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Managing lupus in pregnancy

Adequate pregnancy management in lupus should include pre-conception counselling, coordinated medical–obstetric care, a well-defined management protocol and a good neonatal unit
Rebecca Fischer-Betz MD
Department of Rheumatology,
Düsseldorf, Germany
Systemic lupus erythematosus (SLE) is an autoimmune disorder primarily affecting women in their reproductive years, making the issue of pregnancy planning important to many patients. When compared with population controls, women with SLE are normally fertile. However, fertility may be impaired by anovulation during episodes of active disease or chronic renal failure or by administration of certain therapies such as cyclophosphamide. In fact, women with SLE have fewer children on average than women in the normal population.(1) Due to improvements in both long term prognosis and quality of life more patients with SLE can fulfil their desire to have children. Pregnancy though should be planned in a stable phase of the disease to avoid exacerbation and negative consequences in the course of pregnancy. 
SLE activity during pregnancy
The impact of pregnancy on SLE activity has been discussed in many studies. Today, it is generally agreed that SLE is more likely to flare during pregnancy in unselected women. The frequency of exacerbations varies with the state of lupus activity at conception. Patients with inactive lupus at least six months prior to conception are less likely to experience a flare and most flares during pregnancy are not severe. One factor that has unfavourable effects on the rate of flares is the discontinuation of antimalarial drugs. In pregnant women, there is evidence that Antimalarial drugs, particularly hydroxychloroquine (HCQ), decrease lupus activity without harming the baby.(2) Therefore, HCQ should be not discontinued when women wish to become pregnant, even when their disease is stable. Treatment is compatible with breastfeeding.
Course of pregnancy in women with SLE
Pregnancy outcome in SLE has improved in the past decades: the proportion of pregnancies resulting in live birth increased from 65% (in studies published before 1990) to more than 85% within recent publications.(3) However, the rate of prematurity increased during this time period from 19% to 24.5%.(3) A recently published population-based study showed ongoing significant differences in the risk of preterm birth (14.4% versus  8.5%), low birth weight (14.9% versus 7.2%) and small for gestation babies (28.5% versus 17.5%) for women with SLE compared with the general population.(4) In addition, women with SLE are at higher risks for medical complications during pregnancy. A national study in the US identified 13.555 deliveries among women with a diagnosis of SLE at discharge.(5) Compared with women without SLE, those with lupus were more likely to suffer from pre-gestational diabetes mellitus, hypertension, renal failure and thrombophilia (mainly anti-phospholipid syndrome). During pregnancy, preeclampsia occurred in 22.5% of women with SLE in contrast to 7.6% in the general population. The prevalence of medical complications such as stroke, pulmonary embolism, deep vein thrombosis, major infections, bleeding, and thrombocytopenia was also three-to-sevenfold higher. The rate of maternal mortality with SLE was 325/100 000 pregnancies (20-fold higher than for average women). 
Pregnancy therefore should be considered as a high-risk time period during the course of lupus disease, with a large number of potential complications that can influence the course of the disease as well as pregnancy outcome. There is general agreement that the frequency of pregnancy complications is higher in women with active lupus disease, lupus nephritis or hypertension. In addition, increasing doses of prednisone used to treat flares may contribute to complications. Concerning pre-eclampsia, the risk is also particular high for women with active lupus and with renal disease, but the strongest predictors are a previous pregnancy complicated by pre-eclampsia and the antiphospholipid syndrome.(6) 
Pregnancy in patients with lupus nephritis
Lupus nephritis is a clinical challenge, also during pregnancy. The rate of successful pregnancy outcomes with lupus nephritis (LN) varies and depends particularly on the renal function and the LN activity. Women with a serum creatinine level >2.5 mg/dl have a higher risk for pregnancy complications and worsening of renal function. A meta-analysis showed a significantly higher risk for preterm births, hypertension and preeclampsia in women with active LN.(7) The incidence of renal exacerbations seems to vary but patients with prolonged remission are at lowest risk.
