Chapter 27: Systemic Lupus Erythematosus in the Pregnant Patient

Systemic lupus erythematosus (SLE) is a multisystemic chronic inflammatory disease that affects patients in many different ways over a varying course of time. The disease is typically characterized by periods of remission and relapse, although the causes of exacerbation remain uncertain. SLE, like most autoimmune diseases, has a clear predilection for women. Indeed, women are affected 7 times more frequently than men. The disorder may be diagnosed between the ages of 15 and 50 years, although it is most often detected in women in their twenties. Therefore, SLE is the most commonly encountered autoimmune disease in pregnancy. Although no specific gene mutation for SLE has been identified, the disease likely has a genetic component.¹ Approximately 10% of affected patients have a relative with SLE and monozygotic twin studies demonstrate that 50% of affected twins are concordant for the disease. It is estimated that about 2% of children born to mothers with SLE will develop the disease themselves.² The symptoms of SLE are extremely heterogeneous which can make the diagnosis difficult. The disease may affect joints, skin, kidneys, lung, nervous system, and other organs. The most common presenting complaints are extreme fatigue, arthralgias, fever, and rash (Table 27-1).

In 1982, the American Rheumatism Association (ARA) revised previously set criteria for the diagnosis of SLE³ (Table 27-2). According to the ARA, a person must have had at least 4 of the 11 specific criteria in order to carry the diagnosis of SLE. However, many patients have fewer than 4 clinical or laboratory features of SLE and do not meet strict diagnostic criteria. These patients should not be considered to have SLE, but are often referred to as having lupus-like disease. Such individuals may benefit from therapies for SLE and some will ultimately develop the clinical syndrome.

The Effect of Pregnancy on SLE

Fertility

Typically, patients with SLE do not have impaired infertility. However, patients on high-dose steroids may become amenorrheic or anovulatory. Women with end-stage lupus nephritis requiring dialysis also are frequently amenorrheic. In addition, depending on the cumulative dose of medication and the age of the patient, 10% to 60% of patients who have been treated with cyclophosphamide become permanently amenorrheic. Patients with mild-moderate disease have fertility rates comparable to the general population and should be counseled appropriately about contraception unless they desire to become pregnant. Estrogen-containing oral contraceptives (and other forms of contraception) are considered safe to use in women with SLE as long as they do not have comorbidities such as thrombosis or hypertension.

Maternal Complications

A recent study using a database including detailed information regarding about 20% of all (not necessarily pregnancy related) hospitalizations in the United States estimated a 20-fold increased risk in mortality in women with SLE.⁴ There was a 3- to 7-fold increase in the risk for thrombosis, infection, thrombocytopenia, and the need for blood transfusion. Women with SLE also are more likely to have comorbid conditions such as diabetes and hypertension that are associated with adverse maternal (and fetal) outcomes.

Lupus Flares

There is an association between estrogen and SLE, as evidenced by the female predilection for the disorder.⁵ Thus, conditions such as pregnancy that are associated with high estrogen levels have the potential to exacerbate SLE. The reported incidence of flares during pregnancy ranges between 15% and 63%. Several retrospective, uncontrolled studies performed prior to 1985 suggest that pregnancy exacerbates lupus flares. Table 27-3 reviews multiple, mostly prospective studies on the frequency of lupus flares during pregnancy.^{2,6,7,8,9,10,11,12,13, 14} It is difficult to interpret available data because control groups were often unmatched, and the SLE cohorts among studies vary greatly regarding patient characteristics including race, severity of disease, and the definition of lupus flares. Furthermore, normal physiologic changes of pregnancy such as palmar erythema, facial blushing, proteinuria, and alopecia can be misinterpreted as lupus flares.

Doria and colleagues investigated the relationship of steroid hormone levels in pregnancy to SLE activity.¹⁵ The group prospectively studied 17 women with lupus during pregnancy and matched them to 8 healthy pregnant controls. They reported that women with SLE had significantly lower serum levels of estradiol and progesterone than controls. Furthermore, the highest levels of estrogen and progesterone occurred in the third trimester, when patients with SLE had both the lowest disease activity and serum immunoglobulin levels. These data challenge previous work that supports the association between increased levels of steroid hormones and lupus activity, and raise the question of whether or not estrogens and progesterones suppress humoral immune responses and therefore disease activity.

