Collagen Vascular Diseases in Pregnancy

Lupus Flare and Pregnancy

Historically, pregnancy was thought to increase the risk of SLE flare, and some recent evidence suggests that a woman's first pregnancy may be associated with increased risk of flare. Contemporary studies, however, have found that overall women with well-controlled disease will likely have a successful pregnancy and have raised the question whether pregnancy increases the likelihood of lupus flare . Outcomes in the recently completed Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (PROMISSE) study were reassuring. This large, prospective observational study of over 700 pregnant women with SLE, antiphospholipid antibodies (aPLs), and controls found that mild or moderate flares occurred in fewer than 15% of patients with SLE and that severe lupus flares occurred in only 3% of second trimester patients and 3% of third trimester patients. The authors acknowledged that these rather sanguine outcomes may be due to the study enrolling only patients with mild-to-moderate SLE and normal or near-normal renal function.

The best predictor of the course of SLE during gestation is the state of disease activity at the onset of pregnancy , and flare manifestations in pregnancy tend to reflect prior organ involvement. Active lupus within 6 months of conception is associated with a fourfold increase in pregnancy loss and 58% risk for flare (vs. 8% in women without significant lupus activity). 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. 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 limited utility.

Lupus Nephritis and Pregnancy

Renal manifestations ultimately are present in approximately half of all patients with SLE. Although LN may be suspected on the basis of 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, LN during pregnancy is related to disease status at conception. Women with baseline renal insufficiency are at greatest risk for complications—in one study, women with clinically active disease at conception had a 66% risk of LN flare during pregnancy. Ideally, assessment of baseline renal status—serum creatinine and urine protein excretion—is done prior to 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 per1.73 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 per 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 5% to 10% 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. Thus an isolated increase in proteinuria without new-onset or worsening hypertension or a significant rise in serum creatinine should not per se be an indication for preterm delivery.

Distinguishing between a flare in SLE (and LN) and preeclampsia can pose a clinical dilemma, as both entities can present with hypertension and proteinuria. If the pregnancy is at or near term, delivery may be the most prudent strategy. However, if the pregnancy is still very preterm, distinguishing between a disease flare and preeclampsia is more critical. An SLE flare can usually be treated, such as with corticosteroids, to prolong the pregnancy and optimize neonatal outcomes. Assessing for elevated anti-dsDNA titers and low complement levels, as often seen in active SLE, may aid in distinguishing between a disease flare and preeclampsia. However, 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 on the results.

Nonpregnant women with severe LN are often treated with mycophenolate mofetil (MMF), a significant teratogen that is contraindicated in pregnancy . Azathioprine (AZA) typically replaces MMF in patients intending to become pregnant. 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 months prior to a confirmed pregnancy.

Neonatal Lupus Erythematosus

NLE 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, plaque-like 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, and thrombocytopenia) and hepatosplenomegaly. Fortunately, 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, almost 15% to 20% will have a newborn with any manifestation of NLE. 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 SS, in the future.

The most serious manifestation of NLE is complete heart block (CHB). 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 26 weeks’ gestation and is rarely diagnosed after 26 weeks. CHB 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. Although many clinicians routinely test pregnant women with SLE for anti-Ro/SSA and anti-La/SSB antibodies, this practice is controversial given that CHB is infrequent, antenatal treatment has unproven 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 black (32.1%) than among white (14.3%) women.

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 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. Surveillance techniques are not associated with proven benefit, in part because progression to CHB can occur rapidly and without discernable progression through first- and second-degree block. Despite this, many specialists—including rheumatologists and pediatric cardiologists—recommend serial PR interval monitoring of the fetus in a woman with anti-SSA/Ro and anti-SSB/La antibodies. Fetal echocardiography is recommended if dysrhythmia is suspected.

Even with early detection of cardiac conduction abnormalities or new-onset CHB, there is very limited evidence 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 through echocardiography. Thirty women were treated with dexamethasone and 10 declined treatment. Regardless of treatment, no case of CHB reverted. 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 untreated 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 51.2 outlines management strategies for CHB.

Strategies to prevent conduction abnormalities altogether would certainly appear attractive, and three preventive treatments have been considered. Glucocorticoids are not recommended as preventative treatment for women at high risk of CHB owing 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.

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 in preventing the development of CHB, and it should not be used for this purpose outside of approved research protocols.

Recent data suggest a potential benefit of hydroxychloroquine (HCQ) in decreasing the risk of CHB in fetuses of mothers with anti-Ro/SSA and anti-LA/SSB antibodies. Given this potential benefit and the low risk for fetal harm ( Table 51.3 ), 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.

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.

The European League Against Rheumatism (EULAR) developed recommendations for pregnancies affected by SLE ( Table 51.4 ). Key components include preconception counseling and risk stratification, assessment of disease activity (including renal function and serologic markers), pregnancy monitoring with antenatal resting, and fetal growth surveillance and fetal echocardiography if dysrhythmia is suspected. Comanagement with a rheumatologist is particularly important for women with severe manifestations or active disease and would appear prudent in all cases. Some women experience a disease flare in the postpartum period; therefore the patient should be thoughtfully assessed for disease activity at postpartum visits, and follow-up with rheumatology in the 1 to 3 months following delivery is usually recommended.

The treatment of SLE in pregnancy is influenced by the severity of disease activity and the specific organ systems involved. Low-dose aspirin (LDA) is recommended in women with SLE for risk reduction of preeclampsia in high-risk women. The majority of patients with active disease are treated with AZA or HCQ, the latter of which reduces risk of flare and prevents disease-related damage from accumulating. Patients treated with HCQ prior to pregnancy should be maintained on this medication throughout . Flares in pregnancy are treated with glucocorticoids, although their long-term use is avoided secondary to side effects. MMF, used in the treatment of LN, and leflunomide, used in the treatment of lupus-related skin manifestations, are absolutely contraindicated in pregnancy. Table 51.3 details the safety profile of medications used in the treatment of rheumatic diseases.