Phil Popham BSc, MBBS, FRCA, MD, Robert W. Reid MD
Chapter Outline
Medical and Obstetric Management
SYSTEMIC SCLEROSIS (SCLERODERMA)
Effect on Pregnancy and the Fetus
POLYMYOSITIS AND DERMATOMYOSITIS
Medical and Obstetric Management
In the late 19th century Ehrlich proposed the dictum of horror autotoxicus, the belief that immunity is directed against foreign material and never against one's own body. The demonstration of autoantibodies in the 1950s disproved the theory and demonstrated the failure of self-tolerance.1 Autoimmunity has been described in more than 40 disorders, and it may result in chronic illness and severe disability.
The cause of autoimmunity involves genetic and environmental factors, and consequently the classification of autoimmune diseases has been controversial. The traditional clinical classification recognizes immune responses that are directed against a particular antigen and are limited to a particular organ or cell type (organ-specific disease), and those that are directed against a range of antigens that produce multisystem involvement (systemic disease). Some examples are shown in Box 41-1. Classification now incorporates a “spectrum of autoimmunity” from low-level (possibly beneficial to self) to high-level (clearly detrimental to self) autoimmunity.2
The pathogenesis of autoimmunity is complex. A genetic predisposition underlies abnormal reactivity of B cells and immunoglobulins, T-cell receptors, and genes within the major histocompatibility complex (MHC).3 Specific allotypes within the MHC are associated with certain diseases; for example, HLA-DR2 is strongly positively associated with systemic lupus erythematosus (SLE) but negatively associated with diabetes mellitus type 1, HLA-DR4 is associated with rheumatoid arthritis and diabetes mellitus type 1, and HLA-B27 is associated with ankylosing spondylitis. Recent work using genome-wide association studies has identified genetic associations between single nucleotide polymorphisms (SNPs) and autoimmune conditions4 and may lead to a new classification of autoimmune disease.5 Meta-analyses of HLA subclasses show similar associations with autoimmunity.6
Environmental factors may predispose to autoimmunity. Parasitic infection may reduce the incidence of autoimmunity, whereas bacterial infection with Klebsiella may predispose to ankylosing spondylitis. Drug-induced SLE is well described.
Sex hormones, notably the androgen-estrogen balance and its effect on cytokine production, have been implicated in the development of autoimmunity.7 Autoimmune disorders are more common in women than men, with the highest incidence of several conditions occurring during the childbearing years; occasionally, the initial diagnosis is made during pregnancy. During normal pregnancy, altered immune function allows maternal tolerance of the fetal allograft. Both mother and fetus produce immunologic factors that inhibit maternal cell-mediated immunity,8,9 prevent rejection of the fetus, and limit the expression of autoimmunity. Conversely, the high estrogen environment of pregnancy may enhance immune function.10 Although this may protect the mother and fetus from peripartum infection, it increases the likelihood of autoimmune conditions.
Systemic lupus erythematosus, lupus anticoagulant, scleroderma, and polymyositis/dermatomyositis are discussed in this chapter. Other autoimmune disorders are discussed elsewhere in this text, including diabetes mellitus type 1 (see Chapter 43) autoimmune thrombocytopenic purpura and autoimmune hemolytic anemia (see Chapter 44), rheumatoid arthritis and ankylosing spondylitis (see Chapter 48), and myasthenia gravis (see Chapter 49).
Systemic lupus erythematosus (SLE) is a multisystem inflammatory disease of unknown etiology that is characterized by the production of autoantibodies against nuclear, cytoplasmic, and cell membrane antigens. Although SLE may occur at any age, it is recognized most commonly in women during their childbearing years, with a female-to-male ratio of 9 : 1. African-Americans, Asians, and Native Americans are affected more often than whites.11 An estimated 1 in 1200 deliveries occur in women with SLE.12
The etiology of SLE remains unclear. The principal mechanism is thought to be an immune complex disease involving IgG antibodies to double-stranded DNA and other nuclear proteins. Intracellular autoantigens are released by necrotic and apoptotic cells, leading to aberrant sensitization against these antigens. Impaired clearance of apoptotic cells and prolonged exposure to nuclear autoantigens may be involved.13 Affected individuals have both hyperactivity of the antibody-producing B cells and defects of the helper and suppressor T cells.14 Genetic defects of immune regulation and possibly environmental triggers including viruses and bacteria lead to a proliferation of B cells capable of producing autoantibodies. More than 30 classes of antigens have been identified as targets of these antibodies. A variety of antigen-antibody immune complexes are formed, followed by secondary inflammatory responses. Deposition of immune complexes and continued inflammation within the glomerulus may lead to irreversible renal injury. Deposits also occur within the skin, choroid plexus, and other endothelial surfaces, with or without an inflammatory response. However, SLE is not simply an immune complex disorder because some autoantibodies actively bind to erythrocytes, granulocytes, lymphocytes, and macrophages, leading to their removal from the circulation.11
Clinical manifestations of SLE are diverse, owing to the widespread antigenic targets. Box 41-2 outlines objective criteria for the diagnosis of SLE.15,16 Although epidemiologic studies require the presence of four or more of these criteria, the clinical diagnosis may be suspected if fewer features are present without another explanation. Typically, the diagnosis of SLE is made before conception, but in 20% of cases the initial diagnosis is made during pregnancy.17
Although pregnancy does not worsen the long-term course of SLE,18,19 disease activity may increase during pregnancy.20,21 A preconception history of nephritis predicts adverse maternal outcome.22 The risk for significant disease activity during pregnancy is increased sevenfold if active disease is present in the 6 months before conception.23 Assessments using the SLE Disease Activity Index found that 50% to 65% of women with active disease had deterioration during pregnancy in both retrospective24 and prospective25 studies. Such flares occur most commonly in the second and third trimesters and the puerperium and are not more severe than those in nonpregnant patients; most respond to conservative management.
Most women with SLE do not have renal impairment at conception, possibly because renal insufficiency impairs fertility. If lupus nephritis does preexist, deterioration in renal function may occur during pregnancy. This is generally mild and reversible, but 12% of pregnant women with SLE suffer irreversible progression of renal dysfunction.26,27 Long-term glomerular filtration rate may be preserved.28
The presence of hypertension, edema, and proteinuria in both lupus nephritis and preeclampsia makes distinguishing between the two difficult. It is not clear whether preeclampsia is more common in patients with SLE, but a large meta-analysis suggests an association between lupus nephritis and preeclampsia.29 The distinction is critical because treatments are different (immunosuppressive therapy for lupus nephritis versus delivery for preeclampsia). Increased serum uric acid concentration, proteinuria without active urinary sediment, and liver enzyme abnormalities suggest preeclampsia rather than SLE.
SLE may cause thrombocytopenia. When thrombocytopenia occurs in a pregnant woman, preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome, and disseminated intravascular coagulation must also be considered. Anemia, a common manifestation of SLE, must be differentiated from nutritional anemia and the physiologic anemia of late pregnancy.
Ligamentous relaxation often occurs during late pregnancy and may worsen the pain of lupus arthritis. Patients with SLE occasionally require joint replacement, most commonly of the femoral head. These prostheses may become painful, dislocated, or infected during pregnancy.30 Neurologic complications of SLE are rare during pregnancy but include seizures, chorea gravidarum, and stroke.
Maternal SLE impairs fetal survival and increases the risk for preterm delivery. A systematic review of papers published between 1980 and 2009 showed that preterm delivery occurred in 39.4% of 2751 pregnancies in 1842 patients.29 In the Hopkins Lupus Pregnancy Cohort, preterm birth occurred in 38 of 57 (67%) pregnancies in women with moderate to severe active SLE, compared with 68 of 210 (32%) pregnancies in women with inactive or mild active SLE.31 Improved perinatal management and control of disease activity has reduced the rate of fetal loss from 43% (between 1960 and 1965) to 17% (between 2000 and 2003).32 Data from California showed a preterm delivery rate in SLE that was six times higher than that found in the general population.33
Neonatal lupus erythematosus (NLE) is a syndrome that results from maternal autoantibodies against Ro (SS-A) or La (SS-B) crossing the placenta and binding to fetal tissue. These autoantibodies are found in up to 87% of patients with SLE,34 but NLE occurs in only a small proportion of patients. The condition is generally benign and self-limiting, and reversible manifestations such as cutaneous lupus, elevation in aminotransferase levels, and thrombocytopenia resolve as maternal antibodies disappear from the neonatal circulation within 8 months of birth. Anti-Ro/anti-La antibodies may bind to fetal cardiac conduction cells in utero, leading to cell death and irreversible fetal heart block. Neonatal congenital heart block occurs in 2% of neonates when anti-Ro antibody is detected in the mother.35 Fetal echocardiography reveals atrioventricular dissociation, cardiac dilation, and pericardial effusion. Treatment includes prompt delivery, newborn cardiac pacing, antepartum administration of dexamethasone, and consideration of apheresis to remove maternal antibodies.36
Optimally, women with SLE should delay pregnancy until their disease has been quiescent for at least 6 months, and they should be taking “acceptably safe” medications at the time of conception.21,23,27,37 Medications with acceptable safety are used to minimize disease activity during gestation.
