Rheumatologic and Connective Tissue Disorders in Pregnancy
Gustavo F. Leguizamón
E. Albert Reece
Introduction
Rheumatologic and connective tissue disorders are multisystem conditions that occur most commonly in women of reproductive age. Therefore, it is not unusual for the obstetrician to be challenged by patients with autoimmune disorders seeking preconception counseling or antenatal care. This chapter addresses the effect of systemic lupus erythematosus (SLE), scleroderma, rheumatoid arthritis (RA), ankylosing spondylitis (AS), and Sjögren syndrome (SS), on perinatal outcomes as well as the impact of pregnancy on the natural course of these conditions. Finally, drugs commonly used to treat these disorders during pregnancy are reviewed.
Systemic Lupus Erythematosus
SLE is a chronic autoimmune disorder of unknown etiology. It has an overall incidence in North America of 23.2/100.000 person-year.1 A strong predilection for women is observed with a reported female to male ratio, ranging from 2:1 to 15:1. Furthermore, African Americans have the highest reported prevalence of SLE, followed by Hispanics, and then whites.2
The onset of SLE is often subtle and can compromise one or multiple organ systems. Frequently, the disease is characterized by periods of activity alternating with quiescence (relapsing-remitting). Systemic signs and symptoms are common and usually involve fatigue, fever, malaise, and weight loss. The frequency of involvement of major systems is depicted in Table 40.1.
In 2012, the Systemic Lupus International Collaborating Clinics Group revised and modified the classification of SLE.3 If at least four criteria are met (either simultaneously or serially), the diagnosis of SLE is achieved (Table 40.2) with a sensitivity of 96.7% and a specificity of 83.7%. Recently, a new international classification system was proposed using antinuclear antibodies (ANA) as a key entry criterion. The authors reported similar sensitivity (96.1%) and higher specificity (93.4%).4
Classification criteria are not designed for diagnosis or treatment purposes, their objective is to improve patient selection and research strategies. Patients who do not fulfill criteria for diagnosis that can benefit from treatment should be managed individually based on the evaluation of a trained physician.
Assessment of SLE in Pregnancy
Laboratory Evaluation
ANA are the most sensitive screening laboratory tool for evaluating patients with the clinical suspicion of SLE. Approximately 90% of patients will present a positive test for ANA. False positives have been reported in healthy subjects and those with chronic inflammatory disorders, other autoimmune
diseases, certain drugs, and viral infections.4 A negative ANA result makes the diagnosis of lupus very unlikely, whereas a positive result (>1/80) favors the diagnosis. Antibodies directed against double-stranded DNA (dsDNA) and Smith (Sm) have better specificity; however, they are only present in a minority of the patients. Antibodies against dsDNA are present in approximately 60% of patients with SLE and have been associated with disease activity and nephritis.5 Anti-Sm antibodies are present in approximately 10% of Caucasian and 30% of African American populations with SLE. It has also been suggested that these antibodies are associated with disease activity, as well as renal and neurological involvement.6 Although the ability of antibody testing to predict disease activity is controversial, in general, rising titers of anti-dsDNA antibodies suggest a two- to threefold increased risk of flare in the following 3 to 4 months. In some patients, however, decreasing plasma complement together with other laboratory abnormalities, such as microscopic hematuria, decreased leukocyte count, and increasing proteinuria, is better predictors of lupus exacerbation.6 The presence of anti-Ro (SS-A) and anti-La (SS-B) antibodies is of recognized clinical significance as they were consistently associated with neonatal lupus and heart block.7 These antibodies are present in 20% to 60% of patients with SLE depending on the techniques used for their detection. Table 40.3 depicts relevant clinical information for different antibodies.
