Systemic Lupus Erythematosus and Pregnancy




Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong female predilection. Pregnancy remains a commonly encountered but high-risk situation in this setting. Both maternal and fetal mortality and morbidity are still significantly increased despite improvements in outcomes. Maternal morbidity includes higher risk of disease flares, preeclampsia and other pregnancy-related complications. Fetal issues include higher rates of preterm birth, intrauterine growth restriction, and neonatal lupus syndromes. Treatment options during pregnancy are also limited and maternal benefit has to be weighed against fetal risk. A coordinated approach, with close monitoring by a multidisciplinary team, is essential for optimal outcomes.


Key points








  • Outcomes for pregnancy in the setting of systemic lupus erythematosus have considerably improved but the maternal and fetal risks still remain high.



  • Disease flares, preeclampsia, pregnancy loss, preterm births, intrauterine growth restriction, and neonatal lupus syndromes (especially heart block) remain the main complications.



  • Specific monitoring and treatment protocols need to be used for situations such as presence of specific antibodies (antiphospholipid antibodies and anti-Ro/La).



  • Safe and effective treatment options exist and should be used as appropriate to control disease activity during pregnancy.



  • Close monitoring, tailored multidisciplinary care, and judicious use of medications are the key to achieve optimal outcomes.






Introduction


Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a strong female predilection. Disease onset in a younger age group, coupled with improved survival, makes pregnancy a likely occurrence in the setting of SLE. Although outcomes have improved over time and successful live births can now be achieved in most cases, pregnancy still remains a high-risk situation in SLE. Both maternal and fetal mortality and morbidity are significantly increased, along with health care utilization and costs. A multidisciplinary coordinated approach with involvement of appropriate specialists and close monitoring is essential for optimal outcomes. This article discusses major issues and the management principles to guide clinicians caring for pregnant women with SLE.




Introduction


Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a strong female predilection. Disease onset in a younger age group, coupled with improved survival, makes pregnancy a likely occurrence in the setting of SLE. Although outcomes have improved over time and successful live births can now be achieved in most cases, pregnancy still remains a high-risk situation in SLE. Both maternal and fetal mortality and morbidity are significantly increased, along with health care utilization and costs. A multidisciplinary coordinated approach with involvement of appropriate specialists and close monitoring is essential for optimal outcomes. This article discusses major issues and the management principles to guide clinicians caring for pregnant women with SLE.




Effects of pregnancy on systemic lupus erythematosus disease activity


Although opinions differ, most studies have shown that risk of SLE flare is higher during pregnancy. Variable flare rates of between 25% to 65% have been reported, likely attributable to different study designs, patient populations, and assessment tools being used. Multiple predictors for flares have been identified, including disease activity at the time of conception, lupus nephritis, and discontinuation of medications such as hydroxychloroquine (HCQ). Most of these flares are mild to moderate in severity and involve renal, musculoskeletal, and hematological systems. Recognition and management of the flares during pregnancy can be challenging because features may be altered and therapeutic options limited.


Recognition of Disease Activity During Pregnancy


Recognition of disease activity and flare in pregnancy can be difficult because physiologic changes of pregnancy may overlap with features of active disease ( Table 1 ). Investigations have to be interpreted with caution: mild degrees of anemia, thrombocytopenia, proteinuria, and increased erythrocyte sedimentation rate are common during pregnancy. Complement levels become less informative with the increase in levels during normal pregnancy. The trend becomes more important, and decline in levels of complement during pregnancy has been associated with poor pregnancy outcomes. The use of SLE disease activity indices faces similar issues, because physiologic pregnancy changes were not accounted for in these tools. Pregnancy-specific disease activity scales have been developed but utility remains limited. The clinical judgment of an experienced physician may the best tool to evaluate disease activity in some scenarios.



