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 its overall prevalence is about 50 per 100,000 population, it is recognized most commonly in women during their childbearing years, with a female-to-male ratio of 9:1. Certain groups have a higher prevalence, including individuals of African ancestry, Asians, and Native Americans.

The etiology of SLE remains unclear. The principal mechanism is thought to be immune complex–mediated, involving immunoglobulin G (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. Affected individuals have both hyperactivity of the antibody-producing B cells and defects of the helper and suppressor T cells. Genetic defects of immune regulation and possibly environmental triggers including viruses and bacteria lead to a proliferation of B cells capable of producing autoantibodies that may target more than 30 classes of antigens. A variety of antigen-antibody immune complexes are formed, followed by secondary inflammatory responses. Deposits may occur within the skin, choroid plexus, and other endothelial surfaces, with or without an inflammatory response. In certain locations (e.g., the renal glomerulus), deposition of immune complexes and continued inflammation may lead to irreversible injury. 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.

Clinical manifestations of SLE are diverse, owing to the widespread antigenic targets. Box 40.2 outlines objective criteria for the diagnosis of SLE, which place emphasis on selected clinical and immunological features. Not all epidemiologic studies use these criteria, and 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.

SLE disease activity may increase during pregnancy, and some pregnancy-related complications may have long-term effects on women with SLE. The PROMISSE study, an observational prospective outcome study of 385 women with SLE, with or without antiphospholipid antibodies (aPLs) , used formal measurements of disease activity to delineate risk. Renal disease, SLE disease activity, and the presence of aPLs are considered significant risk factors for maternal deterioration during pregnancy. Assessments using the SLE Disease Activity Index found that 50% to 65% of women with active disease had deterioration during pregnancy in both retrospective and prospective studies. Such flares occur most commonly in the second and third trimesters and the puerperium, are not more severe than those in nonpregnant patients and mostly respond to conservative management. The risk for significant disease activity during pregnancy is increased sevenfold if active disease is present in the 6 months before conception, and a preconception history of nephritis predicts adverse maternal outcome.

Women with SLE have a two- to fourfold increase in the overall rate of pregnancy complications, with increased rates of hypertension, renal disease, preeclampsia, preterm delivery, cesarean delivery, and maternal and neonatal death. Nevertheless, maternal and fetal outcomes have improved with advances in disease management.

Most women with SLE do not have renal impairment at conception, possibly because renal insufficiency impairs fertility. If lupus nephritis preexists, deterioration in renal function may occur during pregnancy and may in some cases be irreversible. Long-term glomerular filtration rate, with or without preexisting lupus nephritis, is usually preserved.

Renal involvement is also associated with maternal hypertension. The presence of hypertension, edema, and proteinuria in both lupus nephritis and preeclampsia makes distinguishing between the two difficult. Although it is controversial whether preeclampsia is more common in patients with SLE, two metaanalyses showed a positive association between a history of lupus nephritis and preeclampsia. Distinction between SLE and preeclampsia is critical because treatments are different (immunosuppressive therapy versus delivery, respectively). Increased serum uric acid concentration, proteinuria without active urinary sediment, and liver enzyme abnormalities suggest preeclampsia. The two conditions may also coexist.

SLE may cause thrombocytopenia in pregnancy. When thrombocytopenia occurs in a pregnant woman, preeclampsia, HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome, and disseminated intravascular coagulation must also be considered. Anemia associated with SLE must be differentiated from nutritional anemia and the physiologic anemia of 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.

Maternal SLE impairs fetal survival and increases the risk for preterm delivery. The primary predictor for adverse pregnancy outcomes is the presence of LAC. A systematic review of papers published up to 2016 showed that the pooled relative risk (RR) of preterm delivery for patients with SLE versus controls was 2.05 (95% confidence interval [CI], 1.72 to 3.32). 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. Improved perinatal management and control of disease activity have reduced the rate of fetal loss from 43% (between 1960 and 1965) to 17% (between 2000 and 2003). Data from California showed a preterm delivery rate in SLE that was six times higher than that found in the general population.

Neonatal lupus erythematosus (NLE) is a syndrome resulting from maternal autoantibodies against Ro (SS-A) or La (SS-B) autoantigens crossing the placenta and binding to fetal tissue. Although these autoantibodies are found in up to 87% of patients with SLE, 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, and mortality occurs in about 18% of affected babies. 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.

