Lupus in Pregnancy Darren Farley, MD Clinical Assistant Professor

Lupus in Pregnancy Darren Farley, MD Clinical Assistant Professor
Division of Maternal-Fetal Medicine Dept. of Obstetrics and Gynecology University of Kansas School of Medicine – Wichita

No financial interests to disclose.

Objectives Physiologic changes Lupus overview Care in pregnancy
Congenital heart block Hydroxychloroquine Lupus flares

Maternal Physiology Robinson, 2012
Pregnancy and pregnancy-associated hormones alter immune responses and disease pathogenesis Dionne P. Robinsona, Sabra L. Kleina, b, , a The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA b Department of Biochemistry and Molecular Biology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 21205, USA Robinson, 2012

Maternal Physiology Estrogens upregulate T-cell responses, immunoglobulin synthesis, and leukocyte production of IL 1, 2, 6, TNFα Cell-mediated immunity is depressed Decreased ratio of T cells to B cells Increased ratio of suppressor T cells to helper T cells Decreased ratio of lymphocytes to monocytes Inhibition of complement activation in the placenta may be essential for fetal survival Trophoblast may be a target of autoimmunity. Estrogens upregulate and androgens downregulate T-cell responses, immunoglobulin synthesis, and leukocyte production of interleukin 1 (IL-1), IL-2, IL-6, and TNF-α, though changes in these cytokines are quantitatively small and remain within physiologic ranges. Cell-mediated immunity is depressed Altered ratios of T cells to B cells – varies with pregnancy Abnormal lymphocyte stimulation the stage of pregnancy. Decreased ratio of T cells to B cells Increased ratio of suppressor T cells to helper T cells Decreased ratio of lymphocytes to monocytes Creasy Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a relatively common disease and has a predilection for women of childbearing age. Its coincidence with pregnancy poses complex clinical problems because of the profound disturbance of the immunologic system, multiorgan involvement, and complicated immunology of pregnancy itself.[84] The outcome of pregnancy for women with SLE is variable and to some extent unpredictable, so careful monitoring, especially for those women with lupus nephritis, is required (see Chapter 51). Decisions regarding the status of the disease and the importance of having a child to the patient and her partner should be made on an individual basis. Most pregnancies succeed, especially when the maternal disease has been in complete clinical remission for 6 months before conception, even if there were marked pathologic changes in the original renal biopsy and heavy proteinuria in the early stages of the disease.[106] Continued signs of disease activity or increasing renal dysfunction reduces the likelihood of an uncomplicated pregnancy and the clinical course thereafter. The effects of gestation on SLE activity and on the course of lupus nephritis have long been debated. Taking into account extrarenal manifestations and renal changes, at least 50% of women show some change in clinical status, often called a lupus flare.[107] Some increments in proteinuria or blood pressure may result from preeclampsia. Women with lupus nephritis and renal insufficiency (serum creatinine level higher than 125 μmol/L or 1.4 mg/dL) that antedates pregnancy have worse outcomes. Lupus nephritis may sometimes become manifest during pregnancy, and when accompanied by hypertension and renal dysfunction, it may be mistaken for preeclampsia. Some patients experience relapse, occasionally severely in the puerperium; therefore, some clinicians prescribe or increase immunosuppression at this time.[108] It is our practice to increase immunosuppression only if there are signs of increased disease activity. SLE serum contains an array of autoantibodies (i.e., lupus serum factor) against nucleic acids, nucleoproteins, cell-surface antigens, and phospholipids. Antiphospholipid antibodies exert a complicated effect on the coagulation system.[109] This led to the definition of a lupus anticoagulant, which is found in 5% to 10% of patients with SLE (see Chapter 40). Because treatment with low-molecular-weight heparin and aspirin may lead to successful pregnancies, it is important to screen for lupus anticoagulant in women with SLE and especially in those with a history of recurrent intrauterine death or thrombotic episodes to identify this particular cohort. -- The systemic rheumatic illnesses commonly complicating pregnancy are systemic lupus erythematosus (SLE), antiphospholipid syndrome, rheumatoid arthritis, scleroderma, juvenile arthritis, spondyloarthropathy, and Takayasu arteritis. SLE and Takayasu arteritis affect 15- to 45-year-old women in a ratio of 9 women to 1 man. Antiphospholipid syndrome has a female-to-male ratio of 7 to 1; rheumatoid arthritis and scleroderma have a ratio of 3 to 1; juvenile arthritis is almost gender neutral; and spondyloarthropathy has a ratio of about 1 to 3. Rheumatoid arthritis and scleroderma affect middle-aged more than young women. SLE has a higher prevalence among African Americans than among whites (4 to 1). Up to 1% of all women have rheumatoid arthritis. One of 5000 to 10,000 women have SLE, and antiphospholipid syndrome may be as common as SLE, whereas the other diseases are less common. Because of these epidemiologic patterns, the autoimmune illnesses most frequently encountered in obstetric practices are SLE and antiphospholipid syndrome. Rheumatoid arthritis is a more common illness, but it occurs most often after the childbearing years and is therefore seen less often in pregnant women. Diagnosis of the systemic rheumatic diseases rests more on clinical than on serologic criteria (discussed with the individual diseases). Features common to all are arthralgia or arthritis; fever, myalgia, and malaise; and markers of inflammation. Current theories consider the systemic rheumatic diseases to be driven by disordered immune mechanisms, probably resulting from a genetic defect in processing exogenous infectious material, but the mechanisms and possible triggers are different among the illnesses. Systemic rheumatic illnesses are chronic and relapsing, with temporary remissions. It is more likely that a new pregnancy will be diagnosed in a woman with an established diagnosis of rheumatic illness than that a new diagnosis will be made for a previously healthy pregnant woman. Table 51-1 provides the epidemiologic, clinical, and laboratory characteristics of the rheumatic diseases most often encountered in pregnant women. TABLE 51-1 -- EPIDEMIOLOGIC, CLINICAL, AND LABORATORY CHARACTERISTICS AND PREGNANCY ISSUES OF COMMON AUTOIMMUNE RHEUMATIC ILLNESSES Disease Epidemiology Common Symptoms Laboratory Results Pregnancy Issues Systemic lupus erythematosus Age yr 9:1 female to male 4:2:1 black to Asian/Hispanic to white Arthritis, rash, fever, anemia, thrombocytopenia, nephritis, neurologic disease, alopecia High positive ANA value Anti-DNA and/or Smith (diagnostic) Antiphospholipid, anti-SSA/Ro, SSB/La, RNP antibodies (common) Raised ESR level Anemia, thrombocytopenia Proteinuria Low complement leve Fetal loss, neonatal upus, organ system flare Antiphospholipid syndrome Age yr Female > male White > black Blood clots, fetal loss, livedo reticularis, thrombocytopenia, cardiac valve disease Anticardiolipin Anti-β2-glycoprotein 1 Lupus anticoagulant test Thrombocytopenia Proteinuria Fetal loss, HELLP syndrome Rheumatoid arthritis Age yr 3:1 female to male White = black Destructive arthritis Anti-cyclic citrullinated peptide antibody Rheumatoid factor Raised ESR, CRP levels Bone erosions at joints Remission in some cases during pregnancy; positioning for delivery a problem Spondyloarthropathy Age yr Male > female HLA-B27 Spinal and sacroiliac arthritis Raised ESR, CRP values HLA-B27 Radiographic sacroiliitis Spinal fusion Enthesitis Arthritis management Takayasu arteritis Age yr 9:1 female to male Large vessel vasculitis, cardiac valve disease Raised ESR, CRP levels Alternating narrowing and aneurysm formation in aorta and great vessels Vascular integrity, measurement of blood pressure, cardiac failure Scleroderma 3:1 female to male Raynaud phenomenon, skin disease, pulmonary hypertension, hypertensive renal failure, esophageal reflux, pulmonary fibrosis Fibrosis on skin biopsy Pulmonary fibrosis Esophageal and intestinal hypomotility Reduced pulmonary diffusion capacity Urinary protein, raised creatinine level Complications related to esophagus, ung, heart, kidneys Juvenile arthritis Before age 18 yr Female > male for some types Polyarthritis; high fever and rash (Still's type) Raised ESR, CRP levels Raised ferritin level Erosions of joints Complications related to joint disease ANAs, antinuclear antibodies; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HELLP, hemolysis, elevated liver enzymes, and low platelets; RNP, ribonucleoprotein. Preg immune changes With regard to immunologic phenomena of pregnancy that may be relevant to autoimmune disease, in vitro data show that estrogens upregulate and androgens downregulate T-cell responses, immunoglobulin synthesis, and leukocyte production of interleukin 1 (IL-1), IL-2, IL-6, and TNF-α, though changes in these cytokines are quantitatively small and remain within physiologic ranges.[10] In pregnancy, cellmediated immunity is depressed, as reflected by abnormal lymphocyte stimulation, decreased ratios of T cells to B cells, increased ratios of suppressor T cells to helper T cells, and decreased ratios of lymphocytes to monocytes, all of which vary with the stage of pregnancy.[11,12] The pregnancy-specific proteins α-fetoprotein, β1-glycoprotein, and β2-macroglobulin suppress in vitro lymphocyte function. IL-1, IL-3, TNF-α, interferon γ, and granulocyte-macrophage colony-stimulating factor are critical in sustaining pregnancy.[13] IL-3 levels are low in women with repeated pregnancy loss. In normal pregnancy, total C3, C4, and hemolytic (CH50) complement levels are usually unchanged or raised relative to nonpregnant levels, but increases in classic pathway complement activation products suggest that low-grade classic pathway activation is a normal phenomenon in pregnant women. Complement activation products can alter the balance of angiogenic factor production by inflammatory cells and result in excess soluble vascular endothelial growth factor receptor type 1 (sFlt-1), which has implications for placental development and the risk for preeclampsia.[14] Inhibition of complement activation in the placenta may be essential for fetal survival,[15] and the trophoblast may be a target of autoimmunity.[16] Theoretically, these pregnancy-related changes may alter the course of specific autoimmune diseases, but clear documentation that they do is lacking. Creasy