Regardless of whether or not the rate of SLE flares increase during pregnancy, flares are common and may occur in any trimester, or in the postpartum period. In general, lupus flares during pregnancy are mild and easily treated. Furthermore, it has been demonstrated that active disease at the time of conception, active nephritis, a systemic lupus erythematosus disease activity index (SLEDAI) score of 5 or more, and abruptly stopping hydroxychloroquine therapy are significant risk factors for lupus flares. Approximately, 50% of patients with active disease at the time of conception experience flares during pregnancy compared to 20% of patients who are in remission when they conceive. Conversely, patients who have been in remission for 6 to 12 months prior to conception have a lower risk of lupus flares and do better than those with active disease.^{16,17, 18}

Preexisting Renal Disease

Approximately, 50% of patients with lupus will develop renal disease. Lupus nephritis is a result of immune complex deposition, complement activation, and inflammation in the kidney. Several reports have emphasized the potential for a permanent decrease in renal function after pregnancy in women with lupus nephritis. On the other hand, more recent series indicate excellent outcome for most women with mild renal disease.^19,20,21 Burkett reviewed several retrospective reports including 242 pregnancies in 156 women with lupus nephritis.²² He demonstrated that 59% of patients had no change in their renal function, 30% experienced transient renal impairment, and 7% had permanent renal insufficiency. Similar results were noted in several recent cohorts.^16,17,23 Most patients with prior nephritis had successful pregnancies and flares were predicted by renal status (remission decreases the risk) at conception.

It is clear that there is a strong correlation between renal insufficiency prior to conception and the risk of deterioration during and after pregnancy. Women with a serum creatinine level greater than 1.5 mg/dL have a significantly increased risk of deterioration in renal function. Conversely, patients with serum creatinine levels less than 1.5 mg/dL can be reassured that pregnancy will not increase the rate of deterioration of renal function. The specific type of renal disease as demonstrated by histologic studies does not appear to influence pregnancy outcome or postnatal renal function.

Preeclampsia

Preeclampsia is among the most common pregnancy complications in patients with SLE. The incidence ranges between 20% and 35%. The cause of the increased incidence of preeclampsia in women with SLE is not clear, but may be due to unrecognized renal disease that is likely present in many patients with SLE. Renal disease, hypertension, and antiphospholipid syndrome, all increase a patient’s risk for developing preeclampsia. In the prospective study of Lockshin et al,¹⁰ 8 of 11 (72%) patients with lupus nephritis developed preeclampsia compared to 12 of 53 (22%) women who did not have nephritis. In some cases, it is difficult to distinguish preeclampsia from a lupus flare manifesting as lupus nephritis. Both disorders may be characterized by increased proteinuria, hypertension, and fetal growth restriction. Table 27-4 lists several features that may aid in the distinction of preeclampsia from nephritis. Despite these parameters, it is often difficult to distinguish between the two, and in some cases a renal biopsy may be required to differentiate between the conditions. For example, confirmation of lupus nephritis may prevent unnecessary iatrogenic preterm birth in an attempt to treat preeclampsia. Although there is a theoretical increased risk of complications from the procedure, it has been performed safely during pregnancy. Preeclampsia and lupus nephrits may also coexist and a definitive diagnosis cannot always be made.

Fetal Complications

Pregnancy Loss

Patients with SLE have an overall increased risk of pregnancy loss. The rate of first trimester spontaneous miscarriage is as high as 35%. The risk of fetal death is also increased and approaches 22% in some series. Several factors have been associated with pregnancy loss in women with SLE including antiphospholipid syndrome (see later), renal disease (especially class III-IV glomerulonephritis), active disease during pregnancy, a history of fetal loss, and African American and Hispanic race/ethnicity.^{24,25,26,27,28} However, in the absence of these, SLE patients have pregnancy loss rates that are similar to the general population.