Disease-modifying antirheumatic drugs (DMARDs) and immunosuppressive agents form the mainstay of treatment. Antimalarial drugs are frequently used to reduce SLE activity.38 Discontinuation of hydroxychloroquinine just before conception or in early pregnancy leads to a significant increase in disease activity.39 A systematic review of English literature (1982-2007) found that antimalarial drugs, particularly hydroxychloroquinine, prevent lupus flares; increase long-term survival; contribute to protection against irreversible organ damage, thrombosis, and bone loss; and have low toxicity.40 Hydroxychloroquinine should be continued in all women who were taking it before conception and may be used to treat flares during gestation. In contrast, mycophenolate mofetil should be discontinued before conception owing to the risk for teratogenicity. Azathioprine is an acceptable substitute and should be continued if used before conception.21,23 The fetal liver does not express the enzyme necessary to convert azathioprine to its active form,41 but maternal use of azathioprine has been associated with reversible neonatal lymphopenia, depressed serum immunoglobulin levels, and decreased thymic size in the newborn.41,42
Corticosteroids may be used to treat flares of SLE disease activity. Antenatal exposure to low-dose prednisone (< 20 mg daily) appears to be safe, and most children develop normally. However, there is concern that prolonged fetal exposure to other corticosteroids such as dexamethasone or betamethasone may lead to fetal growth restriction and abnormal neuronal development.43 Corticosteroid therapy may precipitate gestational diabetes, and patients should be monitored for evidence of glucose intolerance. Striae, gastrointestinal ulceration, and bone demineralization may complicate long-term corticosteroid therapy. Affected patients should receive postprandial and bedtime antacids.44 The pediatrician should be alerted to the possibility of neonatal adrenal suppression.
Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and stronger analgesics may be used to manage lupus arthritis. Although there is no evidence of teratogenicity with these agents,41 concern exists that NSAIDs may cause premature closure of the fetal ductus arteriosus,45 impairment of maternal and neonatal hemostasis,46 and adverse effects on maternal renal function.
Patients with SLE are at increased risk for intrauterine fetal death and preterm delivery. Estimation of the gestational age is obtained with ultrasonography at the first prenatal visit and again at 20 weeks' gestation. Continued surveillance consists of nonstress testing, biophysical profile measurement, and/or umbilical artery Doppler velocimetry beginning at 26 to 28 weeks' gestation and performed weekly until delivery.27
The coexistence of antiphospholipid antibodies predicts a much higher maternal and fetal risk. Maternal serologic markers are checked regularly, together with platelet count, creatinine clearance, 24-hour urine protein level, and presence or absence of anti-Ro/anti-La antibodies.47 Platelet count measurement is repeated monthly. If anti-Ro/anti-La antibodies are detected or the fetal heart rate is 60 beats per minute without variability in the second trimester, fetal echocardiography and fetal heart rate testing are performed to check for signs of congenital heart block or failure.48 Thromboprophylaxis is important in patients with antiphospholipid syndrome (see later discussion). In normal pregnancy, serial complement levels gradually increase. However, declining levels of C3 and C4 suggest active disease and lupus nephritis.21 Aspirin resistance may predict adverse maternal and neonatal outcome.49 Regular assessment of blood pressure, weight gain, and proteinuria is performed to detect the development of preeclampsia.
The timing and route of delivery are individualized. Although vaginal delivery is preferred, the cesarean delivery rate in parturients with SLE is 40%.12
The obstetrician, rheumatologist, and anesthesiologist should formulate a joint plan for delivery. Maternal organ system involvement, current disease severity, and particularly the presence of flares must be assessed.50
Pericarditis is common in patients with SLE and is typically asymptomatic. A history of dyspnea on exertion or unexplained tachycardia may suggest pericarditis or myocarditis. Cardiac tamponade has been reported.51 Prolongation of the PR interval or nonspecific T-wave changes may be seen on the electrocardiogram. Coronary artery vasculitis, accelerated atherosclerosis leading to myocardial ischemia, and even myocardial infarction in young women have been reported.52,53
An echocardiographic study in 69 patients with SLE showed a high incidence of valvular abnormalities, including valvular thickening in 51%, vegetations in 43%, regurgitation in 25%, and stenosis in 4%.54 Current American Heart Association guidelines recommend antibiotic prophylaxis only for patients at highest risk for infective endocarditis in whom there is both significant risk and consequence of infection.55 Prophylactic antibiotics are not recommended for women with common valvular lesions undergoing genitourinary procedures, including vaginal delivery, but are specifically indicated for those with previous infective endocarditis, unrepaired cyanotic congenital heart disease, implanted prosthetic material or devices, or a history of cardiac transplantation with cardiac valvulopathy.
The prevalence and progression of pulmonary hypertension in 28 patients with SLE has been studied.56 The prevalence increased from 14% at initial evaluation to 43% 5 years later. Epidural anesthesia for cesarean delivery in parturients with pulmonary hypertension has been reported (see Chapter 42). The abrupt onset of sympathetic blockade and decreased venous return may cause precipitous systemic hypotension and hypoxemia. One report described the administration of general anesthesia in a parturient with SLE and pulmonary hypertension, with coexisting SLE-related restrictive lung disease, pulmonary edema, and orthopnea.57 In one report of three parturients with pulmonary hypertension secondary to SLE and antiphospholipid syndrome, two died of right-sided heart failure within 48 hours of delivery.58
Subclinical pleuritis is common, but significant pleural effusions occur rarely. Patients may suffer from infectious pneumonia or lupus pneumonitis. The latter condition is characterized by fleeting hemorrhagic infiltrates that may become consolidated. Pulmonary embolism and diaphragmatic dysfunction have been reported.52
Central and peripheral sensorimotor and autonomic neuropathies are observed in as many as 25% of patients with SLE.59 Vocal cord palsy has been reported in SLE.50,60 These deficits should be documented before the administration of either neuraxial or general anesthesia. Migraine headache and cerebral vasculitis resulting from SLE must be considered in the differential diagnosis of a postpartum headache. Psychological disorders and frank psychosis can occur during disease flares.11,61 Seizures can occur, especially if chronic anticonvulsant medications are discontinued inadvertently.
Hematologic abnormalities, including anemia, thrombocytopenia, and coagulopathy, should be documented. An abnormality of the activated partial thromboplastin time (aPTT), which is not corrected with a 1 : 1 control plasma mix, suggests the presence of either lupus anticoagulant (a coexistent but separate disease entity) or, more rarely, true autoantibodies against specific coagulation factors (e.g., VIII, IX, XII). Lupus anticoagulant is a laboratory artifact that does not cause clinical coagulopathy. True coagulation factor autoantibodies (or inhibitors) may result in a significant bleeding diathesis, which contraindicates the administration of neuraxial anesthesia.
Long-term use of NSAIDs leads to qualitative platelet abnormalities but has rarely been associated with epidural or subdural hematoma, and the role of NSAIDs in causing spinal epidural hematoma remains conjectural.62,63 In a prospective study of 924 patients undergoing orthopedic procedures with spinal or epidural anesthesia, preoperative antiplatelet medications were taken by 39% of these patients; no cases of spinal epidural hematoma were observed.64 The same investigators similarly studied 1035 patients undergoing epidural steroid injection.65 NSAID use was reported by 32% of patients undergoing chronic pain management; there were no cases of spinal hematoma. In the CLASP study, a large, multicenter randomized trial, 9364 pregnant women received either low-dose aspirin (60 mg daily) or placebo for prevention and treatment of preeclampsia.66 Of 5000 enrollees, at least 1069 patients received epidural analgesia, and no cases of epidural hematoma were observed.67 Determination of the bleeding time before neuraxial injection in patients taking aspirin or NSAIDs is no longer indicated. Measurement of thromboelastography has been suggested as an alternative but is not widely available.68
Atypical blood antibodies may complicate crossmatching of blood for patients with SLE. Additional time should be allowed for this possibility.