Maternal Physiology AFP suppresses lymphocyte function
IL-1, IL-3, TNF-α, IFN γ, Granulocyte-macrophage colony-stimulating factor are critical in sustaining pregnancy. IL-3 levels - low in women with RPL Pregnancy - Total C3, C4, and hemolytic (CH50) complement levels – unchanged / increased Increase in classic pathway complement activation Complement activation can result in excess soluble vascular endothelial growth factor receptor type 1 (sFlt-1), which has implications for placental development and the risk for preeclampsia. Lupus – flare – C3 decreased, AT III no change Pree – C3 increased, could decrease, no help; AT III decreased Pregnancy-specific proteins α-fetoprotein, β1-glycoprotein, and β2-macroglobulin suppress in vitro lymphocyte function. IL-1, IL-3, TNF-α, interferon γ, and granulocyte-macrophage colony-stimulating factor are critical in sustaining pregnancy. IL-3 levels - low in women with RPL Pregnancy - Total C3, C4, and hemolytic (CH50) complement levels – unchanged / increased Increase in classic pathway complement activation Complement activation products can alter the balance of angiogenic factor production by inflammatory cells and result in excess soluble vascular endothelial growth factor receptor type 1 (sFlt-1), which has implications for placental development and the risk for preeclampsia. Creasy Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a relatively common disease and has a predilection for women of childbearing age. Its coincidence with pregnancy poses complex clinical problems because of the profound disturbance of the immunologic system, multiorgan involvement, and complicated immunology of pregnancy itself.[84] The outcome of pregnancy for women with SLE is variable and to some extent unpredictable, so careful monitoring, especially for those women with lupus nephritis, is required (see Chapter 51). Decisions regarding the status of the disease and the importance of having a child to the patient and her partner should be made on an individual basis. Most pregnancies succeed, especially when the maternal disease has been in complete clinical remission for 6 months before conception, even if there were marked pathologic changes in the original renal biopsy and heavy proteinuria in the early stages of the disease.[106] Continued signs of disease activity or increasing renal dysfunction reduces the likelihood of an uncomplicated pregnancy and the clinical course thereafter. The effects of gestation on SLE activity and on the course of lupus nephritis have long been debated. Taking into account extrarenal manifestations and renal changes, at least 50% of women show some change in clinical status, often called a lupus flare.[107] Some increments in proteinuria or blood pressure may result from preeclampsia. Women with lupus nephritis and renal insufficiency (serum creatinine level higher than 125 μmol/L or 1.4 mg/dL) that antedates pregnancy have worse outcomes. Lupus nephritis may sometimes become manifest during pregnancy, and when accompanied by hypertension and renal dysfunction, it may be mistaken for preeclampsia. Some patients experience relapse, occasionally severely in the puerperium; therefore, some clinicians prescribe or increase immunosuppression at this time.[108] It is our practice to increase immunosuppression only if there are signs of increased disease activity. SLE serum contains an array of autoantibodies (i.e., lupus serum factor) against nucleic acids, nucleoproteins, cell-surface antigens, and phospholipids. Antiphospholipid antibodies exert a complicated effect on the coagulation system.[109] This led to the definition of a lupus anticoagulant, which is found in 5% to 10% of patients with SLE (see Chapter 40). Because treatment with low-molecular-weight heparin and aspirin may lead to successful pregnancies, it is important to screen for lupus anticoagulant in women with SLE and especially in those with a history of recurrent intrauterine death or thrombotic episodes to identify this particular cohort. -- The systemic rheumatic illnesses commonly complicating pregnancy are systemic lupus erythematosus (SLE), antiphospholipid syndrome, rheumatoid arthritis, scleroderma, juvenile arthritis, spondyloarthropathy, and Takayasu arteritis. SLE and Takayasu arteritis affect 15- to 45-year-old women in a ratio of 9 women to 1 man. Antiphospholipid syndrome has a female-to-male ratio of 7 to 1; rheumatoid arthritis and scleroderma have a ratio of 3 to 1; juvenile arthritis is almost gender neutral; and spondyloarthropathy has a ratio of about 1 to 3. Rheumatoid arthritis and scleroderma affect middle-aged more than young women. SLE has a higher prevalence among African Americans than among whites (4 to 1). Up to 1% of all women have rheumatoid arthritis. One of 5000 to 10,000 women have SLE, and antiphospholipid syndrome may be as common as SLE, whereas the other diseases are less common. Because of these epidemiologic patterns, the autoimmune illnesses most frequently encountered in obstetric practices are SLE and antiphospholipid syndrome. Rheumatoid arthritis is a more common illness, but it occurs most often after the childbearing years and is therefore seen less often in pregnant women. Diagnosis of the systemic rheumatic diseases rests more on clinical than on serologic criteria (discussed with the individual diseases). Features common to all are arthralgia or arthritis; fever, myalgia, and malaise; and markers of inflammation. Current theories consider the systemic rheumatic diseases to be driven by disordered immune mechanisms, probably resulting from a genetic defect in processing exogenous infectious material, but the mechanisms and possible triggers are different among the illnesses. Systemic rheumatic illnesses are chronic and relapsing, with temporary remissions. It is more likely that a new pregnancy will be diagnosed in a woman with an established diagnosis of rheumatic illness than that a new diagnosis will be made for a previously healthy pregnant woman. Table 51-1 provides the epidemiologic, clinical, and laboratory characteristics of the rheumatic diseases most often encountered in pregnant women. TABLE 51-1 -- EPIDEMIOLOGIC, CLINICAL, AND LABORATORY CHARACTERISTICS AND PREGNANCY ISSUES OF COMMON AUTOIMMUNE RHEUMATIC ILLNESSES Disease Epidemiology Common Symptoms Laboratory Results Pregnancy Issues Systemic lupus erythematosus Age yr 9:1 female to male 4:2:1 black to Asian/Hispanic to white Arthritis, rash, fever, anemia, thrombocytopenia, nephritis, neurologic disease, alopecia High positive ANA value Anti-DNA and/or Smith (diagnostic) Antiphospholipid, anti-SSA/Ro, SSB/La, RNP antibodies (common) Raised ESR level Anemia, thrombocytopenia Proteinuria Low complement leve Fetal loss, neonatal upus, organ system flare Antiphospholipid syndrome Age yr Female > male White > black Blood clots, fetal loss, livedo reticularis, thrombocytopenia, cardiac valve disease Anticardiolipin Anti-β2-glycoprotein 1 Lupus anticoagulant test Thrombocytopenia Proteinuria Fetal loss, HELLP syndrome Rheumatoid arthritis Age yr 3:1 female to male White = black Destructive arthritis Anti-cyclic citrullinated peptide antibody Rheumatoid factor Raised ESR, CRP levels Bone erosions at joints Remission in some cases during pregnancy; positioning for delivery a problem Spondyloarthropathy Age yr Male > female HLA-B27 Spinal and sacroiliac arthritis Raised ESR, CRP values HLA-B27 Radiographic sacroiliitis Spinal fusion Enthesitis Arthritis management Takayasu arteritis Age yr 9:1 female to male Large vessel vasculitis, cardiac valve disease Raised ESR, CRP levels Alternating narrowing and aneurysm formation in aorta and great vessels Vascular integrity, measurement of blood pressure, cardiac failure Scleroderma 3:1 female to male Raynaud phenomenon, skin disease, pulmonary hypertension, hypertensive renal failure, esophageal reflux, pulmonary fibrosis Fibrosis on skin biopsy Pulmonary fibrosis Esophageal and intestinal hypomotility Reduced pulmonary diffusion capacity Urinary protein, raised creatinine level Complications related to esophagus, ung, heart, kidneys Juvenile arthritis Before age 18 yr Female > male for some types Polyarthritis; high fever and rash (Still's type) Raised ESR, CRP levels Raised ferritin level Erosions of joints Complications related to joint disease ANAs, antinuclear antibodies; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HELLP, hemolysis, elevated liver enzymes, and low platelets; RNP, ribonucleoprotein. Preg immune changes With regard to immunologic phenomena of pregnancy that may be relevant to autoimmune disease, in vitro data show that estrogens upregulate and androgens downregulate T-cell responses, immunoglobulin synthesis, and leukocyte production of interleukin 1 (IL-1), IL-2, IL-6, and TNF-α, though changes in these cytokines are quantitatively small and remain within physiologic ranges.[10] In pregnancy, cellmediated immunity is depressed, as reflected by abnormal lymphocyte stimulation, decreased ratios of T cells to B cells, increased ratios of suppressor T cells to helper T cells, and decreased ratios of lymphocytes to monocytes, all of which vary with the stage of pregnancy.[11,12] The pregnancy-specific proteins α-fetoprotein, β1-glycoprotein, and β2-macroglobulin suppress in vitro lymphocyte function. IL-1, IL-3, TNF-α, interferon γ, and granulocyte-macrophage colony-stimulating factor are critical in sustaining pregnancy.[13] IL-3 levels are low in women with repeated pregnancy loss. In normal pregnancy, total C3, C4, and hemolytic (CH50) complement levels are usually unchanged or raised relative to nonpregnant levels, but increases in classic pathway complement activation products suggest that low-grade classic pathway activation is a normal phenomenon in pregnant women. Complement activation products can alter the balance of angiogenic factor production by inflammatory cells and result in excess soluble vascular endothelial growth factor receptor type 1 (sFlt-1), which has implications for placental development and the risk for preeclampsia.[14] Inhibition of complement activation in the placenta may be essential for fetal survival,[15] and the trophoblast may be a target of autoimmunity.[16] Theoretically, these pregnancy-related changes may alter the course of specific autoimmune diseases, but clear documentation that they do is lacking. Creasy

SLE Chronic autoimmune d/o with disease flares and remissions
Can affect all organs Mild cases – skin, musculoskeletal system More severe – kidney, brain Possible manifestations are arthralgias, rashes, renal abnormalities, neurologic complications, thromboemboli, myocarditis, serositis

Epidemiology Prevalence of lupus varies with population
5-125/100,000 people Affects 1% of pregnancies Lifetime risk of developing lupus is 1/700 peaks at 30 y/o Women : Men – 9:1 Ethnic groups African Americans Hispanics Because of these epidemiologic patterns, the autoimmune illnesses most frequently encountered in obstetric practices are SLE and antiphospholipid syndrome. Rheumatoid arthritis is a more common illness, but it occurs most often after the childbearing years and is therefore seen less often in pregnant women. Prevalence of lupus varies with population 5-125/100,000 people Affects 1% of pregnancies Lifetime risk of developing lupus is 1/700 peaks at 30 y/o Women : Men – 9:1 Ethnic groups African Americans (prevalence - Hispanics (prevalence - - Women : Men – 9:1Affects women 3-10x more than men -- incidence – risk of developing a condition in a pop in a specific period of time; rate with denominator; rate of occurrence of new cases; risk of contracting the disease during a time period prevalence – total number of cases of disease in a population; how widespread the disease is ---when studying etiology of disease, best to study incidence b/c it is a more finite time period by definition whereas prevalence mixes in the duration of the condition and groups all of the cases regardless of time at that point in time For example, consider a disease that takes a long time to cure, and that was spread widely in 2002, but whose spread was arrested in This disease will have a high prevalence and a high incidence in 2002; but in 2003 it will have a low incidence, although it will continue to have a high prevalence because it takes a long time to cure. In contrast, a disease that has a short duration may have a low prevalence and a high incidence

Etiology Unknown Genetic linkage Alterations in HLA system
5-12% of affected individuals have an affected relative 25-50% of monozygotic twins are concordant for the disease Alterations in HLA system HLA-B8, HLA-DR3, HLA-DR2 Abnormal B and T cell biology and immune clearance mechanisms

Pathophysiology Damage due to immune complex deposition, complement activation, inflammation, fibrosis Renal, MSK, hepatic, platelets Autoantibodies Antinuclear antibody – most common, ‘lab is open’ Increased in pregnancy – 10% of asymptomatic pregnant women without autoimmune disease have ANA ab compared to 2% of nonpregnant controls Screening for lupus b/c of high prevalence in gen pop Anti - dsDNA antibody and anti-Smith Ab - more specific for lupus; dsdna ab correlates with disease activity Antiphospholipid antibodies Anti – Ro/SSA, anti- La/SSB more often associated with sjogrens sd, but seen in 20-40% of females with lupus Associated with neonatal lupus syndrome Autoantibodies antinuclear antibody – most common, so good screening antibody for autoimmune syndromes increased in pregnancy – 10% of asymptomatic pregnant women without autoimmune disease have ANA ab compared to 2% of nonpregnant controls screening for lupus b/c of high prevalence in gen pop dsDNA ab and Sm ab are more specific for lupus; dsDNA ab correlates with disease activity AntiSSA/Ro and antiSSB/La more often associated with Sjogrens sd, but seen in 20-40% of females with lupus associated with neonatal lupus sd (more later) Renal damage secondary to immune complex deposition, complement activation, inflammation, fibrosis

Symptom frequency Fatigue – 80-100% Fever – 80-100% Arthritis – 95%
Myalgia – 70% Weight loss – 60% Photosensitivity – 60% Malar rash - 50% Nephritis – 50% Pleurisy – 50% Lymphadenopathy – 50% Pericarditis – 30% Neuropsychiatric – 20%

Criteria for Diagnosis
Per American College of Rheumatology Need 4 of 11 (serially or at one time) Malar rash (erythema over malar eminences) Discoid rash (erythematous raised patches) Photosensitivity (unusual rxn to sunlight) Oral ulcers (oral, nasopharyngeal) Arthritis (nonerosive, 2+ peripheral joints) Serositis (pleuritis, pericarditis) Nephritis (>500mg/d proteinuria or cellular casts) Neurologic disorder (seizures, psychosis, stroke with other causes r/o) Hematologic disorder (hemolytic anemia with reticulocytosis, thrombocytopenia <100k, leukopenia < occasions, lymphopenia < occasions) Immunologic disorder (anti-dsDNA, anti-Sm, positive LAC ACA, false pos RPR or other serologic test for syphilis for 6 months confirmed by treponema pallidum immobilization or fluorescent treponemal ab absorption test) Antinuclear antibodies (without being on drugs associated with drug induced lupus syndrome <4 of 11 = lupus-like syndrome Clinical Criteria for Diagnosing Lupus: 4 or more of these 11 symptoms will help determine diagnosis. Recently, a new Lupus diagnosis criteria was adopted requiring 3 of 10 symptoms similar to the ones below, and appropriate screening of Anti-Nuclear Antibodies (ANA) blood test to make final diagnosis. Criterion Definition Malar Rash Rash over the cheeks Discoid Rash Red raised patches Photosensitivity Reaction to sunlight, resulting in the development of or increase in skin rash Oral Ulcers Ulcers in the nose or mouth, usually painless Arthritis Nonerosive arthritis involving two or more peripheral joints (arthritis in which the bones around the joints do not become destroyed) Serositis Pleuritis or pericarditis (inflammation of the lining of the lung or heart) Renal Disorder Excessive protein in the urine (greater than 0.5 gm/day or 3+ on test sticks) and/or cellular casts (abnormal elements the urine, derived from red and/or white cells and/or kidney tubule cells) Neurologic Disorder Seizures (convulsions) and/or psychosis in the absence of drugs or metabolic disturbances which are known to cause such effects Hematologic Disorder Hemolytic anemia or leukopenia (white blood count below 4,000 cells per cubic millimeter) or lymphopenia (less than 1,500 lymphocytes per cubic millimeter) or thrombocytopenia (less than 100,000 platelets per cubic millimeter). The leukopenia and lymphopenia must be detected on two or more occasions. The thrombocytopenia must be detected in the absence of drugs known to induce it. Antinuclear Antibody Positive test for antinuclear antibodies (ANA) in the absence of drugs known to induce it. Immunologic Disorder Positive anti-double stranded anti-DNA test, positive anti-Sm test, positive antiphospholipid antibody such as anticardiolipin, or false positive syphilis test (VDRL).

General Morbidity/Mortality
Renal and cardiovascular disease Thrombosis Infection Survival rates 5y – 93% 10y – 85% 15y – 79% 20 y – 68% Risk factors for death from lupus Lupus nephritis Thrombocytopenia Lung involvement High disease activity at time of diagnosis Prone to CV disease, VTE, infection, renal disease due to effects on multiple organ systems, pt are prone to CV disease, thromboembolic phenomena, infection, renal disease survival rates 5y – 93% 10y – 85% 15y – 79% 20 y – 68% rf for mortality – renal damage, thrombocytopenia, lung involvement, high disease activity at dx, >50 y/o at dx

Pregnancy Outcomes Effect of SLE on pregnancy
Increased stillbirth rate 25x (150/1000) Esp with antiphospholipid antibodies Increased preeclampsia rate to 20-30% (7-10%) Increased IUGR rate to 12-32% Increased preterm delivery rate to 50-60% (12-15%) Increased PPROM rate Neonatal lupus only in Ro/La antibody positive patients Effect of pregnancy on SLE Worsening renal status if nephropathy (Cr 1.5) present Increased flares if active disease at start of pregnancy Risk of neonatal lupus in ro/la 1-2 %, increased recur risk

Chronic Renal Insufficiency and Pregnancy Outcomes (vs serum creatinine mg/dL)
PTB 13% 50% 100% Perinatal death 5% 17% 33% IUGR 10% 20% Abortion 11% 21% 25% Surviving infants 84% 62% Management of a high risk prgnancy –queenan book 2 Chronic kidney disease – regardless of etiology Queenan 2007

Renal Biopsies in Pregnancy
Complications - Hematoma formation Bleeding Death Usually do not help change management If steroids are the change in management, then steroid administration is of lower risk than a renal biopsy

Evaluation & Management

Goals of Management Disease control/remission before pregnancy
Avoid drugs that harm the fetus Prompt detection of preeclampsia and placental insufficiency Discern between lupus exacerbations and preeclampsia Appropriate detection and treatment of lupus flares

Preconception counseling
Potential complications – preeclampsia, preterm labor, miscarriage, fetal death, fetal growth restriction, and neonatal lupus Evaluate lupus activity – delay pregnancy until remission Evaluate for nephritis (24 hr urine), hematologic abnormalities (CBC), antiphospholipid abnormalities Discontinue NSAIDS and cytotoxic agents

Medications

NSAIDS NSAIDS – inhibits cyclooxygenase, lipoxygenase, reduces prostaglandin synthesis Class D Avoid especially in 3rd trimester Cross placenta, blocks prostaglandin synthesis in fetal tissue Premature closure of ductus arteriosis, fetal pulmonary hypertension, NEC, fetal renal insufficiency Occurs with selective COX-II inhibitors ASA crosses placenta and can affect fetal platelet function and is associated with intracranial fetal hemorrhage in 3rd trimester; avoid in pregnancy Used outside of pregnancy – most common anti-inflammatory agent

