Autoimmune Connective Tissue Disease in Pregnancy

Autoimmune disorders are conditions in which an ongoing, self-directed immune response results in clinical manifestations. Although all normal persons possess cells and antibodies capable of recognizing self-antigens and initiating an immune response, this process is tightly regulated. When this regulation is impaired, circulating endogenous antibodies can interact with self-antigens to form immune complexes. These immune complexes are deposited in tissue, causing tissue damage with resultant clinical disease. Some autoantibodies affect only a single cell type (e.g., platelets in immunologic thrombocytopenia purpura), others affect a single organ (e.g., the thyroid gland in Graves' disease), and still others can result in multiple organ involvement (e.g., systemic lupus erythematosus).

Autoimmune disorders in general are 6 to 10 times more common among women than men, and are most likely to have their onset during the reproductive years. It is therefore not uncommon to encounter patients with these conditions during pregnancy. Interest in these disorders has increased recently for two reasons. First, as evidence accumulates supporting the involvement of the immune system in normal pregnancy development, it is thought that understanding more about abnormal immune activation may give clues about poor pregnancy performance. Second, the recent association of certain autoantibodies (the antiphospholipid antibodies) with recurrent pregnancy loss has suggested an explanation for poor outcomes in patients with previously unexplained complications. Yet most autoimmune disorders are so uncommon that few prospective studies exist to provide accurate information for counseling patients about the risks, outcomes, and appropriate therapies pertinent to pregnancy. In addition to the biases inherent to retrospective reporting, many of the reports are more than a decade old and therefore predate more recent innovations in patient care. This chapter focuses on the effects of some of the more common autoimmune disorders on pregnancy and discusses implications for clinical management.

Systemic lupus erythematosus (SLE) is second only to autoimmune thyroid disease in prevalence among the autoimmune disorders of reproductive age women.¹ The prevalence estimate of SLE in the general population is approximately 40:100,000, but this condition may affect 1:1000 women during pregnancy.² It is estimated that 10% of all women with lupus are diagnosed with the disease either during pregnancy or in the immediate postpartum period. Although in the past the diagnosis of lupus carried a grave prognosis, the current outlook is often more optimistic. Improvement in the mortality and morbidity associated with SLE is related to multiple factors, including the recognition of milder cases and improved therapeutic options. The majority of women with lupus are now able to achieve successful pregnancy outcomes with few maternal complications. Nonetheless, maternal deaths and morbidity related to this condition still occur,³ and special attention to these patients is warranted.

The pathophysiology of SLE involves the overproduction of autoantibodies directed against various nuclear components as well as cell-surface antigens. When the disease is active, antigen-antibody complexes found along the basement membranes of affected organs generate an inflammatory reaction mediated by cytokines, complement activation, and prostaglandin production.¹ When the inflammatory reaction is of sufficient magnitude, clinical symptoms occur. Although antinuclear antibodies (ANAs) can be detected in up to 99% of patients with SLE, other common laboratory findings include anti-double-stranded DNA and anti-Smith (Sm), anti-RNP, anti-Ro (SS-A), and anti-La (SS-B) antibodies. Titers of anti-double-stranded DNA antibodies often correlate with disease activity. In addition, decreased complement levels usually are observed with clinically significant lupus flares.

In 1982, the American Rheumatism Association established criteria for the diagnosis of lupus (Table 1).⁴ This list includes the 11 most common features that distinguish lupus from other connective tissue diseases. If a patient has at least four clinical or laboratory abnormalities, the patient is definitively classified as having lupus. However, patients can develop manifestations that can be attributed to SLE but are not included in this list. In addition, it is not uncommon for a significant time interval to elapse between the onset of clinical symptoms and a definitive diagnosis. In some circumstances, it is therefore reasonable to consider a clinical diagnosis of lupus even if less than four classification criteria are fulfilled.

TABLE 1. Criteria for Diagnosis of Systemic Lupus Erythematosus: American Rheumatism Association, 1982

The most common clinical findings in patients with SLE are arthritis and rash, and the most common laboratory abnormalities are the presence of ANAs and anti-double-stranded DNA antibodies. ANAs are an excellent screening test because of their presence in the vast majority of patients with lupus; however, the ANA test is not specific for lupus, and it can be present in persons with other connective tissue disorders and even in normal individuals. Although laboratory findings can be suggestive of connective tissue disease, the diagnosis of SLE should be based on the presence of both clinical and laboratory abnormalities.