diseases, certain drugs, and viral infections.4 A negative ANA result makes the diagnosis of lupus very unlikely, whereas a positive result (>1/80) favors the diagnosis. Antibodies directed against double-stranded DNA (dsDNA) and Smith (Sm) have better specificity; however, they are only present in a minority of the patients. Antibodies against dsDNA are present in approximately 60% of patients with SLE and have been associated with disease activity and nephritis.5 Anti-Sm antibodies are present in approximately 10% of Caucasian and 30% of African American populations with SLE. It has also been suggested that these antibodies are associated with disease activity, as well as renal and neurological involvement.6 Although the ability of antibody testing to predict disease activity is controversial, in general, rising titers of anti-dsDNA antibodies suggest a two- to threefold increased risk of flare in the following 3 to 4 months. In some patients, however, decreasing plasma complement together with other laboratory abnormalities, such as microscopic hematuria, decreased leukocyte count, and increasing proteinuria, is better predictors of lupus exacerbation.6 The presence of anti-Ro (SS-A) and anti-La (SS-B) antibodies is of recognized clinical significance as they were consistently associated with neonatal lupus and heart block.7 These antibodies are present in 20% to 60% of patients with SLE depending on the techniques used for their detection. Table 40.3 depicts relevant clinical information for different antibodies.
Table 40.1 Frequency of Organ System Involvement in Systemic Lupus Erythematosus | ||||||||||||||||||||
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Table 40.2 Classification Criteria for the Diagnosis of Systemic Lupus Erythematosus (SLE). Systemic Lupus International Collaborating Clinics Group (SLICC) Criteria. Four Criteria (At Least One Clinical and One Immunologic Item for Diagnosis) | ||||||||||||||||
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Effects of Pregnancy on SLE
The impact of pregnancy on SLE has been a matter of debate. The fact that this disorder has a clear predilection for female subjects raises the notion that estrogen levels are involved in the pathophysiology of SLE. Therefore, high estrogen level conditions, such as pregnancy, generate significant concern. Overall, the incidence of lupus flares during pregnancy ranges from 25% to 65%.8 Whether pregnancy presents increased risk for the occurrence of
flares remains debatable. Prospective studies have shown contradictory results. While some authors report no differences in lupus flares during pregnancy,9,10,11,12,13 others observe disease exacerbation.14,15,16 The use of objective methods to determine disease activity suggests an overall increased frequency of lupus flares in pregnancy.8,17 Importantly, the incidence of SLE flares is low among women with inactive disease at conception and higher in those with active disease. Numerous reasons can explain this lack of consistency: inadequate control, differences in patient characteristics, proportion of patients with antiphospholipid syndrome (APS), inconsistencies in flare definition, and methods of assessment of disease activity. Furthermore, physiologic changes of pregnancy, such as anemia, decreased platelet count, increased urinary protein excretion secondary to increased renal blood plasma flow, and changes in facial skin pigmentation, can often lead to over diagnoses of lupus flare in pregnancy.
flares remains debatable. Prospective studies have shown contradictory results. While some authors report no differences in lupus flares during pregnancy,9,10,11,12,13 others observe disease exacerbation.14,15,16 The use of objective methods to determine disease activity suggests an overall increased frequency of lupus flares in pregnancy.8,17 Importantly, the incidence of SLE flares is low among women with inactive disease at conception and higher in those with active disease. Numerous reasons can explain this lack of consistency: inadequate control, differences in patient characteristics, proportion of patients with antiphospholipid syndrome (APS), inconsistencies in flare definition, and methods of assessment of disease activity. Furthermore, physiologic changes of pregnancy, such as anemia, decreased platelet count, increased urinary protein excretion secondary to increased renal blood plasma flow, and changes in facial skin pigmentation, can often lead to over diagnoses of lupus flare in pregnancy.
