Systemic Lupus Erythematosus
1. What every clinician should know
Clinical features and incidence
Systemic lupus erythematosis (SLE) is an immunologic disorder affecting primarily women, with a female:male ratio in adults of approximately 10:1.The prevalence is approximately 1 in 300 reproductive age women, and as such is encountered on occasion among pregnant patients. It is also more prevalent in African-Americans and Hispanic Americans than in Caucasians.
The variable clinical course often involves periods of remission and relapse. The most common symptom of patients diagnosed with SLE is arthralgia, but almost any organ system can be affected. Patients with more severe disease can have hematologic, renal and pulmonary involvement, which can cause significant morbidity and even mortality. Severe disease can result in permanent organ injury, including restrictive lung disease, pulmonary hypertension, heart failure and renal failure. Pregnancy in individuals with any of these complications or with severe uncontrolled disease will have an increased risk of pregnancy loss and maternal mortality.
Onset of symptoms is usually during the reproductive years, and the diagnosis should be considered for patients with arthralgias, Raynaud phenomenon, or the presence of unexplained persistent proteinuria, casts or hematuria. In the absence of hypertension or renal involvement, the prognosis for pregnancy is good. Better pregnancy outcomes also are more likely if the disease has been in remission or well controlled for the 6 months prior to conception. As such, preconception counseling for patients with lupus should include the recommendation to avoid pregnancy until the disease has been quiescent for at least 6 months.
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Medications should be reviewed for their teratogenic potential, but many medications used to control lupus should not be stopped before or during pregnancy, as the benefits of disease control often outweigh the theoretical concerns. Most recent data suggest that the incidence of lupus flares is not increased during pregnancy.
Clinicians encounter two situations related to SLE in pregnancy: (1) management of the patient with the diagnosis prior to pregnancy; and (2) considering the diagnosis in patients who develop suggestive symptoms. These two situations are reviewed.
2. Diagnosis and differential diagnosis
Establishing the diagnosis
The diagnosis of SLE is made based on a combination of clinical and laboratory findings. More common scenarios where lupus needs to be considered in the pregnant or postpartum patient include onset of the characteristic malar rash, arthralgias, pleurisy, pericarditis, persistent unexplained fever or nephritis, as these could represent the initial lupus flare. Initial screening for lupus should include testing for anti-nuclear antibodies. A positive ANA test is suggestive of the presence of a connective tissue disease, with anti-double stranded DNA being more specific for SLE.
To make the diagnosis of lupus, the patient should have multiple criteria listed in Table I, but no single symptom or laboratory test is necessary for the diagnosis. A positive ANA alone is not diagnostic for SLE, as many women will have a low titer (e.g. 1:40) without other criteria of the disorder. Serum complement levels (C 3 and C 4) are usually reduced during a flare, and this can sometimes be helpful in confirming the diagnosis.
Table I.
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Malar rashDiscoid rashPhoto sensitivity rashOral lesionsJoint pain and swelling (2 or more)Pericarditis or pleurisyKidney diseaseSeizures, psychosisAnemia, leucopenia or thrombocytopeniaPositive test for anti-nuclear antibodiesOther tests for auto-antibodies(anti-phospholipid antibodies, falsepositive RPR, anti-double stranded DNA antibodies, anti-Smith antibodies |
Differential diagnosis
Other conditions need to be considered based on the symptomatology that the patient presents with. Unexplained fever is often a sign of infection, and the causes of anemia, leukopenia and thrombocytopenia can be other autoimmune conditions or hematologic disorders. Nephritis can have a number of other etiologies, and a renal biopsy may be helpful in identifying a characteristic histologic lesion for lupus. Joint pain related to rheumatoid arthritis will usually be accompanied by a positive test for the rheumatoid factor. Rheumatology consult is often helpful in confirming a diagnosis of lupus and establishing a plan of care and long term followup.
In a patient known to have lupus, it is sometimes difficult to differentiate a lupus flare during pregnancy from the onset of superimposed severe preeclampsia. A patient with SLE can present with blood pressure exacerbation and onset of or a significant increase in proteinuria in the third trimester. Serum complement levels can be reduced in both situations, although normal complement levels and absence of red cells or casts in the urine would suggest preeclampsia. Reduced platelet count can also be seen with both, but the presence of hemolysis and elevated liver enzymes are probably a sign of HELLP syndrome accompanying severe preeclampsia.
If the patient is stable, a trial of steroids could be attempted and improvement of the maternal condition would then favor lupus flare and allow the pregnancy to continue. However, most of these situations are ultimately shown to be severe preeclampsia, and delivery is usually necessary to prevent further maternal and fetal deterioration.