Hydroxychloroquine Hydroxychloroquine (antimalarial/antirheumatic; binds DNA, interferes with vesicle functions, inhibits phospholipid metabolism; immunosuppressive by inhibiting rheumatoid factor, acute phase reactants, enzymes) Stopping this in pregnancy is associated with increased risk of lupus flares, continuing this drug is recommended if needed to control lupus (prospective study by cortes-hernandez showed the increased risk) Large series show no increased risk of anomalies Used in prevention of malaria with increase of fetal anomalies Not associated with increased r/o fetal malformations Class C Chloroquine possible teratogenic in initial studies Ototoxicity, eye development 800mg po load mg BID; max 800mg /d Hydroxychloroquine (antimalarial/antirheumatic; binds DNA, interferes with vesicle functions, inhibits phospholipid metabolism; immunosuppressive by inhibiting rheumatoid factor, acute phase reactants, enzymes stopping this in pregnancy is associated with increased risk of lupus flares, continuing this drug is recommended if needed to control lupus (prospective study by Cortes-Hernandez showed the increased risk) limited data not associated with increased r/o fetal malformations preg class C chloroquine is teratogenic ?? – tetralogy of fallot, congenital hypothyroidism Buchanan, 1996; Khamashta 1996 Klinger 2001; Motta 2002

Glucocorticoids Glucocorticoids (antiinflammatory, glucocorticoid, mineralocorticoid) Preg class C Avoid fluorinated glucocorticoids b/c they cross the placenta Hydrocortisone, prednisone, prednisolone inactivated by 11-beta hydroxysteroid dehydrogenase in the placenta allowing <10% of active drug to reach fetus High dose associated with maternal/fetal A/E Osteoporosis (tx with vit D, ca2+); glucose intolerance, sodium, h2o retention; hypertension, infection; avascular necrosis Preg complications – GDM, preeclampsia, PPROM, IUGR Incidence of fetal adrenal suppression with maternal tx is low Avoid empiric treatment, use at lowest possible dose Stress dose steroids (hydrocortisone 100mg IV q8hr in labor and for 24 hr PP) Use if chronic steroids (>5mg/day for >2-4 weeks prior to delivery) Glucocorticoids (antiinflammatory, glucocorticoid, mineralocorticoid) Preg class B Avoid fluorinated glucocorticoids b/c they cross the placenta Hydrocortisone, prednisone, prednisolone inactivated by 11-beta hydroxysteroid dehydrogenase in the placenta allowing <10% of active drug to reach fetus High dose associated with maternal/fetal A/E Osteoporosis (tx with vit D, ca2+); glucose intolerance, sodium, h2o retention; hypertension, infection; avascular necrosis Preg complications – GDM, preeclampsia, PPROM, IUGR Incidence of fetal adrenal suppression with maternal tx is low Avoid empiric treatment, use at lowest possible dose Stress dose steroids (hydrocortisone 100mg IV q8hr in labor and for 24 hr PP) Use if chronic steroids (20mg or more of prednisone for >= 3 weeks during last 6 mos)

Azathioprine Azathioprine (inhibits T lymphocytes) Class D
Teratogenic in animals, appears safe in humans Associated with IUGR Neonatal immunosuppression Indicated in pregnancy if chronic high doses of steroids is not controlling symptoms or to lower steroid dose

Cyclophosphamide Cyclophosphamide (alkylates and cross links DNA)
Preg class D Cleft palate, skeletal abnormalities, abnormal renal function Avoid, esp in first trimester May be needed in cases of severe proliferative nephritis (drug of choice in nonpregnant patients with proliferative lupus nephritis) Crosses placenta

Methotrexate Methotrexate (inhibits dihydrofolate reductase; inhibits lymphocyte proliferation) (folate antagonist) Preg class X Avoid Embryolethal, IUFD Congenital anomalies

Cyclosporine Cyclosporine A (inhibits T lymphocytes) Preg class C
Data comes from use in renal transplant patients, not an animal teratogen, appears safe in humans, long term follow up studies are limited

Tacrolimus Tacrolimus (inhibits T lymphocyte activation, immunosuppressant) Dose in liver transplant mg/kg/d po divide q12 hr Preg class C Therapeutic drug levels 5-20 ng/ml just before next dose; time to steady state 3 days Monitor creatinine, K, fasting blood glucose, serum drug levels

Pregnancy - FDA classes
A – controlled studies show no fetal risk in any trimester, probability of fetal harm is remote B – animal studies, no risk; if risk in animal studies, controlled human studies do not confirm harm C – harm in animal studies with no controlled human studies; no available human or animal studies D – human studies show fetal risk but r/b relative to medical state of mother may support use X – animal/human studies show fetal risk or abnormalities, use is contraindicated during pregnancy or in women who may become pregnant

Pregnancy Care

Pregnancy Labs/Evaluation *CBC, CMP, 24hr UA for TP/CC
*Antiphospholipid antibodies *Anti-Ro and anti-La antibodies *Anti-dsDNA antibody Complement (C3 and C4 or CH50) Monthly CBC, Platelet count, Complement and anti-dsDNA antibody Maternal echocardiogram if disease present >3-5 yrs, cardiac complications, associated CHTN, lupus nephritis Pregnancy Management Monitoring recommendations for patients with rheumatic disease are presented in Table Unexplained elevations of maternal αfetoprotein and human chorionic gonadotropin occur in patients with lupus and with antiphospholipid antibodies. These abnormalities correlate with preterm delivery, requirements for a higher prednisone dose, and fetal death.[66] Because intervention with dexamethasone at the earliest sign of cardiac dysfunction may reverse myocarditis and possibly congenital heart block, women with high-titer anti-Ro and anti-La antibodies and those who have previously given birth to a child with any form of neonatal lupus should undergo fetal cardiac monitoring weekly during the vulnerable period of 18 to 25 weeks' gestation. In women known to be strongly positive for lupus anticoagulant and anticardiolipin antibody, repeat testing for these antibodies during pregnancy is unnecessary, because spontaneous correction of the lupus anticoagulant level and a decrease in the anticardiolipin antibody level does not improve prognosis. In women with low antibody levels or negative test results, repetition at least once each trimester is useful because overall prognosis is that of the highest level seen during the pregnancy. The platelet count should be repeated monthly. Women significantly positive for antiphospholipid antibodies and who have had a prior fetal loss should be treated with low-dose aspirin and unfractionated or low-molecular-weight heparin. TABLE RECOMMENDED EVALUATION OF PREGNANT PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASE Recommended Frequency Monitoring Test First visit Complete blood count and urinalysis[*] Creatinine clearance Antiphospholipid antibodies Anti-Ro and anti-La antibodies Anti-dsDNA antibody (SLE patients) Complement (C3 and C4 or CH50) (SLE patients) Monthly Platelet count[†] Each trimester Creatinine clearance[†] A 24-hour urine protein assay if screening urinalysis is abnormal[†] Complement[†] and anti-dsDNA antibody[†] Weekly (last trimester, mothers with antiphospholipid antibodies) Antenatal fetal heart rate testing (nonstress test), and/or biophysical profile[‡] Between 18 and 25 weeks (mothers with anti-Ro/La antibodies) Fetal echocardiogram, fetal electrocardiogram (?) Adapted from Lockshin MD: Pregnancy and rheumatic disease. In Koopman WJ, Moreland LW (eds): Arthritis and Allied Conditions, 15th ed. Philadelphia, Lippincott Williams & Wilkins, 2005, pp 1719–1728. CH50, hemolytic complement level; dsDNA, double-stranded DNA; SLE, systemic lupus erythematosus. * The erythrocyte sedimentation rate is often abnormal in uncomplicated pregnancy. † More frequently if abnormal. ‡ Measure of fetal size, activity, and amniotic fluid volume. Decisions regarding timing and route of delivery are dictated by the status of the fetus but may be influenced by maternal illness and its complications. Approximately one third of SLE patients undergo operative delivery. The usual indications for cesarean delivery are fetal distress, prior cesarean delivery, prolonged ruptured membranes, failure to progress at labor and other obstetric reasons, thrombocytopenia, and severe maternal illness. There is little information about the use of tocolytics or stimulators of labor in pregnant women with rheumatic disease. Ritodrine, magnesium sulfate, and prostaglandin suppositories have been used without incident. At delivery, stress corticosteroid doses (usually 100 mg of hydrocortisone every 8 hours from the onset of labor until 24 hours after delivery) are administered to patients currently or recently taking corticosteroids. Asymptomatic bacteremia occurs in 3.6% of vaginal deliveries. Because of limited hip joint movement or risk of bacterial seeding, osteonecrosis of the hip may justify a decision for operative rather than vaginal delivery. The mode of delivery for patients with total hip replacements need not be surgical; patients have been delivered vaginally with appropriate attention paid to the positioning of the patient.

Lupus and Presence of Antiphospholipid Antibodies
1/3 of lupus patients Risks – thrombosis, fetal loss + APA and history of fetal loss = APLS Heparin/lovenox is recommended Thromboprophylaxis Due to increased thrombosis risk Data is lacking that reveals improved outcomes (less SABs, IUFDs, etc) unless APLS is diagnosed [Pregnancy and antiphospholipid antibodies in systemic lupus erithematosus patients: an outcome evaluation]. [Article in Portuguese] Cordeiro A, Lermann R, Ambrósio P, Nogueira I, Serrano F. Source Serviço de Medicina Materno-Fetal, Maternidade Dr. Alfredo da Costa, Abstract BACKGROUND AND AIMS: Antiphospholipid antibodies (APLAs) have been associated with pregnancy loss and other obstetric complications, such as pre--eclampsia, fetal growth restriction and preterm delivery. Systemic lupus erythematosus (SLE) patients frequently present APLAs and secondary antiphospholipid syndrome. The purpose of this work is to evaluate pregnancy outcome in SLE patients with and without APLAs. MATERIAL AND METHODS: Retrospective analysis of 136 gestations in women with SLE diagnosis previous to pregnancy that underwent surveillance in our maternity from 1993 to Patients with and without APLAs were considered separately. Maternal age, obstetric history, SLE activity and nephropathy, present pregnancy evolution, gestational age at delivery, mode of delivery, birth weight and hypertensive complications were identified. RESULTS: 28% (38) of pregnant SLE patients had APLAs. From these patients, % had past history of second and/or third trimester fetal losses, against 6.12% in patients without APLAs (p<0.05). Evaluation of present pregnancy outcome revealed, for APLAs positive patients, a significant higher rate of non-successful pregnancy (8.1% vs 2.1%, p<0.05). Analysis of mean birth weight and intrauterine growth restriction rates revealed no significant differences related to APLAs presence. Mean gestational age at delivery was 36.9 weeks for both groups with identical preterm delivery rates. Cesarean section was the mode of delivery for 47% and 44.1% of the patients, in APL patients and others, respectively. CONCLUSIONS: SLE patients with APLAs had more spontaneous abortions and worse obstetric history, with no other significant differences in perinatal and obstetric outcome.

Antenatal care Frequent visits to assess lupus status, screen for hypertension Continue hydroxychloroquine Depends on control as to whether to initiate it if patient is not medicated Monitor for exacerbations/flares If chronic hypertension – monitor as such APLS – see above

Antenatal care Between 18 and 25 weeks (mothers with anti-ro/la antibodies) *Screening fetal echocardiogram Fetal electrocardiogram through echocardiography Vs. *weekly FHR checks +/- Dexamethasone Serial ultrasounds to evaluate fetal growth Antenatal surveillance at 32 weeks or earlier if indicated

Neonatal Lupus Rash, thrombocytopenia, hepatitis, hemolytic anemia
Transient Complete heart block – Permanent Only if +SSA/B antibodies 25% risk of rash (recurrence risk 25%) <3% risk of heart block (RR 18%)

Congenital Heart Block
SSA/B + increases risk Prior history of child with heart block increases risk Dexamethasone – limited data that shows clear benefit Hydroxychloroquine Pregnancy Management Monitoring recommendations for patients with rheumatic disease are presented in Table Unexplained elevations of maternal αfetoprotein and human chorionic gonadotropin occur in patients with lupus and with antiphospholipid antibodies. These abnormalities correlate with preterm delivery, requirements for a higher prednisone dose, and fetal death.[66] Because intervention with dexamethasone at the earliest sign of cardiac dysfunction may reverse myocarditis and possibly congenital heart block, women with high-titer anti-Ro and anti-La antibodies and those who have previously given birth to a child with any form of neonatal lupus should undergo fetal cardiac monitoring weekly during the vulnerable period of 18 to 25 weeks' gestation. In women known to be strongly positive for lupus anticoagulant and anticardiolipin antibody, repeat testing for these antibodies during pregnancy is unnecessary, because spontaneous correction of the lupus anticoagulant level and a decrease in the anticardiolipin antibody level does not improve prognosis. In women with low antibody levels or negative test results, repetition at least once each trimester is useful because overall prognosis is that of the highest level seen during the pregnancy. The platelet count should be repeated monthly. Women significantly positive for antiphospholipid antibodies and who have had a prior fetal loss should be treated with low-dose aspirin and unfractionated or low-molecular-weight heparin. Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Doppler study using a pulsed wave of the fetal heart was used to obtain the mechanical Doppler PR interval measurements.30 The 2-dimensional directed pulsed Doppler gate was placed distal to the mitral valve within 20° of parallel to the left ventricular outflow tract. By obtaining the pulsed Doppler signal in this location, we determined the mitral valve Doppler flow pattern (specifically the E/A ratio), as well as the aortic Doppler pattern on the same simultaneous tracing. The tracing was frozen, and the interval between the onset of the mitral valve A wave and the upstroke of the aortic valve flow was measured. The time interval (in milliseconds) between these 2 Doppler samples represents the delay from the onset of atrial contraction to the onset of ventricular contraction, which is representative of the mechanical PR interval. Three measurements per subject were taken and averaged. The fetal heart rate also was determined from sequential Doppler aortic outputs on the same tracing. Izmirly, 2010

Fetal PR Interval Wojakowski 2009
Figure 1 Four-chamber view and position of the simple Doppler volume in the mitral-aortic continuity. The flow waves through the mitral valve (E- and A-waves) and the aortic valve (V-wave) are shown on the left. Figure 2 Mechanical PR interval measured between the onset of atrial contraction (A-wave) and the onset of ventricular contraction (V-wave). Wojakowski 2009

PRIDE study, Friedman 2008 Background—Anti-SSA/Ro–associated third-degree congenital heart block is irreversible, prompting a search for early markers and effective therapy. Methods and Results—One hundred twenty-seven pregnant women with anti-SSA/Ro antibodies were enrolled; 95 completed an evaluable course in 98 pregnancies. The protocol included fetal echocardiograms performed weekly from 16 to 26 weeks’ gestation and biweekly from 26 to 34 weeks. PR intervals 150 ms were considered prolonged, consistent with first-degree block. Ninety-two fetuses had normal PR intervals. Neonatal lupus developed in 10 cases; 4 were neonatal lupus rash only. Three fetuses had third-degree block; none had a preceding abnormal PR interval, although in 2 fetuses 1 week elapsed between echocardiographic evaluations. Tricuspid regurgitation preceded third-degree block in 1 fetus, and an atrial echodensity preceded block in a second. Two fetuses had PR intervals 150 ms. Both were detected at or before 22 weeks, and each reversed within 1 week with 4 mg dexamethasone. The ECG of 1 additional newborn revealed a prolonged PR interval persistent at 3 years despite normal intervals throughout gestation. No first-degree block developed after a normal ECG at birth. Heart block occurred in 3 of 16 pregnancies (19%) in mothers with a previous child with congenital heart block and in 3 of 74 pregnancies (4%) in mothers without a previous child with congenital heart block or rash (P0.067). Conclusions—Prolongation of the PR interval was uncommon and did not precede more advanced block. There was a trend toward more congenital heart block in fetuses of women with previously affected offspring than those without previously affected offspring. Advanced block and cardiomyopathy can occur within 1 week of a normal echocardiogram without initial first-degree block. Echodensities and moderate/severe tricuspid regurgitation merit attention as early signs of injury. (Circulation. 2008;117: )