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. Medications with acceptable safety are used to minimize disease activity during gestation. Medications to treat SLE and other rheumatic diseases such as rheumatoid arthritis fall into four broad categories: nonfluorinated glucocorticoids, synthetic disease-modifying antirheumatic drugs (DMARDs), targeted DMARDs, and biologics.

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 born to mothers who have used antenatal corticosteroids develop normally. However, fluorinated glucocorticoids such as dexamethasone or betamethasone readily cross the placenta and may cause fetal growth restriction and abnormal neuronal development; their use should be restricted to a single course for fetal lung maturation. Prolonged corticosteroid therapy carries the risk of gestational diabetes, striae, gastrointestinal ulceration, and bone demineralization. Regular use of antacids may be required.

DMARDs and immunosuppressive agents form the mainstay of treatment. Synthetic DMARDs such as hydroxychloroquinine (HCQ), azathioprine , and tacrolimus are frequently used to reduce SLE activity, and their use is considered safe in pregnancy. Discontinuation of HCQ just before conception or in early pregnancy leads to a significant increase in disease activity. A systematic review found that antimalarial drugs, particularly HCQ, prevent lupus flares; increase long-term survival; contribute to protection against irreversible organ damage, thrombosis, and bone loss; and have low toxicity. HCQ should be continued in all women who have been taking it before conception, and it may be used to treat flares during gestation. In contrast, mycophenolate mofetil should be discontinued before conception owing to the risk for teratogenicity. There is little evidence to support the use of targeted DMARDs such as apremilast and tofacitinib.

Immunosuppressive agents such as azathioprine and tacrolimus are considered safe for use in pregnancy and may be considered if corticosteroid avoidance is desirable. Azathioprine should be continued if used before conception. The fetal liver does not express the enzyme necessary to convert azathioprine to its active form, but maternal use of azathioprine has been associated with reversible neonatal lymphopenia, depressed serum immunoglobulin levels, and decreased thymic size in the newborn. Transplant registries do not report increased risk for congenital abnormalities after its use.

Biologic agents such as rituximab and belimumab are recombinant proteins that typically incorporate IgG antibodies or receptor-blocking proteins. They are being used more frequently, but concerns exist about their duration of action, placental transfer, and teratogenic potential. If used antenatally, consideration is given to their continuation during pregnancy. Data do not yet support their use as first-line medications during pregnancy.

Aspirin, nonsteroidal antiinflammatory drugs (NSAIDs) , and stronger analgesics may be used to manage lupus arthritis. Although there is no evidence of teratogenicity with these agents, concern exists that NSAIDs may cause premature closure of the fetal ductus arteriosus, and high-dose aspirin and NSAIDs ideally should be discontinued by 30 weeks’ gestation (see Chapter 16 ). Pregabalin and gabapentin have limited safety data during pregnancy and are best avoided.

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.

The coexistence of aPLs (either LAC or triple-positive aPLs; see later discussion) predicts higher maternal and fetal risk. Patients with SLE have an increased risk of preeclampsia (RR 2.99; 95% CI, 2.31 to 3.88). Maternal serologic markers are checked regularly, together with platelet count, creatinine clearance, 24-hour urine protein level, uric acid, and complement levels. In normal pregnancy, serial complement levels gradually increase. However, declining levels of C3 and C4 suggest active disease and lupus nephritis. Thromboprophylaxis is important in patients with antiphospholipid syndrome (see later discussion). Aspirin resistance may predict adverse maternal and neonatal outcomes. Regular assessment of blood pressure, weight gain, and proteinuria is performed to detect the development of preeclampsia. Prediction of cardiovascular risk in women with SLE may be possible using the pulse-mass index.

The timing and route of delivery are individualized. Although vaginal delivery is preferred, a cesarean delivery rate of 48% has been reported in parturients with SLE, primarily due to preeclampsia and maternal SLE activity.

The obstetric and anesthesia providers and the rheumatologist should formulate a joint plan for delivery. Maternal organ system involvement, current disease severity, and particularly the presence of flares must be assessed.

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. 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.