Prosthetic orthopedic joints should be positioned carefully during vaginal or cesarean delivery. Lupus arthritis rarely involves the cervical spine. Women who have undergone long-term corticosteroid therapy should receive a peripartum stress dose of a corticosteroid.
The antiphospholipid syndrome (APS, also known as Hughes' syndrome) was first recognized in the early 1980s69-71 and classified by international consensus in 2005.72 It is a prothrombotic disorder characterized by the presence of two autoantibodies, lupus anticoagulant and anticardiolipin antibody. Affected patients are at risk for both arterial and venous thrombosis. Patients with SLE may show lupus anticoagulant (34%) and anticardiolipin antibody (44%).73 However, APS is a distinct and separate entity from SLE. A long-term cohort study found that among patients with APS, only 11 of 128 (8%) had SLE.74
The population prevalence of APS is unclear. In 1990, commenting on the volume of publications on APS, Harris75 remarked that the syndrome “probably occurs less frequently than the number of papers published on the subject.” But in 2007, with greater clinical recognition, Hughes predicted that the prevalence of APS will exceed that of SLE.70
APS is characterized by two important misnomers. First, the antiphospholipid antibodies do not bind directly to phospholipids but to phospholipid-binding plasma proteins such as β2-glycoprotein I, prothrombin, and annexin V. Second, the lupus anticoagulant has no true anticoagulant activity in vivo but is a laboratory artifact that affects phospholipid-dependent coagulation assays: the aPTT, the kaolin clotting time (KCT), the tissue thromboplastin inhibition (TTI) test, and the dilute Russell viper venom time (dRVVT). These times remain prolonged even when the tests are repeated with a 1 : 1 mixture of the patient's plasma and control plasma. The prothrombin time (PT) typically is normal. Lupus anticoagulant appears to block in vitro assembly of prothrombinase (a phospholipid complex), thus preventing the conversion of prothrombin to thrombin. True bleeding associated with lupus anticoagulant is extremely rare and, in most cases, is caused by an underlying factor deficiency or inhibitor.76
Contrary to expectation, lupus anticoagulant and anticardiolipin antibody are associated with both arterial and venous thrombotic events. The current model by which this thrombotic tendency occurs involves antiphospholipid antibodies binding to β2-glycoprotein I, which then bind to glycoprotein Ibα on platelets, monocytes, and endothelial cells. These complexes cause platelet adhesion, expression of prothrombotic molecules, and local complement activation.76,77
The diagnosis of APS depends on a clinical history of unexplained recurrent venous or arterial thrombosis, pregnancy loss, and laboratory evidence of anticardiolipin antibody or lupus anticoagulant.72 The latter is demonstrated by (1) evidence of abnormal phospholipid-dependent coagulation (elevated aPTT), (2) evidence that this abnormality is caused by an inhibitor rather than a factor deficiency (elevated aPTT with 1 : 1 mix), and (3) proof that the inhibitor is directed against phospholipid rather than specific coagulation factors. Antibodies should be demonstrable on two occasions separated by 12 weeks.78 The presence of lupus anticoagulant, anticardiolipin (aCL), and anti-β2-glycoprotein I (aβ2GPI) antibodies (“triple positivity”) with a clinical diagnosis of APS predicts severe disease.79 Results from different laboratories show considerable variability, and guidelines on diagnostic criteria have been published.80 Tests for syphilis detect the antiphospholipid antibodies present in syphilis, and consequently the Venereal Disease Research Laboratory (VDRL) and Wasserman test results are often falsely positive.
Pregnant women with APS are at risk for venous and arterial thrombosis, pulmonary embolism, myocardial infarction, cerebral infarction and fetal loss. Cohort studies suggest that contemporary management strategies may improve maternal outcome. In 130 women with APS followed over a 3-year period, 48% experienced at least one of the following disorders: transient ischemic attack, peripheral thrombosis (of which one fourth occurred in pregnancy and the puerperium), stroke, amaurosis fugax, autoimmune thrombocytopenia, and SLE.81 Women who were diagnosed with APS on the basis of recurrent pregnancy loss and evidence of antiphospholipid antibody, but without prior thrombotic events, rarely suffered thrombosis during pregnancy.82 A history of thromboembolic events significantly worsens prognosis and increases the likelihood of future events, an effect ameliorated by the use of oral anticoagulants.83 Thrombocytopenia, present in one fourth of patients with APS, may require splenectomy.84 Catastrophic APS, an accelerated form of the condition that results in multisystem organ thrombosis and failure, may be triggered by pregnancy in 4% of cases.85
Pregnant women with APS are at high risk for intrauterine fetal death. Early studies showed that only 7.5% of pregnancies resulted in the delivery of a live newborn,86 whereas recent reports have shown live-birth rates up to 100%.87 Pregnant women with lupus anticoagulant, aCL, and aβ2GPI antibody titers greater than four times the upper limit of normal have a twofold increase in risk for fetal loss, when compared with women with positive titers only (35% versus 77% live-birth rate).88 Placental infarction is the apparent mechanism of mortality, and most fetal deaths occur during mid and late pregnancy. There is no high-level evidence to guide management of pregnant women with high antibody titers.89
Most infants born to women with APS do not have an increased rate of neonatal or childhood complications,90 although cases of antiphospholipid-related fetal and neonatal thrombosis (mainly cerebral thrombosis) have been reported.91
Fetal survival and maternal thrombotic risk may be improved when affected pregnant women are treated with low-dose aspirin and heparin. A 2005 meta-analysis found that combined treatment with unfractionated heparin and aspirin can reduce pregnancy loss by 54%.92 Recommendations on investigation and management of APS have been made.93 Women with more than three unexplained pregnancy losses before 10 weeks' gestation should be tested for antiphospholipid antibodies; women with APS and recurrent pregnancy loss should receive prophylactic doses of heparin and low-dose aspirin throughout pregnancy, and administration for 6 to 8 weeks postpartum should be considered. A history of APS with thrombosis may require full anticoagulation throughout pregnancy and the postpartum period. A meta-analysis suggested that unfractionated heparin in combination with aspirin increases the live-birth rate in women with APS, but the benefit of low-molecular-weight heparin (LMWH) is unclear; neither type of heparin crosses the placental barrier.94
Catastrophic antiphospholipid syndrome (CAPS or Asherson's syndrome) occurs in 1% of patients with APS.85 Diagnosis requires the presence of antiphospholipid antibodies with involvement of at least three organs and rapid onset and progression of disease. Mortality is as high as 50%.72 Aggressive treatment with full anticoagulation, antibiotic cover for a precipitating bacterial infection, intravenous corticosteroids and immunoglobulins, and plasma exchange may be required. Severe thrombocytopenia may respond to rituximab.
Management of the patient with antiphospholipid antibodies is similar to that of the patient with SLE. Coexisting autoimmune disorders, secondary organ involvement, and thrombotic phenomena should be evaluated. The term lupus anticoagulant is a misnomer (as discussed earlier) and does not warrant withholding neuraxial anesthesia. Infrequently, antiphospholipid antibodies can cause coagulation factor deficiencies, and in such patients neuraxial anesthesia is relatively contraindicated. In the absence of an underlying coagulation deficit or anticoagulant therapy, the prolonged aPTT does not suggest a bleeding tendency, and neuraxial anesthesia may be administered safely.
