Epidemiology and Etiology

Systemic lupus erythematosus (SLE) is a chronic inflammatory and autoimmune disorder that can affect multiple organ systems, including the skin, joints, kidneys, central nervous system, heart, lungs, and liver.

SLE is more prevalent among women than men, and most women who are affected by the disease manifest it at some point during their reproductive years. Not infrequently, an initial diagnosis is made during the course of an evaluation for pregnancy complications or during pregnancy or the postpartum period. Significant racial differences are apparent in disease prevalence: black women have a prevalence of 405 per 100,000 compared with a prevalence of 164 per 100,000 among white women.

Genetic predisposition appears to be an important contributing factor to the development of SLE in that 5% to 12% of relatives of SLE patients also have the disease. The concordance for SLE is high (~25%) among monozygotic twins. Rare genetic factors such as deficiencies in complement components and mutations in the TREX1 gene, which encodes a DNA-degrading enzyme—as well as more common single nucleotide polymorphisms (SNPs) in the major histocompatibility complex (MHC)—are associated with the development of SLE. Although an individual may be genetically predisposed to develop SLE, the cause appears to be multifactorial. Studies have identified various exposures—such as to the Epstein-Barr virus, ultraviolet (UV) light, and silica dust—as having associations with SLE. Emerging research suggests that such exposures may mediate the development of SLE through epigenetic changes that cause sustained alterations in gene expression.

Consistent with the higher prevalence of SLE among women, hormonal factors appear to play an important role. Early menarche, oral contraceptives, and postmenopausal hormone replacement have all been associated with an increased risk for SLE.

Clinical Manifestations

The clinical course of SLE is characterized by periods of disease “flares” interspersed with periods of remission. The most common presenting symptoms of SLE include arthralgias, fatigue, malaise, weight change, Raynaud phenomenon, fever, photosensitive rash, and alopecia. Constitutional symptoms will be present in nearly all women at some point in their disease course. More than 90% of individuals with SLE will experience arthralgias, which are typically migratory and most commonly involve the proximal interphalangeal and metacar­pophalangeal joints, wrists, and knees. The arthralgias of SLE typically improve as the day progresses. Most patients also have skin manifestations at some point in the course of the disease, and the classic presentation is a malar “butterfly” rash that worsens with sun exposure. For women who present in the postpartum period, some SLE symptoms—such as fatigue and hair loss—may be easily overlooked. More severe but less common manifestations include discoid lupus (inflammatory skin lesions that result in scarring), lupus nephritis (LN), pleurisy, pericarditis, and seizures or psychosis.

Diagnosis

The American College of Rheumatology (ACR) has devised a set of diagnostic criteria for SLE. These criteria were most recently revised in 1997 ( Table 46-1 ) and are highly sensitive and specific for SLE. To be diagnosed with SLE, a patient must have at least four of the 11 clinical and laboratory criteria, either serially or simultaneously. It should be emphasized, however, that some women with features of SLE might not meet the strict diagnostic criteria but can still be at risk for pregnancy complications. These women may benefit from increased surveillance and even treatment.

Because nearly all individuals with SLE will have a positive antinuclear antibody (ANA) titer, this is a reasonable initial screening test for women with suggestive symptoms. If the ANA test is negative, a diagnosis of SLE is highly unlikely. However, an elevated ANA titer is not specific for SLE because it can also be seen in other autoimmune conditions such as Sjögren syndrome, scleroderma, and rheumatoid arthritis (RA). Anti–double-stranded DNA (anti-dsDNA) and anti-Smith (anti-Sm) antibodies are more highly specific for SLE, albeit less sensitive. Anti-dsDNA titers are frequently elevated in the setting of a disease flare, whereas Anti-Sm antibodies are detected in 30% to 40% of individuals with SLE and are associated with LN. Antiribonucleoprotein (anti-RNP) antibodies are associated with myositis and Raynaud phenomenon. Patients with either SLE or Sjögren syndrome may also have anti-Ro/SSA and anti-La/SSB antibodies, which are particularly relevant to the obstetric patient because of the association with neonatal lupus erythematosus (NLE) and congenital heart block (CHB).