Table 1

Overlapping features of pregnancy and systemic lupus erythematosus






















Pregnancy Changes SLE Activity
Clinical Features Facial flush
Palmar erythema
Arthralgias
Fatigue
Mild edema
Mild resting dyspnea
Photosensitive rash
Oral or nasal ulcers
Inflammatory arthritis
Fatigue, lethargy
Moderate to severe edema
Pleuritis
Laboratory Features Mild anemia
Mild thrombocytopenia
Immune hemolytic anemia
Thrombocytopenia
Leukopenia, lymphopenia
Mildly increased ESR Increased inflammatory marker levels
Physiologic proteinuria <300 mg/d Proteinuria >300 mg/d
Active urinary sediment

Abbreviation: ESR, erythrocyte sedimentation rate.


Management of Disease Activity Pregnancy


Treatment of disease activity and flares during pregnancy requires the use of medications that are effective but safe for the growing fetus. However, patients and sometimes even physicians discontinue medications because of concerns over presumed toxicity, resulting in avoidable disease flares and associated consequences. The fear is compounded by lack of information because the data on safety of drugs during pregnancy are generally limited to registries, case reports, or animal studies. However, although choices are limited and maternal benefit has to be weighed against fetal toxicity, multiple effective options exist and should be used ( Table 2 ).



Table 2

Immunosuppressant use during systemic lupus erythematosus pregnancy
















Drugs Comments



  • Corticosteroids




    • Prednisolone/pulse methyl prednisolone



    • Fluorinated compounds (betamethasone/dexamethasone)


Use lowest possible dose
Higher doses can lead to maternal complications
Pulse therapy can be used for acute flares
Limit to 1 course, for fetal lung maturation
Repeated use associated with impaired neuropsychological development of the child



  • Antimalarials




    • Hydroxychloroquine


Reduced risk of disease flares, CHB, and NLS
Should be continued in all SLE pregnancies



  • Immunosuppressants




    • Azathioprine



    • Calcineurin inhibitors (cyclosporine/tacrolimus)


Limit azathioprine dose to 2 mg/kg/d

Abbreviations: CHB, complete heart block; NLS, neonatal lupus syndromes.


Steroids can be continued during pregnancy for optimal disease control but attempts should be made to minimize the exposure. High doses of steroids are associated with an increased risk of diabetes, hypertension, preeclampsia, and premature rupture of membranes, but short-term use for flares and disease control is permissible. Similarly, use of fluorinated compounds, such as dexamethasone and betamethasone, should be limited to single courses for fetal lung maturity in cases of premature delivery. Repeated use should be avoided in view of association with impaired neuropsychological development of the offspring in later life.


HCQ has multiple proven benefits in SLE and continued use throughout pregnancy is strongly recommended. Pregnancy-specific benefits include reduction in disease activity, lower risk of flares, and reduced risk of heart block in at-risk pregnancies. HCQ discontinuation was shown to increase disease flares during pregnancy and should be discouraged.


Commonly used immunosuppressive agents, such as cyclophosphamide, methotrexate, and mycophenolate, have teratogenic potential and ideally should be discontinued before conception. Safe immunosuppressants for pregnancy use include azathioprine and the calcineurin inhibitors, tacrolimus and cyclosporine. Multiple studies have shown them to be safe and effective therapies for use during pregnancy. An association between maternal azathioprine therapy and late developmental delays (specifically, increased use of special education services) in offspring was suggested by 1 study but remains to be confirmed. Some risk of fetal cytopenias and immune suppression has been reported with higher doses and it is recommended to limit the dose to a maximum of 2 mg/kg/d. Although safety of inadvertent exposure to leflunomide (usually followed by cholestyramine washout) has been reported, data are limited. It should be discontinued before pregnancy with consideration of washout procedure. Use of biologic drugs during pregnancy is increasing but is still limited to anti–tumor necrosis factor agents, which are not an option for SLE. Data on other biologic agents, such as rituximab and belimumab, are very limited, and use should be limited to situations in which no other pregnancy-safe option is viable. Intravenous immunoglobulin (IVIG) and plasmapheresis remain alternative options in selected situations.