The anesthetic management of pregnancies complicated by APS has been reviewed.95,96 All subjects received aspirin (75 to 150 mg daily) throughout pregnancy, and aspirin therapy alone was not considered a contraindication to neuraxial anesthesia. In parturients who received thromboprophylaxis with standard unfractionated heparin, spinal or epidural anesthesia was administered 4 hours after the last dose of heparin. The use of LMWH for thromboprophylaxis precludes administration of neuraxial anesthesia until at least 12 hours have elapsed since the time of the last dose.97 Further, therapeutic anticoagulation with high-dose LMWH precludes the administration of neuraxial anesthesia until at least 24 hours have elapsed since the time of the last dose (see Chapters 39 and 44). The use of thromboelastography to document clearance of heparin before administration of neuraxial anesthesia in parturients with lupus anticoagulant has been described.98
If fetal compromise secondary to multi-infarct placental insufficiency exists, hypotension from sympathetic blockade should be prevented. Neuraxial anesthesia with an epidural, intrathecal, or combined spinal-epidural technique is not contraindicated, provided that blood pressure is closely controlled. Parturients with APS who undergo general anesthesia are at risk for venous thrombosis. Compression stockings, warm intravenous fluids, and early ambulation should be used, whereas hypothermia and dehydration should be avoided.95,96,99 There is no evidence that a “walking epidural” confers benefit.
Systemic sclerosis or scleroderma is a chronic progressive autoimmune disease of unknown etiology characterized by deposition of fibrous connective tissue in the skin and other tissues, microvascular changes, and chronic inflammation. It is a heterogeneous disorder and may be in the form of limited or diffuse cutaneous scleroderma. A subset of patients exhibit systemic sclerosis without cutaneous involvement.100
The annual incidence of scleroderma in the United States is 19 per million. The prevalence is 240 per million, which is four to nine times greater than the reported global prevalence. Scleroderma is almost five times more common among women than men and occurs primarily between 30 and 50 years of age.101
The stimulus for fibroblasts to produce excessive collagen and other matrix constituents is unknown; however, their accumulation leads to microvascular obliteration and fibrosis in the skin and other target organs. Endothelial cells undergo vasomotor and permeability changes, producing cyclic vasoconstriction-vasodilation and edema. Patients with scleroderma produce autoantibodies against nuclear and centromere structures, although their significance is unclear. Scleroderma exhibits a strong female predilection, a steep rise in incidence after the childbearing years, and features that are similar to graft-versus-host disease after bone marrow transplantation, prompting some to postulate that microchimerism may be involved in its pathogenesis. Fetal cells gain access to the maternal circulation during gestation and may be detected in maternal blood for decades after delivery. After some unknown stimulus (that possibly includes environmental factors), these fetal cells may differentiate and initiate a reaction similar to graft-versus-host disease.102,103
Raynaud's phenomenon, characterized by cyclic pallor and cyanosis of the digits in response to cold or emotion, is a common prodrome to scleroderma, with 1% of patients progressing to scleroderma. The triad of Raynaud's phenomenon, nonpitting edema, and hidebound skin establishes the diagnosis of scleroderma.
Limited cutaneous scleroderma, also termed CREST syndrome, involves calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia. Skin involvement is limited to the hands, face, and feet in this form of the disease. The more extensive clinical manifestations of diffuse cutaneous scleroderma are summarized in Box 41-3.
Progression of scleroderma tends to be slow. More than 70% of patients with diffuse cutaneous scleroderma and more than 90% of those with limited cutaneous scleroderma are alive 15 years after diagnosis.104 Renal failure and malignant hypertension are the most common causes of death. Successive reviews by Steen105-107 indicate that improvements in management allow patients with scleroderma to have successful maternal and fetal outcomes. Maternal symptoms were unchanged in 62% of pregnancies and improved in 20%. In the other 18% of pregnancies, esophageal reflux, cardiac arrhythmias, arthritis, skin thickening, and/or renal crisis occurred or worsened.105-107 Deterioration of renal function is of greatest concern.108
The frequency of preterm births and small-for-dates infants is higher in pregnant women with scleroderma.108 Preterm birth occurs in 25% of pregnancies (compared with 5% in control pregnancies), and most preterm deliveries occur in women with unstable diffuse scleroderma of less than 4 years' duration. Miscarriage occurs more commonly in women with long-standing diffuse scleroderma.105
Management is symptomatic rather than curative, and is directed toward slowing end-organ damage. When lifestyle alterations (e.g., avoidance of cold, cessation of smoking) are no longer effective, management may include calcium entry–blocking agents for skin manifestations, proton-pump inhibitors and occasionally esophageal dilation for gastrointestinal tract symptoms, and phosphodiesterase inhibitors and prostaglandins for pulmonary arterial hypertension. No disease modification benefits have been shown by administration of penicillamine, methotrexate, or other immunosuppressive agents (other than the use of glucocorticoids for inflammatory myositis).109,110
Drugs with unproven or potential teratogenicity are relatively contraindicated during pregnancy. However, angiotensin-converting enzyme (ACE) inhibitors are the agents of choice for treating scleroderma-associated renal crisis and malignant hypertension, despite the potential for fetal teratogenicity, renal atresia, pulmonary hypoplasia, anhydramnios, and fetopathy.106 ACE inhibitors provide the only effective control of hypertension during scleroderma-associated renal crisis and should be started immediately if maternal hypertension occurs. Their use should be avoided if hypertension or overt renal crisis is not present.
Nitric oxide donors and possibly heparin may provide some protection against placental dysfunction in pregnant women with scleroderma.111
Pregnant women with scleroderma should be specifically evaluated for evidence of renal, pulmonary, and cardiac dysfunction. Preterm delivery or termination of pregnancy may be required in the presence of advanced or rapidly progressive disease. Frequent assessment of renal function and intensive observation for the onset of systemic or pulmonary hypertension, cardiac dysfunction, and fetal compromise, combined with improvements in monitoring and treatment, allow most mothers to deliver healthy infants. Obstructive uropathy may result from an enlarging uterus trapped within a noncompliant abdomen.112 Uterine and cervical wall thickening may lead to ineffective uterine contractions or cervical dystocia at delivery.107 Even the tightest abdominal skin usually heals if cesarean delivery is necessary.107
The pregnant woman with scleroderma presents several challenges to the anesthesia provider and should be assessed before labor and delivery. Early multidisciplinary involvement is required.
History and physical examination should be directed toward detection of underlying systemic dysfunction. Laboratory tests include complete blood cell count, coagulation screen, electrolyte concentrations and creatinine clearance, arterial blood gas analysis, urinalysis, and urine protein determination. An electrocardiogram and pulmonary function testing should be performed in all patients. Echocardiography is increasingly used to assess ventricular dysfunction, pericardial and pleural effusions, and pulmonary hypertension.113 Particular attention should be paid to arterial pulses, noninvasive blood pressure measurement, peripheral venous access, extent of Raynaud's phenomenon involvement, and special positioning requirements.
Severe limitation of mouth opening caused by hidebound perioral skin may make direct laryngoscopy impossible and mandates careful airway assessment.114 Maximal mouth opening, the ability to sublux the mandible, visualization of oropharyngeal structures, degree of atlanto-occipital joint extension, and presence of oral or nasal telangiectases should be checked and a determination made as to whether direct laryngoscopy will be difficult if general anesthesia is required.115 The patient should be prepared for the possibility of an awake tracheal intubation. Specialized airway equipment (e.g., fiberoptic laryngoscope, videolaryngoscope, emergency cricothyrotomy set) should be immediately available. The changes in graded intubation scores that occur during labor should also be borne in mind.116
Epidural anesthesia has been used successfully in parturients with scleroderma.117,118 Early administration of epidural analgesia in laboring women in whom tracheal intubation is likely to be difficult is to be encouraged. Even when severe diffuse cutaneous involvement is present, the skin of the lumbar back is spared. Spinal anesthesia for cesarean delivery complicated by precipitous hypotension in a parturient with scleroderma has been reported.119 Recovery was uneventful in this woman, with full return of motor function within 3.5 hours. However, prolonged duration of regional anesthesia has been observed in some patients with scleroderma. An axillary block performed with 1% lidocaine with epinephrine was reported to have persisted for 24 hours,120 a digital nerve block performed with 1% lidocaine without epinephrine persisted for 10 hours,121 and a sciatic nerve block persisted for 16 hours.122 Prolonged epidural anesthesia with 2% 2-chloroprocaine has also been reported.123
Unduly prolonged analgesia and anesthesia may be due to reduced uptake of the local anesthetic agent as a consequence of microvasculature changes. This is not a contraindication to neuraxial techniques but should prompt the use of small incremental boluses of the local anesthetic agent. The patient should be warned of the possibility of prolonged neural blockade. Because continuous infusion techniques may result in the administration of an excessive dose with prolonged neural blockade, incremental bolus or patient-controlled injection techniques may be preferable. Whether this consideration makes epidural (with the ability to titrate the dose) rather than spinal anesthesia preferable for cesarean delivery is unclear.
