Systemic Lupus Erythematosus, Part II: Treatment

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So how do we manage lupus in pregnancy? 

  • Medications 

    • Hydroxychloroquine

      • Can decrease disease activity, prednisone use, and adverse pregnancy outcomes.

      • SMFM: We recommend that all patients with SLE, other than those with quiescent disease, either continue or initiate HCQ in pregnancy. 

      • ACR: conditionally recommends starting HCQ in pregnant patients with SLE who are not on it.

      • Some investigators recommend that patients with quiescent disease who have anti-SSA, anti-SSB, or APLS to consider starting HCQ because some studies suggest improved maternal and fetal outcomes in this specific population.  

    • Corticosteroids 

      • Recommended where SLE is not controlled simply with HCQ 

      • Un-fluorinated corticosteroids are largely inactivated by the placenta and preferred:

        • Prednisone, hydrocortisone, prednisolone.

      • Recent evidence suggests corticosteroids are not associated with fetal malformations 

      • However, steroids use can increase risk of gestational diabetes, preeclampsia, FGR, PPROM and PTB 

    • Other immunosuppressive agents 

      • Azathioprine - ok to use, not usually associated with fetal teratogenicity 

      • Cyclosporine - can also be used for refractory lupus flares 

      • Tacrolimus - calcineurin inhibitor - can be used, and has been reported to be more effective than cyclosporine 

    • What should I avoid? 

      • Prolonged use of NSAIDs - can lead to oligohydramnios, increased risk of NEC, premature closure of ductus arteriosus, and pulmonary hypertension 

      • Methotrexate discontinue 1-3 months prior to pregnancy due to teratogenicity 

      • Mycophenolate discontinue at least 6 weeks before attempting pregnancy 

      • Leflunomide - teratogen, and pregnancy should be delayed 2 years after use because of its long half-life and enterohepatic circulation 

    • Biologics 

      • There have been a lot used recently, including TNF-alpha inhibitors (ie. certolizumab, infliximab, adalimumab, golimumab) and other biologics 

      • Certolizumab can be safely used throughout pregnancy 

      • Decision to initiate or continue biologics should be made in collaboration with rheumatology and also be individualized for each patient

What about antenatal considerations? 

  • APLS 

    • If someone has met clinical and laboratory criteria for APLS, goal is to improve maternal, fetal, and neonatal outcomes.

    • For those who have not had previous thrombotic event: recommend prophylactic anticoagulation during pregnancy + 6 weeks postpartum 

    • For those with history of thrombotic event: recommend therapeutic anticoagulation throughout pregnancy + 6 weeks postpartum 

  • Antiphospholipid antibodies without APLS 

    • Patients with antibodies, especially lupus anticoagulant, who don’t meet clinical criteria for APLS remain at risk for preeclampsia

      • The risk of other adverse pregnancy outcomes and optimal management remains unclear 

    • Meta-analysis of those with asymptomatic APL antibodies with or without SLE found no difference in adverse pregnancy outcomes in those who had prophylactic treatment (aspirin) and those who did not 

    • SMFM recommend treatment with low-dose aspirin alone (i.e., no prophylactic anticoagulation)

  • SSA, SSB antibodies 

    • Given risk of neonatal lupus syndrome with or without SLE in those with these antibodies, recommendation is to treat 

    • Treatment with HCQ throughout pregnancy has been proposed to decrease the occurrence of congenital heart block in at-risk fetuses 

      • However, data is still lacking due to adequately powered clinical trials 

    • Another method proposed is to screen for 1st and 2nd degree heart block with echocardiograms, and then use steroids to try and prevent 3rd degree heart block 

      • However, in the PR Interval and Dexamethasone Evaluation (PRIDE) study, they showed that treatment with dexamethasone in some women did reverse first degree heart block 

        • However, some first degree heart block resolved on its own 

        • Several cases of complete heart block occurred without a graded progression through 1st and 2nd degree heart block 

      • There is some retrospective data as well to look at this, but overall, the utility of screening for or treating early heart block remains unproven 

      • Current studies ongoing = STOP BLOQ (Surveillance and Treatment to Prevent Fetal AV Block Likely to Occur Quickly)

    • Current recommendation: steroids should not be used routinely for treatment of fetal heart block due to anti-SSA/SSB antibodies given their unproven benefits nad known risks 

    • Serial fetal echos for assessment of PR interval not be routinely performed in patients with anti-SSA or SSB antibodies outside of clinical trial settings 

    • Doppler assessment of fetal heart rate during routine prenatal visits can be used to screen for fetal complete heart block 

  • Mild lupus flares 

    • Clinical and lab evaluation of possible SLE flare 

      • Physical exam, CBC, anti-dsDNA, complement levels 

      • Start HCQ 200 mg BID, if not already on it 

      • If already on it, can increase to 400 mg 2x/day 

      • If not responding, then can start 15-20 mg of prednisone a day.

  • Severe lupus flares 

    • Same clinical and lab evaluation 

    • Can also look for preeclampsia 

    • Start glucocorticoid dosage 1.0-1.5 mg/kg, then tapered per improvement 

    • Hospitalization may be needed 

    • Rheumatology consultation 

Other recommendations in pregnancy and labor

  • Pre-pregnancy counseling 

    • Patients with SLE should get prepregnancy counseling with MFM and rheumatology - discuss risks for both mom and fetus 

    • In those with severe maternal risk, pregnancy should be discouraged 

      • Active nephritis

      • Severe pulmonary, cardiac, renal, or neurologic disease

      • Recent stroke

      • Pulmonary hypertension 

  • Antenatal Testing

    • Antenatal testing and serial growth scans recommended in patients with SLE due to increased risk of FGR and stillbirth 