The clinical course of patients with SLE is quite variable, but it often consists of episodes of clinical disease activity separated by periods of clinical remission of variable length. Reactivation of disease activity most often involves the same symptoms with which the patient originally presented. Occasionally, these disease flares will be more fulminant, with additional clinical findings or disease progression. The appearance of nephritis, hypertension, or neurologic complications is associated with a poorer prognosis and can occur as life-threatening crises. The mortality rate within 10 years for patients with SLE is approximately 10%, the most common causes of death being infection and renal failure.²

Treatment for lupus is indicated for the amelioration of clinical symptoms and for the prevention of disease progression. Although nonsteroidal anti-inflammatory drugs (NSAIDs) may be helpful in controlling arthritis and serositis, the use of steroids, antimalarials, immunosuppressive or cytotoxic agents may be necessary to control nephritis, hematologic or neurologic complications, or systemic manifestations, such as fever or vasculitis (Table 2). It currently is thought that more aggressive use of immunosuppressive or cytotoxic agents in patients with visceral organ involvement has contributed to the recently observed improvement in survival with SLE; however, this approach also may have contributed to some degree to the increased development of atherosclerosis in young women with SLE and to their increased susceptibility to infection.^2,5

TABLE 2. Treatment of Systemic Lupus Erythematosus

CNS = central nervous system; NSAIDs = nonsteroidal anti-inflammatory drugs.

Systemic Lupus Erythematosus and Pregnancy

Because SLE most often affects women in their reproductive years, it is important to determine the effect of pregnancy on the underlying disease. Although some contradictory data exist,⁶ most studies comparing pregnant SLE patients with nonpregnant SLE patients have found no differences in the frequency of exacerbations, suggesting that pregnancy is not a risk factor for a flare in disease activity.^7,8 Further, most studies have shown that pregnancy does not alter the long-term disease course or survival rate among most patients with SLE. This appears to be true even among patients with more concerning findings, such as nephritis.⁹ It is therefore reasonable to counsel patients that, although significant flares in disease activity may occur, pregnancy is not likely to alter their long-term prognosis.

The incidence of SLE exacerbation during pregnancy varies considerably among different reports, ranging from 13% to 70%; the majority of flares of disease activity are mild.¹⁰ Some authors have reported that the likelihood of a flare is related to disease activity at pregnancy onset. Only 10% to 30% of patients experience an exacerbation if SLE is inactive at the time of conception; there is a twofold to threefold increase in frequency of exacerbations if SLE is active at the time of conception.¹¹ These flares can occur during any trimester, but are more likely to occur in the second half of pregnancy and the early postpartum period.

Even without a flare of disease activity, both the mother and fetus are at increased risk for complications of pregnancy. SLE patients have a higher risk of preeclampsia, especially those patients with renal involvement or preexisting hypertension. The rate of pregnancy loss is also elevated, with reports ranging from 11% to 29% in prospective studies.¹² These loss rates, however, often include spontaneous abortions, stillbirths, and neonatal deaths, and the contribution of each type of death to the total pregnancy loss rate is difficult to determine. The extent to which pregnancy loss rates are affected by disease activity at pregnancy onset or the presence of renal involvement also is unclear. It is likely that antiphospholipid antibody status and prior pregnancy history affect prognosis significantly and should be controlled for in studies of pregnancy outcome. The fetus is also at risk for growth retardation and other effects of uteroplacental insufficiency, with hypertension and active disease increasing this risk.¹³ Preterm birth as well as its associated risks to the neonate is also more common among pregnancies complicated by maternal SLE. Premature delivery can be a result of preterm labor, but is more often associated with either fetal or maternal indications for delivery.

In light of the above findings, preconception counseling may be of significant value to patients with SLE. Patients should be encouraged to delay conception until their disease has been quiescent for at least 6 months. Attempts should be made to decrease medications to the lowest dose that allows them to remain symptom-free. They should be counseled as to the risk to themselves of flare and preeclampsia, and to the risks to the fetus of spontaneous abortion, growth retardation, and prematurity. Although these risks are significantly greater among SLE patients than women in the general population, there is room for cautious optimism for most women with this condition.

During the pregnancy, close attention should be paid to both the mother and the fetus. Baseline blood pressure, renal function, complement levels, and serologic tests such as anti-double-stranded DNA antibodies should be assessed early in pregnancy and reexamined if clinical symptomatology suggests an increase in disease activity. Patients receiving angiotensin-converting enzyme (ACE) inhibitors for control of hypertension should be given another medication when pregnancy is diagnosed because of concerns regarding adverse effects on fetal renal function. Patients should be seen at 2- to 4-week intervals, with assessment of maternal blood pressure, proteinuria, and SLE symptoms at each visit. Routine testing of serologies and complement levels in each trimester may be of value in identifying the asymptomatic patient before a clinically recognizable flare in disease activity. Rising titers of anti-double-stranded DNA or decreasing levels of C3 or C4 are suggestive of disease activation. With clinical and laboratory evidence of SLE flare, treatment should be started or increased promptly in an effort to limit complications. Control of disease activity often is successful with prednisone, but additional agents are occasionally necessary.