Effect of systemic lupus erythematosus on pregnancy outcomes


The interaction of SLE, an immune-mediated disease, and immunologic adaptations of pregnancy lead to unique challenges in this setting. Both mother and baby are at high risk of adverse pregnancy outcomes (APOs), including preeclampsia, preterm delivery, pregnancy loss, and intrauterine growth restriction (IUGR). The predictors of APO include active maternal disease, nephritis, proteinuria, hypertension, thrombocytopenia, and presence of antiphospholipid antibodies (aPLs), especially lupus anticoagulant. Ethnic differences have also been reported, likely reflective of racial differences in disease and access to health care.


Pregnancy loss has declined significantly over the decades and live birth rates of 80% to 90% have been reported. Preterm births are now the most frequent problem, occurring in up to half of the pregnancies with poor prognostic markers listed earlier. In addition, thyroid disease is associated with preterm birth in SLE pregnancy.


Higher rates of maternal death, thrombosis, infection, and hematologic complications during SLE pregnancy have been reported, although nonpregnant patients with SLE also have higher risks of these medical complications and mortality. Neurodevelopmental disorders in offspring of mothers with SLE represent an emerging concern that requires further study.


Preeclampsia in Systemic Lupus Erythematosus Pregnancy


Preeclampsia affects 16% to 30% of SLE pregnancies compared with 5% to 7% in healthy women. In addition to the general predisposing factors (advanced maternal age, previous personal or family history of preeclampsia, preexisting hypertension or diabetes mellitus, obesity), SLE-specific predictors for preeclampsia include active or history of lupus nephritis, presence of aPLs, thrombocytopenia, declining complement levels, and mutations in complement regulatory proteins.


The high risk of preeclampsia in SLE pregnancy is compounded by the difficulty in differentiating it from lupus nephritis. Both conditions can manifest with increasing proteinuria, deteriorating renal function, hypertension, and thrombocytopenia, and can even coexist. Guidelines and biomarkers have been proposed but have limited utility. Ultrasonography findings such as abnormal uterine artery waveforms have shown good utility as diagnostic tools, and predictive modeling has been attempted for early recognition. However, all these measures have limitations and differentiation may be extremely difficult. Renal biopsy could guide management in selected cases and is safe in experienced hands. However, at times, delivery of the baby may be the only definitive answer.




Management guidelines for pregnancy in systemic lupus erythematosus


Ideally, pregnancy should be timed during a period of disease quiescence because active disease at the time of conception is known to be one of the strongest predictors of APO. However, unplanned pregnancies are common, highlighting the often neglected need for contraceptive counseling in this group of women. Effective contraceptive choices include combined oral contraceptives in women with stable disease and negative aPL, progesterone-only contraceptives, and intrauterine devices, whereas barrier methods are ineffective, with high failure rate (see Lisa R. Sammaritano’s article, “ Contraception in Rheumatic Disease Patients ,” in this issue). Caution is required when making decisions regarding contraception in women with aPL and active disease in view of limited data.


Pregnancy may carry a very high maternal risk in a subset of patients with SLE, and should be avoided in these women ( Box 1 ). However, successful pregnancy is possible for most women with SLE, albeit with a higher risk. Prepregnancy evaluation with assessment of autoantibody profile, end-organ function, disease activity, and medication use helps to risk stratify, identify optimal timing, and plan the management strategy for each pregnancy ( Fig. 1 ).



Box 1


Avoid pregnancy if:




  • Severe pulmonary hypertension (systolic pulmonary artery pressure >50 mm Hg)



  • Severe restrictive lung disease (forced vital capacity <1 L)



  • Advanced renal insufficiency (creatinine level >2.8 mg/dL)



  • Advance heart failure



  • Previous severe preeclampsia or HELLP (hemolysis, elevated liver enzyme levels, low platelet count) despite therapy



  • Stroke within the previous 6 months



  • Severe disease flare within last 6 months


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Sep 28, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Systemic Lupus Erythematosus and Pregnancy

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