An echocardiographic study showed a high incidence of valvular abnormalities in patients with SLE, including valvular thickening (51%), vegetation (43%), regurgitation (25%), and stenosis (4%). The American Heart Association does not recommend prophylactic antibiotics for women with common valvular lesions undergoing genitourinary procedures, including vaginal delivery. The recommendations are discussed in Chapter 41 .

The prevalence and progression of pulmonary hypertension in 28 patients with SLE have been studied. 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 41 ).

Subclinical pleuritis is common, but significant pleural effusion is rare. 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.

Central and peripheral sensorimotor and autonomic neuropathies are observed in as many as 25% of patients with SLE, and vocal cord palsy has been reported. 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. 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 LAC (a coexistent but separate disease entity) or, more rarely, true autoantibodies against specific coagulation factors (e.g., VIII, IX, XII). LAC 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 their role in causing spinal epidural hematoma remains conjectural. In prospective studies of patients undergoing orthopedic procedures (924 patients receiving spinal or epidural anesthesia, of whom 39% were taking preoperative antiplatelet medications) and epidural steroid injection for chronic pain management (1035 patients, of whom 32% reported NSAID use), no cases of spinal epidural hematoma were observed. In the Collaborative Low-dose Aspirin Study in Pregnancy (CLASP), a large, multicenter randomized trial, 9364 pregnant women received either low-dose aspirin (60 mg daily) or placebo for prevention and treatment of preeclampsia. Of 5000 enrollees, at least 1069 patients received epidural analgesia, and no cases of epidural hematoma were observed. Current recommendations are that neuraxial anesthesia should not be withheld from patients taking aspirin.

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.

Antiphospholipid syndrome (APS, also known as Hughes’ syndrome) was first recognized in the early 1980s and classified by international consensus in 2006. It is an autoimmune prothrombotic disorder characterized by the presence of three aPLs: LAC, anticardiolipin antibodies (aCL), and anti-beta ₂ -glycoprotein I (aβ ₂ GPI). Affected patients are at risk for arterial and venous thrombosis and pregnancy-related complications.

Although initially described as a subset of patients with SLE, it is now accepted that APS is a distinct and separate disease entity. About 40% of patients with SLE may have aPLs (LAC in 34% and aCL in 44%), but few will progress to develop thrombotic events. Long-term follow-up suggests that more than half of patients with SLE and aPLs will progress to APS, but few with APS progress to SLE.

The prevalence of APS is unclear. Most information has been derived from the “Euro Phospholipid” cohort of 1000 patients. Prevalence of aPLs in the general population is 1% to 5%, but APS occurs in only a small proportion of people with aPLs; the estimated population prevalence is 40 to 50 per 100,000. Initially APS was thought to be uncommon, but improved clinical recognition suggests that the prevalence of APS may exceed that of SLE.

APS is associated with two important misnomers. First, the aPLs do not bind directly to phospholipids but to phospholipid-binding plasma proteins such as β ₂ GPI, prothrombin, and annexin V. Second, the LAC 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. Typically the prothrombin time (PT) is normal. LAC appears to block in vitro assembly of prothrombinase (a phospholipid complex), thus preventing the conversion of prothrombin to thrombin. True bleeding associated with LAC is extremely rare and, in most cases, is caused by an underlying factor deficiency or inhibitor.

Contrary to expectation, LAC and aCL are associated with both arterial and venous thrombotic events . The binding of aPL and aβ ₂ GPI to cellular β ₂ GPI receptors causes activation of endothelial cells, platelets, and monocytes, with complement activation and production of prothrombotic mediators that lead to thrombosis. Complement activation may lead to inflammation, placental insufficiency, and fetal loss, while aPL interference with fibrinolysis may predispose patients to thrombotic events.

The diagnosis of APS depends on a clinical history of unexplained recurrent venous or arterial thrombosis, pregnancy loss, and laboratory evidence of aCL or LAC. The latter is demonstrated by abnormal phospholipid-dependent coagulation (elevated aPTT), evidence that this abnormality is caused by an inhibitor rather than a factor deficiency (elevated aPTT with 1:1 mix), and proof that the inhibitor is directed against phospholipid rather than specific coagulation factors. Antibodies should be demonstrable on two occasions separated by 12 weeks. The presence of LAC, aCL, and aβ ₂ GPI antibodies (triple positivity) with a clinical diagnosis of APS predicts severe disease, particularly if aPLs are present in high titer. Results from different laboratories show considerable variability, and guidelines on diagnostic criteria have been published.