Preterm Delivery

There is a higher incidence of preterm birth in patients with lupus than in healthy women. Preterm delivery less than 37 weeks has been reported in as few as 3% and as many as 73% of SLE pregnancies (median 30%). The variation in preterm birth in these studies may be due, in part, to the tendency of some obstetricians to intentionally deliver patients with SLE in order to avoid fetal morbidity. However, a well-designed cohort study by Johnson et al²⁹ including careful obstetric detail, reported a 50% rate of preterm birth in patients with SLE. Preterm delivery typically occurs because of preeclampsia, fetal growth impairment, abnormal fetal testing, and preterm premature rupture of membranes.²⁹ Increased disease activity, chronic hypertension, and antiphospholipid antibodies are all associated with an increased risk for both medically indicated and spontaneous preterm delivery.

Neonatal Lupus Erythematosus

Neonatal lupus erythematosus (NLE) is a rare condition that occurs in approximately 1:20,000 live births. The disease is characterized by neonatal or fetal heart block, skin lesions, or less commonly, anemia, thrombocytopenia, and hepatitis. Approximately, 50% of fetuses with NLE have skin lesions, 50% have heart block, and 10% have both. NLE is an immune-mediated disease and is a result of transplacental passage of maternal autoantibodies. Most cases are associated with antibodies to the cytoplasmic ribonucleoproteins SSA (Ro), more specifically the 5 anti-SS2-kDa epitope of SSA. SSB (La) antibodies are also detected in 50% to 75% of these women. However, NLE is rarely associated with isolated antibodies to SSB.

Typical skin lesions associated with NLE are erythematous, scaling plaques usually seen on the scalp or face of the infant. The lesions appear within the first weeks after delivery and last only for a few months. Skin biopsies of the lesions show changes typical of cutaneous lupus in adults. The hematologic abnormalities of NLE also resolve within a few months, coinciding with the disappearance of maternal autoantibodies.

Cardiac lesions associated with NLE are heart block and endocardial fibroelastosis.^30,31 The anti-SSA (most specifically anti-SSA-52), binds to myocardial tissue. Histologic analysis of affected fetal hearts demonstrates mononuclear cell infiltration, fibrin deposition, calcification of the conduction system (specifically the AV and SA nodes), and diffuse fibroelastosis throughout the myocardium. It is hypothesized that the earliest effect of the antibody-mediated disease is global pancarditis with subsequent fibrosis of the conduction system. Congenital heart block is usually detected as fetal bradycardia with a rate between 60 and 80 beats/min between 16 and 25 weeks’ gestation. Fetal echocardiography demonstrates a structurally normal heart with AV dissociation. In some cases, fetal hydrops develop in utero.

The presence of autoantibodies alone is insufficient to cause NLE. This is demonstrated by the fact that approximately 30% of patients with SLE have anti-SSA antibodies, and 15% to 20% of patients have anti-SSB autoantibodies. However, prospective studies indicate that the incidence of congenital heart block in infants born to women with SLE is only 2%. Also, the recurrence risk ranges between 15% and 20% and there are reports of twins who are discordant for NLE. Thus, anti-SSA alone does not always lead to NLE. It is also important to recognize that maternal SLE is not a prerequisite for NLE. In fact, up to 50% of cases occur in the offspring of healthy women with circulating autoantibodies. Some, but not all of these women eventually develop connective-tissue disorders. Prospective studies of women with anti-SSA or anti-SSB antibodies (regardless of SLE status) have confirmed that about 2% will have a child with NLE.

The clinical course of NLE is highly variable. Cutaneous and hematologic abnormalities resolve by 6 months of age. However, heart block is a permanent condition that is associated with significant morbidity and even mortality. Approximately, 15% to 20% of fetuses affected with heart block die within 3 years of age due to a fatal cardiomyopathy. Up to 60% of neonates require pacing during the neonatal period and most affected children eventually require permanent pacemakers before adulthood. There are few data regarding long-term outcomes. However, preliminary reports suggest that anti-SSA may be associated with an increased risk of dyslexia. Thus, long-term neuropsychological evaluation may be useful.