Lupus Flare in Pregnancy

Studies on the risk of SLE flare in pregnancy have yielded inconsistent results. In the 1960s and 1970s, studies suggested a significant risk for disease flare in pregnancy with accompanying high rates of adverse maternal and fetal/neonatal outcomes. However, more recent studies indicate that pregnancy may not significantly increase the risk of an SLE flare. If flares do occur in pregnancy, they are generally not severe and are relatively easily treated. The best predictor of the course of SLE during gestation is the state of disease activity at the onset of pregnancy . In one study, approximately one third of women who were in remission for at least 6 months prior to pregnancy suffered an SLE flare compared with two thirds of women with active disease at the beginning of pregnancy. Thus women with SLE should be counseled to delay pregnancy until their disease has been in remission for at least 6 months.

The detection of SLE flare in pregnancy requires frequent clinical assessment and astute clinical judgment. Flares in pregnancy most commonly manifest as fatigue, joint pain, rash, and proteinuria. Assessing anti-dsDNA titers and complement (C3 and C4) levels may provide additional evidence of disease flares in women with clinical symptoms. The routine assessment of anti-dsDNA and complement levels in asymptomatic women is of doubtful clinical utility.

Lupus Nephritis in Pregnancy

Renal manifestations are present in approximately half of all patients with SLE. Although LN may be suspected based on hematuria, proteinuria, and casts on urinalysis, confirmation of the diagnosis requires a renal biopsy. According to the International Society of Nephrology and the Renal Pathology Society, six classes of LN have been defined, with the most common and severe form being class IV, or diffuse LN. All patients with active diffuse LN have proteinuria and hematuria, and a significant subset of patients will progress to nephrotic syndrome, hypertension, and renal insufficiency. Women with LN, particularly active disease, are at especially increased risk for adverse pregnancy outcomes that include hypertensive disorders of pregnancy, disease flares, low birthweight infants, and indicated preterm delivery. Similar to SLE in general, the activity of LN during pregnancy is related to disease status at conception. In one study, an LN flare was seen in only 9% of cases in which the disease was in remission for at least 5 months prior to pregnancy, compared with 66% of cases in which disease was clinically active at conception. Women with baseline renal insufficiency are at greatest risk. Ideally, assessment of baseline renal status—serum creatinine and urine protein excretion—is done prior to planning a pregnancy. If the patient is already pregnant, assessment as early as feasible in the pregnancy is recommended. As a general rule, a serum creatinine of 1.4 to 1.9 mg/dL (estimated glomerular filtration rate [EGFR] ~30 to 59 mL/min/1.73 m ² ) is a relative contraindication to pregnancy given the substantial risk of midterm pregnancy complications that might require preterm delivery. Most experts consider a serum creatinine of 2.0 mg/dL or greater (EGFR ~15 to 29 mL/min/1.73 m ² ) to be an absolute contraindication to pregnancy, again because of the substantial risk of pregnancy complications requiring extreme preterm birth (PTB) and the threat to long-term renal function. Women with moderate and especially severe baseline renal insufficiency should be counseled regarding the small (5% to 10%) but real risk of an irreversible decline in renal function during pregnancy.

Women with LN often have increasing proteinuria across gestation, related in part to increased glomerular filtration. However, an isolated increase in proteinuria without new-onset or worsening hypertension or a significant rise in serum creatinine should not be an indication for preterm delivery. Furthermore, the American College of Obstetricians and Gynecologists (ACOG) no longer considers proteinuria a necessary diagnostic criterion for preeclampsia.

Distinguishing between a flare in SLE (and LN) and preeclampsia can pose a clinical dilemma. Both entities can present with hypertension and proteinuria. If the pregnancy is at or near term, delivery may be the most prudent strategy. Preeclampsia should resolve after delivery. However, if the pregnancy is still very preterm, distinguishing between a disease flare and preeclampsia is more critical. A SLE flare can usually be treated, such as with corticosteroids, to prolong the pregnancy and optimize neonatal outcomes. Because elevated anti-dsDNA titers and low complement levels are often seen in active SLE, assessing them may aid in distinguishing between a disease flare and preeclampsia. However, it should be emphasized that hypocomplementemia can also be seen in preeclampsia. Examination of the urine sediment may also provide useful information because hematuria and cellular casts often accompany an LN flare but are not characteristic of preeclampsia. Renal biopsy may be considered in difficult cases but is usually avoided during pregnancy unless management of the pregnancy is incumbent upon the results.