Diagnostic criteria for systemic lupus
The diagnosis of SLE has always been and continues to be based on the clinical judgment of the practitioner. The diagnostic criteria of the American College of Rheumatology were originally derived for the purpose of standardizing research definitions and have never been formally validated for clinical use. It is recognized that the disease changes over time, such that four criteria may not yet be present when the disease is first suspected. As such, the diagnosis can be made even if four criteria are not present; however, more than serologic findings need to be present. It is also recognized that certain individual criteria are more prevalent in some races and ethnicities, and variation is also seen in different parts of the world.
3. Management
Antepartum
Initial evaluation
For the patient with lupus who becomes pregnant, the initial evaluation should be focused on determining the status of her condition. The history should include determining what symptoms led to the diagnosis and any other organ systems that have been identified as being affected. The patient’s current symptomatology and disease activity for the 6 months prior to conception should be reviewed, as well as any medications currently being used to control the disease.
Physical examination should include blood pressure assessment for hypertension and a search for rashes and swollen or tender joints. Laboratory evaluation should include urinalysis looking for protein, red cells and casts, serum creatinine to assess renal function, CBC to look for anemia and thrombocytopenia, and anti-DNA antibodies and complement levels to assess current disease activity and as a baseline for future comparisons.
Testing for anti-SSa and anti-SSb (also known as anti-Ro and anti-La) should be performed as well. These auto-antibodies are present in 10% or more of patients with lupus and can cross the placenta into the fetal circulation. In 3% of patients with these antibodies, the fetus will develop congenital heart block, so further evaluation and monitoring of the fetal condition will be necessary. Lupus anticoagulant and anti-cardiolipin also are more commonly identified in patients with lupus and have been associated with adverse pregnancy outcome.
However, the incidental finding of these antibodies in a patient does not warrant treatment, so testing should be reserved for patients with a history of thrombosis or a prior unexplained adverse pregnancy outcome, such as fetal death or early severe preeclampsia. Alternatively, some experts argue that patients identified with anti-phospholipid antibodies could benefit from closer surveillance.
Medications
Hydroxychloroquine is a commonly used medication to suppress disease activity and should be continued in pregnancy. This medication has not been associated with congenital anomalies in humans and any theoretical risk is outweighed by the benefit of disease control. Similarly, oral steroids such as prednisone can be continued in pregnancy if needed to control disease activity, but should be maintained at the lowest dose necessary to control symptoms because of potential side effects. Conversely, non-steroidal anti-inflammatory prostaglandin inhibitors such as ibuprofen for symptom control are best avoided in pregnancy because of potential effects on the fetal kidneys, ductus arteriosus and amniotic fluid volume.
In addition, ACE inhibitors used to control hypertension have been associated with congenital anomalies with first trimester use and should be replaced with other medications for blood pressure control, such as calcium channel blockers. Clinical trials have not been performed to evaluate any benefit of routinely recommending the use of low dose aspirin for patients with lupus during pregnancy in the absence of anti-phospholipid antibodies. Some observational studies have noted an association between low dose aspirin use and improved pregnancy outcomes in patients with more severe disease.
Medications sometimes used for patients with difficult to control disease include cyclophosphamide, methotrexate, cyclosporin and azathiaprine. Methotrexate is contraindicated in pregnancy and carries the FDA category X label. Cyclophosphamide is also thought to cause birth defects or fetal loss, although use in late pregnancy may be safer. Cyclosporin and azathiaprine have some concern for adverse effects on fetal growth and development, but most pregnancies appear unaffected by exposure to these medications.
Consideration can be given to stopping these medications prior to pregnancy, but restarting them after the first trimester if the disease cannot be controlled with other more accepted agents, as the benefits of disease control may still outweigh the risks of fetal exposure to these medications.
Other issues
For patients identified with anti-SSa or anti-SSb, monitoring of the fetal cardiac status is important. This should begin around 16 weeks gestation. This is the gestational age when IgG antibodies are first able to cross the placenta and continue until delivery. Some experts recommend frequent fetal echocardiograms to identify rhythm abnormalities that precede bradycardia, but without proven interventions to prevent progression this expensive testing is of unproven value. Auscultation of the fetal heart rate on an every other week basis should be sufficient to detect developing fetal bradycardia. If bradycardia does develop, referral to a pediatric cardiologist may then be helpful in planning appropriate surveillance of cardiac function until delivery.
Subsequent antepartum prenatal visits should include a review of the patient’s symptoms to evaluate for signs of a flare in disease activity. Urine should also be evaluated for the presence of protein and blood. Some signs and symptoms of lupus flare are seen commonly in normal pregnancy, including joint pains, fatigue, skin discoloration, drop in platelet count and swelling. In the second half of pregnancy, attention also should be paid to signs of developing hypertension or lagging fetal growth. If a flare in disease activity does occur, collaboration with the patient’s rheumatologist is important for starting or increasing current medication dosing sufficient to control the flare.
Patients may benefit from more frequent visits in the last trimester for the earlier diagnosis of preeclampsia. Data do not exist as to whether fetal surveillance improves outcome in patients with well controlled disease and appropriate fetal growth, so decisions regarding surveillance should be individualized based on the severity of the maternal condition and the assessment of fetal growth. Delivery prior to term should be reserved for routine obstetric indications such as worsening preeclampsia or deteriorating fetal condition.