After viability is confirmed in the first trimester, assessment of fetal growth assumes importance in the second and third trimesters. Ultrasound examinations can be helpful in identifying poor growth, especially if uterine fundal height measurements are less than expected. Fetal surveillance has a role in preventing stillbirth in this clinical setting, especially if growth retardation is suspected or if the mother has hypertension, renal involvement, or active disease. Multiple forms of surveillance have been proposed (nonstress testing, biophysical testing, fetal movement counts), but these methods have not been compared to demonstrate whether one method is superior to any other in this setting. Initiation of routine testing may be appropriate at 32- to 34-weeks' gestation; however, it may be prudent to begin testing earlier if there are signs of worsening hypertension or poor fetal growth. Patients receiving prolonged courses of oral glucocorticoids during pregnancy should receive high-dose steroids intravenously at the time of delivery to compensate for adrenal suppression.

When hypertension and proteinuria develop after 20-weeks' gestation in an SLE patient, it often is difficult to distinguish between an SLE flare and preeclampsia. Although preeclampsia is probably a more common cause of new onset hypertension and proteinuria in SLE patients, it is important to distinguish between the two diagnoses because the treatments are quite different. Patients with an SLE flare will benefit from increasing doses of corticosteroids with or without the addition of azathioprine, and premature delivery, with its associated risks to the neonate, may not be necessary. Conversely, patients with severe preeclampsia may have increased maternal and fetal morbidity if delivery is delayed. Although many of the clinical features of these two conditions are similar, laboratory findings may be helping in distinguishing them (Table 3). Specifically, an SLE flare is often associated with rising anti-DNA titers and decreasing complement levels (C3 and C4),¹⁴ whereas preeclampsia is not. Some authors have found CH50 levels to be an even better means of distinguishing between these two entities: Decreasing levels are seen in patients with SLE flare, and normal levels are found in those with preeclampsia.¹⁵

TABLE 3. Differentiating Between Lupus Flare and Preeclampsia

Controversy exists as to the role of antiphospholipid antibody screening in SLE patients. Although initial studies showed that the presence of anticardiolipin antibody was a strong predictor of an adverse pregnancy outcome in SLE patients,¹⁶ subsequent studies have shown a weaker relationship after controlling for prior pregnancy performance.¹⁷ With a prior history consistent with antiphospholipid antibody-related loss, such as maternal thrombosis, second-trimester fetal death, or placental abruption with early growth retardation, the finding of lupus anticoagulant or immunoglobulin G anticardiolipin antibody likely predicts poor performance in future pregnancies. In the SLE patient with no history of thrombosis or thrombocytopenia and who has never been pregnant, the presence of these antibodies are of unknown significance. Patients with antiphospholipid antibodies can have normal pregnancies without therapy, and treatments used for this situation are not without risks.¹⁸ If antiphospholipid antibodies are present in a patient with characteristic prior pregnancy complications, heparin plus low-dose aspirin may improve pregnancy outcome.¹⁹ If these antibodies are detected in a patient who has had successful prior pregnancies without treatment, no therapy is indicated. In the absence of a prior pregnancy, no data exist to direct management decisions.

Some physicians have begun to recommend the use of low-dose aspirin during pregnancy for SLE patients. This recommendation is based on a number of observations. First, SLE patients were found to have higher thromboxane levels than those of non-SLE control patients, and as little as 50 mg of aspirin was found to decrease thromboxane production without affecting prostacyclin production.²⁰ Thromboxane overproduction has been identified in patients with preeclampsia, a condition which SLE patients are at increased risk for developing. Some studies have demonstrated a benefit with aspirin use for other conditions in which the risk of developing preeclampsia is increased.^21,22 Yet no trials have examined the benefits of low-dose aspirin on the prevention of preeclampsia or other adverse pregnancy outcomes specifically in SLE patients. Therefore, the benefit of using aspirin prophylactically should be considered theoretic.

A question exists as to whether patients not receiving prednisone should be given a pulse of steroids around the time of delivery in order to decrease the incidence of SLE flare in the postpartum period. Although several retrospective studies have demonstrated an increased frequency of SLE exacerbations during the puerperium, more recent prospective studies do not confirm this finding.^7,23 No prospective studies have been conducted to evaluate the benefits of prophylactic steroids in this setting, and their value for preventing maternal morbidity remains controversial.