Women with severe LN are often treated with mycophenolate mofetil (MMF), a significant teratogen that is contraindicated in pregnancy. MMF is typically replaced by azathioprine (AZA) when a pregnancy is planned or soon after conception in an unplanned pregnancy. In one study, preconceptional replacement of MMF with AZA among women with inactive disease did not lead to an increase in LN flares in the 3 to 6 months prior to a confirmed pregnancy.

Pregnancy Complications

Women with SLE do not appear to be less fertile than women without SLE, but they are at increased risk for multiple adverse pregnancy outcomes that include pregnancy loss, PTB, preeclampsia, and intrauterine growth restriction (IUGR).

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus is an acquired autoimmune condition related to the transplacental transfer of anti-Ro/SSA and anti-La/SSB antibodies. NLE most commonly presents as an erythematous, scaling, plaquelike rash that begins in the early neonatal period and may persist for 1 to 2 months. Less common manifestations of NLE include hematologic abnormalities (leukopenia, hemolytic anemia, thrombocytopenia) and hepatosplenomegaly. Fortunately, the incidence of NLE is low. Among all pregnant women with SLE, the risk of NLE is less than 5%. Of those women with SLE who test positive for anti-Ro/SSA and anti-La/SSB antibodies, at most 15% to 20% will have an affected newborn. Many mothers of newborns with NLE will not carry a current diagnosis of SLE. However, a significant number of these women will develop symptomatic autoimmune disease, often Sjögren syndrome, in the future. They should therefore be counseled to seek medical evaluation if symptoms of SLE or Sjögren syndrome develop.

The most serious manifestation of NLE is complete heart block. It is most frequently diagnosed at a routine prenatal visit when a fixed fetal bradycardia of 50 to 80 beats/min is detected. CHB is most commonly diagnosed between 16 and 24 weeks’ gestation, and it is rarely diagnosed in the third trimester. It is caused by the binding of antibodies to antigens in fetal cardiac tissue with subsequent damage to the cardiac conduction system and, ultimately, complete atrioventricular (AV) dissociation. Some cases progress to endocardial fibroelastosis, which can result in cardiac failure that leads to fetal hydrops and fetal death. Among women with anti-Ro/SSA and anti-La/SSB antibodies, the risk for CHB in the fetus is only 1% to 2%. However, women with a prior affected child have a recurrence risk for CHB of 15% to 20% in subsequent pregnancies. Fetal genetic factors, such as certain human leukocyte antigen (HLA) polymorphisms, may modify susceptibility to the development of CHB. Although many clinicians routinely test pregnant women with SLE for anti-Ro/SSA and anti-La/SSB antibodies, this practice is not without controversy given that CHB is infrequent, antenatal treatment to alter outcome is of uncertain efficacy, and a positive test result may cause unnecessary maternal anxiety.

Complete CHB is irreversible and is associated with an overall mortality rate of at least 20% (5% stillborn). The majority of survivors require a pacemaker. In one series of 102 cases, a prenatal diagnosis of CHB was associated with a 43% risk of mortality in the first two decades of life. Among a registry of 325 offspring with cardiac manifestations of NLE, predictors of a stillbirth or postnatal death included hydrops, endocardial fibroelastosis, earlier diagnosis, and a lower ventricular rate. In addition, the case fatality rate was significantly higher among minorities (32.1% for blacks compared with 14.3% for whites).

Management of Pregnancies Complicated by Systemic Lupus Erythematosus

Because SLE commonly affects women at some point during their reproductive years, the clinician should be familiar with the high-risk nature of these pregnancies and the altered management and increased surveillance required. Ideally, women with SLE would present for a preconceptional visit such that disease remission could be ensured, medications reviewed, and counseling performed.

Table 46-2 outlines recommendations for the management of pregnancies complicated by SLE. Key components include the assessment of disease activity and renal manifestations, surveillance for preeclampsia, surveillance of fetal growth, and antenatal testing. Co-management with a rheumatologist is particularly important for women with severe manifestations or active disease. Furthermore, some women experience a disease flare in the postpartum period; therefore the obstetrician should carefully assess disease activity at postpartum visits, and follow-up with rheumatology in the 1 to 3 months following delivery is usually recommended.