PRIDE Study 127 women evaluated, 95 completed course – all had Ro or La Ab Fetal echo, weekly weeks PR >150msec – 1st degree 92 - Normal PR intervals 3 with complete heart block, without prolonged PR interval preceding it Tricuspid regurgitation, atrial echodensity 2 had PR intervals >150msec, 22 weeks Dexamethasone initiated, reported to prevent progression and resolved the 1st degree Recurrence – 19% with previous heart block 3% without previous heart block

Evaluation Of The Risk Of Anti-ssa/Ro-ssb/La Antibody-associated Cardiac Manifestations Of Neonatal Lupus In Fetuses Of Mothers With Systemic Lupus Erythematosus Exposed To Hydroxychloroquine TLR signaling in pathogenesis of neonatal heart block Hydroxychloroquine is a TLR inhibitor A TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibody associated cardiac manifestations of NL Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and SLE Ro/La +; SLE dx Results Seven (14%) of the cardiac-NL children were exposed to HCQ compared with 56 (37%) of the controls (p=0.002; OR 0.28; 95% CI 0.12 to 0.63). Concluded – in mothers with SLE with anti-SSA/Ro/SSB/La antibodies, exposure to HCQ during pregnancy may decrease the risk of fetal development of cardiac-NL Evaluation of the risk of anti-SSA/Ro-SSB/La antibody-associated cardiac manifestations of neonatal lupus in fetuses of mothers with systemic lupus erythematosus exposed to hydroxychloroquine Peter M Izmirly,1 Mimi Y Kim,2 Carolina Llanos,1 Phuong U Le,3 Marta M Guerra,3 Anca D Askanase,1 Jane E Salmon,3 Jill P Buyon1 ABSTRACT Background Based on the potential involvement of Toll-like receptor (TLR) signalling in the pathogenesis of neonatal lupus (NL), it was hypothesised that fetal exposure to hydroxychloroquine (HCQ), a TLR inhibitor, might reduce the risk of anti-SSA/Ro/SSB/La antibodyassociated cardiac manifestations of NL (cardiac-NL). Methods Cardiac-NL children (N=50) and controls (N=151) were drawn from the following overlapping pregnancy studies: Research Registry for NL; PR Interval and Dexamethasone Evaluation in Cardiac-NL; and Predictors of Pregnancy Outcomes: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus (SLE). Pregnancies met the following inclusion criteria: documentation of maternal anti-SSA/ Ro/SSB/La antibodies at pregnancy, confi rmation of medication use and child’s outcome, a diagnosis of SLE before pregnancy and birth by 31 December 2007. Results Seven (14%) of the cardiac-NL children were exposed to HCQ compared with 56 (37%) of the controls (p=0.002; OR 0.28; 95% CI 0.12 to 0.63). Cases and controls were similar with respect to demographic and antibody status. Multivariable analysis adjusting for birth year, maternal race/ethnicity, antibody status, nonfl uorinated steroid use and prior cardiac-NL risk yielded an OR associated with HCQ use of 0.46 (95% CI 0.18 to 1.18; p=0.10). Conclusion This case–control study suggests that, in mothers with SLE with anti-SSA/Ro/SSB/La antibodies, exposure to HCQ during pregnancy may decrease the risk of fetal development of cardiac-NL. Prospective studies are needed for confi rmation. Izmirly, 2010

Maternal Autoantibody Levels In Congenital Heart Block And Potential Prophylaxis With Antiinflammatory Agents Retrospective, , Ro/La + N =33 Higher Anti La titers in pregnancies c/b heart block; no difference if Ro Ab Did not have to have SLE, etc 94% of fetuses maintained normal conduction when the mother was treated with hydroxychloroquine or daily prednisone therapy throughout pregnancy, compared to 59% in the untreated group (odds ratio, 0.1; P = .04). Maternal treatment with either hydroxychloroquine or daily low-dose prednisone throughout pregnancy may provide a protective effect. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents Objective The importance of maternal autoantibody levels in congenital heart block and elucidation of maternal factors that may reduce disease burden require further clarification. Study Design Pregnancies complicated by maternal anti-Ro antibodies from 2007 through 2011 were retrospectively reviewed. Results In all, 33 women were followed up throughout pregnancy. Semiquantitative maternal anti-La levels were significantly higher in pregnancies complicated by fetal heart block of any degree (median difference, 227.5; P = .04), but there was no difference in maternal anti-Ro levels. In all, 94% of fetuses maintained normal conduction when the mother was treated with hydroxychloroquine or daily prednisone therapy throughout pregnancy, compared to 59% in the untreated group (odds ratio, 0.1; P = .04). Conclusion Pregnancies complicated by fetal heart block did not have higher levels of maternal anti-Ro antibodies. Maternal anti-La level may be a useful predictor of fetal heart block. Maternal treatment with either hydroxychloroquine or daily low-dose prednisone throughout pregnancy may provide a protective effect. Key words: autoantibodies , congenital heart block , fetal echocardiography , prevention Cite this article as: Tunks RD, Clowse MEB, Miller SG, et al. Maternal autoantibody levels in congenital heart block and potential prophylaxis with antiinflammatory agents. Am J Obstet Gynecol 2013;208:64.e1-7. Tunks 2013

Lupus Flares Incidence in pregnancy 15-63% Risk factors
Studies support and refute that pregnancy increases the incidence of flares Risk factors Active disease at conception (50% vs 20%) Active nephritis Abrupt discontinuation of hydrochloroquine Incidence in pregnancy 15-63% Studies support and refute that pregnancy increases the incidence of flares Regardless they are common Risk factors Active disease at conception (50% vs 20%) Active nephritis Abrupt discontinuation of hydrochloroquine

Diagnosis Of Flare Symptoms Titers of antibodies
Ratigue, fever, arthralgias/myalgias, weight loss, rash, renal deterioation, serositis, LAD, CNS symptoms Titers of antibodies Rising titers of dsDNA Ab with falling complement levels suggest impending flare

Lupus Vs Preeclampsia Lupus flare
Arthritis, leukopenia, thrombocytopenia, rashes, pleuritis, fevers Htn, proteinuria, coagulopathy possible Rising antidsdna titer, active urinary sediment, low complement levels suggest lupus flare Complement levels (C3, C4, CH50) generally rise in pregnancy and are unaffected by uncomplicated preeclampsia Normal uric acid Differentiation near term likely not worthwhile, deliver for suspected preeclampsia and initiate tx for lupus flare if patient does not get better

Lupus Flare vs. Preeclampsia
Finding/test Preeclampsia SLE Decreased complement + +++ Increased anti-ds DNA Ab - Antithrombin III decreased ++ +/- Microangiopathic hemolytic anemia (Ab screen -) Coombs positive hemolytic anemia (Ab screen +) Thrombocytopenia Leukopenia Hematuria Cellular casts Increased serum creatinine Hypocalciuria Increased liver transaminases Foley OB ICU care manual

Uterine Artery Notching – Present in Preeclampsia

Renal Biopsies in Pregnancy
Complications - Hematoma formation Bleeding Death Usually do not help change management If steroids are the change in management, then steroid administration is of lower risk than a renal biopsy

Renal Biopsy Risks in pregnancy Lupus Nephritis
Hematoma formation Renal dysfunction Lupus Nephritis Increased mesangial matrix and mesangial hypercellularity (increased leukocytes) Preeclampsia - Endotheliosis Lupus - diffuse proliferative lupus nephritis showing increased mesangial matrix and mesangial hypercellularity Widespread endothelial swelling is present, with endothelial foam cells (Panel A, arrows; periodic acid–Schiff stain). Endothelial swelling has been described as the characteristic feature of preeclampsia (“endotheliosis”), but it is also found in cases of thrombotic microangiopathy. Segmental glomerular necrosis and congestion are prominent (Panel B, periodic acid–Schiff stain), with karyorrhexis and fibrin deposition. Red cells are seen in tubules (top inset). The afferent and efferent arterioles of this glomerulus are thrombosed (arrows), and the bottom inset shows another artery with thrombosis. The cortex shows patchy necrosis (Panel C, hematoxylin and eosin), with sloughing of the tubular epithelial cells. Immunofluorescence microscopy of glomeruli (Panel D) shows that IgM is prominent in the mesangium and along capillary loops. C3 was present in a distribution similar to that of IgM. The inset in Panel D shows fibrin in segments with necrosis and also in capillaries with less severe damage. Immunoperoxidase staining for the complement fragment C4d in formalin-fixed, paraffin-embedded tissue specimens (Panel E) shows prominent deposition of C4d along the glomerular, but not peritubular, capillaries, a feature that has been described in preeclampsia but not in thrombotic microangiopathy. Electron microscopy (Panel F) shows destruction and loss of the normal glomerular endothelial lining, with amorphous deposits and cell debris filling the lumen.

Renal Biopsy Preeclampsia A – endothelial swelling
B – Glomerular necrosis C – sloughing of tubular epithelial cells Lupus - diffuse proliferative lupus nephritis showing increased mesangial matrix and mesangial hypercellularity Widespread endothelial swelling is present, with endothelial foam cells (Panel A, arrows; periodic acid–Schiff stain). Endothelial swelling has been described as the characteristic feature of preeclampsia (“endotheliosis”), but it is also found in cases of thrombotic microangiopathy. Segmental glomerular necrosis and congestion are prominent (Panel B, periodic acid–Schiff stain), with karyorrhexis and fibrin deposition. Red cells are seen in tubules (top inset). The afferent and efferent arterioles of this glomerulus are thrombosed (arrows), and the bottom inset shows another artery with thrombosis. The cortex shows patchy necrosis (Panel C, hematoxylin and eosin), with sloughing of the tubular epithelial cells. Immunofluorescence microscopy of glomeruli (Panel D) shows that IgM is prominent in the mesangium and along capillary loodfps. C3 was present in a distribution similar to that of IgM. The inset in Panel D shows fibrin in segments with necrosis and also in capillaries with less severe damage. Immunoperoxidase staining for the complement fragment C4d in formalin-fixed, paraffin-embedded tissue specimens (Panel E) shows prominent deposition of C4d along the glomerular, but not peritubular, capillaries, a feature that has been described in preeclampsia but not in thrombotic microangiopathy. Electron microscopy (Panel F) shows destruction and loss of the normal glomerular endothelial lining, with amorphous deposits and cell debris filling the lumen.

Treatment Of Lupus Exacerbations
Mild to moderate Hydroxychloroquine Start prednisone 15-20mg/day or increase dose to 20-30mg/day if already on glucocorticoids Severe exacerbations without renal/CNS manifestations Rheumatology consult, hospitalize Glucocorticoid treatment (prednisone 1-1.5mg/kg/d; expect improvement in 5-10 days) Taper once significantly improving If patient cannot be tapered off high dose steroids – add cyclosporine or azathioprine Severe, life threatening disease – with renal/CNS involvement – Plasmapharesis, IVIG Lupus cerebritis Abrupt or subacute onset of any focal neurologic deficit in systemic lupus erythematosus (SLE) may result from local vasculitis with thrombosis, distant artery-to-artery embolization, or cardiac emboli. Mass lesions (eg, subdural or parenchymal hemorrhages) or brain abscess remain in the differential diagnosis. Paraparesis implicates cauda equina, thoracic-lumbar spinal cord, partial lesions of the cervical cord, brainstem lesions, or parasagittal cerebral lesions. Extensor toe signs localize to the cord or above, excluding cauda equina. Acute lesions at either cauda or cord levels may be associated with hyporeflexia, areflexia, or sphincter disturbances. If an areflexic paraparesis is unaccompanied by a sensory level or spreads to the arms, acute demyelinating polyneuropathy (Guillain-Barré syndrome) should be considered. Sensory loss to pain and temperature with sparing of posterior column function (position sense, graphesthesia with or without vibration sense) suggests an anterior spinal artery syndrome. Clinically involved cord levels require immediate imaging (ie, myelography or magnetic resonance imaging [MRI]) to exclude compressive lesions. If myelography is performed, spinal fluid should be collected for analysis before introducing contrast media. Cranial neuropathies most commonly result from lupus vasculitis affecting the vasa nervorum supplying the involved nerve. Although optic neuritis (painful or painless subacute loss of visual acuity, usually accompanied by visible inflammation of the optic nerve head) and retrobulbar neuritis are most common, any cranial nerve may be affected. Imaging studies can exclude compressive lesions that result from opportunistic infection, tumor, or aneurysm. Diffuse weakness may result from polyneuropathy, myopathy, neuromuscular junction disease, or systemic fatigue. Examination findings of objective, symmetric proximal muscle weakness (with or without concomitant pain) support myopathy, whereas distal symmetric weakness (with distal sensory loss) implicates a peripheral polyneuropathy. Myopathy should never be accompanied by sensory loss, but it may at times be asymmetric. Mononeuritis multiplex results in patchy, asymmetric weakness, sensory loss, or both in the distribution of multiple peripheral nerves or roots. Clinical distinction between proximal myopathy and polyradiculopathy or proximal mononeuritis multiplex may be difficult, requiring electromyogram (EMG) or nerve conduction velocity (NCV) studies or even nerve and muscle biopsies for an accurate diagnosis. Weakness that improves or worsens with repetitive testing suggests a neuromuscular junction defect. Painful give way weakness without organic muscle weakness supports arthralgia or other musculoskeletal etiology. Fatigue from autoimmune disorder is rarely accompanied by objective muscular weakness. Orthostatic hypotension should be excluded. Conventional blood studies have varying utility in diagnosing systemic lupus erythematosus (SLE), depending on the associated conditions and manifestations. With systemic or other organ system involvement suggestive of autoimmune dysfunction (eg, low-grade fevers, fatigue, arthralgias or arthritis, renal dysfunction, malar or other skin rashes) laboratory evaluation should include at minimum antinuclear antibody (ANA) testing and anti-DNA binding to confirm a positive ANA result. Other autoantibody testing is dependent on clinical judgment and test availability. In the patient with SLE who has risk factors for conventional small-vessel cerebrovascular disease (eg, diabetes, hypertension), the clinical distinction between SLE and atherosclerotic (lipohyalinoid) disease as a cause of a given stroke may be difficult. Under these circumstances, additional studies such as lumbar puncture for evidence of central nervous system (CNS) inflammation, antinuclear antibodies (ANAs), or intrathecal immunoglobulin (IgG) synthesis may support a diagnosis of SLE over atherosclerotic small vessel disease. Clinical–radiologic correlations are not always obvious; more importantly, magnetic resonance imaging (MRI) lesions may resolve completely within days in keeping with clinical improvement or persist despite clear remission. The complete blood cell (CBC) count in SLE may demonstrate a hemolytic anemia with reticulocytosis or reductions of neutrophils, lymphocytes, or platelets. Although Fcgamma receptor genes have been suggested to play an important role in the pathogenesis of SLE and lupus nephritis, Yuan et al's study results suggested that FcgammaRIIIb polymorphism might not be a susceptibility gene for SLE and lupus nephritis.[12] AlSaleh et al reported a high prevalence of positive anti-Ro antibodies (52.3%) among their Arab patients, which they felt probably reflected a common characteristic in SLE patients of Middle East origin.[13] Serum chemistry studies Electrolytes, glucose, and calcium are especially worth checking in the setting of new-onset generalized seizures or acute encephalopathy. Acid-based disturbances may be obvious on review of electrolytes, but an arterial blood gas (ABG) analysis may be useful to assess or follow such a disturbance, especially in the obtunded, acutely ill patient. Lupus nephritis activity is customarily followed by assessing casts in the urine and proteinuria measured by dipstick or 24-hour collection but may be followed more roughly by the blood urea nitrogen (BUN) and creatinine levels. Acute increases in BUN may produce metabolic encephalopathy, but on a chronic basis, very high BUN elevations may be surprisingly well tolerated. Hepatocellular and muscle enzyme levels Liver function studies are rarely affected by SLE per se. (Lupoid hepatitis is not part of the SLE spectrum.) Elevations of hepatocellular enzyme levels more likely point to a medication-related or viral hepatitis, and obstructive patterns point to medications or to biliary obstruction. Muscle enzyme levels (creatine kinase, aldolase) may be moderately or severely elevated with lupus myopathy, although normal levels also may be seen with clinical or biopsy-proven disease. Normal creatine kinase levels, therefore, do not reliably distinguish between SLE myositis and drug-related (steroid, hydroxychloroquine) myopathy