If cesarean delivery is required, the decision to use epidural or general anesthesia depends on the urgency of delivery, anticipated airway difficulty, and the operator skills. Gastric hypomotility increases the risk for esophageal reflux and aspiration. Diffuse cutaneous involvement may indicate the need for central venous catheterization if venous access is difficult, and for invasive arterial monitoring if noninvasive blood pressure measurement is inaccurate. Radial artery catheterization is contraindicated in patients with Raynaud's phenomenon because of the risk for hand ischemia. Brachial artery catheterization may be necessary. Pulmonary artery catheterization may be indicated in the presence of cardiac dysfunction or pulmonary hypertension.124 The use of noninvasive assessment of cardiac function with transthoracic echocardiography is likely to increase.125 Warming of the patient, and especially of the extremities affected by Raynaud's phenomenon, is required. Scleroderma reduces tear production, and the eyes should be protected against corneal abrasions.
Polymyositis and dermatomyositis represent two members of a larger disease group, the idiopathic inflammatory myopathic diseases. Polymyositis is characterized by nonsuppurative inflammation of muscle, primarily skeletal muscles of the proximal limbs, neck, and pharynx. This inflammation leads to symmetric weakness, atrophy, and fibrosis of affected muscle groups. Dermatomyositis represents the same disorder, with the addition of a characteristic heliotrope eruption (blue-purple discoloration of the upper eyelid) and Gottron's papules (raised, scaly, violet eruptions over the knuckles). These disorders are quite rare, with a prevalence of 10 per million and an annual incidence of 5.5 per million. Women are affected twice as often as men. The age at onset is bimodal, with peaks before puberty and during the fifth decade.126
Both polymyositis and dermatomyositis are associated with other autoimmune disorders, notably scleroderma. The etiology of inflammatory muscle disease is unknown and probably multifactorial. An initial insult mediated by viral or other infectious agent, or exposure to environmental substances, may lead to initial muscle damage in genetically susceptible individuals. This initial process may then trigger an autoimmune response involving chronic muscle inflammation. A viral etiology is suggested by seasonal and geographic clustering of new cases. However, viral genomic material has not been identified in affected muscle tissue. Many drugs, including lipid-lowering drugs in the statin group and antiretroviral drugs, are associated with the development of myopathy. The presence of cellular infiltrates within affected muscle tissue and complement-mediated capillary damage are features of inflammatory muscle diseases. More than 12 autoantibodies have been identified within affected individuals. Underlying malignancy has been associated with both polymyositis and dermatomyositis, although causality is unclear; the association is stronger for dermatomyositis than polymyositis.126,127
The diagnostic criteria proposed by Bohan and Peter remain the standard of classification for polymyositis and dermatomyositis (Box 41-4).128 After exclusion of other conditions that can mimic polymyositis or dermatomyositis, clinical features together with electromyographic and laboratory evidence of myositis (both through blood tests and muscle biopsy) establish the diagnosis. Serum creatine kinase concentration correlates with disease activity. Variable systemic involvement may be present. Pharyngeal muscle involvement leads to dysphagia and reflux, and most patients exhibit impairment of gastric and esophageal motility.129 Pulmonary involvement is present in 50% of patients with polymyositis/dermatomyositis, and chronic aspiration pneumonitis and pneumonia are the most common pulmonary manifestations. Pulmonary fibrosis is present in 30% of patients and may rarely lead to pulmonary hypertension.130,131 Myositis of the respiratory muscles may cause respiratory insufficiency. Cardiac involvement includes nonspecific repolarization abnormalities, conduction disturbances, arrhythmias, coronary artery vasculitis, and, rarely, heart failure.132 Arthritis generally involves the small joints of the hands and fingers. Renal or hematologic involvement is rare. The onset of a pregnancy-associated form of dermatomyositis has been described postpartum.133
Reports of polymyositis or dermatomyositis during pregnancy are rare. Ishii et al.134 reviewed 12 reports of 29 pregnancies during a 30-year period. In 11 (40%) of the patients, the initial diagnosis was made during gestation or the immediate postpartum period. Pregnancy may be a trigger for induction of dermatomyositis in some women. Among the 18 patients with previously diagnosed disease, the disease remained inactive in 11 (61%) of the patients, and 2 (11%) had an exacerbation of disease activity.
Fetal survival is affected by concurrent polymyositis/dermatomyositis. In a literature review, 10 of 29 (32%) pregnancies ended with fetal death or spontaneous abortion; eight infants (26%) were delivered preterm.134 Fetal outcome was strongly influenced by disease activity. Of the women who had minimal disease activity, nearly 60% delivered healthy newborns at term. Silva et al.135 observed a similar correlation between outcome and disease activity in four pregnancies in four women with polymyositis/dermatomyositis, two with active disease and fetal death and two with disease remission and uneventful outcome.
Pregnancy should be planned during periods of disease inactivity. Serum creatine kinase, glutamic oxaloacetic transaminase, and aldolase determinations can guide this decision.
Glucocorticoid treatment is the mainstay of medical management of active disease. Efficacy of steroids has not been demonstrated in controlled studies, but improvement in muscle strength and decreased creatine kinase concentration are usually seen after 1 to 2 months of either continuous or pulsed steroid therapy. Methotrexate, azathioprine, and intravenous immunoglobulin may be beneficial; there is limited evidence for their use and safety in pregnant patients.136-138 Obstetric management involves frequent monitoring of disease activity and fetal well-being.
Anesthetic management of the pregnant woman with polymyositis/dermatomyositis begins with the evaluation of disease activity and underlying cardiopulmonary involvement. If muscle weakness is present, spirometry should be performed to determine whether respiratory muscles are affected. Maximum breathing capacity and peak expiratory flow rate are the most helpful measurements. Pharyngeal weakness may cause chronic aspiration and pulmonary diffusion defects. Arterial blood gas analysis and a chest radiograph should be obtained in patients with a history of aspiration. An electrocardiogram should be obtained to exclude conduction abnormalities and arrhythmias.
Use of neuraxial anesthesia in a patient with muscle weakness requires caution because excessive cephalad spread may further impair intercostal muscle function and lead to ventilatory failure. Abdominal muscle paralysis may slow progress of the second stage of labor. Careful epidural administration of a dilute solution of local anesthetic should provide effective pain relief without adverse effect on the progress of labor. Intrathecal opioid administration is an attractive, alternative method of labor analgesia in these patients.
Patients with polymyositis/dermatomyositis may exhibit atypical responses to muscle relaxants. A short-lived thumb contracture after succinylcholine administration in a child with dermatomyositis has been reported.139 Direct laryngoscopy was not impaired, the contracture resolved in 3 minutes, and normal neuromuscular recovery occurred. Plasma potassium concentration increased by 20%, although this response is similar to that seen in normal subjects after succinylcholine administration. Prolonged paralysis of 50 minutes after succinylcholine administration in a patient with dermatomyositis has been noted.140 The patient was found to be homozygous for an atypical pseudocholinesterase. Of four other patients with dermatomyositis in whom dibucaine numbers were measured, one was heterozygous for atypical pseudocholinesterase. The occurrence of benign contractures and the possibility of atypical pseudocholinesterase do not preclude the use of succinylcholine if it is required for cesarean delivery, although newer agents such as rocuronium may provide an alternative. Neuromuscular recovery should be documented before extubation. Some investigators have advocated the avoidance of agents known to trigger malignant hyperthermia in patients with polymyositis/dermatomyositis and elevated creatine kinase levels.141,142 This approach is speculative and is not supported by published clinical experience.
An atypical response to nondepolarizing muscle relaxants has been reported. A case of prolonged paralysis (9.5 hours) after administration of vecuronium in a patient with polymyositis has been reported.143 Underlying malignancy with associated myasthenic syndrome can prolong neuromuscular blockade. Other reports of nondepolarizing neuromuscular blockade in patients with polymyositis/dermatomyositis have indicated a normal response and recovery.142,144,145 Parturients who have undergone long-term corticosteroid therapy should receive a peripartum stress dose of a corticosteroid.
1. Burnet F. A modification of Jerne's theory of antibody production using the concept of clonal selection. Aust J Sci. 1957;20:67–69.