Tests for syphilis detect the aPLs present in syphilis, and consequently, the Venereal Disease Research Laboratory (VDRL) and Wasserman test results may be falsely positive. Some 20% of patients with APS may present with an initial diagnosis of idiopathic thrombocytopenic purpura.

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. The PROMISSE study showed that higher risk was indicated by African or Hispanic descent, presence of LAC, moderate clinical disease activity when pregnancy was diagnosed, thrombocytopenia, and flare activity.

Silver et al. reported that of 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 . Clark et al. reported that women diagnosed with APS on the basis of recurrent pregnancy loss and evidence of aPLs, but without prior thrombotic events, rarely suffered thrombosis during pregnancy. A history of thromboembolic events significantly worsens prognosis and increases the likelihood of future events, an effect ameliorated by the use of oral anticoagulants. A systematic review estimated an odds ratio of 33 for thrombosis with triple positivity (95% CI, 7.0 to 157.6), while a metaanalysis identified the most important predictors of adverse pregnancy outcomes as previous thrombosis, triple positivity and the presence of LAC.

Low-dose aspirin (ceased 4 weeks prior to delivery) plus low-molecular-weight heparin (LMWH) (e.g., enoxaparin 40 mg daily, continued for 3 to 6 weeks after delivery) is a typical standard regimen for thromboprophylaxis. Thrombocytopenia, present in one-fourth of patients with APS, is generally mild and responds to prednisone therapy.

Direct oral anticoagulants (DOACs) such as rituximab and rivaroxaban have been used as alternatives to warfarin in nonpregnant women. Two clinical trials, however, failed to demonstrate clinical advantage, and their use in obstetric patients is not recommended.

The use of HCQ for women with pregnancies at particular risk, in the absence of study findings, has been the subject of expert consensus, with the conclusion that its use may be justified in certain cases or when treatment with aspirin and heparin has been ineffective. Clinical trials for primary and secondary thromboprophylaxis continue.

Catastrophic antiphospholipid syndrome (CAPS or Asherson’s syndrome) occurs rarely and is discussed below.

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. Outcomes have improved, but with a greater incidence of preterm birth. Pregnant women with high positive aPL titers (four times the upper limit of normal) were found to have a 5.7 times higher risk of adverse fetal/neonatal outcome (fetal/neonatal loss, preterm birth and/or low birthweight). The retrospective cohort PREGNANTS study recorded that only 30% of women with triple positivity had a live-born neonate. Placental infarction is the apparent mechanism of fetal demise, of which most occur during mid and late pregnancy. Recommendations for the management of nonpregnant and pregnant patients with APS have been formulated and center around anticoagulation therapy (see later discussion).

Most infants born to women with APS do not have an increased rate of neonatal or childhood complications. Cases of antiphospholipid-related fetal and neonatal thrombosis (mainly cerebral thrombosis) and neurodevelopmental abnormalities have been reported.

The mainstay of obstetric management is thromboprophylaxis. Fetal survival and maternal thrombotic risk may be improved when affected pregnant women are treated with combined anticoagulation (low-dose unfractionated heparin) and antiplatelet (low-dose aspirin) medication. Live-birth rates of 70% to 80% have been reported. Neither type of heparin crosses the placental barrier. Recommendations on investigation and management of APS have been made. Women with more than three unexplained pregnancy losses before 10 weeks’ gestation should be tested for aPLs; 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.

Catastrophic antiphospholipid syndrome occurs in 1% of patients with APS. It is characterized by rapidly progressive thromboses with organ damage, thrombotic microangiopathy, and a systemic inflammatory response syndrome. Diagnosis requires the presence of aPLs with involvement of at least three organs and rapid onset and progression of disease. Urgent management strategies include elimination of precipitating causes, antibiotic cover for a precipitating bacterial infection, full anticoagulation, intravenous corticosteroids and immunoglobulin, and plasma exchange. HCQ and rituximab are increasingly used. Mortality is as high as 50%.

There are no large-scale studies describing anesthetic management of patients with APS, and management 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 (see earlier discussion) and does not warrant withholding neuraxial anesthesia. Infrequently, aPLs 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. All subjects received aspirin (75 to 150 mg daily) throughout pregnancy. 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 for 12 or 24 hours depending on the dose. (see Chapters 38 and 44 ). The use of thromboelastography to document clearance of heparin before administration of neuraxial anesthesia in parturients with LAC has been described.