Lupus Nephritis 50% of patients with lupus develop renal disease
Pathophysiolgy Immune complex deposition Complement activation Inflammation in kidney Retrospective review (burkett, 1985) 242 pregs in 156 women with lupus nephritis 59% no change in renal function 30% with transient decrease in function 7% with permanent renal insufficiency Critical creatinine level is 1.5mg/dl Above this - risk is increased of decreased renal function Below this – risk is not increased Cyclophosphamide in extreme cases, would try IVIG, plasmapharesis first

Delivery Consider delivery at 39 weeks to avert ongoing risks of fetal loss, development of preeclampsia Cesarean for obstetrical indications Stress dose steroids if indicated Thromboprophylaxis IP/PP management

Conclusions Goal is control at conception Continue hydroxychloroquine
Rheumatologic evaluation – the Obstetrical version APA - +/- thromboprophylaxis Esp if true APLS Fetal surveillance Hydroxychloroquine 200mg BID may be preventative of fetal heart block in Ro/La patients

End ?? OMNY

References Email – dfarley@awhobgyn.com Provided on request
Friedman 2008 PRIDE study Izmirly 2010 Hydroxychloroquine study

Maternal Physiology Inhibition of complement activation in the placenta may be essential for fetal survival Trophoblast may be a target of autoimmunity. Creasy Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a relatively common disease and has a predilection for women of childbearing age. Its coincidence with pregnancy poses complex clinical problems because of the profound disturbance of the immunologic system, multiorgan involvement, and complicated immunology of pregnancy itself.[84] The outcome of pregnancy for women with SLE is variable and to some extent unpredictable, so careful monitoring, especially for those women with lupus nephritis, is required (see Chapter 51). Decisions regarding the status of the disease and the importance of having a child to the patient and her partner should be made on an individual basis. Most pregnancies succeed, especially when the maternal disease has been in complete clinical remission for 6 months before conception, even if there were marked pathologic changes in the original renal biopsy and heavy proteinuria in the early stages of the disease.[106] Continued signs of disease activity or increasing renal dysfunction reduces the likelihood of an uncomplicated pregnancy and the clinical course thereafter. The effects of gestation on SLE activity and on the course of lupus nephritis have long been debated. Taking into account extrarenal manifestations and renal changes, at least 50% of women show some change in clinical status, often called a lupus flare.[107] Some increments in proteinuria or blood pressure may result from preeclampsia. Women with lupus nephritis and renal insufficiency (serum creatinine level higher than 125 μmol/L or 1.4 mg/dL) that antedates pregnancy have worse outcomes. Lupus nephritis may sometimes become manifest during pregnancy, and when accompanied by hypertension and renal dysfunction, it may be mistaken for preeclampsia. Some patients experience relapse, occasionally severely in the puerperium; therefore, some clinicians prescribe or increase immunosuppression at this time.[108] It is our practice to increase immunosuppression only if there are signs of increased disease activity. SLE serum contains an array of autoantibodies (i.e., lupus serum factor) against nucleic acids, nucleoproteins, cell-surface antigens, and phospholipids. Antiphospholipid antibodies exert a complicated effect on the coagulation system.[109] This led to the definition of a lupus anticoagulant, which is found in 5% to 10% of patients with SLE (see Chapter 40). Because treatment with low-molecular-weight heparin and aspirin may lead to successful pregnancies, it is important to screen for lupus anticoagulant in women with SLE and especially in those with a history of recurrent intrauterine death or thrombotic episodes to identify this particular cohort. -- The systemic rheumatic illnesses commonly complicating pregnancy are systemic lupus erythematosus (SLE), antiphospholipid syndrome, rheumatoid arthritis, scleroderma, juvenile arthritis, spondyloarthropathy, and Takayasu arteritis. SLE and Takayasu arteritis affect 15- to 45-year-old women in a ratio of 9 women to 1 man. Antiphospholipid syndrome has a female-to-male ratio of 7 to 1; rheumatoid arthritis and scleroderma have a ratio of 3 to 1; juvenile arthritis is almost gender neutral; and spondyloarthropathy has a ratio of about 1 to 3. Rheumatoid arthritis and scleroderma affect middle-aged more than young women. SLE has a higher prevalence among African Americans than among whites (4 to 1). Up to 1% of all women have rheumatoid arthritis. One of 5000 to 10,000 women have SLE, and antiphospholipid syndrome may be as common as SLE, whereas the other diseases are less common. Because of these epidemiologic patterns, the autoimmune illnesses most frequently encountered in obstetric practices are SLE and antiphospholipid syndrome. Rheumatoid arthritis is a more common illness, but it occurs most often after the childbearing years and is therefore seen less often in pregnant women. Diagnosis of the systemic rheumatic diseases rests more on clinical than on serologic criteria (discussed with the individual diseases). Features common to all are arthralgia or arthritis; fever, myalgia, and malaise; and markers of inflammation. Current theories consider the systemic rheumatic diseases to be driven by disordered immune mechanisms, probably resulting from a genetic defect in processing exogenous infectious material, but the mechanisms and possible triggers are different among the illnesses. Systemic rheumatic illnesses are chronic and relapsing, with temporary remissions. It is more likely that a new pregnancy will be diagnosed in a woman with an established diagnosis of rheumatic illness than that a new diagnosis will be made for a previously healthy pregnant woman. Table 51-1 provides the epidemiologic, clinical, and laboratory characteristics of the rheumatic diseases most often encountered in pregnant women. TABLE 51-1 -- EPIDEMIOLOGIC, CLINICAL, AND LABORATORY CHARACTERISTICS AND PREGNANCY ISSUES OF COMMON AUTOIMMUNE RHEUMATIC ILLNESSES Disease Epidemiology Common Symptoms Laboratory Results Pregnancy Issues Systemic lupus erythematosus Age yr 9:1 female to male 4:2:1 black to Asian/Hispanic to white Arthritis, rash, fever, anemia, thrombocytopenia, nephritis, neurologic disease, alopecia High positive ANA value Anti-DNA and/or Smith (diagnostic) Antiphospholipid, anti-SSA/Ro, SSB/La, RNP antibodies (common) Raised ESR level Anemia, thrombocytopenia Proteinuria Low complement leve Fetal loss, neonatal upus, organ system flare Antiphospholipid syndrome Age yr Female > male White > black Blood clots, fetal loss, livedo reticularis, thrombocytopenia, cardiac valve disease Anticardiolipin Anti-β2-glycoprotein 1 Lupus anticoagulant test Thrombocytopenia Proteinuria Fetal loss, HELLP syndrome Rheumatoid arthritis Age yr 3:1 female to male White = black Destructive arthritis Anti-cyclic citrullinated peptide antibody Rheumatoid factor Raised ESR, CRP levels Bone erosions at joints Remission in some cases during pregnancy; positioning for delivery a problem Spondyloarthropathy Age yr Male > female HLA-B27 Spinal and sacroiliac arthritis Raised ESR, CRP values HLA-B27 Radiographic sacroiliitis Spinal fusion Enthesitis Arthritis management Takayasu arteritis Age yr 9:1 female to male Large vessel vasculitis, cardiac valve disease Raised ESR, CRP levels Alternating narrowing and aneurysm formation in aorta and great vessels Vascular integrity, measurement of blood pressure, cardiac failure Scleroderma 3:1 female to male Raynaud phenomenon, skin disease, pulmonary hypertension, hypertensive renal failure, esophageal reflux, pulmonary fibrosis Fibrosis on skin biopsy Pulmonary fibrosis Esophageal and intestinal hypomotility Reduced pulmonary diffusion capacity Urinary protein, raised creatinine level Complications related to esophagus, ung, heart, kidneys Juvenile arthritis Before age 18 yr Female > male for some types Polyarthritis; high fever and rash (Still's type) Raised ESR, CRP levels Raised ferritin level Erosions of joints Complications related to joint disease ANAs, antinuclear antibodies; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; HELLP, hemolysis, elevated liver enzymes, and low platelets; RNP, ribonucleoprotein. Preg immune changes With regard to immunologic phenomena of pregnancy that may be relevant to autoimmune disease, in vitro data show that estrogens upregulate and androgens downregulate T-cell responses, immunoglobulin synthesis, and leukocyte production of interleukin 1 (IL-1), IL-2, IL-6, and TNF-α, though changes in these cytokines are quantitatively small and remain within physiologic ranges.[10] In pregnancy, cellmediated immunity is depressed, as reflected by abnormal lymphocyte stimulation, decreased ratios of T cells to B cells, increased ratios of suppressor T cells to helper T cells, and decreased ratios of lymphocytes to monocytes, all of which vary with the stage of pregnancy.[11,12] The pregnancy-specific proteins α-fetoprotein, β1-glycoprotein, and β2-macroglobulin suppress in vitro lymphocyte function. IL-1, IL-3, TNF-α, interferon γ, and granulocyte-macrophage colony-stimulating factor are critical in sustaining pregnancy.[13] IL-3 levels are low in women with repeated pregnancy loss. In normal pregnancy, total C3, C4, and hemolytic (CH50) complement levels are usually unchanged or raised relative to nonpregnant levels, but increases in classic pathway complement activation products suggest that low-grade classic pathway activation is a normal phenomenon in pregnant women. Complement activation products can alter the balance of angiogenic factor production by inflammatory cells and result in excess soluble vascular endothelial growth factor receptor type 1 (sFlt-1), which has implications for placental development and the risk for preeclampsia.[14] Inhibition of complement activation in the placenta may be essential for fetal survival,[15] and the trophoblast may be a target of autoimmunity.[16] Theoretically, these pregnancy-related changes may alter the course of specific autoimmune diseases, but clear documentation that they do is lacking. Although SLE patients may have intrinsic hormonal abnormalities, they are quantitatively minor and have no discernible effect on pregnancy outcome.[30–32] Pregnancy probably does not induce serious lupus flare.[33,34] Diagnosing flare during pregnancy is difficult because pregnancy-induced thrombocytopenia, preeclamptic proteinuria, and palmar and facial erythema resemble SLE flare. Flare is most confidently diagnosed when a pregnant patient has new or increasing diagnostic rash (not erythema alone), lymphadenopathy, arthritis, fever, or anti–double-stranded DNA (anti-dsDNA) antibody. Fetal health is threatened because approximately one third of all SLE patients have anti-Ro or anti-La antibodies, or both, as do a few patients with discoid lupus, most with subacute cutaneous lupus, and most with Sjögren syndrome. These antibodies predispose to neonatal lupus. One third to one half of SLE patients have antiphospholipid antibodies, predisposing to fetal loss (discussed later). Maternal Complications Maternal complications are best considered by affected organ system, because global SLE exacerbation is rare. Approximately one fourth of all SLE patients develop thrombocytopenia during pregnancy, compared with about 7% of normal women.[35] Patients with antiphospholipid antibodies often have asymptomatic, low-grade thrombocytopenia (>50 × 109/L) that worsens slightly during pregnancy. Abrupt, severe thrombocytopenia of the immune thrombocytopenia (ITP) type and lupus-related, low-grade chronic thrombocytopenia occur independent of pregnancy. No specific test clearly differentiates types of thrombocytopenia in pregnant patients with SLE. In our experience, in pregnant patients with lupus, thrombocytopenia equally often results from antiphospholipid antibodies, active SLE, and preeclampsia. In patients with proteinuria, clinical signs of active SLE, rising levels of anti-dsDNA antibody, very low concentrations of complement, and urinary erythrocyte casts favor a diagnosis of lupus nephritis rather than preeclampsia. Rapid worsening over days suggests preeclampsia. Hypertension, thrombocytopenia, hyperuricemia, and hypocomplementemia occur in both; normal complement levels suggest preeclampsia. Two thirds of pregnant lupus patients who entered pregnancy with renal disease develop preeclampsia, compared with less than 20% of those without prior kidney disease.[36] In women with preexisting renal disease who develop preeclampsia, renal function may not return to its pre-pregnancy baseline. Because skin blood flow increases in pregnancy, existing rash may become more prominent as pregnancy progresses. Patients who discontinue hydroxychloroquine for pregnancy often have recurrence of rash. Joints previously damaged by lupus arthritis may develop noninflammatory effusions when ligament loosening occurs in late pregnancy. Neurologic lupus during pregnancy is rare, but case reports document chorea and transverse myelitis induced or exacerbated by pregnancy. In patients with seizures late in pregnancy accompanied by hypertension and renal failure, it may not be possible to distinguish between cerebral SLE and eclampsia. Treatment for both is usually indicated. Pulmonary hypertension may develop or worsen during pregnancy. Concomitant care with the obstetrician and rheumatologist is advisable. Fetal Complications If antiphospholipid antibodies, anti-Ro and anti-La antibodies, maternal fever, severe anemia, uremia, hypertension, and preeclampsia are absent, active SLE itself does not compromise the fetus. Infants born of SLE mothers with IgG-induced thrombocytopenia usually have normal platelet counts. Rarely, Coombs antibody causes hemolysis in the fetus; anti-dsDNA antibody has no apparent pathologic effect. Thrombosis due to antiphospholipid antibodies rarely occurs in the fetus. The neonatal lupus syndrome includes photosensitive rash, thrombocytopenia, hepatitis, and hemolytic anemia, all of which are transient, and congenital complete heart block, which is not.[37] The syndrome occurs exclusively in neonates of women with high-titer anti-Ro/SSA or anti-La/SSB antibodies, or both, many of whom are clinically well (a small number later develop SLE or Sjögren syndrome). With the exception of neonatal lupus syndrome, there are no congenital abnormalities associated with SLE. Congenital heart block is first diagnosable in utero by fetal electrocardiography, ultrasound, or cardiac rate monitoring between 18 and 25 weeks' gestation (average, 23 weeks). Among SLE patients with anti-Ro antibody, the risk that a liveborn child will have neonatal lupus rash is 25%, and congenital complete heart block is less than 3%. However, the risks of recurrent congenital heart block and neonatal lupus rash are 18% and 25%, respectively. Cardiac injury may be related to expression of the cardiac 52B Ro antigen after apoptosis of cardiomyocytes and to induction of profibrotic cytokines around the conducting system.[38,39] No specific antibody pattern predicts neonatal lupus rash. Several dizygotic twins and at least one monozygotic twin pair have been discordant for neonatal lupus, suggesting fetal contribution to illness. Dexamethasone and plasmapheresis for the mother and early delivery have been used, with variable success, to treat fetal incomplete heart block, myocarditis, heart failure, and hydrops fetalis. Complete heart block in a newborn usually requires a permanent pacemaker. Even with a pacemaker, progressive fibrosis of the conducting system, cardiac failure, and sudden death may occur before age 5. Preliminary data suggest that boys of SLE mothers have increased risk for learning disabilities but have normal intelligence, compared with sex- and gestational age-matched controls.[40] Children with complete congenital heart block remain at risk for cardiac death. Although case reports have described survivors of neonatal lupus who developed systemic lupus when they became adults, such events are rare. Other than the inherited tendency to develop rheumatic illness, there are no other known risks to children of other rheumatic disease mothers Renal disease and lupus and creasy SLE serum contains an array of autoantibodies (i.e., lupus serum factor) against nucleic acids, nucleoproteins, cell-surface antigens, and phospholipids. Antiphospholipid antibodies exert a complicated effect on the coagulation system.[109] This led to the definition of a lupus anticoagulant, which is found in 5% to 10% of patients with SLE (see Chapter 40). Because treatment with low-molecular-weight heparin and aspirin may lead to successful pregnancies, it is important to screen for lupus anticoagulant in women with SLE and especially in those with a history of recurrent intrauterine death or thrombotic episodes to identify this particular cohort Creasy