2. McGonagle D, McDermott MF. A proposed classification of the immunological diseases. PLoS Med. 2006;3:e297.
3. Davidson A, Diamond B. Autoimmune diseases. N Engl J Med. 2001;345:340–350.
4. Cotsapas C, Voight BF, Rossin E, et al. Pervasive sharing of genetic effects in autoimmune disease. PLoS Genet. 2011;7:e1002254.
5. Sirota M, Schaub MA, Batzoglou S, et al. Autoimmune disease classification by inverse association with SNP alleles. PLoS Genet. 2009;5:e1000792.
6. Cruz-Tapias P, Pérez-Fernández OM, Rojas-Villarraga A, et al. Shared HLA Class II in six autoimmune diseases in Latin America: a meta-analysis. Autoimmune Dis. 2012;2012:569728.
7. Weckerle CE, Niewold TB. The unexplained female predominance of systemic lupus erythematosus: clues from genetic and cytokine studies. Clin Rev Allergy Immunol. 2011;40:42–49.
8. Olding LB, Murgita RA, Wigzell H. Mitogen-stimulated lymphoid cells from human newborns suppress the proliferation of maternal lymphocytes across a cell-impermeable membrane. J Immunol. 1977;119:1109–1114.
9. Rocklin RE, Kitzmiller JL, Carpenter CB, et al. Maternal-fetal relation: absence of an immunologic blocking factor from the serum of women with chronic abortions. N Engl J Med. 1976;295:1209–1213.
10. González DA, Diaz BB, Rodriguez Pérez Mdel C, et al. Sex hormones and autoimmunity. Immunol Lett. 2010;133:6–13.
11. D’Cruz D, Khamashta M, Hughes G. Systemic lupus erythematosus. Lancet. 2007;369:587–596.
12. Chakravarty EF, Nelson L, Krishnan E. Obstetric hospitalizations in the United States for women with systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum. 2006;54:899–907.
13. Munoz L, van Bavel C, Franz S, et al. Apoptosis in the pathogenesis of systemic lupus erythematosus. Lupus. 2008;17:371–375.
14. Varghese S, Crocker I, Bruce IN, Tower C. Systemic lupus erythematosus, regulatory T cells and pregnancy. Expert Rev Clin Immunol. 2011;7:635–648.
15. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40:1725.
16. Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1982;25:1271–1277.
17. Gimovsky ML, Montoro M. Systemic lupus erythematosus and other connective tissue diseases in pregnancy. Clin Obstet Gynecol. 1991;34:35–50.
18. Meehan RT, Dorsey JK. Pregnancy among patients with systemic lupus erythematosus receiving immunosuppressive therapy. J Rheumatol. 1987;14:252–258.
19. Tincani A, Balestrieri G, Faden D, DiMario C. Systemic lupus erythematosus in pregnancy. Lancet. 1991;338:756–757.
20. Cortés-Hernández J, Ordi-Ros J, Paredes F, et al. Clinical predictors of fetal and maternal outcome in systemic lupus erythematosus: a prospective study of 103 pregnancies. Rheumatology (Oxford). 2002;41:643–650.
21. Petri M. The Hopkins Lupus Pregnancy Center: ten key issues in management. Rheum Dis Clin North Am. 2007;33:227–235.
22. Kwok LW, Tam LS, Zhu T, et al. Predictors of maternal and fetal outcomes in pregnancies of patients with systemic lupus erythematosus. Lupus. 2011;20:829–836.
23. Clowse ME. Lupus activity in pregnancy. Rheum Dis Clin North Am. 2007;33:237–252.
24. Liu J, Zhao Y, Song Y, et al. Pregnancy in women with systemic lupus erythematosus: a retrospective study of 111 pregnancies in Chinese women. J Matern Fetal Neonatal Med. 2012;25:261–266.
25. Ruiz-Irastorza G, Khamashta M, Hughes GR. Does SLE flare during pregnancy? Scand J Rheumatol Suppl. 1998;107:76–79.
26. Petri M. Systemic lupus erythematosus and pregnancy. Rheum Dis Clin North Am. 1994;20:87–118.
27. Witter FR. Management of the high-risk lupus pregnant patient. Rheum Dis Clin North Am. 2007;33:253–265.
28. Bramham K, Hunt BJ, Bewley S, et al. Pregnancy outcomes in systemic lupus erythematosus with and without previous nephritis. J Rheumat. 2011;38:1906–1913.
29. Smyth A, Oliveira GH, Lahr BD, et al. A systematic review and meta-analysis of pregnancy outcomes in patients with systemic lupus erythematosus and lupus nephritis. Clin J Am Soc Nephrol. 2010;5:2060–2068.
30. Lockshin MD. Pregnancy associated with systemic lupus erythematosus. Semin Perinatol. 1990;14:130–138.
31. Clowse ME, Magder LS, Witter F, Petri M. The impact of increased lupus activity on obstetric outcomes. Arthritis Rheum. 2005;52:514–521.
32. Clark CA, Spitzer KA, Laskin CA. Decrease in pregnancy loss rates in patients with systemic lupus erythematosus over a 40-year period. J Rheumatol. 2005;32:1709–1712.
33. Yasmeen S, Wilkins EE, Field NT, et al. Pregnancy outcomes in women with systemic lupus erythematosus. J Matern Fetal Med. 2001;10:91–96.
34. Petri M, Watson R, Hochberg MC. Anti-Ro antibodies and neonatal lupus. Rheum Dis Clin North Am. 1989;15:335–360.
35. Brucato A, Doria A, Frassi M, et al. Pregnancy outcome in 100 women with autoimmune diseases and anti-Ro/SSA antibodies: a prospective controlled study. Lupus. 2002;11:716–721.
36. Buyon JP, Clancy RM. Neonatal lupus: basic research and clinical perspectives. Rheum Dis Clin North Am. 2005;31:299–313.
37. Dhar JP, Sokol RJ. Lupus and pregnancy: complex yet manageable. Clin Med Res. 2006;4:310–321.
38. Lee SJ, Silverman E, Bargman JM. The role of antimalarial agents in the treatment of SLE and lupus nephritis. Nat Rev Nephrol. 2011;7.
39. Clowse ME, Magder L, Witter F, Petri M. Hydroxychloroquine in lupus pregnancy. Arthritis Rheum. 2006;54:3640–3647.
40. Ruiz-Irastorza G, Ramos-Casals M, Brito-Zeron P, Khamashta MA. Clinical efficacy and side effects of antimalarials in systemic lupus erythematosus: a systematic review. Ann Rheum Dis. 2010;69:20–28.
41. Ostensen M, Ostensen H. Safety of nonsteroidal antiinflammatory drugs in pregnant patients with rheumatic disease. J Rheumatol. 1996;23:1045–1049.
42. Coté CJ, Meuwissen HJ, Pickering RJ. Effects on the neonate of prednisone and azathioprine administered to the mother during pregnancy. J Pediatr. 1974;85:324–328.
43. Scott JR. Risks to the children born to mothers with autoimmune diseases. Lupus. 2002;11:655–660.
44. Samuels P, Pfeifer SM. Autoimmune diseases in pregnancy: the obstetrician's view. Rheum Dis Clin North Am. 1989;15:307–322.
45. Moise KJ, Huhta JC, Sharif DS, et al. Indomethacin in the treatment of premature labor: effects on the fetal ductus arteriosus. N Engl J Med. 1988;319:327–331.
46. Stuart MJ, Gross SJ, Elrad H, Graeber JE. Effects of acetylsalicylic-acid ingestion on maternal and neonatal hemostasis. N Engl J Med. 1982;307:909–912.
47. Lockshin MD, Sammaritano LR. Lupus pregnancy. Autoimmunity. 2003;36:33–40.
48. Lockshin MD. Lupus pregnancies and neonatal lupus. Springer Semin Immunopath. 1994;16:247–259.
49. Wojtowicz A, Undas A, Huras H, et al. Aspirin resistance may be associated with adverse pregnancy outcomes. Neuroendocrinol Lett. 2011;32:334–339.
50. Ben-Menachem E. Systemic lupus erythematosus: a review for anesthesiologists. Anesth Analg. 2010;111:665–676.
51. Averbuch M, Bojko A, Levo Y. Cardiac tamponade in the early postpartum period as the presenting and predominant manifestation of systemic lupus erythematosus. J Rheumatol. 1986;13:444–445.