Management of Congenital Heart Block

Given that complete CHB is irreversible and that the prognosis is grave, efforts have focused on trying to predict and prevent the development of CHB. Some experts have proposed serial fetal echocardiograms with Doppler monitoring of the PR interval or kinetocardiography in women with anti-Ro/SSA and anti-La/SSB antibodies, particularly in those with a prior fetus affected by CHB. However, these practices are controversial, and no formal guidelines for the type and frequency of monitoring have been established. Neither fetal Doppler PR interval monitoring nor kinetocardiography have been associated with proven benefit, in part because progression to CHB can occur rapidly and without discernable progression through first- and second-degree block. In spite of this, many experts—including expert rheumatologists and pediatric cardiologists—recommend serial PR interval monitoring of the fetus in a woman with anti-SSA/Ro and anti-SSB/La antibodies. In our experience, the inclinations of the local pediatric cardiology team play a dominant role in deciding upon the nature and frequency of such monitoring.

Even with early detection of cardiac conduction abnormalities or new-onset CHB, no credible evidence suggests that medical interventions alter outcomes. Current treatment recommendations are based on expert opinion and relatively small studies, all nonrandomized. Several case series have described use of fluorinated steroids such as dexamethasone for the treatment of either cardiac conduction abnormalities or new-onset CHB. The PR Interval and Dexamethasone Evaluation (PRIDE) study enrolled 40 women with anti-Ro/SSA antibodies and a fetus with any degree of heart block diagnosed echocardiographically. Thirty women were treated with dexamethasone and 10 declined treatment. No cases of CHB reverted, treated or untreated. Among six treated fetuses with second-degree block, three remained in second-degree block, two reverted to normal sinus rhythm (NSR), and one progressed to complete block. Two treated fetuses had first-degree block, and both reverted to NSR after initiation of dexamethasone. However, the one untreated fetus with first-degree block was in NSR at birth. Although case selection in this nonrandomized study likely played a role, no perinatal deaths were reported in the nontreated group compared with deaths (20%) in the dexamethasone group. Treatment with steroids was associated with more preterm and SGA infants; the potential adverse effects of steroids must thus be weighed against the limited data that support a benefit in cases of early cardiac conduction abnormalities.

Although experts generally agree that steroid treatment should not be expected to reverse CHB, at least one group of investigators has concluded that steroid treatment might reverse or improve hydrops, reduce morbidity, and improve 1-year survival. Others disagree. In addition to steroid treatment, β-stimulation—such as with terbutaline, ritodrine, or salbutamol—has been administered in some cases of a very low fetal heart rate (<55 beats/min) in an attempt to increase the heart rate and prevent hydrops. Once again, data to support this treatment strategy are very limited. Table 46-3 outlines management strategies for CHB.

Strategies to prevent conduction abnormalities altogether would certainly seem attractive, and three preventive treatments have been considered. Glucocorticoids are not recommended as preventative treatment for women at high risk of CHB due to lack of proven benefit and because most fetuses will not develop CHB. Furthermore, chronic glucocorticoid therapy is associated with some maternal and fetal risks, including potential programming effects on offsprings’ hypothalamic-pituitary-adrenal axis and neurodevelopment (see Chapter 5 ).

Two multicenter prospective observational studies have evaluated intravenous immunoglobulin (IVIG) as a preventative agent. The two studies enrolled a total of 44 women at high risk for CHB. The results do not indicate that IVIG is effective at preventing the development of CHB, and it should not be used for this purpose outside of approved research protocols.

More recent data suggest a potential benefit of hydroxychloroquine (HCQ) in decreasing the risk of NLE cardiac complications among high-risk women. In a historic cohort of 257 pregnancies in women with anti-Ro/SSA antibodies and a previous child affected with CHB, HCQ use beginning in the first trimester was associated with significantly decreased odds of cardiac NLE (0.23; 95% confidence interval [CI], 0.06 to 0.92), defined as second- or third- degree block or isolated cardiomyopathy. Given the low risk for fetal harm (see the section on medications) and potential benefit, initiation of HCQ in the first trimester should be considered among women positive for anti-Ro/SSA antibodies who have had a prior affected child.

Drug Used to Treat Systemic Lupus Erythematosus and Pregnancy Considerations

It should be noted that as of June of 2015, the U.S. Food and Drug Administration (FDA) Pregnancy and Lactation Labeling Final Rule requires that the pregnancy safety letter categories of A, B, C, D, and X be removed from drug labels and replaced by a risk summary, clinical considerations, and available data. The goal of this change is to better assist health care providers in assessing the benefits versus risks of medications in pregnancy. This rule also requires that labels be updated when the information is outdated.