Lupus Exacerbations Severe exacerbation with renal or CNS involvement
Hospitalize, rheumatology consult IV methylprednisolone 10-30mg/kg/day for 3-6 days Maintain on oral prednisone 1-1.5mg/kg/day When patient responds, taper steroids If no response, add cyclophosphamide, or move to plasmapharesis

The Lupus Placenta Reduction in size Placental infarctions
Intraplacental hemorrhage Deposition of immunoglobulin and complement Thickening of trophoblast basement membrane Above are reasons for pregnancy complications (later) – pree, IUGR, preterm delivery)

Fetal PR interval Glickstein 2000
Figure 1. A, pulsed Doppler sample volume placed in the left ventricle at the junction of the anterior leaflet of the mitral valve and left ventricular outflow tract. B, fetal heart displaying the pulsed Doppler sample volume at the junction of the anterior leaflet of the mitral valve and the left ventricular outflow tract. The Fetal Doppler Mechanical PR Interval: A Validation Study Julie Glicksteina, Jill Buyonb, Mimi Kimc, Deborah Friedmand, and the PRIDE investigators aDepartment of Pediatrics/Pediatric Cardiology, Children’s Hospital of New York, Columbia University School of Medicine, bDepartment of Medicine, Hospital of Joint Diseases, NYU School of Medicine, cDepartment of Statistics, NYU School of Medicine, and dDepartment of Pediatrics/Pediatric Cardiology, St. Luke’s/Roosevelt Hospital, New York, N.Y., USA Address of Corresponding Author Fetal Diagn Ther 2004;19:31-34 (DOI: / ) -- Fetal Diagn Ther Jan-Feb;19(1):31-4. The fetal Doppler mechanical PR interval: a validation study. Glickstein J, Buyon J, Kim M, Friedman D; PRIDE investigators. Source Department of Pediatrics/Pediatric Cardiology, Children's Hospital of New York, Columbia University School of Medicine, New York, NY 10032, USA. Abstract OBJECTIVE: To evaluate the accuracy of pulsed Doppler-derived fetal PR interval measurements obtained by physicians participating in a multicenter prospective fetal echocardiographic study. METHODS: Echocardiograms on healthy fetuses were performed and evaluated by 15 pediatric cardiologists/perinatologists across the United States who are participating in a larger clinical trial involving fetuses at risk for autoantibody-associated congenital heart block. Prior to enrolling women in the main trial, each physician was provided with a teaching tape to demonstrate how the pulsed Doppler-derived PR interval is measured. The procedure involves placing a gated pulsed Doppler sample volume in the left ventricle at the junction of the anterior leaflet of the mitral valve and the left ventricular outflow tract in an apical 5-chamber view, and simultaneously obtaining left ventricular filling and emptying. Time intervals are measured from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler tracing (ventricular systole). This represents the mechanical PR interval. Each physician measured the pulsed Doppler-derived fetal PR interval on 5 different subjects recruited from the physician's specific site. To validate each physician's technique, the tapes were sent to a central facility and the same intervals were remeasured by an experienced central reader (D.M.F.). A physician was determined to have adequate ability to measure the fetal PR interval if all 5 measurements were within +/- 30 ms of the central reader's measurements, where 30 ms corresponds to 25% of the mean observed in normative PR interval data. This difference was deemed to be the minimum clinically important difference in Doppler PR interval. RESULTS: Fourteen of the 15 physicians were considered to have adequate ability to measure the fetal PR interval according to our established criterion. The overall mean difference between the physicians and the central reader's measurements was / ms (p = 0.84). In addition, 95% of the observed differences were included in the interval ( to 21.81), which is well within our clinically acceptable range of +/- 30 ms. CONCLUSIONS: The pulsed Doppler assessment of the mechanical PR interval in the fetus can be accurately performed after minimal training. This technique may be a valuable tool for identification of early and potentially reversible conduction abnormalities in fetuses at risk for more advanced and permanent forms of heart block associated with maternal antibodies to SSA/Ro-SSB/La.

Fetal PR interval Glickstein 2000
Figure 2. Time intervals were measured from the onset of the mitral A wave (atrial systole) to the onset of the aortic pulsed Doppler (ventricular systole), representing the mechanical PR interval.

Neonatal Lupus Occurs in 1-2% of women with antissa or antissb regardless of whether pt has SLE Immune mediated damage of fetus by transplacental passage of autoab that affect the fetus Congenital heart block, skin lesions, thrombocytopenia, anemia, hepatitis CHB permanent Antissa and SSB maternal ab cross placenta and damage AV conducting system; varying degrees of heart block, poss myocarditis 1st 2nd 3rd Typically dx at weeks Ab act by apoptosis or directly interfere with cardiac conduction through calcium channels R/o CHB in women with antissa ab and no previous affected infants is 1-2% ~50% of women with fetus/infant with CHB are asymptomatic but more than 85% are antissa or antissb + ½ of these women develop sx of rheumatic disease, typically sjogren’s sd with dry eyes and mouth; <50% chance of developing SLE

Neonatal Lupus; CHB Cardiac lesions – heart block from endocardial fibroelastosis from anti SSA-52 binding to myocardial tissue Histo – mononuclear cell infiltration, fibrin deposition, calcification of conduction system (AV, SA nodes, diffuse fibroelastosis t/o myocardium Typically seen as FHR of bpm at wks gestation with structurally normal heart with AV dissociation, hydrops possible 3rd degree heart block; complete Permanent 1st or 2nd degree (defs??? Reversed with antenatal fluorinated (crosses placenta) steroid therapy b/c of prevention of progression to more severe forms +/- Rationale of steroids is that cardiac histo has diffuse inflammation, igg, firbrin, complement deposition Risk of chronic steroids wihout any proven benefit especially in a condition that is permanent once it is diagnosed M/f risks osteoporosis, glucose intolerance, fetal growth restriction, development delay Reversal of hydrops case reports? No evidence supporting use of ppx steroid tx in women with antissa or antissb ab to prevent onset of chb 1/3 of fetuses with heart block die within 3 yrs of age Remaining 2/3 require permanent pacemakers

Heart Block

Pathophysiology Of NLE
Autoantibodies alone are insufficient to cause NLE 30% of SLE pt have antissa ab and 15-20% have antissb ab Incidence of CHB in infants of SLE mothers is 2% Recurrence risk 5-25%; reports of twins discordant for NLE Therefore antissa alone does not always lead to NLE Maternal SLE is NOT a prerequisite for NLE 50% of NLE cases occur in healthy pregnant women with circulating autoantibodies Some develop connective tissue d/o

NLE 1 in 20,000 live births Heart block 50%
Skin lesions 50% - erythematous scaling plaques on scalp or face, typically resolve within first few months like hematologic changes as the maternal autoantibodies disappear Both 10% Most cases from maternal autoantibodies Antibodies to cytoplasmic ribonucleo-proteins SSA (ro) more specifically the 5 anti-ss2-kda epitope of SSA And SSB (la) – detected 50-75% of the time Rare to have just SSB antibodies

Multidisciplinary Prenatal Diagnosis Conference
8/7/08-SLE

Case 27 y/o G5 P3 with good prenatal care PMH –
SLE dx 2005 (rheumatology); 4 of 11 Arthritis, malar rash, pericardial effusion, leukopenia Medications Hydroxychloroquine 200mg BID Prednisone 10mg daily Azathioprine 150mg up to 6 weeks (d/c w/+hcg) POB history – 3 term deliveries (1 CD, 2 VBAC); h/o GDM, gestational hypertension; h/o first trimester loss Social and family history (-)

Systemic Lupus Erythematosus
Autoimmune d/o (need 4 of 11 Rheum criteria) Prevalence /100,000 1% of pregnancies Survival rates decrease with duration of disease

Criteria for diagnosis
Per American College of Rheumatology Need 4 of 11 (serially or at one time) Malar rash (erythema over malar eminences) Discoid rash (erythematous raised patches) Photosensitivity (unusual rxn to sunlight) Oral ulcers (oral, nasopharyngeal) Arthritis (nonerosive, 2+ peripheral joints) Serositis (pleuritis, pericarditis) Nephritis (>500mg/d proteinuria or cellular casts) Neurologic disorder (seizures, psychosis, stroke with other causes r/o) Hematologic disorder (hemolytic anemia with reticulocytosis, thrombocytopenia <100k, leukopenia < occasions, lymphopenia < occasions) Immunologic disorder (anti-dsDNA, anti-Sm, positive LAC ACA, false pos RPR or other serologic test for syphilis for 6 months confirmed by treponema pallidum immobilization or fluorescent treponemal ab absorption test) Antinuclear antibodies (without being on drugs associated with drug induced lupus syndrome <4 of 11 = lupus-like syndrome 76

Pregnancy outcomes effect of SLE on pregnancy
increased stillbirth rate 25x increased preeclampsia rate % increased IUGR rate % increased preterm delivery rate to 50-60% increased PPROM rate Neonatal lupus (1-2% if anti SSA/SSB present) effect of pregnancy on SLE worsening renal status if nephropathy (cr 1.5) present increased flares if active disease at start of pregnancy

Case Physical exam - obese, no evidence of lupus flare at initial visit Lab findings Rh +; negative RPR, HepBsAg, HIV, GBS 24hr urine analysis revealed normal renal function ECG normal Rheumatologic labs ESR - slightly elevated Complement levels normal t/o pregnancy ANA antibodies not available -dsDNA antibodies negative (high spec; 75% sens) Anti-cardiolipin antibodies negative + SSA, - SSB

Case Lupus meds – Hydroxycholorquine continued Prednisone continued
Immunosuppressive class C stopping this in pregnancy - increased risk of lupus flares, continue if needed for control no increased r/o fetal malformations Prednisone continued class B use non-fluorinated like prednisone that do not cross placenta M/F side effects with high dose steroids > 20mg prednisone/day; stress dose in labor if high dose used Azathioprine not restarted, unless needed for control (inhibits T lymphocytes; class D; possible IUGR) high dose associated with maternal/fetal side effects Maternal Osteoporosis, glucose intolerance, sodium/water retention, hypertension, infection Adverse pregnancy outcomes - GDM, preeclampsia, PPROM, IUGR Incidence of fetal adrenal suppression with maternal tx is low Plan for pregnancy (Avoid harmful drugs; detection of preeclampsia, placental insufficiency; detection, treatment of lupus flares) RHEUM LDA STARTED?