Table 40.3 Antibodies of Clinical Significance in Systemic Lupus Erythematosus (SLE) | |||||||||||||||||||||
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Most flares are mild to moderate and well controlled with medical treatment. However, approximately 15% to 30% will have severe disease involving other major organ functions.17,18 The most frequent organs involved in flares during pregnancy are kidneys, blood, skin, and joints. Furthermore, renal and hematological compromise is more frequent during gestation.19
Moderate to severe flares during pregnancy increase maternal and perinatal morbidity and are mostly associated with lupus nephritis. Therefore, it is of outmost importance to identify predictors for this condition. Active disease within 6 months of conception, active lupus nephritis at conception, and discontinuation of disease modifying agents, such as hydroxychloroquine, are main risk factors for developing lupus flares during pregnancy or the postpartum period.8,20,21 Gladman et al evaluated in 193 pregnancies the impact of occurrence of lupus nephritis up to 6 months before conception. The authors reported a significant increase in lupus flare (45% vs 13.4%) throughout pregnancy.22
Because history of renal disease is always a concern in pregnancy, it is important to differentiate active renal involvement from women with history of renal disease but who are in remission at the time of pregnancy. To address the risk of renal flares during gestation in women with lupus and history of renal disease, Buyon et al23 prospectively evaluated 373 women enrolled in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Antibody Syndrome and Systemic Lupus Erythematosus) study. Three groups were analyzed: those with a history of nephritis with complete remission (proteinuria <500 mg/day), those with partial remission (500-1000 mg/day), and those without history of lupus-associated renal disease. The authors concluded that occurrence of renal flares was infrequent among patients without history (<2%). Furthermore, complete and partial remission were associated with 7.9% and 20.7% flare occurrence, respectively.23
There is a paucity of data regarding the impact of pregnancy on long-term outcome of lupus nephritis. Gianfreda et al compared the outcome of lupus nephritis in 32 women 10 years after pregnancy with 64 matched controls (lupus nephritis and no pregnancy). The authors observed that pregnancy does not increase the rate of renal or extrarenal flares. Furthermore, pregnancy was not associated with decline in renal function.24 These findings need further investigation with larger prospective studies and are probably limited to a population that shows remission of renal disease before or at early pregnancy. Table 40.4 summarizes relevant information about pregnancy influencing the natural course of SLE.
Effects of SLE on Pregnancy
SLE can affect pregnancy in different ways. It increases the risk of early and late pregnancy losses owing to hypertension, renal dysfunction, placental insufficiency, and its association with APS. Furthermore, it is an important cause of fetal and neonatal heart block. Finally, it also increases the
risk of spontaneous as well as medically indicated preterm labor. In the following sections, the relevant aspects of such complications are discussed.
risk of spontaneous as well as medically indicated preterm labor. In the following sections, the relevant aspects of such complications are discussed.
Table 40.4 Effects of Pregnancy on the Natural Course of Systemic Lupus Erythematosus | |
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Preeclampsia
Women with SLE have an increased risk of developing preeclampsia with an incidence of 16% to 30%.8,25,26 Several predictors have been identified, such as lupus nephritis, APS, chronic hypertension, thrombocytopenia, and declining complement levels during the second half of pregnancy.8,26,27 The differential diagnosis between the onset of preeclampsia and the occurrence of lupus flare could be challenging for the obstetrician. Making an accurate diagnosis is of utmost importance because the therapeutic approach differs substantially: while the lupus flare is treated with high doses of steroids, preeclampsia is most likely treated with seizure prophylaxis, control of hypertension, and, eventually, delivery. Both conditions can coexist in a patient with SLE and, even when they present as a single complication, both can cause hypertension, deteriorating renal function, proteinuria, and edema. Laboratory evaluation can be helpful in making the differential diagnosis. Mainly, decreased complement levels (C3-C4-CH50), increased anti-dsDNA, leukopenia, hematuria, and the presence of casts in urine raise the suspicion for SLE flare, while the presence of microangiopathic hemolytic anemia, abnormal liver function tests, and hyperuricemia most likely indicate preeclampsia. Although renal biopsy could help in the differential diagnosis, the enhanced risk of bleeding complications during pregnancy needs to be carefully considered and limits its use. Occasionally, this challenging clinical dilemma needs to be approached with either delivery or a trial of empiric therapy, and gestational age is a critical factor when considering these options.
Fetal Outcomes
Most investigations are consistent with the notion that women with SLE present an excess risk of fetal complications. A meta-analysis28 of 11 studies compared pregnancy outcomes of over 3000 women with SLE with a control group of healthy pregnant women. The authors observed significant increased probability (38%) of a live birth among the control population. Furthermore, several important fetal complications were more frequent among patients with lupus such as preterm birth (relative risk [RR] 3.05), intrauterine growth restriction (IUGR) (RR 1.69), admission to neonatal intensive care unit (RR 2.76), and perinatal death (RR 1.70).
