Managing Lupus in Pregnancy

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

1997 ACR Classification Criteria

• Malar rash

• Discoid rash

• Photosensitivity

• Oral ulcers

• Arthritis

• Serositis

• Renal disorder

• Neurologic disorder

• Hematologic disorder

• Immunologic disorder

• Anti-nuclear antibodies

SYSTEMIC LUPUS ERYTHEMATOSUS

• Chronic

Inflammatory

Autoimmune

Disorder

• Predominantly

affecting women in

their reproductive

years

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

• Acute cutaneous

• Chronic cutaneous

• Oral ulcers

• Non-scarring alopecia

• Synovitis

• Serositis

• Renal

• Neurologic

• Hemolytic anemia

• Leucopenia / Lymphopenia

• Thrombocytopenia

IMMUNOLOGIC

• ANA

• Anti-dsDNA

• Anti-Sm

• Anti-Phospholipid

• Low complement

• Direct Coomb’s test

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

43%

17%

0%

10%

20%

30%

40%

50%

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

Mortality Odds Ratio 20

Lupus

Flares Frequency

27-70%

Cesarean

Section Odds Ratio 1.7

Preterm

Labor Odds Ratio 2.4

Pre-

eclampsia Odds Ratio 3.0

Premature

Birth Frequency

39.4%

Abortion Frequency

16%

Stillbirth Frequency 3.6%

Neonatal

Death Frequency 2.5%

IUGR Odds Ratio 2.6

Neonatal

Lupus

Congenital

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


• 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

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

14%

32%

5%

37%

49%

5%

20%

49%

24%

2%

42%

54%

7%

12% 10% 10%

0%

6%

58%

0% 0%

Pre/eclampsia Abortion Neonatal

death

Preterm birth Live birth Maternal

death

Severe organ

damage

New onset SLE during pregnancy (n 41) Flare of SLE during pregnancy (n 41)

Stable SLE in preganancy (n 73)

Outcomes in Pregnant SLE Patients

Before Conception

1

2

3

4

Monitor organ involvement Target disease remission; Delay pregnancy if

high disease activity OR SLEDAI>8

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.

Check for autoantibody profile Determine anti-PL, anti-Ro/ La

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



Before Conception

1

2

3

4



Identify organ damage Look into contraindications to pregnancy




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

1

2

3

4



Identify organ damage Look into contraindications to pregnancy


Review treatment regimen Replace contraindicated meds with safer ones

Wait for 2-3 months on new regimen to ensure

disease control is maintained



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

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.

1

2

3

Monitor disease activity Differentiate symptoms of pregnancy vs SLE

Flares During Pregnancy

New onset lupus

during pregnancy

(n 41)

Flare of lupus

during pregnancy

(n 41)

Non pregnant

SLE patients

(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%)



WHAT causes these findings?

Facial flush / Melasma

Palmar erythema

Post partum hair loss

Photosensitive rash

Malar rash

Alopecia / lupoid hair

Arthralgias, Myalgias

Bland effusion of knees Synovitis

Fatigue

Mild edema

Pleuritis

Pericarditis

Fever (T>38oC)

Lymphadenopathy




WHAT causes these findings?

ESR 18-46mm/hr <20 weeks

30-70mm/hr >20 weeks

ESR Increased

Hgb >11 during 1st 20 weeks

Hgb >10.5 beyond 20 weeks

Hemoglobin <10.5

Mild thrombocytopenia in <8% Platelet <95,000

Proteinuria <300mg/24hours Proteinuria >300mg/24hours

Rare hematuria from vaginal

contamination

Hematuria or

cellular casts

Anti-dsDNA Negative or stable Anti-dsDNA Rising

Normal or increasing complement Low or >25%drop in complement




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

Seizure 8

Psychosis 8

Organic Brain syndrome 8

Visual disturbance 8

Cranial nerve disorder 8

Lupus Headache 8

CVA 8

Vasculitis 8

Arthritis 4

Myositis 4

Urinary casts 4

Hematuria 4

Feature Score

Proteinuria 4

Pyuria 4

Rash 2

Alopecia 2

Mucosal ulcers 2

Pleurisy 2

Pericarditis 2

Low complement 2

Anti-dsDNA increasing 2

Fever 1

Thrombocytopenia 1

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

• CBC with platelet count

• PT/ PTT

• Anti-Phospholipid Abs

• Anti-Ro/ La/ Sm

• Anti-dsDNA titers/ C3/ C4/ CH50

• Chemistry (include BUA)

• Urinalysis, 24 hour urine protein or urine protein/ creatinine ratio in a single sample

Quarterly Visits

• CBC with platelet count

• Anti-ds DNA titers/ C3/ C4/

CH50

• Chemistry (include BUA)

• Urinalysis, 24 hours urine

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.