Case – pregnancy course
Ultrasound findings Anatomy normal at 20 weeks, no heart block EFW 382g Growth at 30 weeks, no heart block EFW 1541g (48th%ile) Delivered b/c of 3rd trimester bleeding occurred at 34 weeks (repeat CD for suspected abruption) Female, birth weight 2373gm, APGAR scores 9/9 Placenta – ? Abruption; 435g; villous edema, dystrophic calcification seen

Fetal complete heart block (CHB)
Cardiac anatomy is normal up to 50% of cases Most common bradyarrhythmia 1 in 20-25,000 live births Ultrasound Structure Cord doppler (immune deposits in placenta can precipitate heart failure) EFW (? IUGR) cardiothoracic ratio (pulm hypoplasia/heart failure) Differential diagnosis structural heart disease immunologic/SSA/B disease sinus brady in premorbid fetus Bradyarrhythmias - 9% of all arrythmias Cardiac anatomy is normal up to 50% of cases; severe congenital heart disease up to 53% of cases Most common is complete (3rd deree, complete disassociation of A-V conduction 1st – prolonged P-R interval (hard to see) 2nd – progressive lengthening of P-R interval with dropped beats (Wenckebach); fixed P-R interval wit ratio of transmission of atrial beats to ventricular beats CHB 1 in 20-25,000 live births Ck for structure, doppler cord to detect resistance, EFW to detect IUGR; cardiothoracic ratio to detect pulm hypoplasia/ cardiomeg/heart failure DDX- structural heart disease; immunologic/SSA/B disease; sinus brady in premorbid fetus Antenatal natural history (presents at mean GA of 26 weeks) Nonimmune hydrops develops in 25% due to cardiac decompensation (IUFD or neonatal death) Survival is 15% when hydrops is present; 14% if structural heart dz is present AV valve incompetence tends to precede devel of NI hydrops Structurally normal heart and CHB = SSA/B uniformly Fetal/neonatal heart contains body’s highest concentration of Ro antigen (SSA binds) In vitro studies show SSA/B binds to newborn myocardium (and not adult); this binding inhibits repolarization ? Cofactor b/c while mothers of infants with CHB almost uniformly have SSA/B, the majority of pt with these antibodies have normal pregnancies; suggest cofactor that is triggered for some reason (viruses being immunogenic?); increased incidence of CMV antibodies Generalized myocarditis from Ab deposition and inflammatory response Subendocardial fibroelastosis – marker of endstage myocardial injury Sono = echogenic papillary muscles or areas of subendocariddial myocardium Heart rate <55 – 14% survival; no survivors reported <50bpm

CHB – Antenatal natural history
Mean GA of 26 weeks Nonimmune hydrops - 25% Survival 14-15% if + hydrops or structural disease AV valve incompetence preecede NI hydrops Structurally normal heart and CHB = SSA/B uniformly Fetal/neonatal heart - highest concentration of Ro antigen (SSA binds) In vitro studies - SSA/B binds newborn (not adult) myocardium this binding inhibits repolarization ? Cofactor b/c while mothers of infants with CHB almost uniformly have SSA/B, the majority of pt with these antibodies have normal pregnancies; suggest cofactor that is triggered for some reason (viruses being immunogenic?); increased incidence of CMV antibodies in some reports Generalized myocarditis from Ab deposition and inflammatory response Subendocardial fibroelastosis – marker of endstage myocardial injury Sonographically = echogenic papillary muscles or areas of subendocariddial myocardium Heart rate <55 – 14% survival; no survivors reported <50bpm

CHB – fetal intervention
Medical Lessen immunologic injury maternal IVIG, plasmapharesis No reversal of heart block Increase ventricular rate (beta-mimetics doses too high Prophylaxis? Maternal risk > benefit Steroids in CHB - avert further immunologic damage from evolving myocarditis? (rec from Fetology) PERMANENT Surgical – inutero pacing (transcutaneous, open fetal surgery) described in hydropic fetuses; pacing accomplished, but fetal death was result Newborn treatment…

Fetal complete heart block
Pregnancy management Rheumatology evaluation Fetal echo If rate <65bpm, increased surveillance to detect AV valve incompetance or early signs of NI hydrops 2x weekly scans, dopplers (deposition of immune complexes in placental bed can ppt heart failure), cardiothoracic ratios NSTs not helpful b/c of AV node dissociation Indications for delivery Deteriorating cardiac status NI hydrops CD for fetuses >30 weeks with CHB and hemodynamic compromise, ventricular rate <55, AV valve insufficiency, poor contractility CD for all cases? Intrapartum monitoring with scalp pH, echo difficult but have been reported

Fetal CHB Outcome Genetics, recurrence risk Risk factors
Mortality rate – 25% 90% survival after neonatal period? Monitor for autoimmune disease Genetics, recurrence risk No genetic predisposition Previous baby with CHB has a recurrence risk range of 25-64% Autoimmune d/o, +SSA 7.6% rate of CHB vs 0.6% rate of Autoimmune disease and NO SSA Ab Healthy women with SSA/B Ab are majority of cases, but difficult to ID Risk factors Previous child with CHB High titer of SSA Ab (>1:16) + SSA and + SSB Maternal HLA DR3

Neonatal lupus erythmatosus (NLE)
1 in 20,000 live births occurs in 1-2% of women with antiSSA or antiSSB regardless of whether pt has SLE congenital heart block, skin lesions, thrombocytopenia, anemia, hepatitis heart block 50% skin lesions 50% - erythematous scaling plaques on scalp or face, typically resolve within first few months like hematologic changes as the maternal autoantibodies disappear both 10% most cases from maternal autoantibodies that cause immune mediated damage of fetus by transplacental passage of autoantibodies antibodies to cytoplasmic ribonucleo-proteins SSA (Ro) more specifically the 5 anti-SS2-kDa epitope of SSA and SSB (La) – detected 50-75% of the time rare to have just SSB antibodies

Congenital heart block
Pathophysiology of autoantibody mediated disease SSA and SSB Ab cross placenta, damage AV conducting system; Apoptosis Direct interference with cardiac conduction through calcium channels varying degrees of heart block, Myocarditis possible Histology - heart block from endocardial fibroelastosis from anti SSA-52 binding to myocardial tissue, mononuclear cell infiltration, fibrin deposition, calcification of conduction system (AV, SA nodes, diffuse fibroelastosis t/o myocardium) Typically dx at weeks typically seen as FHR of bpm at wks gestation with structurally normal heart with AV dissociation, hydrops possible Conduction system (affected AV node- delayed, intermittent, absent) first degree (slowed conduction without missed beats), second degree (missed beats, often in a regular pattern, eg, 2:1, 3:2, or higher degrees of block), third degree or complete AV block (permanent) CHB = complete heart block Recurrence r/o CHB in women with antiSSA ab and no previous affected infants is 1-2% The conduction can be delayed, intermittent, or absent. The commonly used terminology includes first degree (slowed conduction without missed beats), second degree (missed beats, often in a regular pattern, eg, 2:1, 3:2, or higher degrees of block), and third degree or complete AV block. The etiology of AV block is considered elsewhere

Prevention/Treatment of CHB?
3rd degree heart block; complete permanent 1st or 2nd degree (defs??? reversed with antenatal fluorinated (crosses placenta) steroid therapy b/c of prevention of progression to more severe forms +/- rationale of steroids is that cardiac histo has diffuse inflammation, IgG, firbrin, complement deposition risk of chronic steroids wihout any proven benefit especially in a condition that is permanent once it is diagnosed m/f risks osteoporosis, glucose intolerance, fetal growth restriction, development delay reversal of hydrops case reports? no evidence supporting use of ppx steroid tx in women with antiSSA or antiSSB ab to prevent onset of CHB 1/3 of fetuses with heart block die within 3 yrs of age remaining 2/3 require permanent pacemakers

end Refs Fetology Creasy MFM Uptodate
High risk pregnancy – epi approach Foley ICU manual

Symptom frequency Fatigue – 80-100% Fever – 80-100% Arthritis – 95%
Myalgia – 70% Weight loss – 60% Photosensitivity – 60% Malar rash - 50% Nephritis – 50% Pleurisy – 50% Lymphadenopathy – 50% Pericarditis – 30% Neuropsychiatric – 20%

pathophysiology Autoantibodies
antinuclear antibody – most common, so good screening antibody for autoimmune syndromes increased in pregnancy – 10% of asymptomatic pregnant women without autoimmune disease have ANA ab compared to 2% of nonpregnant controls screening for lupus b/c of high prevalence in gen pop dsDNA ab and Sm ab are more specific for lupus; dsDNA ab correlates with disease activity? AntiSSA/Ro and antiSSB/La more often associated with Sjogrens sd, but seen in 20-40% of females with lupus associated with neonatal lupus sd (more later) renal damage secondary to immune complex deposition, complement activation, inflammation, fibrosis

Management Preconception counseling
Potential complications – preeclampsia, preterm labor, miscarriage, fetal death, fetal growth restriction, and neonatal lupus Evaluate lupus activity – delay pregnancy until remission Evaluate for nephritis (24 hr urine), hematologic abnormalities (CBC), antiphospholipid abnormalities Discontinue NSAIDS and cytotoxic agents

Antenatal care Frequent visits to assess lupus status, screen for hypertension Serial ultrasounds to evaluate fetal growth Antenatal surveillance at 32 weeks or earlier if indicated

Goals of management Avoid drugs that harm the fetus
Prompt detection of preeclampsia and placental insufficiency Discern between lupus exacerbations and preeclampsia Appropriate detection and treatment of lupus flares

Lupus meds - NSAIDS used outside of pregnancy – most common anti-inflammatory agent inhibits cyclooxygenase, lipoxygenase, reduces prostaglandin synthesis Preg class B Avoid in 3rd trimester cross placenta, blocks prostaglandin synthesis in fetal tissue premature closure of ductus arteriosis, fetal pulmonary hypertension, NEC, fetal renal insufficiency ASA crosses placenta and can affect fetal platelet function and is associated with intracranial fetal hemorrhage in 3rd trimester; avoid in pregnancy

Lupus meds - Hydroxychloroquine
Hydroxychloroquine (antimalarial/antirheumatic; binds DNA, interferes with vesicle functions, inhibits phospholipid metabolism; immunosuppressive by inhibiting rheumatoid factor, acute phase reactants, enzymes) stopping this in pregnancy - increased risk of lupus flares, continue if needed for control limited data not associated with increased r/o fetal malformations Preg class C Chloroquine is teratogenic

Lupus meds - steroids Preg class B
avoid fluorinated glucocorticoids b/c they cross the placenta hydrocortisone, prednisone, prednisolone inactivated by 11-beta hydroxysteroid dehydrogenase in the placenta allowing <10% of active drug to reach fetus high dose associated with maternal/fetal side effects Maternal Osteoporosis, glucose intolerance, sodium/water retention, hypertension, infection Adverse pregnancy outcomes - GDM, preeclampsia, PPROM, IUGR Incidence of fetal adrenal suppression with maternal tx is low Avoid empiric treatment, use at lowest possible dose Stress dose steroids (hydrocortisone 100mg IV q8hr in labor and for 24 hr PP) use if chronic steroids (20mg or more of prednisone for >= 3 weeks during last 6 mos)

Lupus meds - Azathioprine
Azathioprine (inhibits T lymphocytes) Preg class D teratogenic in animals, appears safe in humans associated with IUGR indicated in pregnancy if chronic high doses of steroids is not controlling symptoms or to lower steroid dose

Lupus meds cyclosporine A (inhibits T lymphocytes) preg class C
data comes from use in renal transplant patients, not an animal teratogen, appears safe in humans, long term follow up studies are limited

Lupus meds cyclophosphamide (alkylates and cross links DNA)
preg class D cleft palate, skeletal abnormalities; avoid if possible may be needed in cases of severe proliferative nephritis (drug of choice in nonpregnant patients with prolif lupus nephritis) crosses placenta

Lupus meds methotrexate (inhibits dihydrofolate reductase; inhibits lymphocyte proliferation (folate antagonist) preg class X avoid, embryolethal, congenital anomalies

Lupus flares Incidence in pregnancy 15-63% Regardless they are common
Studies support and refute that pregnancy increases the incidence of flares Regardless they are common Risk factors Active disease at conception (50% vs 20%) Active nephritis Abrupt discontinuation of hydrochloroquine

Diagnosis of flare sx include fatigue, fever, arthralgias/myalgias, weight loss, rash, renal deterioation, serositis, LAD, CNS sx titers of ab rising titers of dsDNA Ab with falling complement levels suggest impending flare

lupus vs preeclampsia Lupus flare
arthritis, leukopenia, thrombocytopenia, rashes, pleuritis, fevers htn, proteinuria, coagulopathy possible rising antidsDNA titer, active urinary sediment, low complement levels suggest lupus flare complement levels (C3, C4, CH50) generally rise in pregnancy and are unaffected by uncomplicated pree normal uric acid differentiation near term likely not worthwhile, deliver for suspected preeclampsia and initiate tx for lupus flare if patient does not get better

Treatment of lupus exacerbations
Mild to moderate hydroxychloroquine Start prednisone 15-20mg/day or increase dose to 20-30mg/day if already on glucocorticoids Severe exacerbations without renal/CNS manifestations Rheumatology consult, hospitalize Glucocorticoid treatment (prednisone 1-1.5mg/kg/d; expect improvement in 5-10 days) Taper once significantly improving If patient cannot be tapered off high dose steroids – add cyclosporine or azathioprine

Lupus exacerbations Severe exacerbation with renal or CNS involvement
Hospitalize, rheumatology consult IV methylprednisolone 10-30mg/kg/day for 3-6 days Maintain on oral prednisone 1-1.5mg/kg/day When patient responds, taper steroids If no response, add cyclophosphamide, or move to plasmapharesis

Lupus nephritis 50% of patients with lupus develop renal disease
Pathophys Immune complex deposition Complement activation Inflammation in kidney Retrospective review (Burkett, 1985) 242 pregs in 156 women with lupus nephritis 59% no change in renal function 30% with transient decrease in function 7% with permanent renal insufficiency Critical creatinine level is 1.5mg/dL Above this - risk is increased of decreased renal function Below this – risk is not increased

the lupus placenta reduction in size placental infarctions
intraplacental hemorrhage deposition of immunoglobulin and complement thickening of trophoblast basement membrane above are reasons for pregnancy complications (later) – preE, IUGR, Preterm delivery)

preg FDA classes A – controlled studies show no fetal risk in any trimester, probability of fetal harm is remote B – animal studies, no risk; if risk in animal studies, controlled human studies do not confirm harm C – harm in animal studies with no controlled human studies; no available human or animal studies D – human studies show fetal risk but r/b relative to medical state of mother may support use X – animal/human studies show fetal risk or abnormalities, use is contraindicated during pregnancy or in women who may become pregnant

tacrolimus tacrolimus (inhibits T lymphocyte activation, immunosuppressant) dose in liver transplant mg/kg/d po divide q12 hr preg class C therapeutic drug levels 5-20 ng/mL just before next dose; time to steady state 3 days monitor creatinine, K, fasting blood glucose, serum drug levels

NLE 1 in 20,000 live births heart block 50%
skin lesions 50% - erythematous scaling plaques on scalp or face, typically resolve within first few months like hematologic changes as the maternal autoantibodies disappear both 10% most cases from maternal autoantibodies antibodies to cytoplasmic ribonucleo-proteins SSA (Ro) more specifically the 5 anti-SS2-kDa epitope of SSA and SSB (La) – detected 50-75% of the time rare to have just SSB antibodies

