancies and is managed
differently from non-pregnant
patients