Whether treatment of heart block detected in utero is beneficial is not clear. Many clinicians advocate the use of flourinated corticosteroids since they cross the placenta. The rationale for steroid treatment is based on the fact that the cardiac histology of fetuses with congenital heart block (CHB) demonstrates diffuse inflammation, IgG, fibrin, and complement deposition. Initially, improvement in myocardial function was reported by some investigators. However, it is now clear that once heart block is complete it is irreversible even with steroid treatment. Thus, steroids should not be routinely used once heart block is complete. Some authorities advocate their use in cases of myocarditis, heart failure, or mild hydrops but efficacy is uncertain.³¹

It is even more controversial as to whether screening for first- or second-degree heart block and treating such patients with steroids can reduce progression to complete heart block. A cohort of pregnancies in women with anti-SSA and anti-SSB antibodies was prospectively followed with serial fetal echocardiograms (PRIDE study). The investigators noted rapid progression from normal sinus rhythm to complete heart block without a graded progression through early stage heart block. In some cases steroids appeared to reverse a prolonged PR interval. However, spontaneous reversal may also occur. Thus, the benefit of screening for and/or treating prolonged PR intervals in women with anti-SSA or anti-SSB remains unproven.^32,33

Importantly, there are significant maternal and fetal risks to treatment with high-dose, chronic fluorinated corticosteroids including osteoporosis, glucose intolerance, adrenal suppression, fetal growth restriction, decreased brain growth, learning disabilities, and developmental delay. Therefore, steroid therapy in the treatment of CHB diagnosed in utero should be considered experimental and used with extreme caution.

Intravenous immune globulin also seemed promising as a prophylactic or therapeutic agent for the prevention of CHB in at-risk pregnancies. However, 2 recent, large clinical trials did not show benefit.^34,35 Hydroxychloroquine may reduce the rate of CHB but proof of efficacy is lacking.

The Management of Pregnancies Complicated by SLE

Table 27-5 summarizes the management of a patient with SLE during pregnancy. Ideally, women with SLE should have preconceptual counseling to discuss both medical and obstetric risks including lupus flares, preeclampsia, fetal growth restriction, pregnancy loss, and preterm delivery. Patients should also be made aware of the risk of NLE and the clinical implications of the disease. All patients with SLE should have an assessment of their renal function in the form of a serum creatinine level and a 24-hour urine analysis for protein and creatinine clearance. In addition, a hematocrit and platelet count should be determined to exclude hematologic abnormalities associated with SLE. Finally, all patients should be tested for antiphospholipid antibodies (see later in lupus and antiphospholipid syndrome). A number of studies have demonstrated that active lupus at the time of conception increases the risk of lupus flares, preeclampsia, and fetal loss. Thus, the optimal timing of conception in SLE patients is after a patient has been in remission for 6 months. In addition, nonsteroidal anti-inflammatory drugs (NSAIDs) and cytotoxic agents should be stopped prior to conception (see later in medications).

During pregnancy, patients with the disease should be comanaged by an obstetrician and a rheumatologist. Obstetric visits should be as frequent as every 2 weeks during the first and second trimesters, and weekly during the third. Blood pressure, urinalysis, and symptoms of lupus flare should be assessed at each visit. Serial ultrasounds should be performed to screen for fetal growth restriction. Nonstress testing and evaluation of the amniotic fluid volume should begin at 32 weeks’ gestation or sooner if intrauterine growth restriction (IUGR) is suspected or other complications, such as preeclampsia occur. There may be a role for Doppler velocimetry as part of the fetal assessment.

Routine testing for antinuclear antibody (ANA) titers and complement levels do not improve obstetric outcome and are unnecessary. Many physicians advocate routine testing for anti-SSA and SSB antibodies in all patients with SLE. However, benefit is not clear since one would neither advise a patient against a pregnancy, nor institute a specific treatment if the serum titers were positive.

Medications

The medical management of SLE includes 4 categories of drugs: NSAIDs, antimalarials, corticosteroids, and cytotoxic agents (Table 27-6).

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs are the most common anti-inflammatory agents used in the treatment of SLE. Unfortunately, their use during pregnancy is associated with significant fetal morbidity. NSAIDs readily cross the placenta and can block prostaglandin synthesis in fetal tissue. The use of NSAIDs during pregnancy is associated with premature closure of the ductus arteriosus, fetal pulmonary hypertension, necrotizing enterocolitis, and fetal renal insufficiency. There was speculation that selective COX-II inhibitors might cause fewer fetal side effects than nonselective inhibitors. However, untoward fetal effects occur even with selective COX-II inhibitors. Aspirin crosses the placenta and may adversely affect fetal platelet function. The use of aspirin in the third trimester is associated with intracranial fetal hemorrhage. Thus, regular-dose aspirin (325 mg) should be avoided in pregnancy. Low-dose aspirin (typically 81 mg/d in the United States) is considered to be safe during pregnancy and decreases the chances of developing preeclampsia in women at risk. However, this dose is unlikely to be effective in the treatment of joint and muscle pain due to SLE.