Neonatal Lupus Erythematosus

The immune activation associated with maternal SLE can have effects on the fetus and neonate, and these effects commonly are referred to as neonatal lupus erythematosus (NLE). Many autoantibodies found in SLE mothers are of the immunoglobulin G class, and these antibodies can be transported across the placenta into the fetal circulation. Specifically, anti-Ro (also known as anti-SS-A) antibody is directed against a cytoplasmic RNA-binding protein and is present in approximately 30% of SLE patients and 60% of patients with Sjögren's syndrome.²⁴ In adults, anti-Ro has been associated with photosensitivity. This antibody and anti-La (also known at anti-SS-B) have been associated with two manifestations in the fetus or newborn with NLE. First, newborns can develop a rash within the first 2 months of life, typically on light-exposed skin, such as the face, scalp, and arms. This rash usually resolves within 6 months without scarring. The second, more concerning manifestation of NLE is congenital heart block (CHB). In 80% of cases of CHB, anti-Ro is found in the mother, whereas 40% of cases the mothers are found to have antibodies to the ribonucleoprotein La (SS-B). Conversely, CHB develops in less than 5% of fetuses of mothers with anti-Ro.²⁵

Pathophysiologically, the antibodies are thought to interact with the conduction system, resulting in endomyocardial fibrosis and obliteration of the A-V node. The diagnosis of CHB can be made by detecting fetal bradycardia (a sustained fetal heart rate less than 120 beats/min) on routine auscultation, with the detection of maternal anti-Ro or anti-La antibodies suggesting an autoimmune etiology. Fetal echocardiography can be of value in ruling out structural cardiac defects that also can be a cause of CHB and in detecting fetal heart failure. Occasionally, a progressive decline in fetal heart rate can be observed for a period of weeks or months, with some fetuses eventually progressing to a state of hydrops fetalis or stillbirth. Most fetuses, however, survive the antenatal period and require evaluation at the time of delivery. The reported fatality rate is 15%, with 20% of surviving infants requiring pacemakers. In the remainder, CHB is permanent but well tolerated.¹¹ Because there are no interventions with proven value in preventing CHB, and most patients found to have the antibodies have unaffected newborns, screening for anti-Ro and anti-La antibodies is of questionable value in SLE patients. Affected fetuses can be ascertained by noting the fetal heart rate at prenatal visits.

Systemic Sclerosis

Systemic sclerosis, or scleroderma, is another chronic autoimmune connective tissue disease. Although it usually affects women after their reproductive years, some women are affected earlier, and occasionally a pregnant patient with scleroderma is encountered. Multiple organ systems often are involved, including the skin, joints, gastrointestinal tract, and kidneys. The diagnosis of scleroderma is made on the basis of clinical findings; however, several antibodies (e.g., anti-centromere, anti-Sci-70 antibodies) are now associated with this disease and can aid in its diagnosis.

No prospective studies have evaluated the effect of pregnancy on patients with systemic sclerosis. Some reports have described cases of infertility, abortion, premature labor, fetal death, and even maternal death, while others have documented successful pregnancy outcomes with minimal morbidity. In their study, Steen and associates²⁶ did not find that pregnancy in patients with systemic sclerosis shortened life expectancy. More than 80% of patients reported that disease-related symptoms were unchanged during and after pregnancy. In addition, although preterm delivery and fetal growth restriction were more frequent among pregnant patients with scleroderma versus normal pregnant control patients, the rates of spontaneous abortion and perinatal death were similar. It is likely that most patients with systemic sclerosis will have successful pregnancy outcomes. Nevertheless, there is still concern that some patients will develop renal crisis and concomitant malignant hypertension, threatening the lives of both the mother and fetus.

Pregnancy care for patients with systemic sclerosis should be focused on assessment of maternal disease status and fetal growth. Patients with rapid progression of skin thickening are of concern because this has been associated with the development of renal crisis. Therapy should be instituted or increased for significant disease activity, and it should be directed by the symptoms. If the patient remains relatively symptom-free and fetal growth is normal, the pregnancy can be allowed to go to term with the expectation of a good outcome.

Rheumatoid Arthritis

Rheumatoid arthritis is an inflammatory arthropathy that can be progressive or intermittent. Occasionally, other systems are involved, including the heart, blood, lung, and vasculature. Drug treatment for patients with rheumatoid arthritis varies with the severity of symptoms, ranging from NSAIDs to immunosuppressive agents. Rheumatoid arthritis is the only connective tissue disease for which most reports consistently show clinical improvement during pregnancy. Although most patients note having milder symptoms by the end of the first trimester, they also note exacerbation of symptoms shortly after delivery. Similarly, the postpartum period is commonly when an initial diagnosis of rheumatoid arthritis is made.²⁷ There appear to be few fetal consequences of maternal rheumatoid arthritis, considering that this condition has not been associated with an increased risk of spontaneous abortion, preterm birth, fetal growth restriction, or perinatal mortality.