CHB cardiac lesions – heart block from endocardial fibroelastosis from anti SSA-52 binding to myocardial tissue histo – mononuclear cell infiltration, fibrin deposition, calcification of conduction system (AV, SA nodes, diffuse fibroelastosis t/o myocardium typically seen as FHR of bpm at wks gestation with structurally normal heart with AV dissociation, hydrops possible 3rd degree heart block; complete permanent 1st or 2nd degree (defs??? reversed with antenatal fluorinated (crosses placenta) steroid therapy b/c of prevention of progression to more severe forms +/- rationale of steroids is that cardiac histo has diffuse inflammation, IgG, firbrin, complement deposition risk of chronic steroids wihout any proven benefit especially in a condition that is permanent once it is diagnosed m/f risks osteoporosis, glucose intolerance, fetal growth restriction, development delay reversal of hydrops case reports? no evidence supporting use of ppx steroid tx in women with antiSSA or antiSSB ab to prevent onset of CHB 1/3 of fetuses with heart block die within 3 yrs of age remaining 2/3 require permanent pacemakers

Following is slides, notes, long version of above shortened for PNDX conf

Case 27 y/o G5 P3 PMH – systemic lupus erythematosus diagnosed in 2005 by rheumatology Diagnosed based on arthritis, malar rash, pericardial effusion, leukopenia\ NKDA Medications Hydroxychloroquine 200mg BID Prednisone 10mg daily Azathioprine 150mg up to 6 weeks (d/c w/+hcg) Fish oil, iron, calcium, prenatal vitamins POB history – 3 term deliveries (1 CD, 2 VBAC); h/o GDM, gestational hypertension; h/o first trimester loss Social and family history unremarkable

Case Physical exam Normotensive, obese, vitiligo, no evidence of lupus flare at initial visit Lab findings Rh +; negative RPR, HepBsAg, HIV, GBS 24hr urine analysis revealed normal renal function ECG normal Rheumatologic labs Sedimentation rate slightly elevated Complement levels (C3, C4) normal t/o pregnancy ANA antibodies not available -dsDNA antibodies negative (high spec; 75% sens) Anti-cardiolipin antibodies negative + SSA, - SSB

Case Plan for pregnancy (Avoid harmful drugs; detection of preeclampsia, placental insufficiency; detection, treatment of lupus flares) Lupus meds – Hydroxycholorquine continued (immunosuppressive; class C; stopping this in pregnancy - increased risk of lupus flares, continue if needed for control; no increased r/o fetal malformations) Prednisone continued (immunosuppressive; class B; use non-fluorinated like prednisone that do not cross placenta; M/F side effects with high dose steroids > 20mg prednisone/day; stress dose in labor if high dose used Azathioprine not restarted, unless needed for control (inhibits T lymphocytes; class D; possible IUGR) Follow with rheumatology Low dose aspirin started

Maternal serum screen for aneuploidy and neural tube defects was normal Ultrasound findings Anatomy normal at 20 weeks, no heart block EFW 382g Growth at 30 weeks, no heart block EFW 1541g (48th%ile) Diabetes screen – abnormal 1-hr test, 3-hr test normal Fetal testing reassuring

3rd trimester bleeding occurred at 34 weeks Patient delivered by repeat C-section (with sterilization) for suspected abruption Female, birth weight 2373gm, APGAR scores 9/9 Placenta – 435g; villous edema, dystrophic calcification seen Postoperative course uncomplicated Repeat anti-cardiolipin antibodies? Avoid estrogen containing medications

Systemic Lupus Erythematosus
chronic autoimmune d/o with disease flares and remissions can affect all organs mild cases – skin, musculoskeletal system more severe – kidney, brain possible manifestations are arthralgias, rashes, renal abnormalities, neurologic complications, thromboemboli, myocarditis, serositis 120

Epidemiology prevalence of lupus varies with population
5-125/100,000 people affects 1% of pregnancies lifetime risk of developing lupus is 1/700 peaks at 30 y/o affects women 3-10x more than men Ethnic groups African Americans (prevalence - Hispanics (prevalence - incidence – risk of developing a condition in a pop in a specific period of time; rate with denominator; rate of occurrence of new cases; risk of contracting the disease during a time period prevalence – total number of cases of disease in a population; how widespread the disease is ---when studying etiology of disease, best to study incidence b/c it is a more finite time period by definition whereas prevalence mixes in the duration of the condition and groups all of the cases regardless of time at that point in time For example, consider a disease that takes a long time to cure, and that was spread widely in 2002, but whose spread was arrested in This disease will have a high prevalence and a high incidence in 2002; but in 2003 it will have a low incidence, although it will continue to have a high prevalence because it takes a long time to cure. In contrast, a disease that has a short duration may have a low prevalence and a high incidence 121

General morbidity/mortality
Survival rates 5y – 93% 10y – 85% 15y – 79% 20 y – 68% Risk factors for mortality – renal damage, thrombocytopenia, lung involvement, high disease activity at dx, >50 y/o at dx 122

Criteria for diagnosis
Per American College of Rheumatology Need 4 of 11 (serially or at one time) Malar rash (erythema over malar eminences) Discoid rash (erythematous raised patches) Photosensitivity (unusual rxn to sunlight) Oral ulcers (oral, nasopharyngeal) Arthritis (nonerosive, 2+ peripheral joints) Serositis (pleuritis, pericarditis) Nephritis (>500mg/d proteinuria or cellular casts) Neurologic disorder (seizures, psychosis, stroke with other causes r/o) Hematologic disorder (hemolytic anemia with reticulocytosis, thrombocytopenia <100k, leukopenia < occasions, lymphopenia < occasions) Immunologic disorder (anti-dsDNA, anti-Sm, positive LAC ACA, false pos RPR or other serologic test for syphilis for 6 months confirmed by treponema pallidum immobilization or fluorescent treponemal ab absorption test) Antinuclear antibodies (without being on drugs associated with drug induced lupus syndrome <4 of 11 = lupus-like syndrome 123

Significance of SSA, SSB antibodies
Antibodies to extractable nuclear antigens 52, 60 kD SSA Found in 10-60% of SLE patients Of these patient’s, 50% will have antibodies positive for SSB ‘ANA negative SLE’ Occasionally SSA (Ro) is positive in persistently negative ANA – SLE patients Used to be more frequent in 1970s

Neonatal lupus erythmatosus (NLE)
1 in 20,000 live births occurs in 1-2% of women with antiSSA or antiSSB regardless of whether pt has SLE congenital heart block, skin lesions, thrombocytopenia, anemia, hepatitis heart block 50% skin lesions 50% - erythematous scaling plaques on scalp or face, typically resolve within first few months like hematologic changes as the maternal autoantibodies disappear both 10% most cases from maternal autoantibodies that cause immune mediated damage of fetus by transplacental passage of autoantibodies antibodies to cytoplasmic ribonucleo-proteins SSA (Ro) more specifically the 5 anti-SS2-kDa epitope of SSA and SSB (La) – detected 50-75% of the time rare to have just SSB antibodies 125

CHB - fetology Bradyarrhythmias - 9% of all arrythmias Cardiac anatomy is normal up to 50% of cases; severe congenital heart disease up to 53% of cases Most common is complete (3rd deree, complete disassociation of A-V conduction 1st – prolonged P-R interval (hard to see) 2nd – progressive lengthening of P-R interval with dropped beats (Wenckebach); fixed P-R interval wit ratio of transmission of atrial beats to ventricular beats CHB 1 in 20-25,000 live births Ck for structure, doppler cord to detect resistance, EFW to detect IUGR; cardiothoracic ratio to detect pulm hypoplasia/ cardiomeg/heart failure DDX- structural heart disease; immunologic/SSA/B disease; sinus brady in premorbid fetus Antenatal natural history (presents at mean GA of 26 weeks) Nonimmune hydrops develops in 25% due to cardiac decompensation (IUFD or neonatal death) Survival is 15% when hydrops is present; 14% if structural heart dz is present AV valve incompetence tends to precede devel of NI hydrops Structurally normal heart and CHB = SSA/B uniformly Fetal/neonatal heart contains body’s highest concentration of Ro antigen (SSA binds) In vitro studies show SSA/B binds to newborn myocardium (and not adult); this binding inhibits repolarization ? Cofactor b/c while mothers of infants with CHB almost uniformly have SSA/B, the majority of pt with these antibodies have normal pregnancies; suggest cofactor that is triggered for some reason (viruses being immunogenic?); increased incidence of CMV antibodies Generalized myocarditis from Ab deposition and inflammatory response Subendocardial fibroelastosis – marker of endstage myocardial injury Sono = echogenic papillary muscles or areas of subendocariddial myocardium Heart rate <55 – 14% survival; no survivors reported <50bpm

Fetal complete heart block
Pregnancy management Rheumatology evaluation Fetal echo If rate <65bpm, increased surveillance to detect AV valve incompetance or early signs of NI hydrops 2x weekly scans, dopplers (deposition of immune complexes in placental bed can ppt heart failure), cardiothoracic ratios NSTs not helpful b/c of AV node dissociation Indications for delivery Deteriorating cardiac status NI hydrops CD for fetuses >30 weeks with CHB and hemodynamic compromise, ventricular rate <55, AV valve insufficiency, poor contractility CD for all cases? Intrapartum monitoring with scalp pH, echo difficult but have been reported

CHB – fetal intervention
Medical Lessen immunologic injury (maternal IVIG to bind Ab to prevent placental passage; plasmapharesis to remove Ab directly) No reversal of heart block Increase ventricular rate (beta-mimetics in doses large enough to have an effect on fetus are not tolerated by mother) Prophylaxis? Maternal risk > benefit Steroids in CHB to avert further immunologic damage from evolving myocarditis? (rec from Fetology) PERMANENT Surgical – inutero pacing (transcutaneous, open fetal surgery) described in hydropic fetuses; pacing accomplished, but fetal death was result Newborn treatment…

Fetal CHB Outcome Genetics, recurrence risk Risk factors
Mortality rate – 25% 90% survival after neonatal period? Monitor for autoimmune disease Genetics, recurrence risk No genetic predisposition Previous baby with CHB has a recurrence risk range of 25-64% Autoimmune d/o, +SSA 7.6% rate of CHB vs 0.6% rate of Autoimmune disease and NO SSA Ab Healthy women with SSA/B Ab are majority of cases, but difficult to ID Risk factors Previous child with CHB High titer of SSA Ab (>1:16) + SSA and + SSB Maternal HLA DR3

Structural heart defects most commonly associated with complete heart block
Left atrial isomerism Transposition of the great arteries Atrioventricular septal defect Pulmonic atresia Anomalous pulmonary venous connection Double outlet right ventricle Atrioventricular discordance Absent right atrioventricular connection Double-inlet ventricle Right atrial isomerism Pulmonic stenosis Fetology, p350

Congenital heart block
Pathophysiology of autoantibody mediated disease SSA and SSB Ab cross placenta, damage AV conducting system; Apoptosis Direct interference with cardiac conduction through calcium channels varying degrees of heart block, Myocarditis possible Histology - heart block from endocardial fibroelastosis from anti SSA-52 binding to myocardial tissue, mononuclear cell infiltration, fibrin deposition, calcification of conduction system (AV, SA nodes, diffuse fibroelastosis t/o myocardium) Typically dx at weeks typically seen as FHR of bpm at wks gestation with structurally normal heart with AV dissociation, hydrops possible Conduction system (affected AV node- delayed, intermittent, absent) first degree (slowed conduction without missed beats), second degree (missed beats, often in a regular pattern, eg, 2:1, 3:2, or higher degrees of block), third degree or complete AV block (permanent) CHB = complete heart block Recurrence r/o CHB in women with antiSSA ab and no previous affected infants is 1-2% The conduction can be delayed, intermittent, or absent. The commonly used terminology includes first degree (slowed conduction without missed beats), second degree (missed beats, often in a regular pattern, eg, 2:1, 3:2, or higher degrees of block), and third degree or complete AV block. The etiology of AV block is considered elsewhere 131

Neonatal lupus (NLE) and congenital heart block
Neonatal lupus (due to maternal antibodies that cross the placenta) is responsible for 60-90% of cases of complete heart block (CHB) overall Presence of maternal lupus or autoantibodies (SSA or SSB Ab) does not always lead to NLE or complete heart block ~50% of women with fetus/infant with CHB are asymptomatic but more than 85% are antiSSA or antiSSB + ½ of these women develop sx of rheumatic disease, typically Sjogren’s sd with dry eyes and mouth; <50% chance of developing SLE 50% of NLE cases occur in healthy pregnant women with circulating autoantibodies Women that give birth to children with CHB almost uniformly test positive to SSA or SSB; BUT most do not have lupus or Sjogren’s syndrome 30% of SLE patients have anti-SSA Ab and 15-20% have anti-SSB Ab Incidence of CHB in infants of SLE mothers is 2% Among women with SSA or SSB Ab, 2% develop CHB Recurrence risk 5-25%; reports of twins discordant for NLE 132

Prevention/Treatment of CHB?
3rd degree heart block; complete permanent 1st or 2nd degree (defs??? reversed with antenatal fluorinated (crosses placenta) steroid therapy b/c of prevention of progression to more severe forms +/- rationale of steroids is that cardiac histo has diffuse inflammation, IgG, firbrin, complement deposition risk of chronic steroids wihout any proven benefit especially in a condition that is permanent once it is diagnosed m/f risks osteoporosis, glucose intolerance, fetal growth restriction, development delay reversal of hydrops case reports? no evidence supporting use of ppx steroid tx in women with antiSSA or antiSSB ab to prevent onset of CHB 1/3 of fetuses with heart block die within 3 yrs of age remaining 2/3 require permanent pacemakers

Pregnancy outcomes effect of SLE on pregnancy
increased stillbirth rate 25x (150/1000); esp w/ APLS increased preeclampsia rate to 20-30% (7-10%) increased IUGR rate to 12-32% increased preterm delivery rate to 50-60% (12-15%) increased PPROM rate Neonatal lupus (1-2% if anti SSA/SSB present) effect of pregnancy on SLE worsening renal status if nephropathy (cr 1.5) present increased flares if active disease at start of pregnancy 134

end Refs Fetology Creasy MFM Uptodate
High risk pregnancy – epi approach Foley ICU manual

Lupus in Pregnancy Darren Farley, MD Clinical Assistant Professor

Similar presentations

Presentation on theme: "Lupus in Pregnancy Darren Farley, MD Clinical Assistant Professor"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Lupus in Pregnancy Darren Farley, MD Clinical Assistant Professor

Similar presentations

Presentation on theme: "Lupus in Pregnancy Darren Farley, MD Clinical Assistant Professor"— Presentation transcript:

Similar presentations

About project

Feedback