Glucocorticoids

Glucocorticoids are the first line of treatment for SLE in pregnancy.³⁶ They are not considered to be human teratogens. Hydrocortisone, prednisone, and prednisilone are the steroids of choice since these agents are inactivated by 11-β-hydroxysteroid in the placenta, allowing fewer than 10% of active drugs to reach the fetus. The incidence of fetal adrenal suppression after maternal gucocorticoid use is extremely low.

There are severe maternal side effects from glucocorticoid use including osteoporosis, glucose intolerance, sodium and water retention, infection, hypertension, and avascular necrosis. There is also an increased risk of obstetric complications such as gestational diabetes, preeclampsia, preterm premature ruptured membranes, and fetal growth restriction. Typically, the benefits of glucocorticoid use for controlling lupus flares in pregnancy outweigh the risks. However, patients should be maintained on the lowest possible dose and weaned off if symptoms permit. Patients receiving chronic steroids (20 mg or more of prednisone for a duration of greater than or equal to 3 weeks during the last 6 months) should receive stress doses in labor.

Antimalarials

Chloroquine has been associated with congenital anomalies raising concern for the safety of using antimalarial medications during pregnancy. However, hydroxychloroquine is not associated with an increased risk for fetal malformations and is considered safe during pregnancy. In fact, a prospective study by Cortes-Hernandez and colleagues demonstrated that stopping hydroxychloroquine treatment during pregnancy was associated with a significant increase in the risk of lupus flares.²⁶ Therefore, if a patient requires this medication to control her disease, stopping the drug is ill adversed.

Immunosuppressive Agents

Cyclosporine is a pregnancy category C drug. There is abundant data obtained from transplant patients regarding the use of cyclosporine in pregnancy. The use of this medication appears to be safe, but long-term follow-up studies are limited. Azathioprine does not appear to be a teratogen in humans. However, its use in pregnancy has been associated with fetal growth restriction. In severe cases of SLE in pregnancy requiring chronic high doses of glucocorticoids, either cyclosporine or azathioprine may be added to help control symptoms and to lower the dose of steroids used. Tacrolimus is also considered to be a reasonable choice during pregnancy in women with persistent disease activity.

Cyclophosphamide is an alkylating agent and is the drug of choice in nonpregnant patients for the treatment of proliferative lupus nephritis. However, this drug is known to cross the placenta and is associated with fetal cleft palate and skeletal abnormalities. It should be used only with extreme caution in pregnancy. Methotrexate, an antimetabolite, is sometimes used in SLE patients. It is embryolethal in early pregnancy and is also a known human teratogen when used later in gestation. It is pregnancy category X and is absolutely contraindicated in the treatment of pregnant women with SLE. Mycophenolate mofetil and leflunomide also are considered contraindicated during pregnancy. There are limited data regarding the biologic agents rituximab and belimumab. Accordingly, they are best avoided until more data are acquired.

Treatment of Lupus Flares

Lupus flares in pregnancy are usually mild, and most commonly are manifested by skin lesions or joint pain. However, patients may present with severe nephritis, stroke, seizures, or psychosis as a result of a lupus exacerbation. Treatment of lupus flares depends on the severity of the patient’s symptoms, and with few exceptions can be controlled with NSAIDs, hydroxychloroquine, and glucocorticoids.

Lupus Nephritis

Patients with severe nephritis may present with acute renal insufficiency. As discussed earlier, the differential diagnosis includes preeclampsia and in transplant patients, acute rejection. Interestingly, there are only rare case reports of recurrent lupus nephritis in transplanted kidneys. Therefore, acute renal insufficiency in transplant patients is likely due to transplant rejection or preeclampsia. However, the distinction between rejection, nephritis, and preeclampsia is often difficult and may require a renal biopsy.