52. Carette S. Cardiopulmonary manifestations of systemic lupus erythematous. Rheum Dis Clin North Am. 1988;14:135–147.
53. Ozaki M, Minami K, Shigematsu A. Myocardial ischemia during emergency anesthesia in a patient with systemic lupus erythematosus resulting from undiagnosed antiphospholipid syndrome. Anesth Analg. 2002;95:255.
54. Roldan C, Shively B, Crawford M. An echocardiographic study of valvular heart disease associated with systemic lupus erythematosus. N Engl J Med. 1996;335:1424–1430.
55. Wilson W, Taubert K, Gewitz M, et al. Prevention of infective endocarditis: guidelines from the American Heart Association. Circulation. 2007;116:1736–1754.
56. Winslow T, Ossipov M, Fazio G, et al. Five-year follow-up study of the prevalence and progression of pulmonary hypertension in systemic lupus erythematosus. Am Heart J. 1995;129:510–515.
57. Cuenco J, Tzeng G, Wittels B. Anesthetic management of the parturient with systemic lupus erythematosus, pulmonary hypertension, and pulmonary edema. Anesthesiology. 1999;91:568–570.
58. McMillan E, Martin W, Waugh J, et al. Management of pregnancy in women with pulmonary hypertension secondary to SLE and anti-phospholipid syndrome. Lupus. 2002;11:392–398.
59. Huynh C, Ho S, Fong K, et al. Peripheral neuropathy in systemic lupus erythematosus. J Clin Neurophysiol. 1999;16:164–168.
60. Lee J, Sung I, Park J, Roh J. Recurrent laryngeal neuropathy in a systemic lupus erythematosus (SLE) patient. Am J Phys Med Rehabil. 2008;87:68–70.
61. Brey RL, Holliday SL, Saklad AR, et al. Neuropsychiatric syndromes in lupus: prevalence using standardized definitions. Neurology. 2002;58:1214–1220.
62. Greensite FS, Katz J. Spinal subdural hematoma associated with attempted epidural anesthesia and subsequent continuous spinal anesthesia. Anesth Analg. 1980;59:72–73.
63. Locke GE, Giorgio AJ, Biggers SL, et al. Acute spinal epidural hematoma secondary to aspirin-induced prolonged bleeding. Surg Neurol. 1976;5:293–296.
64. Horlocker TT, Wedel DJ, Schroeder DR, et al. Preoperative antiplatelet therapy does not increase the risk of spinal hematoma associated with regional anesthesia. Anesth Analg. 1995;80:303–309.
65. Horlocker TT, Bajwa ZH, Ashraf Z, et al. Risk assessment of hemorrhagic complications associated with nonsteroidal antiinflammatory medications in ambulatory pain clinic patients undergoing epidural steroid injection. Anesth Analg. 2002;95:1691–1697.
66. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343:619–629.
67. de Swiet M, Redermatomyositisan CW. Aspirin, extradural anaesthesia and the MRC Collaborative Low-dose Aspirin Study in Pregnancy (CLASP). Br J Anaesth. 1992;69:109–110.
68. Armstrong S, Fernando R, Ashpole K, et al. Assessment of coagulation in the obstetric population using ROTEM thromboelastometry. Int J Obstet Anesth. 2011;20:293–298.
69. Carreras LO, Defreyn G, Machin SJ, et al. Arterial thrombosis, intrauterine death and “lupus” anticoagulant: detection of immunoglobulin interfering with prostacyclin formation. Lancet. 1981;1:244–246.
70. Hughes G. Hughes syndrome: the antiphospholipid syndrome—a clinical overview. Clin Rev Allergy Immunol. 2007;32:3–12.
71. Hughes GR. Thrombosis, abortion, cerebral disease, and the lupus anticoagulant. Br Med J (Clin Res Ed). 1983;287:1088–1089.
72. Tripodi A, de Groot PG, Pengo V. Antiphospholipid syndrome: laboratory detection, mechanisms of action and treatment. J Intern Med. 2011;270:110–122.
73. Love PE, Santoro SA. Antiphospholipid antibodies: anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (SLE) and in non-SLE disorders: prevalence and clinical significance. Ann Intern Med. 1990;112:682–698.
74. Gómez-Puerta JA, Martín H, Amigo MC, et al. Long-term follow-up in 128 patients with primary antiphospholipid syndrome: do they develop lupus? Medicine (Baltimore). 2005;84:225–230.
75. Harris EN. A reassessment of the antiphospholipid syndrome. J Rheumatol. 1990;17:733–735.
76. Vermylen J, Carreras LO, Arnout J. Attempts to make sense of the antiphospholipid syndrome. J Thromb Haemost. 2007;5:1–4.
77. Ware Branch D, Eller AG. Antiphospholipid syndrome and thrombosis. Clin Obstet Gynecol. 2006;49:861–874.
78. Sangle NA, Smock KJ. Antiphospholipid antibody syndrome. Arch Pathol Lab Med. 2011;135:1092–1096.
79. Pengo V. APS: controversies in diagnosis and management, critical overview of current guidelines. Thromb Res. 2011;127(Suppl 3):S51–S52.
80. Pengo V, Tripodi A, Reber G, et al. Update of the guidelines for lupus anticoagulant detection. Subcommittee on Lupus Anticoagulant/Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. J Thromb Haemost. 2009;7:1737–1740.
81. Silver RM, Draper ML, Scott JR, et al. Clinical consequences of antiphospholipid antibodies: an historic cohort study. Obstet Gynecol. 1994;83:372–377.
82. Clark CA, Spitzer KA, Crowther MA, et al. Incidence of postpartum thrombosis and preterm delivery in women with antiphospholipid antibodies and recurrent pregnancy loss. J Rheumatol. 2007;34:992–996.
83. Pengo V, Ruffatti A, Legnani C, et al. Clinical course of high-risk patients diagnosed with antiphospholipid syndrome. J Thromb Haemost. 2010;8:237–242.
84. Galindo M, Khamashta M, Hughes G. Splenectomy for refractory thrombocytopaenia in the antiphospholipid syndrome. Rheumatology. 1999;38:848–853.
85. Asherson R. The catastrophic antiphospholipid (Asherson's) syndrome. Autoimmun Rev. 2006;6:64–67.
86. Lubbe WF, Liggins GC. Lupus anticoagulant and pregnancy. Am J Obstet Gynecol. 1985;153:322–327.
87. Tincani A, Lojacono A, Taglietti M, et al. Pregnancy and neonatal outcome in primary antiphospholipid syndrome. Lupus. 2002;11:649.
88. Simchen MJ, Dulitzki M, Rofe G, et al. High positive antibody titers and adverse pregnancy outcome in women with antiphospholipid syndrome. Acta Obstet Gynecol Scand. 2011;90:1428–1433.
89. Branch W. Report of the Obstetric APS Task Force: 13th International Congress on Antiphospholipid Antibodies, 13th April 2010. Lupus. 2011;20:158–164.
90. Pollard JK, Scott JR, Branch DW. Outcome of children born to women treated during pregnancy for the antiphospholipid syndrome. Obstet Gynecol. 1992;80:365–368.
91. Boffa MC, Aurousseau MH, Lachassinne E, et al. European register of babies born to mothers with antiphospholipid syndrome. Lupus. 2004;13:713–717.
92. Empson M, Lassere M, Craig J, Scott J. Prevention of recurrent miscarriage for women with antiphospholipid antibody or lupus anticoagulant. Cochrane Database Syst Rev. 2005;(2).
93. Keeling D, Mackie I, Moore GW, et al. Guidelines on the investigation and management of antiphospholipid syndrome. Br J Haematol. 2012;157:47–58.
94. Ziakas PD, Pavlou M, Voulgarelis M. Heparin treatment in antiphospholipid syndrome with recurrent pregnancy loss: a systematic review and meta-analysis. Obstet Gynecol. 2010;115:1256–1262.
95. Ralph CJ. Anaesthetic management of parturients with the antiphospholipid syndrome: a review of 27 cases. Int J Obstet Anesth. 1999;8:249–252.
96. Ringrose D. Anaesthesia and the anti-phospholipid syndrome: a review of 20 obstetric patients. Int J Obstet Anesth. 1997;6:107–111.