      • Currently no evidence to support optimal approach 

      • Usually, will start interval growths at 28 and assess every 4 weeks 

      • Fetal surveillance may start at around 32 weeks 

  • Delivery considerations 

    • Timing, mode, and management of delivery should be individualized 

    • If uncomplicated, early delivery is not recommended, but can be considered at term - ie. at 39 weeks 

    • If other complications, should manage per complication

    • Stress dose steroids in those with prolonged use of steroids 

  • Postpartum management 

    • Incidence of relapse or flare will increase in SLE - as with other autoimmune disease 

    • Can discuss with rheumatology regarding treatment postpartum - not all patients will need prophylactic treatment 

    • NSAIDs can be used for joint pain  

    • Can breastfeed if desired (NSAIDs, HCQ, and corticosteroids are considered compatible by AAP) 

  • Contraception 

    • LARCs such as IUD (with or without levonorgestrel) and etonogestrel implants are good options for patients with SLE 

    • Estrogen-containing oral contraceptives pose a theoretical risk for SLE flares 

      • Can be used in patients with SLE 

      • However, patients with history of active and severe SLE were excluded from randomized trials proving estrogen safety in those with SLE 

      • Contraindicated in those with previous thrombosis or those with APLS  

    • Progesterone only contraception is also safe

Systemic Lupus Erythematosus, Part I: Diagnosis and Risks

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Reading: SMFM Consult Series #64: SLE in Pregnancy

What is systemic lupus erythematosus?

  • Definition

    • Chronic, multisystem, inflammatory autoimmune disease characterized by relapses and remission

    • Many organs can be involved and manifestations are variable between individuals

  • Why do we care about SLE in pregnancy?

    • The prevalence of SLE is about 28-150/100,000 individuals

    • More prevalent in females than males; often affects young adults, so it is a condition that can be encountered in pregnant individuals – currently 3300 deliveries per year are in people with SLE

How do we diagnose lupus?

  • Lupus = a syndrome and diagnosis requires presence of characteristic clinical features + confirmatory laboratory studies

    • Unfortunately, there are broad clinical manifestations, lack of pathognomic features or lab tests

    • Usually, you won’t have to diagnose lupus and someone will come into pregnancy already with the diagnosis

    • However, knowing the diagnostic criteria can be helpful in recognizing individuals who may have lupus

    • Can help the patient have faster recognition + referral to rheumatology

  • Diagnostic criteria – will include 2

    • From The European Alliance of Associations for Rheumatology (EULAR) – sensitivity of 96%, specificity is 93%

    • From the Systemic Lupus International Collaborating Clinics (SLICC) – sensitivity is 97%, specificity is 84%

smfm sTATEMENT ON sle; eular cRITERIA FOR sle

smfm; slicc criteria for sle

smfm; aplas criteria

Pregnancy and lupus

  • Increased maternal morbidity and mortality

    • Complications include nephritis, hematologic complications, neurologic abnormalities

    • Several fold increased risk of thrombosis, thrombocytopenia, infection, multiorgan disease

    • Pregnancy can also increase risk of disease flare, and 15-30% of flares are severe, and some can be life-threatening  

  • Lupus nephritis

    • Active renal disease is defined as >1g/day of proteinuria or GFR <60 in non-pregnant state

    • There is increased risk of permanent renal damage if GFR going into pregnancy is <40 or creatinine is >/= 1.5 mg/dL

    • One issue: difficult to differentiate lupus nephritis from preeclampsia

      • We discussed this in our episode “Imitators of Pre-eclampsia”

      • Features more common with lupus flare and less likely to be preeclampsia: increased anti-dsDNA ab, decreased levels of complements, usually will not have thrombocytopenia or elevated LFTs

      • Also, kidney biopsy that showed glomerulendotheliosis can yield a definitive diagnosis

      • Important to differentiate because the treatment for lupus nephritis can be medical, while severe preeclampsia may require delivery à if we don’t differentiate, could deliver extremely premature infant with no need

  • Hematologic Complications

  • Central Nervous System and Neurologic Complications

    • Can include headache, seizures, neuropathy, chorea, cerebritis, and even psychosis

    • CNS vasculitis is the most serious CNS disorder  

  • Other organ manifestation:

    • Cutaneous lupus erythematousus

    • Can also affect bones, joints, lungs, heart

  • So… how does all this affect pregnancy?

    • Obstetric outcomes:

      • 3x increased risk of pregnancy loss; however, if well controlled, risk ranges from 8-32%, which may not be substantially different from rates reported in the general obstetrical population for early pregnancy loss

      • Increased risk of preeclampsia: 15-35%

        • Risk is highest in those with active disease at time of conception, renal disease, chronic hypertension, those on high-dose prednisone, or those with APLS antibodies  

        • Prevention: low dose aspirin beginning at 12 weeks of gestation until delivery to decrease risk of preeclampsia

    • Fetal outcomes:

      • Risk of fetal growth restriction is 6-35% depending on the study

      • Increased risk of preterm birth, ranging from 19%-49%

        • The risk of preterm birth is associated with increased disease activity at time of conception, nephritis, chronic hypertension, and APLS antibodies

    • Neonatal complications 

      • Occurs in 1/20,000 live births, so it is rare but it is a serious complication

      • Caused by antibodies that can cross the placenta, usually anti-SSA, though anti-SSB antibodies can also cause this

      • Manifestations include skin lesions, congenital heart block, anemia, hepatitis, and thrombocytopenia

        • Skin lesions occur in approximately 50% of affected infants

      • Recurrence risk in patients with history of neonatal lupus and positive antibodies is 15-20% 

      • Because it is due to antibodies, skin, hematologic manifestations, and hepatitis usually resolves 3-6 months after birth; however, congenital heart block will not resolve as SSA antibodies lead to fibrosis of myocardial tissue and conduction system