Ankylosing Spondylitis

Ankylosing spondylitis is a chronic form of arthritis primarily affecting the spine. It has been strongly associated with the specific human leukocyte antigen (HLA) B27. Previously it was thought to have an overwhelming male-to-female preponderance, but more thorough investigations plus HLA testing have led to a higher proportion of cases identified among women. Occasionally peripheral manifestations are present, so this type of arthritis should be differentiated from rheumatoid arthritis by the predominant spinal involvement and the absence of peripheral nodules and rheumatoid factor. Drug treatment for ankylosing spondylitis usually consists of NSAIDs.

Because of the rarity of this diagnosis among women of childbearing age, there exist few data regarding the effects of pregnancy on ankylosing spondylitis. From the data that do exist, the course of the disease appears to be variable: 20% experience improvement, 20% report a worsening of symptoms, and the remaining 60% have unchanged disease activity.²⁸ With many affected patients having symptoms in the sacroiliac joint, it is not surprising to see worsening discomfort as pregnancy progresses because of increasing joint laxity, increased weight-bearing, increased lordosis, and altered spinal alignment. Exacerbation of symptoms was reported in approximately 50% of patients after delivery.²⁸ There does not appear to be a higher incidence of pregnancy complications, including spontaneous abortion, preterm birth, fetal growth restriction, and preeclampsia.

For patients who experience significant pain related to ankylosing spondylitis during pregnancy, pain management is a challenge. The prolonged use of NSAIDs is of concern because of the potential risks to the fetus. Attention to proper posture and strengthening exercises in association with physical therapy may be of some benefit, and some patients can benefit from short courses of steroids.

Polymyositis and Dermatomyositis

Polymyositis is a condition of widespread weakness of striated muscle. When a characteristic rash occurs in conjunction with the onset of weakness, the term dermatomyositis is used. Specific antinuclear and cytoplasmic antibodies now have been associated with these conditions.²⁹ In polymyositis, proximal weakness of the limbs is characteristically progressive during a period of months to years. In dermatomyositis, the rash is often maculopapular, found on the face, trunk, knees, elbows, and knuckles.

The diagnoses of polymyositis and dermatomyositis are based on history, physical examination, and the finding of elevated levels of serum creatine kinase. Muscle biopsy can be definitive for polymyositis, showing muscle cell necrosis and a mononuclear inflammatory infiltrate. Electromyography can be of further help in differentiating this condition from progressive muscular dystrophies. Primary treatment for both polymyositis and dermatomyositis is glucocorticoids in high doses, but in patients with severe or unresponsive disease, other treatment options include cytotoxic agents and intravenous immunoglobulin.

Because of the paucity of reports and the potential for bias, the course of polymyositis and dermatomyositis during pregnancy is not known. Exacerbation of symptoms appear to occur in up to one third of patients who enter pregnancy in remission, but the symptoms usually are easy to control with relatively low doses of steroids. For patients with disease onset during pregnancy, clinical remission may be more difficult to attain. The risk of adverse pregnancy outcome does not appear to be increased for patients who enter pregnancy in clinical remission. In patients with disease onset or more serious manifestations occurring during pregnancy, however, the risk of adverse pregnancy outcome appears to be elevated.³⁰ Because of this, these patients should be treated aggressively in an effort to induce clinical remission.

Sjögren's Syndrome

Sjögren's syndrome is an autoimmune disorder occasionally encountered during pregnancy. It primarily affects the lacrimal and salivary glands, with resultant eye and mouth dryness as the most common symptoms. Similar to SLE, Sjögren's syndrome often is accompanied by the presence of serum anti-Ro and anti-La, and therefore pregnancies in patients with Sjögren's syndrome are at risk for CHB. No data exist to suggest that this diagnosis is otherwise associated with an increased risk of other adverse pregnancy outcomes. As with SLE, the fetal heart rate should be determined at prenatal visits as a screen for CHB.

Mixed Connective Tissue Disease

Mixed connective tissue disease is the name given to multisystem rheumatic disease with overlapping features of SLE, systemic sclerosis, rheumatoid arthritis, and polymyositis. This syndrome has been described in conjunction with ANAs and antibodies to ribonucleoprotein. Clinical features often seen with these patients include arthritis or arthralgias, lupus-like rash, telangiectasis, Raynaud's phenomenon, hypomotility of the gastrointestinal tract, myalgias, and proximal muscle weakness. The severity of these symptoms is variable, and corticosteroids often are helpful in controlling exacerbations.

The course of mixed connective tissue disease during pregnancy is similar to that seen in SLE patients. Some patients experience disease exacerbations, but most without any significant worsening of their condition. In one retrospective study, an increased rate of spontaneous abortions and stillbirths was noted in these patients compared with pregnant SLE patients and pregnant control patients.³¹ Although the reported experience with this condition and pregnancy is small, it is reasonable to counsel patients that they may be at increased risk for maternal and fetal complications.