97. Horlocker TT. Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy. Br J Anaesth. 2011;107(Suppl 1):i96–106.
98. Harnett M, Kodali BS. Thromboelastography assessment of coagulation status in parturients with lupus anticoagulant receiving heparin therapy. Int J Obstet Anesth. 2006;15:177–178.
99. Madan R, Khoursheed M, Kukla R, et al. The anaesthetist and the antiphospholipid syndrome. Anaesthesia. 1997;52:72–76.
100. Walker JG, Pope J, Baron M, et al. The development of systemic sclerosis classification criteria. Clin Rheumatol. 2007;26:1401–1409.
101. Mayes MD, Lacey JV, Beebe-Dimmer J, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246–2255.
102. Jimenez SA, Artlett CM. Microchimerism and systemic sclerosis. Curr Opin Rheumatol. 2005;17:86–90.
103. Nelson JL. Pregnancy immunology and autoimmune disease. J Reprod Med. 1998;43:335–340.
104. Scussel-Lonzetti L, Joyal F, Raynauld J-P, et al. Predicting mortality in systemic sclerosis: analysis of a cohort of 309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival. Medicine (Baltimore). 2002;81:154–167.
105. Steen VD. Pregnancy in women with systemic sclerosis. Obstet Gynecol. 1999;94:15–20.
106. Steen VD. Pregnancy in scleroderma. Rheum Dis Clin North Am. 2007;33:345–358.
107. Steen VD, Conte C, Day N, et al. Pregnancy in women with systemic sclerosis. Arthritis Rheum. 1989;32:151–157.
108. Miniati I, Guiducci S, Mecacci F, et al. Pregnancy in systemic sclerosis. Rheumatology (Oxford). 2008;47(Suppl 3):iii16–iii18.
109. Seibold J. Scleroderma. WB Saunders: Philadelphia; 1989.
110. Tuffanelli DL. Systemic scleroderma. Med Clin North Am. 1989;73:1167–1180.
111. Carbonne B, Mace G, Cynober E, et al. Successful pregnancy with the use of nitric oxide donors and heparin after recurrent severe preeclampsia in a woman with scleroderma. Am J Obstet Gynecol. 2007;197:e6–e7.
112. Moore M, Saffran JE, Baraf HS, Jacobs RP. Systemic sclerosis and pregnancy complicated by obstructive uropathy. Am J Obstet Gynecol. 1985;153:893–894.
113. Plastiras SC, Papazefkos V, Pamboucas C, et al. Scleroderma heart: pericardial effusion with echocardiographic signs of tamponade during pregnancy. Clin Exp Rheumatol. 2010;28:447–448.
114. Albilia JB, Lam DK, Blanas N, et al. Small mouths … Big problems? A review of scleroderma and its oral health implications. J Can Dent Assoc. 2007;73:831–836.
115. Benumof JL. Management of the difficult adult airway: with special emphasis on awake tracheal intubation. Anesthesiology. 1991;75:1087–1110.
116. Boutonnet M, Faitot V, Katz A, et al. Mallampati class changes during pregnancy, labour, and after delivery: can these be predicted? Br J Anaesth. 2010;104:67–70.
117. Derksen RH, de Groot PG. The obstetric antiphospholipid syndrome. J Reprod Immunol. 2008;77:41–50.
118. Picozzi P, Lappa A, Menichetti A. Mitral valve replacement under thoracic epidural anesthesia in an awake patient suffering from systemic sclerosis. Acta Anaesthesiol Scand. 2007;51:644.
119. Bailey AR, Wolmarans M, Rhodes S. Spinal anaesthesia for caesarean section in a patient with systemic sclerosis. Anaesthesia. 1999;54:355–358.
120. Eisele JH, Reitan JA. Scleroderma, Raynaud's phenomenon, and local anesthetics. Anesthesiology. 1971;34:386–387.
121. Lewis GB. Prolonged regional analgesia in scleroderma. Can Anaesth Soc J. 1974;21:495–497.
122. Neill RS. Progressive systemic sclerosis. Prolonged sensory blockade following regional anaesthesia in association with a reduced response to systemic analgesics. Br J Anaesth. 1980;52:623–625.
123. Thompson J, Conklin KA. Anesthetic management of a pregnant patient with scleroderma. Anesthesiology. 1983;59:69–71.
124. Scully R, Mark E, McNeely W, Ebeling S. Case records of the Massachusetts General Hospital: Case 4-1999: A 38-year-old woman with increasing pulmonary hypertension after delivery. N Engl J Med. 1999;340:455–464.
125. Dennis A. Transthoracic echocardiography in obstetric anaesthesia and obstetric critical illness. Int J Obstet Anesth. 2011;20:160–168.
126. Plotz PH, Dalakas M, Leff RL, et al. Current concepts in the idiopathic inflammatory myopathies: polymyositis, dermatomyositis, and related disorders. Ann Intern Med. 1989;111:143–157.
127. Bronner IM, van der Meulen MFG, de Visser M, et al. Long-term outcome in polymyositis and dermatomyositis. Ann Rheum Dis. 2006;65:1456–1461.
128. Bohan A, Peter JB. Polymyositis and dermatomyositis (second of two parts). N Engl J Med. 1975;292:403–407.
129. Horowitz M, McNeil JD, Maddern GJ, et al. Abnormalities of gastric and esophageal emptying in polymyositis and dermatomyositis. Gastroenterology. 1986;90:434–439.
130. Dickey BF, Myers AR. Pulmonary disease in polymyositis/dermatomyositis. Semin Arthritis Rheum. 1984;14:60–76.
131. Okada R, Miyabe YS, Kasai S, et al. [Successful treatment of interstitial pneumonia and pneumomediastinum associated with polymyositis during pregnancy with a combination of cyclophosphamide and tacrolimus: a case report]. Nihon Rinsho Meneki Gakkai Kaishi. 2010;33:142–148.
132. Senechal M, Crete M, Couture C, Poirier P. Myocardial dysfunction in polymyositis. Can J Cardiol. 2006;22:869–871.
133. Yassaee M, Carrie L, Kovaric M, Werth VP. Pregnancy-associated dermatomyositis. Arch Dermatol. 2009;145:952–953.
134. Ishii N, Ono H, Kawaguchi T, Nakajima H. Dermatomyositis and pregnancy: case report and review of the literature. Dermatologica. 1991;183:146–149.
135. Silva CA, Sultan SM, Isenberg DA. Pregnancy outcome in adult-onset idiopathic inflammatory myopathy. Rheumatology (Oxford). 2003;42:1168–1172.
136. Mosca M, Strigini F, Carmignani A, et al. Pregnant patient with dermatomyositis successfully treated with intravenous immunoglobulin therapy. Arthritis Rheum. 2005;53:119–121.
137. Nozaki Y, Ikoma S, Funauchi M, Kinoshita K. Respiratory muscle weakness with dermatomyositis during pregnancy: successful treatment with intravenous immunoglobulin therapy. J Rheumatol. 2008;35:2289.
138. Williams L, Chang PY, Park E, et al. Successful treatment of dermatomyositis during pregnancy with intravenous immunoglobulin monotherapy. Obstet Gynecol. 2007;109:561–563.
139. Johns RA, Finholt DA, Stirt JA. Anaesthetic management of a child with dermatomyositis. Can Anaesth Soc J. 1986;33:71–74.
140. Eielsen O, Stovner J. Dermatomyositis, suxamethonium action and atypical plasmacholinesterase. Can Anaesth Soc J. 1978;25:63–64.
141. Farag HM, Naguib M, Gyasi H, Ibrahim AW. Anesthesia for a patient with eosinophilic myositis. Anesth Analg. 1986;65:903–904.
142. Saarnivaara LH. Anesthesia for a patient with polymyositis undergoing myectomy of the cricopharyngeal muscle. Anesth Analg. 1988;67:701–702.
143. Flusche G, Unger-Sargon J, Lambert DH. Prolonged neuromuscular paralysis with vecuronium in a patient with polymyositis. Anesth Analg. 1987;66:188–190.
144. Brown S, Shupak RC, Patel C, Calkins JM. Neuromuscular blockade in a patient with active dermatomyositis. Anesthesiology. 1992;77:1031–1033.
145. Ganta R, Campbell IT, Mostafa SM. Anaesthesia and acute dermatomyositis/polymyositis. Br J Anaesth. 1988;60:854–858.