Patients frequently respond well to glucocorticoids. However, patients with proliferative nephritis may require cyclophosphamide. A recent study comparing low-dose to high-dose cyclophosphamide for the treatment of proliferative nephritis demonstrated that low doses were as effective as high doses and associated with fewer maternal side effects. Patients who do not respond to medical therapy, and have serum creatinine levels greater than 3.5 mg/dL should be started on dialysis in order to optimize pregnancy outcome.

Neuropsychiatric SLE

There are many different central nervous system manifestations of SLE, making the treatment of neuropsychiatric SLE complex. These include peripheral neuropathy, headaches, seizures, chorea, stroke, mood disorders, and psychosis. It is also essential to exclude other causes of neurologic symptoms such as metabolic abnormalities, infection, and intracranial lesions. Infection is especially common in SLE patients with chronic steroid use. Thus, a complete evaluation for infection including cerebral spinal fluid analysis is required. In addition, brain imaging and electroencephalography (EEG) are often helpful in excluding other causes of neurologic abnormalities.

Unfortunately, there are no randomized-controlled studies regarding the appropriate treatment of lupus cerebritis. As such, treatment is empiric. Patients presenting with recurrent psychosis, mood changes, or delirium do not readily respond to mood stabilizing medications, but instead typically respond to high-dose steroids. Cyclophosphamide may be added, if needed, to help lower the dose of steroids required to control symptoms. Patients with mild neuropsychiatric symptoms (infrequent seizures, mild depression, headaches, peripheral neuropathy) and no other manifestations of systemic disease may be treated symptomatically. Lupus patients presenting with a thrombotic stroke often also have antiphospholipid antibodies. The primary treatment for these women is anticoagulation with heparin.

In general, with the exception of methotrexate, cyclophosphamide, and NSAIDs, the benefits of medical therapy for the treatment of severe lupus flares far exceed the risks. Although these medications should be used prudently, there are circumstances wherein they are indicated in pregnancy.

Antiphospholipid syndrome (APS) is an autoimmune disorder defined by distinct clinical and laboratory features³⁷ including the presence of antiphospholipid antibodies (aPL) (Table 27-7). aPL are a heterogeneous group of autoantibodies that bind phospholipids, proteins, or a phospholipid-protein complex. Approximately, 30% of patients with SLE also have antiphospholipid antibodies. Individuals with SLE and APS are considered to have secondary APS, while those with APS and no other connective tissue disorders have primary APS.

Although several aPL have been described, lupus anticoagulant, anticardiolipin antibodies, and anti-β₂-glycoprotein-I antibodies are the 3 best characterized, and are recommended for clinical use.³⁸ Lupus anticoagulant is a misnomer because patients may not have SLE and they are hypercoagulable as opposed to anticoagulated. It is also an unusual name for an antibody. Lupus anticoagulant is detected in plasma using one of several phospholipid-dependent clotting tests (eg, activated partial thromboplastin time or dilute Russel viper venom time). If the autoantibody is present, it will interfere with clotting, thus prolonging the clotting time. Confirmatory tests are then performed to exclude other reasons for prolongation of clotting assays (such as clotting factor deficiency). Clinicians may order a lupus anticoagulant screen in a blue top tube, which is reported as either present or absent. In a recent cohort study, lupus anticoagulant (LA) was the aPL that most strongly correlated with adverse pregnancy outcomes.²⁸

Anticardiolipin antibodies are detected in a more traditional fashion via immunoassay. Results are reported in a semiquantitative manner and the assay is standardized using standard sera. Medium-high titers of the IgG isotype are most strongly associated with the clinical features of APS. Low-positive results and isolated IgM or IgA antibodies are common, nonspecific, and are of questionable clinical relevance. They are not considered diagnostic criteria for APS.

Over the past decade, medium to high titers of IgG or IgM antibodies against β₂-glycoprotein-I also have become accepted as criteria for APS. As with anticardiolipin antibodies, anti- β₂-glycoprotein-I antibodies are detected by a standardized immunoassay and reported in a semiquantitative fashion.

Several other autoantibodies have been associated with APS. Some are aPL such as the false-positive serologic test for syphilis and antiphosphatidylserine antibodies. Although these antibodies may eventually prove to be clinically useful, they are not recommended for routine testing in the absence of further study.