Intrapartum
In most instances, management of the patient with lupus during labor should not be altered. However, for those patients who have received oral corticosteroids for disease management, stress dose steroids are usually recommended. Cesarean delivery should be reserved for the usual obstetric indications. The exception may be the fetus with congenital heart block and baseline bradycardia where interpretation of electronic fetal monitoring during labor is not feasible.
Postpartum
There are data to suggest that there is an increase in lupus flares soon after pregnancy, but the precise risk is not known. Some physicians have routinely recommended a course of steroids for all patients with lupus after delivery in an effort to prevent flares, but studies evaluating the benefit of such prophylaxis are inconsistent. As such, routine steroid administration to prevent a flare is not recommended. However, patients should report increasing signs and symptoms of a flare, so that treatment can be initiated early to control disease activity. Most medications used to control disease activity, including hydroxychloroquine and prednisone, are compatible with nursing, so most patients can be encouraged to breast feed.
Fetal congenital heart block
Congenital heart block related to anti-SSA and anti-SSB has potential for significant morbidity and mortality. It can be accompanied by endocardial fibroelastosis, pericardial effusion and the development of hydrops fetalis. There is an increased risk of intrauterine and neonatal death, and pacemaker placement soon after birth may be necessary. Small series have suggested a benefit of steroid therapy in this situation, but others have suggested no improvement in the condition after the heart block has progressed to bradycardia.
A recent study has suggested some ability to detect early cardiac rhythm changes with weekly fetal echocardiography, when these changes are still reversible with steroids, but very few affected fetuses in this series were identified in this manner, and most infants who developed heart block did not have rhythm abnormalities noted beforehand. As such, this type of monitoring is not standard and treatment with steroids is not of proven efficacy for the prevention of congenital heart block.
4. Complications
Complications due to the condition
The main pregnancy complications seen more frequently in patients with lupus include preeclampsia, preterm birth, intrauterine growth restriction, and fetal loss. Low dose aspirin is generally thought to be of little risk and of benefit in reducing the incidence and consequences of preeclampsia in other high risk situations, but has not been formally evaluated for patients with lupus.
Complications due to management
The primary concerns for the medications used to control lupus in pregnancy relate to congenital anomalies and effects on fetal growth. Nonetheless, the importance of disease control during pregnancy argues for the use of agents needed for disease suppression. Attention should then be focused on the identification of anomalies with mid-trimester ultrasound and assessment of fetal growth in the third trimester.
5. Prognosis and outcome
Maternal and fetal/neonatal outcomes
Overall, most patients can be reassured that the prognosis for pregnancy is good. However, patients with SLE may be at increased risk for developing preeclampsia and fetal growth restriction. These risks are increased if the patient has renal involvement with or without hypertension. The risk of lupus flare is also increased in pregnancy if the disease has not been well controlled for at least 6 months prior to conception. In general, patients should not stop the medications used to suppress or control disease activity. Pregnancy in patients with uncontrolled disease involving major organs, or with significantly compromised pulmonary, cardiac or renal function have a much higher risk of pregnancy complications, perinatal loss and maternal mortality.
Long term health impact
For most patients with lupus, pregnancy should not affect the long term course of their disease, and as such pregnancy should not be discouraged. However, patients with renal impairment can see further deterioration in kidney function that most likely will not return to baseline after the pregnancy.
6. What is the evidence for specific management and treatment recommendations
Pons-Estel, GJ, Alarcon, GS, Scofield, L, Reinlib, L, Cooper, GS. “Understanding the epidemiology and progression of systemic lupus erythematosus”. Semin Arthritis Rheum. vol. 39. 2010. pp. 257
Tan, EM, Cohen, AS, Fries, JF. “The 1982 revised criteria for the classification of systemic lupus erythematosus”. Arthritis Rheum. vol. 25. 1982. pp. 1271
Hochberg, MC. “Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus”. Arthritis Rheum. vol. 40. 1997. pp. 1725(Most recent classification criteria.)
Petri, M. “Review of classification criteria for systemic lupus erythematosus”. Rheum Dis Clin N Am. vol. 31. 2005. pp. 245-54. (Describes strengths and weaknesses of the classification criteria for diagnosing SLE.)
Ramsey-Goldman, R, Schilling, E. “Immunosuppressive drug use during pregnancy”. Rheum Dis Clin N Am. vol. 23. 1997. pp. 149-67.
Friedman, DM, Kim, MY, Copel, JA. “Utility of cardiac monitoring in fetuses at risk for congenital heart block: the PR interval and dexamethasone evaluation (PRIDE) prospective study”. Circulation. vol. 17. 2008. pp. 485(Large trial of fetal echocardiography for the prediction and prevention of fetal heart block.)
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