Pregnancy should be ideally planned in patients with inactive LN for at least six months, proteinuria < 3g/day, normal renal function and normal blood pressure. This is also the time to evaluate the safety of the treatment received by the patient. Mycophenolate mofetil should not be used during pregnancy due to increases in both first trimester pregnancy loss and congenital malformations. Replacing Mycophenolate mofetil with azathioprine in patients with quiescent LN for pregnancy planning rarely leads to renal flares.(8) An ongoing therapy with azathioprine should be continued in order to maintain remission. The EULAR has recently published recommendations concerning pregnancy planning in patients with LN.(9) The administration of low dose aspirin is probably of benefit for patients with LN, because studies on non-SLE high risk pregnancies show that low-dose aspirin can decrease the risk for pre-eclampsia.
Antiphospholipid syndrome 
Antiphospholipid syndrome (APS) is characterised by thrombosis and adverse outcomes in pregnancy (recurrent miscarriage, preeclampsia, premature delivery and foetal death) in the presence of antiphospholipid antibodies (aPL) (Lupus anticoagulant, anticardiolipin and anti-beta(2) glycoprotein I antibodies). Between 30% and 50% of patients with SLE have aPL, and approximately one-third develop APS. It is generally accepted that patients carrying multiple positivity have a more severe disease and higher recurrence rate despite treatment. In addition, previous thromboembolic events are risk factors for pregnancy complications in aPL-positive women.(10) Several strategies have been proposed to prevent maternal thrombotic complications and improve the outcome of pregnancy in women with APS. Few well designed trials have been carried out in heterogeneous populations, so the level of evidence for all treatment options is low. The most important requirement is to identify patients at risk in order to bring more of those pregnancies to a successful conclusion.
A close surveillance, with monitoring of blood pressure, proteinuria, foetal growth and placental blood flow by Doppler studies helps the early diagnosis and treatment of complications such as preeclampsia and foetal distress. Drug therapy should be individualised and the different options discussed with the patient. Today, the recommendation for all women with aPL is treatment with low-dose aspirin (LDA), if possible before conception, in order to decrease the risk of miscarriage (and pre-eclampsia).(11) In patients with previous poor obstetric history, there is agreement in treating those with foetal (late) deaths with LDA plus low-dose heparin. Warfarin must be avoided if possible throughout the first trimester. In any case, adequate thromboprophylaxis is essential in all women with aPL four to six weeks post-partum.
Neonatal lupus
Neonatal lupus is a passively transferred autoimmune disease that occurs in some children born to mothers with anti-SSA(Ro)/SSB(La) antibodies. The clinical spectrum includes transient neonatal abnormalities affecting the skin, liver, and blood elements. The most serious complication is neonatal complete heart block (CHB). The prevalence of CHB in the offspring of anti-SSA/Ro-positive women is 1–2%. The overall rate of recurrence of cardiac NL is much higher (15–20%). 
CHB carries a substantial morbidity and mortality. Pacemakers are required in approximately 70% of these children. The cumulative probability of survival at ten years for a child born alive is 86%.(12) The mechanisms by which maternal autoantibodies damage foetal atrioventricular nodes have not been cleared. Standard therapy therefore is still matter of investigation. The clinical approach includes obstetric and rheumatologic management of the foetus identified with CHB, and the foetus with a normal heart beat but at high risk for developing CHB. At present, the only clear recommendation that can be made in these women is that in the presence of reliable positivity for anti-Ro/SSA antibodies, serial foetal echocardiograms should be performed, focusing on 16–24 weeks’ gestation. The goal is to detect early foetal cardiac abnormalities, that might precede complete CHB and that might be a target of preventive therapy with fluorinated corticosteroids. Routine prophylactic therapy with fluorinated steroids is not recommended even in women who previously had children with CHB or skin rash because this therapy has its own side-effects. Maternal use of HCQ may be associated with reduced rates of the cardiac manifestations: a retrospective evaluation of the Neonatal Lupus Registry showed that mothers of children with CHB had taken HCQ significantly less often (14% versus 37% of mothers with children without CHB).(13)
Table 1. Preconceptional visit checklist
  • Age?