APS is associated with significant medical problems including arterial and venous thrombosis, recurrent pregnancy loss, and autoimmune thrombocytopenia. Pregnancies resulting in live births are often complicated by obstetric disorders associated with uteroplacental insufficiency such as preeclampsia, fetal growth restriction, and abnormal antenatal testing.^39,40 Preeclampsia has been reported in one-fourth to one-half of women with well-characterized APS. It is often severe and occurs prior to 34 weeks’ gestation. Although women with APS are at increased risk for preeclampsia, most women with preeclampsia do not have APS. This is not surprising given the relative frequency of preeclampsia compared to APS.

In utero fetal growth restriction is also associated with antiphospholipid antibodies, occurring in 15% to 30% of women with APS. It appears that fetal growth restriction is more likely in patients with higher levels of IgG anticardiolipin antibodies. Abnormal fetal heart rate tracings indicative of uteroplacental insufficiency are also more common in APS patients. In a large cohort study of women with APS, 50% of patients had abnormal antenatal testing which ultimately prompted obstetric intervention and delivery. Placental insufficiency, manifested by abnormal fetal heart rate tracings, may occur as early as the second trimester.

The increased incidence of preeclampsia, fetal growth restriction, and abnormal fetal heart rate tracings all contribute to iatrogenic preterm birth in women with APS. Preterm birth occurs in up to one-third of women with APS. Delivery prior to 34 weeks is most likely in women with strict clinical and laboratory criteria for APS.

Treatment for APS

Initially, high-dose prednisone (40 mg daily or greater) in combination with low-dose aspirin was the accepted treatment for antiphospholipid syndrome in pregnancy. This regimen resulted in a 60% to 70% successful pregnancy rate. Subsequently, the use of heparin in the treatment of antiphospholipid syndrome was proposed. Several case series demonstrated a success rate comparable to that of high-dose prednisone. A small, randomized trial comparing heparin and prednisone demonstrated that heparin and prednisone are equally efficacious. However, patients treated with prednisone had a higher rate of adverse obstetric events including preeclampsia, preterm premature rupture of membranes, and preterm labor.⁴¹ Success with heparin has been confirmed by other studies. Thus, heparin (or low-molecular-weight heparin [LMWH; see later in this section]) is the treatment of choice for APS in pregnancy. Intravenous immune globulin has been used as adjunctive therapy in patients who are refractory to heparin. It is not recommended for use as primary therapy due to cost and a lack of improved efficacy compared to heparin alone.⁴² Heparin is also potentially useful for the treatment of APS during pregnancy due to an increased risk of thrombosis, even in women without history of thromboembolism. Patients without a prior history of thrombosis should be treated with thromboprophylactic doses of heparin (10,000-20,000 units of unfractionated heparin daily). Patients with a history of thrombosis should receive a dose of heparin that will provide full anticoagulation. The goal of therapy is to maintain the activated partial thromboplastin time (aPTT) 1.5 to 2.5 times the normal value. Patients with no history of thrombosis should continue anticoagulation therapy until 6 weeks’ postpartum. Individuals with APS and prior thromboses should be anticoagulated for life. Heparin may be exchanged for sodium warfarin in the postpartum period. Despite initial concerns about transfer through breast milk, it is safe to take warfarin while breast-feeding.

It is important to remember that the LA causes a prolongation of the aPTT. Therefore, this test cannot be used to monitor anticoagulation in patients who test positive for the lupus anticoagulant. Rather, antifactor Xa levels can be followed. To achieve full anticoagulation using unfractionated heparin, antifactor Xa levels should fall between 0.4 and 0.7 U/mL.

Side effects of heparin are uncommon but potentially serious and include bleeding, osteopenia, and thrombocytopenia. Heparin-induced osteoporosis with fractures occurs in 1% to 2% of women treated during pregnancy with unfractionated heparin. Patients should therefore be encouraged to engage in weight-bearing exercise and take calcium supplements. In addition, heparin causes an immune-mediated thrombocytopenia in up to 5% of patients. Thrombocytopenia is detected within 10 days after the initiation of therapy. Accordingly, platelet counts should be checked serially for the first 10 days of therapy.