Antinuclear Antibodies

The predictive value of screening patients for subclinical autoimmune disease has been a matter of controversy for decades. This debate stems from data suggesting that antibodies can be detected in some patients before a clinical diagnosis can be made, and that the risk of pregnancy loss is increased in these patients even before disease diagnosis. Testing for ANAs has been proposed as a screening tool for patients with otherwise unexplained adverse pregnancy outcomes, yet the significance of a positive result is unclear. Pattison and colleagues³² screened a cohort of 1000 consecutive pregnant patients for ANAs and did not use the results to influence pregnancy management. In this low-risk population, ANAs were identified among 3.2% of patients. All of these patients had successful pregnancies unless lupus anticoagulant was also present. In another study, 277 patients with recurrent pregnancy loss were screened for ANAs and compared with both pregnant and nonpregnant control patients. The prevalence of ANA titers of 1:40 or greater were similar in all groups, but titers of 1:80 or greater were found more frequently among the patients with recurrent pregnancy losses. Nevertheless, among patients with recurrent spontaneous abortion, the outcomes of subsequent pregnancies were similar with or without the presence of ANAs.³³ Thus, although testing for ANAs occasionally will identify a patient who later develops a connective tissue disease, it is a poor predictor of pregnancy success. Because most women with ANAs but no preexisting diagnosis of autoimmune disease have normal pregnancy outcomes, no therapy is indicated.

Numerous agents have been used to treat autoimmune disorders, with varying degrees of success and toxicity. The pregnant patient with connective tissue disease often requires treatment before conception and during the pregnancy. The physician must confront the dilemma of regulating the maternal disease while considering the effects of the medications on both the mother and developing fetus. This section will review the reported experience with various agents during pregnancy and the observed effects on fetal well-being.

Nonsteroidal Anti-Inflammatory Drugs

NSAIDs commonly are used for many different autoimmune disorders. Their anti-inflammatory properties are helpful in modulating disease activity and in directly ameliorating specific symptoms, such as arthralgia, serositis, and fever. These drugs usually are well tolerated by the patient, but with prolonged exposure, side effects such as gastritis, peptic ulcer disease, and coagulation abnormalities can occur. Patients with underlying renal disease can experience decreased renal function and worsening hypertension.

Acetylsalicylic acid (aspirin) is a potent NSAID that is very effective in treating arthralgia and fever. It inhibits platelet cyclo-oxygenase and can cross the placenta into the fetal circulation after maternal ingestion. Before the formulation of acetaminophen, aspirin use was widespread during pregnancy with few reported problems. In addition, aspirin use in early pregnancy does not appear to increase the likelihood of congenital malformations.³⁴ Concerns have been raised, however, that chronic aspirin intake may prolong pregnancy and labor and may increase the risk for maternal hemorrhage at the time of delivery.³⁵ Hemorrhage in the fetus and neonate and premature closure of the ductus arteriosus also have been reported. Although these reports are of concern, their clinical significance is uncertain because the frequency of these complications with aspirin use is not known. Nevertheless, aspirin use (5 to 10 g) in the last week before delivery has been associated with abnormal platelet aggregation and increased blood loss in the mother, as well as abnormal platelet aggregation and bleeding complications in the neonate.³⁶ Because of these concerns, caution is advised when recommending the use of aspirin at high doses during pregnancy if other alternatives are available, especially in the weeks preceding delivery.

Other NSAIDs are also quite effective in controlling symptoms of autoimmune disorders, but concerns regarding their safety have been raised as well. Indomethacin has been found to inhibit labor and to decrease fetal urinary output, which has led to its use as a tocolytic agent and as a treatment for hydramnios.^37,38 Its use for more than 72 hours in patients without hydramnios, however, can lead to decreased amniotic fluid volume.³⁹ The prolonged use of indomethacin also has been associated with premature closure of the ductus arteriosus,⁴⁰ although this finding usually resolves with the discontinuation of medication. Although short courses can be helpful in certain clinical situations, use for extended periods of time should be accompanied by assessment of the fetus for ductus closure and amniotic fluid volume. As with aspirin, use of this type of drug in early pregnancy has not been associated with an increased risk of teratogenesis.

Glucocorticoids

Glucocorticoids, such as prednisone, have been an important part of treatment for many autoimmune disorders, and are credited with much of the improvement in prognosis for SLE patients. they produce rapid suppression of inflammation, most likely through impairment of antigen opsonization, interference with inflammatory cell adhesion and migration, interruption of cell-to-cell communication by alteration of release or antagonism of cytokines, decreased immunoglobulin generation, and impaired transit of immune complexes across basement membranes.⁴¹ There is now considerable experience with the use of glucocorticoids during pregnancy, not only in patients with collagen vascular disease, but also in patients with asthma.