Clinical presentation of SLE is frequently subtle, and immune system alterations are usually observed preceding clinical diagnosis. In fact, autoantibodies were reported to be present up to 5 years before clinical diagnosis.29,30 To determine if this altered immunologic state has a negative impact on perinatal outcome, Arkema et al prospectively studied pregnant women with pre-SLE (first presenting with SLE up to 5 years postpartum). The authors observed significant increased risk for preterm birth, preeclampsia, and IUGR in women with pre-SLE. Furthermore, the frequency of these complications was higher among women developing SLE at 0 to 2 years after pregnancy than those with SLE diagnosis after 2 to 4 years.31 Eudy et al further evaluated the causes of increased preterm delivery in this population. The authors found that the majority of preterm births (70%) were medically indicated secondary to preeclampsia or unstable maternal or fetal condition.32
Selected patients with immune diseases have an excess risk of perinatal morbidity and mortality. The most significant factors influencing outcome are most likely activity of disease at conception, as well as 6 months before pregnancy, renal involvement, and the presence of APS.
In summary, although most pregnancies in women with SLE do well, those presenting with risk factors need to be monitored aggressively throughout pregnancy.
Antiphospholipid Syndrome
APS is an autoimmune disorder frequently associated with other immunologic-related diseases with significant impact on perinatal and maternal
outcomes. Primary APS occurs in patients without other immune disorders, whereas the so-called secondary APS occurs in conjunction with autoimmune disease, mainly SLE.
outcomes. Primary APS occurs in patients without other immune disorders, whereas the so-called secondary APS occurs in conjunction with autoimmune disease, mainly SLE.
An international consensus has been generated to orient research efforts and aid in clinical diagnosis of APS33 (Table 40.5). At least one clinical and one laboratory criterion must be met to achieve the diagnosis of APS. Clinical criteria consist of either vascular thrombosis or pregnancy complications such as one or more unexplained deaths of a morphologically normal fetus at or beyond the 10th week of gestation; one or more premature births before 34 weeks of a morphologically normal fetus that was secondary to eclampsia, severe preeclampsia, or placental insufficiency; or three or more unexplained consecutive spontaneous abortions before 10 weeks of gestation.
Laboratory criteria for APS center around detection of antiphospholipid antibodies (aPLs). Although many aPLs have been described, only lupus anticoagulant (LAC), anti-β2 glycoprotein-1 IgG or IgM antibodies, and moderate to high levels of IgG and IgM anticardiolipin detected on two occasions separated by no less than 12 weeks are recognized criteria. Laboratory detection of LAC must follow the guidelines of the International Society of Thrombosis and Haemostasis34 including (1) prolongation of at least one phospholipid-dependent coagulation test (eg, activated partial thromboplastin time, dilute Russell viper venom time, kaolin clotting time); (2) failure to correct the initial phospholipid-dependent clotting test when mixed with normal plasma; and (3) correction of the abnormal coagulation assay when excess phospholipid is added.
Table 40.5 International Consensus Statement on Preliminary Criteria for the Classification of the Antiphospholipid Syndrome | |||||||
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Among patients with aPLs antibodies, excess vascular and obstetric morbidity is observed when these antibodies react against the phospholipid-binding protein β2 glycoprotein I. In contrast, antibodies reacting directly against negatively charged phospholipids are commonly transient and associated with intravenous drug exposure. Therefore, laboratory detection of the anticardiolipin antibodies must be performed by standardized enzyme-linked immunosorbent assay (ELISA) methods measuring β2 glycoprotein I-dependent anticardiolipin antibodies.33 These antibodies are highly prevalent among women with SLE. In fact, anticardiolipins were reported to be present in 12% to 44% of patients, while LAC and anti-β2 glycoprotein-1 antibodies are present in 15% to 34% and 10% to 19% of patients, respectively.21
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