Low-molecular-weight heparin has been used with increasing frequency in pregnancy. Initially, it was thought that LMWH might cross the placenta and cause fetal hemorrhage. However, several studies have shown that this does not occur and LMWH is safe in pregnancy. In order to achieve full anticoagulation, the recommended dose of enoxaparin is 1 mg/kg, administered subcutaneously in 2 equal doses 12 hours apart. However, due to the increased plasma volume and renal blood flow in the pregnant patient, the pharmacokinetics of enoxaparin is altered by pregnancy. It may be necessary to monitor antifactor Xa levels in order to ensure adequate dosing. The target antifactor Xa level for full anticoagulation using LMWH is 0.5 to 1.1 U/mL. LMWH appears to have less risk for osteopenia and thrombocytopenia than unfractionated heparin. However, it is more expensive and has a slightly longer half-life, making it less convenient for intrapartum anticoagulation. The advantages of LMWH are usually worth the downside in women who require full anticoagulation. However, unfractionated heparin may be preferable in women taking only prophylactic doses. In women taking LMWH, it may be useful to switch to unfractionated heparin at 34 to 36 weeks’ gestation. The shorter half-life of unfractionated heparin and ease of rapidly obtaining an aPTT on labor and delivery increases the chances that neuraxial anesthesia mat be safely administered if the patient spontaneously labors of ruptures membranes. Table 27-8 summarizes the management of pregnant women with APS.

Catastrophic APS

A majority of patients with APS experience single large vessel thrombotic events. In patients with recurrent thrombosis, the subsequent event typically occurs months to years after the initial episode. In 1992, Asherson et al described a small subset of patients with APS who presented with what has been described as catastrophic APS.⁴³ Unlike the majority of patients with APS, those with catastrophic APS suffer microvascular thromboses in multiple organs, most commonly the kidneys, lungs, and gastrointestinal tract. The heart, brain, liver, and adrenal glands are less frequently involved. Catastrophic APS has a 50% to 65% mortality rate.

In a retrospective review of 50 patients with catastrophic APS, Asherson found that 78% presented with renal involvement, which typically resulted in concurrent malignant hypertension. Renal biopsies in these patients demonstrated frank microangiopathy and occasional renal infarctions. Sixty-six percent of patients had pulmonary involvement. The most common presenting symptom was severe dyspnea. Approximately, half of patients with pulmonary involvement developed acute respiratory distress syndrome (ARDS) and 25% had pulmonary embolism. In this series, 56% of patients had central nervous system involvement. Symptoms were highly variable and included confusion, drowsiness, stupor, seizures, and infarction of either large or small vessels. Half of the patients had myocardial involvement and 38% had gastrointestinal involvement. The most common symptom of patients with gastrointestinal involvement is severe abdominal pain. Occlusion of the mesenteric vessels (both arterial and venous) was frequently noted. Other organs that were less commonly affected were liver (35%), adrenal (26%), spleen (20%), and pancreas (1%). Up to 50% of patients had skin involvement manifested as superficial necrosis and gangrene, splinter hemorrhages, and purpura.

Diagnosis

The diagnosis of catastrophic APS can be difficult, and the differential diagnosis includes disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and SLE nephritis. Furthermore, Drenkard and colleagues⁴⁴ reported a decrease in anticardiolipin antibody titer at the time of thrombosis in 6 patients with previously high antibody titers. The authors speculate that acute thrombosis may cause transient antibody consumption, which could complicate the diagnosis of APS at the time of the acute event. The laboratory diagnosis of catastrophic APS can be made by the presence of lupus anticoagulant and high titers of anticardiolipin IgG antibodies, both of which are detected in approximately 95% of patients. Patients may also demonstrate thrombocytopenia and anti-dsDNA if they also carry a diagnosis of SLE. There may also be evidence of hemolytic anemia and laboratory values consistent with DIC.

Treatment

There is no standard treatment for catastrophic APS. Patients often are critically ill and require admission to intensive care units. Supportive treatment depends on presenting symptoms, and may include aggressive antihypertensive therapy, assisted ventilation, dialysis, and vasopressors. Some authorities recommend plasmapheresis. However, others report improved outcome in patients who are treated with a combination of anticoagulation, steroids, and either intravenous immunoglobins or plasmapheresis in order to rapidly decrease the titer of antiphospholipid antibodies.