Initially, it was thought that prednisone was associated with an increased risk of teratogenesis. Animal studies linked its use with cleft palate and low birth weight. Nevertheless, human studies have not demonstrated an association between fetal exposure to glucocorticoids and cleft lip.⁴² Furthermore, prednisone is rapidly converted to prednisolone in the maternal circulation. Because of placental metabolism of prednisolone to inactive metabolites, fetal prednisolone levels are approximately 10% of those found in the maternal circulation.⁴³ Fetuses exposed to glucocorticoids have a higher risk of growth restriction, but this probably is due to the underlying maternal medical condition rather than to a medication effect. Therefore, it is thought that prednisone poses no known risk to the fetus, and that its use during pregnancy often is warranted in patients with autoimmune disorders.

Although fetal risks of glucocorticoid exposure may not be significant, maternal risks are clearly present and dose-related. Documented risks include glucose intolerance, susceptibility to infection, cataracts, osteopenia, hypertension, and avascular necrosis of the femoral head. Therefore, exacerbations of autoimmune disorders should be treated aggressively, but consideration should be given to treating the patient with the lowest effective dose. Tapering of glucocorticoids should be attempted whenever it can be accomplished without aggravating the underlying maternal condition.

Disease-Remittive Drugs

CHLOROQUINE AND HYDROXYCHLOROQUINE.

The 4-aminoquinoline antimalarials chloroquine (Aralen) and hydroxychloroquine (Plaquenil) are used to treat patients with rheumatoid arthritis and SLE. The mechanism of action of these antimalarial drugs is unknown, but they are known to have a high affinity for DNA and to intercalate between adjacent base pairs to inhibit cellular division and RNA transcription and translation.⁴⁴ Hydroxychloroquine may be less toxic and currently is used more frequently than chloroquine in clinical practice. The doses of chloroquine and hydroxychloroquine used for treatment of rheumatic diseases are 500 mg chloroquine phosphate daily or 200 to 400 mg hydroxychloroquine daily. An eye examination is recommended every 6 to 12 months to screen for retinal toxicity.

These antimalarial agents accumulate in human fetal tissues.⁴⁵ Although chromosomal damage has been shown in vitro,⁴⁶ the in vivo clinical significance has not been determined. Case reports have described retinal degeneration, hemihypertrophy, Wilms' tumor and cochleovestibular paresis in infants exposed to chloroquine in utero.⁴⁷ Conversely, MacKenzie reviewed the experience with antimalarial drug use during pregnancy in patients with rheumatoid arthritis and no malformations were noted.⁴⁸ The use of antimalarials during pregnancy remains controversial. Nevertheless, continuing antimalarial therapy during pregnancy at the lowest dose required to control disease may be appropriate in some clinical situations.

CYCLOSPORINE.

Cyclosporine (Sandimmune), a neutral, lipophilic fungal peptide, has been used as an immunosuppressive agent since the mid 1970s. The mechanism of action of cyclosporine is through the inhibition of DNA transcription, which prevents accumulation of mRNA for several cytokines, especially interleukin-2 (IL-2).⁴⁹ The major use for this drug has been in organ transplantation. More recently, it has been used as therapy for various autoimmune diseases; however, concerns regarding nephrotoxicity, hypertension, increased frequency of cancer, and a higher incidence of viral infections have tempered its use.⁵⁰ If cyclosporine levels are monitored, plasma through levels should be obtained 12 to 18 hours after an oral dose, and the dose should be adjusted downward if the trough level is greater than 300 ng/mL. In an effort to maintain cyclosporine plasma concentrations as low as possible during pregnancy, the total daily dose may be given in split doses.

No increased risk of congenital anomalies has been observed among infants exposed to cyclosporine in utero. In 1992, Østensen reviewed 75 pregnancies of 70 mothers in whom the majority were treated with cyclosporine and glucocorticoids to prevent allograft rejection.⁵¹ Renal and liver function were normal in exposed infants. Growth restriction and premature delivery occurred in approximately 40% of the pregnancies, and several neonates had minor laboratory abnormalities. There is limited experience with long-term follow-up of children exposed to cyclosporine in utero. The pregnancies in women treated with cyclosporine are considered high risk, and the contribution of the underlying maternal disease and concomitant use of other medications to problems such as intrauterine growth restriction are unknown.

GOLD.