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.

Systemic sclerosis or scleroderma is a rare 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. 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 in women and occurs primarily between 30 and 50 years of age.

Epigenetic regulation of gene expression through cellular transcription, without changes in gene sequence, plays a key role in phenotypic expression and is a possible mechanism by which the same genotype can be expressed as different phenotypes. Possible mechanisms include chemical modification of DNA (particularly methylation), histone coding, modification of RNA, and environmental influences. Although the stimulus for fibroblasts to produce excessive collagen and other matrix constituents is unknown, 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 but possibly including environmental factors, they may differentiate and initiate a reaction similar to graft-versus-host disease.

Raynaud’s phenomenon , characterized by cyclic pallor and cyanosis of the digits in response to cold or emotion, may be a 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, formerly 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 classification of systemic sclerosis has been updated by The American College of Rheumatology/European League Against Rheumatism and is summarized in Box 40.3 .

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. Renal failure and malignant hypertension are the most common causes of death. 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. Deterioration of renal function is of greatest concern.

In a retrospective study from a single center, the risk of adverse pregnancy outcomes (a composite endpoint that included fetal death, small-for-dates and growth-restricted babies, preeclampsia, preterm birth, and neonatal death) was increased compared with healthy controls and patients with scleroderma. 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.

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. Recent work suggests that tyrosine kinase inhibitors may have a beneficial effect in slowing the development of interstitial lung disease. 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).

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; captopril is most favored. 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.

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. Although the prevalence of left ventricular diastolic dysfunction is known to be higher in patients with scleroderma than in the general population, an association with pregnancy has not been noted. However, additional monitoring based on clinical findings may be indicated. Obstructive uropathy may result from an enlarging uterus trapped within a noncompliant abdomen. Uterine and cervical wall thickening may lead to ineffective uterine contractions or cervical dystocia at delivery. Even the tightest abdominal skin usually heals if cesarean delivery is necessary.

Anesthetic management can be challenging and 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 commonly used to assess ventricular dysfunction, pericardial and pleural effusions, and pulmonary hypertension. Patients with scleroderma may develop pulmonary hypertension as a consequence of vascular changes, fibrosis, or left ventricular dysfunction. Administration of a pulmonary vasodilator may increase the likelihood of a favorable outcome. 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, mandates careful airway assessment and may necessitate awake tracheal intubation. The changes in airway assessment scores that occur during labor should also be borne in mind (see Chapter 29 ).

If cesarean delivery is required, the decision to use neuraxial or general anesthesia depends on the urgency of delivery, anticipated airway difficulty, and operator skills. A report of two pregnant women with scleroderma and pulmonary hypertension described administration of neuraxial anesthesia in one and general anesthesia in the other, highlighting the complexity of management choices. Gastric hypomotility increases the risk for esophageal reflux and aspiration. Early administration of epidural analgesia in laboring women is encouraged if tracheal intubation is likely to be difficult. Even when severe diffuse cutaneous involvement is present, the skin of the lumbar back is usually spared.

Prolonged duration of neuraxial anesthesia has been observed in some patients with scleroderma and may be caused by 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, and the patient should be warned of the possibility of prolonged neural blockade.

Venous access may be difficult. Diffuse cutaneous involvement may indicate the need for central venous catheterization, 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. 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 myopathies. Polymyositis is characterized by nonsuppurative inflammation of muscle, primarily skeletal muscles of the proximal limbs, neck, and pharynx. This inflammation leads to symmetrical weakness, atrophy, and fibrosis of affected muscle groups, with the hip and thigh muscles most frequently affected. 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 rare and more common in women and with increasing age. A systematic review reported the incidence of inflammatory myopathies as a whole as 1.16 to 19/million/year with prevalence 2.4 to 33.8/100,000.

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 agents, or exposure to environmental substances, may lead to muscle damage in genetically susceptible individuals, which 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. Recent findings show that infection with SARS-Cov-2 (COVID-19) may induce myositis and trigger inflammation in patients with autoimmune conditions. 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 in affected individuals. Underlying malignancy has been associated with both conditions, although causality is unclear; the association is stronger for dermatomyositis than for polymyositis.