  • Evidence of recent or current lupus activity?
  • Presence of severe irreversible damage?
  • History of pregnancy complications or thromboembolic events?
  • Current treatment: any ‘forbidden’ drugs?*
  • Positivity of Anti-Ro/SS-A/Anti-La/SSB antibodies?
  • Presence of antiphospholipid antibodies/syndrome?
  • Other chronic medical conditions? (hypertension, diabetes, etc.)
  • Recommend intake of folic acid 
*Including cyclophosphamide, methotrexate, mycophenolate, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, diuretics and statins.
During pregnancy: 
  • Monitoring at least once each trimester (or more often in women with active lupus)
  • Evidence of lupus activity?
  • Anti-Ro/SS-A /anti-La/SSB antibodies positive women: serial fetal echocardiography
  • Antiphospholipid antibody-positive women: foetal ultrasound/Doppler at least four-weekly from 16–20th gestation week
Adequate pregnancy management in SLE should include pre-conception counselling (Table 1), coordinated medical–obstetric care, an agreed and well-defined management protocol and a good neonatal unit. Particular attention should be given to women with prior history of poor obstetric outcome, renal involvement, evidence of active SLE and antiphospholipid antibodies/syndrome. Women with severe active disease or a high degree of irreversible damage, such as those with severe chronic renal failure, symptomatic pulmonary hypertension or severe restrictive pulmonary disease should best avoid pregnancy. It is widely accepted that the risk for flares is especially increased in women with active SLE in the months prior to pregnancy and in those who discontinue needed medication. The prognosis for both mother and child is best when SLE has been quiescent for at least six months prior to conception.
  1. Clowse ME et al. The effects of infertility, pregnancy loss, and patient concerns on family size of women with rheumatoid arthritis and systemic lupus erythematosus. Arthritis Care Res (Hoboken) 2012;64(5):668–74.
  2. Ruiz-Irastorza G et al. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis 2010;69:20–8.
  3. Yan Yuen S et al. Pregnancy outcome in systemic lupus erythematosus (SLE) is improving: Results from a case control study and literature review. Open Rheumatol J.2008;2: 89–98.
  4. Chen CY et al.  Increased risk of adverse pregnancy outcomes for hospitalisation of women with lupus during pregnancy: a nationwide population-based study. Clin Exp Rheumatol 2010;28:49–55.
  5. Clowse ME et al. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127:.e1–6.
  6. Chakravarty EF et al. Factors that predict prematurity and preeclampsia in pregnancies that are complicated by systemic lupus erythematosus. Am J Obstet Gynecol 2005;192(6):1897–904.
  7. Smyth A et al. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol 2010; 5(11):2060–8.
  8. Fischer-Betz R et al. Low risk of renal flares and negative outcomes in women with lupus nephritis conceiving after switching from mycophenolate mofetil to azathioprine. Rheumatology (Oxford) 2013;52(6):1070–6.
  9. Bertsias GK et al. Joint European League Against Rheumatism and European Renal Association-European Dialysis and Transplant Association (EULAR/ERA-EDTA) recommendations for the management of adult and paediatric lupus nephritis. Ann Rheum Dis 2012;71(11):1771–82.
  10. Ruffatti A et al. Laboratory and clinical features of pregnant women with antiphospholipid syndrome and neonatal outcome. Arthritis Care Res (Hoboken) 2010; 62(3): 302–7.
  11. Lockshin MD. Anticoagulation in management of antiphospholipid antibody syndrome in pregnancy. Clin Lab Med 2013;33(2):367–76. 
  12. Izmirly PM et al. Neonatal lupus syndromes. Rheum Dis Clin North Am 2007;33(2):267–85.
  13. Izmirly PM et al. Maternal use of hydroxychloroquine is associated with a reduced risk of recurrent anti-SSA/Ro-antibody-associated cardiac manifestations of neonatal lupus. Circulation 2012;126(1):76–82.