Sulfhydryl-containing organic gold compounds are used for the treatment of rheumatoid arthritis, juvenile rheumatoid arthritis, and psoriatic arthritis. Gold sodium thiomalate (Myochrysine) and aurothioglucose (Solganal) are the two injectable preparations available in the United States. An oral form, auranofin (Ridaura), also is available, but it is generally less effective than injectable gold. Gold compounds interfere with lymphocyte, monocyte, and neutrophil function, as well as with immunoglobulin and antibody production. Because rheumatoid arthritis tends to improve during pregnancy, the dose of gold may be decreased or discontinued. The toxicity profile of gold includes stomatitis, pruritic rash, proteinuria, leukopenia, and thrombocytopenia. Monitoring for drug toxicity includes a complete blood count with white blood cell differential, platelet count, and urinalysis before each injection or every other injection to detect drug-related cytopenias or proteinuria. Oral gold (auranofin) causes fewer symptoms of mucocutaneous, bone marrow, and renal toxicity then injectable gold, but it has a greater association with the side effects of diarrhea and other gastrointestinal symptoms. Mothers have taken intramuscular gold injections throughout pregnancy without obvious fetal toxicity. There have been reports of musculoskeletal problems (congenital hip dislocation and a flattened acetabulum) and fetal growth restriction among children exposed to gold during gestation, but the clinical significance of these reports is unclear.^51,52 Little is known about the effects of auranofin on the human fetus.

SULPHASALAZINE.

Sulphasalazine has been used to treat rheumatoid arthritis and seronegative spondyloarthropathies as well as inflammatory bowel disease. It is a conjugate of salicylate 5-aminosalicylic acid and sulfonamide sulfapyridine and is split into these two components by colonic bacteria. Its mechanism of action is threefold: inhibition of polymorphonuclear migration, reduction of lymphocyte responses, and inhibition of angiogenesis.⁴¹

Sulphasalazine is considered a category B drug because animal studies have not demonstrated an increased risk of congenital anomalies. Similarly, no increase in malformations has been identified among human fetuses exposed to this agent in utero. Unlike aspirin, sulphasalazine use has not been associated with prolonged pregnancy, premature closure of the ductus arteriosus, or fetal or neonatal bleeding.

Cytotoxic Drugs

AZATHIOPRINE.

The only cytotoxic drug recommended for use during pregnancy is azathioprine (Imuran). Other cytotoxic drugs commonly used in patients with rheumatic diseases, such as methotrexate and cyclophosphamide, are not recommended when these patients are pregnant unless a life-threatening illness is present and other measures are deemed inadequate.

Azathioprine, an antimetabolite metabolized to 6-mercaptopurine, is used as an immunosuppressive agent in the management of renal transplantation and SLE and as a disease-modifying agent for rheumatoid arthritis. Azathioprine is a purine analog that interferes with the synthesis of adenine and guanine ribonucleosides and impedes immunologic functions by decreasing natural killer cell activity, antibody production, antibody-dependent cellular cytotoxicity, and cellular immune responses, such as IL-2 secretion.⁵³

The usual oral maintenance dose of azathioprine is 1 to 3 mg/kg/day. Monitoring for drug toxicity includes a complete blood count, platelet count, and liver function tests every 1 to 3 months. Monthly monitoring during the third trimester has been suggested because several infants exposed to azathioprine in utero have had leukopenia and thrombocytopenia at birth. For example, if the maternal leukocyte count falls significantly below the normal range, the dose of azathioprine should be cut in half.⁵⁴ Theoretically, the fetus should be protected from the effects of azathioprine in early pregnancy because the fetal liver lacks the enzyme inosinate pyrophosphorylase, which converts azathioprine to its active metabolites. Azathioprine has not been associated with an increased risk of spontaneous abortion, congenital defects, or still-birth in humans; however, rates of fetal growth restriction from 15% to 40% have been reported for patients treated during pregnancy with azathioprine and glucocorticoids because of a renal transplant, even when they had normal renal function during the pregnancy.^55,56 Whether the abnormal fetal growth was drug related or a consequence of the underlying maternal condition is uncertain. Monitoring for adequate fetal growth and the status of maternal disease in pregnant women treated with azathioprine is strongly recommended. Neonatal immunosuppression, characterized by lymphopenia and decreased immunoglobulin levels, and neonatal cytomegalovirus infection have been observed after fetal exposure to azathioprine.⁵⁷ Therefore, although the benefits of azathioprine use during pregnancy may outweigh its risks, this agent should be used with caution.

Women with rheumatic diseases frequently need treatment throughout pregnancy. Glucocorticoids have been used extensively and safely in pregnant patients with SLE and rheumatoid arthritis; there is no increased risk of congenital malformations in exposed infants. Limited information exists regarding the safety during pregnancy of other disease-modifying antirheumatic medications, including hydroxychloroquine, cyclosporine, gold salts, and sulphasalazine. Considerable experience with azathioprine during pregnancy supports its use if the maternal condition requires use of a cytotoxic drug; there has been no reported increase in the risk of congenital malformation in exposed infants. The other cytotoxic drugs frequently used in the treatment of rheumatic diseases, cyclophosphamide and methotrexate, are contraindicated during pregnancy unless a life-threatening illness is present and other measures are deemed inadequate.