1

2

3


Consider low-dose Aspirin To reduce risks of pre-eclampsia esp in those

with lupus nephritis

Up to 30% may develop pre-eclampsia

Risk factors for Pre-

eclampsia in SLE

• Pre-existing hypertension

• Anti-phospholipid

syndrome

• Obesity

• Anti-dsDNA

• Anti-RNP

• Low Complement


Consider low dose ASA (40-

160mg/d) before 16 weeks

AOG in high risk patients

• Preeclampsia (RR 0.6 95%

CI 0.27- 0.83)

• Severe preeclampsia (RR

0.3 95% CI 0.11-0.69)

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

lupus pregnancy. Autoimmune Dis 2014; 2014: ID 920467.





1

2

3


Consider low-dose Aspirin To reduce risks of pre-eclampsia esp in those

with lupus nephritis

Treat for APAS Will discuss later

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%

• Background rate for congenital

anomalies ranges from 1-5%

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.

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 CLASSIFICATION

A Studies in pregnant women failed to

demonstrate a risk to the fetus

B

No studies in pregnant women but animal

studies failed to show risk OR No studies in

pregnant women but animal studies show a

risk

C

No studies in pregnant women but animal

studies show an adverse event but benefits

outweigh risks in humans OR No studies in

humans and animals

D Evidence of fetal risk in humans but benefits

outweigh risks

X Evidence of fetal risk in humans or animals

and risks outweighs benefits

US FDA Pregnancy Categories: http://chemm.nlm.nih.gov/pregnancycategories.htm

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

Ciclosporin

Tacrolimus

Aspirin

Heparin or LMWH

IVIG

TNF-inhibitors*

Rituximab

Belimumab

Tofacitinib

Tocilizumab

Ustekinumab

Methorexate

Leflunomide

Mycophenolate MMF

Cyclophosphamide

Warfarin

* 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.


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

Steroids

Hydroxychloroquine

Aspirin

Heparin or LMWH

IVIG

Azathioprine

Ciclosporin

Tacrolimus

Rituximab

Belimumab

Tofacitinib

Tocilizumab

TNF-inhibitors

Methorexate

Leflunomide

Mycophenolate MMF

Cyclophosphamide

Warfarin


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


• Hemolytic Anemia

• Livedo reticularis

• Cardiac valve vegetations

• Renal thrombotic

microangiopathy

• Cognitive dysfunction

• Catastrophic APS (CAPS)

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.

Pregnancy

Morbidity

Vascular

Thrombosis

Anti-Phospholipid (aPL)

Antibodies

2006 Sydney (modified Sapporo) Criteria

Pregnancy

Morbidity

Vascular Thrombosis

• Arterial thrombosis (e.g. stroke)

• Venous thrombosis (e.g. DVT, PTE)

• Small vessel occlusion

• >3 consecutive spontaneous abortions (REM)

<10 weeks

• >1 fetal death beyond 10 weeks

• >1 premature birth <34 weeks due to severe

pre-eclampsia, eclampsia or placental

insufficiency

Anti-Phospholipid (aPL)

Antibodies

Documented 12 weeks apart

• Positive Lupus anticoagulant (LAC)

• Anti-Cardiolipin (aCL) IgM / IgG (> 40 GPU/ MPU)

• Anti-2 Glycoprotein I (a2GPI) IgM/ IgG (>40 units)




Nuances of aPL Testing

Anti-Phospholipid Pregnancy

Morbidity

Vascular

Thrombosis

Lupus anticoagulant (LAC)

Anti-Cardiolipin (aCL)

Anti-2 Glycoprotein I (a2GPI)

Giannalopoulos B, et al. How we diagnose the antiphospholipid syndrome. Blood 2009; 113: 985-994




59.6

42.3

11.4

OR Thrombosis

LAC + aCL + 2GPI

LAC + a2GPI

LAC

34.3

5

OR Pregnancy Morbidity

LAC + aCL + 2GPI

aCL + a2GPI

TREATMENT

THROMBOSIS

VENOUS EVENT

Warfarin to target INR 2-3

? Long term treatment

ARTERIAL EVENT

Warfarin to target INR 3-4 OR

Target INR 1.5-2.5 and ASA 325

mg/day

Indefinitely

PREGNANCY MORBIDITY

WITHOUT PRIOR THROMBOSIS

Heparin 5000 u SC BID +

ASA 75-81mg/d

Conception to 6-12 weeks

postpartum

WITH PRIOR THROMBOSIS

Heparin 10000 u SC BID

+ ASA 75-81-100mg/d

Conception to Indefinitely

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

Date post:	15-Feb-2017
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Managing Lupus in Pregnancy

Health & Medicine